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PubMed1999

Site-specific immune regulation in the brain: differential modulation of major histocompatibility complex (MHC) proteins in brainstem vs. hippocampus.

Although neurotransmitters and neuropeptides are known to affect immune function in vitro and in non-neural tissues, little is known about how the local mix of neurochemicals affects immune function in the brain. Here, we study local modulation of the class II major histocompatibility complex (MHC) proteins, which present antigen to T cells in a key pathway for cell-mediated immune activity. Two sites that are well-separated anatomically and have very different neuroregulatory environments, the brainstem and hippocampus, were compared. The class II-upregulating cytokine, gamma interferon (IFN-gamma, 0.1 to 10,000 U/site), was injected stereotaxically into the hippocampus and contralateral brainstem of adult Charles-derived Fischer rats. Four days later, monoclonal antibody staining was used to detect class II MHC proteins on cryostat sections, followed by computer-assisted image analysis. As compared to hippocampus, the brainstem showed enhanced class II expression at lower IFN-gamma doses, and reached a higher plateau. Site-specific class II modulation was also seen within the layers of the hippocampus, and among other brain sites. Injection of marker protein to visualize the spread of injected protein, plus injection of IFN-gamma into alternative sites, suggested that preferential flow cannot explain all of the site-specific effects. We suggest that the local neuroregulatory environment and/or intrinsic differences among target microglia are likely to play a role. Implications for the distribution of pathological changes, such as multiple sclerosis plaques, and for local immunotherapy are discussed.

Animals↗
PubMed2006

Purinergic signalling between axons and microglia.

Neurons are delicate elements unable to withstand prolonged exposure to the many toxic factors that gain access to the CNS or which are made by activated leukocytes. The well-being of neurons and their functional properties are dependent on glial cells. Microglia have a unique role in this context because they are involved in both neuronal support and immunological defence. We now know that neuron-microglia communication is bidirectional: neurons and microglia continuously exchange messages and integrate information received from neighbouring cells. It is now generally accepted that purinergic signalling is a key pathway in this continuous flow of information in health and disease. Release of ATP from neurons directly modulates microglial cell function eliciting secretion of neurotrophic or, in some cases, neurotoxic factors that deeply affect neuronal physiology. Purinergic stimulation of microglia P2 receptors might in turn elicit a burst of ATP release that feeds back onto the neurons. Development of sophisticated techniques for the measurement of extracellular ATP now makes possible real-time measurement of ATP release into the pericellular space and allows validation of the purinergic hypothesis for neuron-microglia signalling.

Adenosine Triphosphate↗
PubMed2006

Apoptolidin: induction of apoptosis by a natural product.

Apoptolidin is a natural product that selectively induces apoptosis in several cancer cell lines. Apoptosis, programmed cell death, is a biological key pathway for regulating homeostasis and morphogenesis. Apoptotic misregulations are connected with several diseases, in particular cancer. The extrinsic way to apoptosis leads through death ligands and death receptors to the activiation of the caspase cascade, which results in proteolytic degradation of the cell architecture. The intrinsic pathway transmits signals of internal cellular damage to the mitochondrion, which loses its structural integrity, and forms an apoptosome that initiates the caspase cascade. Compounds which regulate apoptosis are of high medical significance. Many natural products regulate apoptotic pathways, and apoptolidin is one of them. The known synthetic routes to apoptolidin are described and compared in this Review. Selected further natural products which regulate apoptosis are introduced briefly.

Animals↗
PubMed2004

PolyADP-ribose polymerase-1 (PARP-1) and the evolution of learning and memory.

PARP-1 is a multifunctional enzyme that can modulate gene expression. Cohen-Armon et al.(1) found that a homologue of PARP-1 is activated in the Aplysia nervous system as the animal responds to an aversive stimulus, which leads to sensitization, and during a more complex form of learning that involves feeding behavior. Significantly, inhibiting PARP-1 activation blocked the learning. Several key pathways in Aplysia neurons are activated both during learning and after injury, suggesting that mechanisms of learning evolved from primitive responses to injury. Since PARP-1 is evolutionarily conserved as a responder to various forms of stress, the finding that PARP-1 is activated during learning supports this idea.

Animals↗
PubMed1993

The assembly of signalling complexes by receptor tyrosine kinases.

Cell proliferation in response to growth factors is mediated by specific high affinity receptors. Ligand-binding by receptors of the protein tyrosine kinase family results in the stimulation of several intracellular signal transduction pathways. Key signalling enzymes are recruited to the plasma membrane through the formation of stable complexes with activated receptors. These interactions are mediated by the conserved, non-catalytic SH2 domains present in the signalling molecules, which bind with high affinity and specificity to tyrosine-phosphorylated sequences on the receptors. The assembly of enzyme complexes is emerging as a major mechanism of signal transduction and may regulate the pleiotropic effects of growth factors.

Models, Biological↗
PubMed2004

Nogo and Nogo-66 receptor in human and chick: implications for development and regeneration.

Antibodies to the myelin protein Nogo increase axonal regrowth after central nervous system injury. We have investigated whether Nogo expression contributes to loss of regenerative potential during development by using chick embryos, which regenerate their spinal cord until embryonic day (E) 13, when myelination begins. We show that Nogo-A and the Nogo receptor (NgR) are developmentally regulated both in chick and human embryos, are first detected at developmental stages when the chick spinal cord regenerates, and are not down-regulated after injury at permissive stages for regeneration. Therefore, expression of Nogo-A and NgR in pre-E13 chick spinal cords is not sufficient to inhibit regeneration. Nogo-A expression in the chick early embryo is primarily observed in axons, whereas NgR is mainly located on neuronal cell bodies, both in spinal cord and eye, and in striated muscle including the heart. With the onset of myelination, there is down-regulation of Nogo-A expression in neurons. Therefore, loss of regenerative potential might be linked to changes in its cellular localization. The possibility that only Nogo expressed in mature oligodendrocytes can exercise inhibitory effects would reconcile the lack of inhibition we observe in developing chick spinal cords before the onset of myelination with evidence from other laboratories on the inhibitory effects of Nogo in mature central nervous system. The distinctive and complementary patterns of Nogo-A and NgR expression and their conservation throughout evolution support the view that Nogo signaling represents a key pathway in nervous system and striated muscle development. Its putative role in target innervation and establishment of neural circuitry is discussed.

Amino Acid Sequence↗
PubMed2002

The cognitive-behavioral model of bulimia nervosa: a direct evaluation.

OBJECTIVE: This study represented the first attempt to directly evaluate Fairburn et al's (1986) cognitive-behavioral model of bulimia nervosa--the model on which the most widely used treatment for bulimia nervosa is based. METHOD: The major predictions of the model were tested using structural equation modeling. Data were collected from the responses of 526 subjects to a number of self-report measures. RESULTS: The factors of self-esteem, overconcern with weight and shape, and dietary restraint accounted for a large proportion of the variance in binge eating and purging. The key pathway in the model was the link between overconcern with weight and shape and the adoption of purgative behaviors, which then fed into a vicious cycle of binge eating and purging. Contrary to Fairburn's hypothesis, high levels of dietary restraint did not predict increased binge eating. DISCUSSION: The results suggest that the components of Fairburn's model may operate to maintain the bulimic cycle in a slightly different way to that originally proposed.

Body Image↗
PubMed2005

p53 is required for spontaneous autoantibody production in B6/lpr lupus mice.

The p53 tumor suppressor molecule triggers a key pathway of apoptosis in injured cells, in part through induction of Fas. The importance of Fas as a receptor mediating apoptosis is highlighted by the lupus-like systemic autoimmunity seen in animals and humans with nonfunctional Fas molecules. We set out to see if the absence of p53, superimposed on the Fas defect of lpr mice, might further accelerate or exacerbate their systemic autoimmunity. We generated double mutant mice (p53(-/-) lpr) having defects in both p53- and Fas-dependent pathways, hypothesizing that animals with lesions in both Fas- and p53-dependent pathways would show reduced ability to delete autoreactive or injured cells, thereby producing more severe autoimmune disease. Surprisingly, these mice have lower autoantibody levels than the single mutant lpr mice. These studies suggest an unanticipated role for p53 in the progression of autoimmunity and the production of autoantibodies.

Animals↗
PubMed2004

The molecular mechanism of sensitization to Fas-mediated apoptosis by 2-methoxyestradiol in PC3 prostate cancer cells.

It is widely known that death receptor Fas-dependent apoptotic signals are associated with development of prostate cancer, but the key pathways involved in sensitivity to the apoptosis remain unclear. Here we investigated the molecular mechanism by which 2-methoxyestradiol (2-ME) effectively sensitizes a human prostate cancer cell line, PC3, to Fas-mediated apoptosis. 2-ME significantly inhibited nuclear factor-kappaB (NF-kappaB) activation and downregulated Fas-associated death domain (FADD) protein interluekin-1beta-converting enzyme inhibitory protein (FLIP). Overexpression of the dominant negative mutant form of IkappaBalpha (d/n IkappaBalpha) or treatment with Ikappa kinase-specific inhibitor Bay117082 gave the same results, although the sensitizing effect was not as pronounced. A selective inhibitor of Akt phosphorylation, LY294002, accelerated formation of the death-inducing signaling complex (DISC) not only by FLIP reduction but also by enhancement of recruitment of the FADD to Fas, thereby sensitizing PC3 cells to apoptosis similar to the case with 2-ME stimulation. Moreover, we found that inhibition of 2-ME-induced extracellular signal-regulated kinase (ERK) activation by the upstream kinase inhibitor PD98059 significantly enhanced 2-ME-mediated suppression of Akt activation, resulting in much greater sensitization to apoptosis. Taken together, the present findings indicate that 2-ME suppresses NF-kappaB/FLIP signaling and enhances DISC formation through inhibition of Akt, and that PC3 cells thereby are being sensitized to Fas-mediated apoptosis and by a process closely associated with ERK.

2-Methoxyestradiol↗
PubMed1998

Cloning oncogenic ras-regulated genes by differential display.

The coordinated regulation of gene expression is a key cellular function that specifies cell characteristics as well as controls normal physiological processes of the organism. Deregulation of this gene expression leads to a variety of abnormal conditions such as cancer. The ras oncogene is one of the most frequently found mutations in various types of human cancer. The mutated Ras protein constitutively elicits multiple mitogenic signals to the nucleus to alter gene expression of target genes that are involved in a broad range of normal cellular functions. Thus the identification of these genes may provide an important tool toward the understanding of these pathogenic processes. As a first step to reveal these processes at the molecular level and to dissect the key pathway employed by oncogenic Ras protein, we have looked for its target genes in rodent model cell lines using the differential display method. Our initial screening has isolated a number of genes either up- or downregulated by oncogenic ras activation. Although the functional analyses of these genes in terms of ras-mediated cell transformation will be the major challenge, differential display has come to be a very efficient tool that helped us move to the next step. In this short report, we focus primarily on the technical aspects of differential display and experimental designs used in this study.

Animals↗
PubMed1993

SERP1, a serine proteinase inhibitor encoded by myxoma virus, is a secreted glycoprotein that interferes with inflammation.

Myxoma virus is a leporipoxvirus that causes a rapidly lethal, generalized infection known as myxomatosis in the European rabbit (Oryctolagus cuniculus). A characteristic feature of myxomatosis is the specific downregulation of key pathways important for numerous host defenses against the viral infection. The SERP1 gene has significant sequence similarity to the serpin superfamily of serine proteinase inhibitors and is one of many virulence factor genes located within the terminal regions of the myxoma virus genome. Transcriptional analysis of the SERP1 gene in myxoma virus (strain Lausanne) indicates that it is expressed as a late gene and studies using a polyclonal anti-SERP1 antiserum indicate that it encodes a secreted protein with an apparent molecular weight of 55 kDa. Using myxoma virus and recombinant vaccinia virus constructs for experiments with tunicamycin and peptide N-glycosidase F, it is shown that the secreted SERP1 protein is modified by N-linked glycosylation. Mutation of both copies of the SERP1 gene in myxoma virus results in a significant attenuation of the virus, such that more than 50% of infected animals are able to recover from the otherwise lethal infection. Histological analyses of lesions taken from infected animals suggest that in the absence of the SERP1 protein, a more effective inflammatory response occurs, allowing a more rapid resolution of the infection. This suggests that SERP1 contributes to viral pathogenesis by interacting with cellular component(s) involved in the regulation of inflammation.

Animals↗
PubMed2000

Local somatothermal stimulation inhibits motility of the internal anal sphincter through nitrergic neural release of nitric oxide.

PURPOSE: A somatoanal reflex had been demonstrated in our previous work. Because nitric oxide plays an important role in mediating relaxation of the internal anal sphincter, our purpose was to examine whether and how local somatothermal stimulation inhibits the function of the internal anal sphincter by stimulating nitric oxide release via nitrergic neurons and to elucidate the possible mechanism. METHODS: The activity of the internal anal sphincter in anesthetized rabbits was measured by use of continuously perfused, open-tip manometric methods. Local somatothermal stimulation was achieved by applying an electroheating rod 1 cm away from the skin area at the right popliteal region. The responses were further manipulated by pre-treating the rabbits with agonists or antagonists linked to nitric oxide synthesis. RESULTS: The motility of the internal anal sphincter before and during local somatothermal stimulation was significantly different (tonic pressure (mean +/-standard error of the mean), 5.4 +/- 0.3 vs. 4.9 +/- 0.3 mmHg, P = 0.0195; phasic pressure, 3.9 +/- 0.6 vs. 2.9 +/- 0.4 mmHg, P = 0.0002; frequency distribution of the phasic contractions (peak-to-peak interval), 28.9 +/- 3.7 vs. 65.3 +/- 10.4 seconds, P = 0.0001). The response began at approximately one minute after local somatothermal stimulation when the skin temperature was 41 +/- 0.3 degrees C. No anal response was observed when local somatothermal stimulation was applied at the control area. The local somatothermal stimulation-induced internal anal sphincter relaxation was not inhibited by pretreatment with atropine, propranolol, or phentolamine (tonic pressure, 5.8 +/- 1 vs. 5.2 +/- 0.8 mmHg, P = 0.038; phasic pressure, 4.2 +/- 0.9 vs. 3.1 +/- 0.6 mmHg, P = 0.020; peak-to-peak interval, 27.2 +/- 4.3 vs. 52.9 +/- 14.5 seconds, P = 0.043) but was completely blocked by pretreatment with a nitric oxide synthesis inhibitor. The effect of the nitric oxide synthesis inhibitor could be reversed by pretreatment with L-arginine (tonic pressure, 6 +/- 0.7 vs. 5.6 +/- 0.7 mmHg, P = 0.047; phasic pressure, 4.7 +/- 0.7 vs. 3.9 +/- 0.5 mmHg, P = 0.048; peak-to-peak interval, 23.8 +/- 3 vs. 33 +/- 3.7 seconds, P = 0.048), but not by D-arginine. CONCLUSION: Local somatothermal stimulation inhibits internal anal sphincter motility through the activation of nonadrenergic noncholinergic neural release of nitric oxide. This procedure may represent a simplified approach for the treatment of anorectal diseases with hypofunction of the L-arginine/nitric oxide pathway. [Key words: Local somatothermal stimulation; Nitric oxide; Internal anal sphincter; Motility; Moxibustion] Jiang J-K, Chiu J-H, Lin J-K. Local somatothermal stimulation inhibits motility of the internal anal sphincter through nitrergic neural release of nitric oxide.

Anal Canal↗
PubMed1998

Social psychophysiology, social circumstances, and health.

Health varies markedly with social circumstances. While we are still without a comprehensive account of the mechanisms which underlie this variation, it is clear that psychological factors are involved and that key pathways may prove to be psychophysiological. Thus, social psychophysiological research of the kind illustrated in this Special Issue is ideally placed to help unravel some of the mechanisms by which social circumstances impact on health. Nevertheless, the success of this sort of social psychophysiological enterprise most likely depends on reconceptualizing psychophysiological reactivity as a situational, or psychological exposure, concept rather than as an individual difference concept. This shifts the research goal from one of identifying individuals at risk for disease to identifying the psychological exposures that put individuals and groups at risk.

Adaptation, Psychological↗
PubMed2006

Biodegradation of methyl parathion and p-nitrophenol: evidence for the presence of a p-nitrophenol 2-hydroxylase in a Gram-negative Serratia sp. strain DS001.

A soil bacterium capable of utilizing methyl parathion as sole carbon and energy source was isolated by selective enrichment on minimal medium containing methyl parathion. The strain was identified as belonging to the genus Serratia based on a phylogram constructed using the complete sequence of the 16S rRNA. Serratia sp. strain DS001 utilized methyl parathion, p-nitrophenol, 4-nitrocatechol, and 1,2,4-benzenetriol as sole carbon and energy sources but could not grow using hydroquinone as a source of carbon. p-Nitrophenol and dimethylthiophosphoric acid were found to be the major degradation products of methyl parathion. Growth on p-nitrophenol led to release of stoichiometric amounts of nitrite and to the formation of 4-nitrocatechol and benzenetriol. When these catabolic intermediates of p-nitrophenol were added to resting cells of Serratia sp. strain DS001 oxygen consumption was detected whereas no oxygen consumption was apparent when hydroquinone was added to the resting cells suggesting that it is not part of the p-nitrophenol degradation pathway. Key enzymes involved in degradation of methyl parathion and in conversion of p-nitrophenol to 4-nitrocatechol, namely parathion hydrolase and p-nitrophenol hydroxylase component "A" were detected in the proteomes of the methyl parathion and p-nitrophenol grown cultures, respectively. These studies report for the first time the existence of a p-nitrophenol hydroxylase component "A", typically found in Gram-positive bacteria, in a Gram-negative strain of the genus Serratia.

Bacterial Proteins↗
PubMed2026

Role of semaphorin 4f in cardiac fibroblasts to regulate matrix production through actin remodeling and YAP/TAZ activation.

Cardiac fibrosis remains a critical determinant of adverse outcomes in heart disease, yet effective anti-fibrotic therapies are lacking. While multiple semaphorin family members participate in cardiovascular pathophysiology, the role of semaphorin 4f (Sema4f) in cardiac fibrosis remains unexplored. This study investigates the role and mechanisms of Sema4f in fibrotic remodeling post-myocardial infarction (MI). We employed flow cytometry to characterize cell type-specific Sema4f expression patterns in post-MI hearts. Lineage-specific knockout mice (fibroblast vs. myeloid) were subjected to left anterior descending ligation to assess functional consequences. Proteomic analysis of Sema4f-deficient cardiac fibroblasts was conducted to identify downstream effectors. Key pathways were subsequently validated using pharmacological inhibitors. We found that Sema4f expression was markedly upregulated during the fibrotic phase post-MI, primarily due to fibroblast activation. Fibroblast-, but not myeloid-, specific Sema4f deletion significantly reduced fibrosis and improved cardiac function. Proteomic profiling revealed that Sema4f deficiency led to downregulation of pro-fibrotic gene expression, which was associated with impaired actin cytoskeletal remodeling and decreased nuclear translocation of YAP/TAZ. Pharmacological inhibition of either actin remodeling or YAP/TAZ activity attenuated fibrosis, whereas YAP/TAZ activation abolished the anti-fibrotic effects of Sema4f knockout. Our study provides the first evidence demonstrating the functional role of Sema4f in cardiac fibroblast activation and fibrosis progression. We have identified a fibroblast-specific mechanism mediated by the Sema4f-actin cytoskeleton-YAP/TAZ axis, offering novel mechanistic insights into fibrosis regulation and revealing a promising therapeutic target for cardiac fibrosis with potential clinical applications.

Animals↗
PubMed2006

Glucocorticoids increase repair potential in a novel in vitro human airway epithelial wounding model.

Airway epithelial damage is a cardinal feature of chronic asthma. Agents which enhance epithelial repair without triggering uncontrolled fibrosis of the mesenchyme would be predicted to be useful in the management of asthma. We have developed a repeat wound model using mucociliated human bronchial epithelial cell (HBEC) cultures to define the key pathways involved in airway epithelial repair, and to study the effects of potential therapeutic agents on epithelial repair in a chronic setting. We show that repair occurs primarily by cell migration to close a defect; this process requires activation of the EGF receptor (EGFR) and subsequent tyrosine kinase signalling. Migration is accompanied by up-regulation of CD44 in motile cells at the wound margins with proliferation of non-migrating cells adjacent to the wound area. In long-term studies beta2 adrenoceptor agonists and phosphodiesterase (PDE) inhibitors have no effect on repair potential, in contrast chronic treatment with the glucocorticoid dexamethasone extends the lifespan of repeatedly wounded differentiated cultures. We suggest part of the beneficial effects of glucocorticoids in asthma is related to this ability to prolong repair potential following repeated episodes of epithelial injury.

Asthma↗
PubMed2000

Hypertension and single nucleotide polymorphisms.

Hypertension is a common, complex disease phenotype that has been intensively studied to identify susceptibility loci in humans. Candidate genes continue to be uncovered via genetic analysis in model organisms through linkage analysis with families and/or sib-pairs and through association studies using sequence variants in genes that play a role in key pathways regulating blood pressure in humans, such as the renin-angiotensin system (RAS). Recent studies exploring the sequence diversity in human candidate genes suggest that the distribution and organization of single nucleotide polymorphisms (SNPs) within and among human populations is complex. Issues related to the use of SNPs in analyzing the genetic determinants of hypertension are illustrated using recent studies on the angiotensin-converting enzyme (ACE).

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Association of depression, CD8+ T lymphocytes, and natural killer cell activity: implications for morbidity and mortality in Human immunodeficiency virus disease.

A heightened risk of mood disorders, such as major depression, and acute depressive symptoms has been observed among HIV-seropositive individuals since the start of the AIDS epidemic, and an accumulating body of data now shows that depression may have an impact on morbidity and mortality among individuals with HIV disease. Although the specific physiologic mechanisms involved in this process have not been delineated, there is some evidence to suggest that certain components of innate immunity, including killer lymphocytes such as CD8+ T lymphocytes and natural killer cells, may represent key pathways through which depression affects HIV disease progression. This paper reviews some of the main studies examining the effects of depression on immunity and HIV disease progression and discusses the potential role of killer lymphocytes as an underlying mechanism by which depression may impact morbidity and mortality.

CD8-Positive T-Lymphocytes↗