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PubMed1984

Vasopressin and oxytocin in the neural control of the circulation.

Catecholamine innervation originating in dorsal medial and ventral lateral medulla terminates on parvocellular and magnocellular subnuclei, respectively, of the paraventricular nucleus of the hypothalamus. In turn, parvocellular pathways terminate in brain stem and spinal cord, whereas magnocellular pathways terminate in median eminence and posterior pituitary. Consistent with the neuroanatomy, we find that baroreceptor regulation of neuroendocrine (plasma vasopressin) and autonomic (blood pressure) functions can be dissociated. Further, studies indicate that sympathetic vasomotor pathways are activated by injections of vasopressin and oxytocin into the nucleus tractus solitarii and vasopressin into the lateral cerebral ventricles. Also, parasympathetic pathways to the heart and baroreflex function are activated and augmented, respectively, by i.v. administered vasopressin. These results are consistent with at least three central sites of action and suggest a complex role of vasopressin (and possibly oxytocin) in the central neural regulation of the heart and circulation.

Afferent Pathways↗
PubMed1985

Dissociation of tolerance to the hypothermic and tachycardic effects of ethanol.

Tolerance to the cardioacceleratory and hypothermic effects of ethanol was studied in unanesthetized, freely-moving rats surgically implanted with EKG electrodes and biotelemetric temperature sensors. Different groups received 0.0, 1,0 or 2.0 g ethanol/kg body weight in injections given every other day for a total of nine injections. Heart rate and body temperature were recorded for 1 hr before and 2 hr after each injection. Ethanol initially induced a monophasic dose-related cardioacceleration (80 bpm) and hypothermia (1.0 degrees C) that persisted throughout the 2-hr sample period. Tolerance developed to the hypothermic, but not to the tachycardic effect of ethanol. Assuming that tolerance depends on level of impairment in specific neuronal pathways, this outcome suggests that these two effects of ethanol are not mediated through a common autonomic mechanism (e.g., vasomotor depression) and/or that tolerance to the hypothermic effect is due to alterations in pathways unique to the thermoregulatory system. Overall, the finding is consistent with those of studies showing development of tolerance to depressant, but not to excitatory drug effects.

Animals↗
PubMed2003

Mechanisms of human hepatocarcinogenesis.

The major risk factors and etiological agents responsible for development of hepatocellular carcinoma in humans have been identified and characterized. Among these are chronic infection with hepatitis B virus or hepatitis C virus, exposure to aflatoxin B1, and cirrhosis of any etiology (including alcoholic cirrhosis and cirrhosis associated with genetic liver diseases). Both chronic hepatitis and cirrhosis represent major preneoplastic conditions of the liver as the majority of hepatocellular carcinomas arise in these pathological settings. Hepatocarcinogenesis represents a linear and progressive process in which successively more aberrant monoclonal populations of hepatocytes evolve. Regenerative hepatocytes in focal lesions in the inflamed liver (chronic hepatitis or cirrhosis) give rise to hyperplastic hepatocyte nodules, and these progress to dysplastic nodules, which are thought to be the direct precursor of hepatocellular carcinoma. In most cases, the neoplastic transformation of hepatocytes results from accumulation of genetic damage during the repetitive cellular proliferation that occurs in the injured liver in response to paracrine growth factor and cytokine stimulation. Hepatocellular carcinomas exhibit numerous genetic abnormalities (including chromosomal deletions, rearrangements, aneuploidy, gene amplifications, and mutations), as well as epigenetic alterations (including modulation of DNA methylation). These genetic and epigenetic alterations combine to activate positive mediators of cellular proliferation (including cellular proto-oncogenes and their mitogenic signaling pathways) and inactivate negative mediators of cellular proliferation (including tumor suppressor genes), resulting in cells with autonomous growth potential. However, hepatocellular carcinomas exhibit a high degree of genetic heterogeneity, suggesting that multiple molecular pathways may be involved in the genesis of subsets of hepatocellular neoplasms. Continued investigation of the mechanisms of hepatocarcinogenesis will refine our current understanding of the molecular and cellular basis for neoplastic transformation in liver, enabling the development of effective strategies for prevention and/or more effective treatment of hepatocellular carcinoma.

Carcinoma, Hepatocellular↗
PubMed1999

ovo/svb integrates Wingless and DER pathways to control epidermis differentiation.

In Drosophila, as in mammals, epidermal differentiation is controlled by signalling cascades that include Wnt proteins and the ovo/shavenbaby (svb) family of zinc-finger transcription factors. Ovo/svb is a complex gene with two genetic functions corresponding to separate control regions: ovo is required for female germline development and svb for epidermal morphogenesis. In the Drosophila embryo, the ventral epidermis consists of the segmental alternance of two major cell types that produce either naked cuticle or cytoplasmic extrusions known as denticles. Wingless signalling specifies smooth cells that produce naked cuticle, whereas the activation of the Drosophila epidermal growth factor (EGF) receptor (DER) leads to the production of denticles. Here we show that expression of the ovo/svb gene controls the choice between these cell fates. We find that svb is a key selector gene that, cell autonomously, directs cytoskeletal modifications producing the denticle. The DER pathway promotes denticle formation by activating svb expression. Conversely, Wingless promotes the smooth cell fate through the transcriptional repression of svb by the bipartite nuclear factor Armadillo/dTcf. Our data indicate that transcriptional regulation of svb integrates inputs from the Wingless and DER pathways and controls epidermal differentiation.

Animals↗
PubMed2002

Dual role of protein kinase C on mitogen-activated protein kinase activation and human keratinocyte proliferation.

Subconfluent normal human keratinocytes exhibit autonomous (autocrine growth factor driven) proliferation and express the specific markers for keratinocyte proliferation K#5 and K#14. In keratinocyte autocrine culture, the exogenously added epidermal growth factor (EGF) has no effect on cell proliferation and mitogen-activated protein kinase (MAPK) activity. PD98059 inhibits MAPK pathway and autocrine keratinocyte proliferation. Staurosporine and Gö6976 strongly inhibit autonomous keratinocyte proliferation. In contrast, Gö6983 (which does not inhibit PKC micro ) inhibits only 20% of autocrine keratinocyte proliferation. Staurosporine inhibits MAPK activity, whereas Gö6976 and Gö6983 strongly increase it. We have concluded that MAPK, PKC micro and probably PKCalpha take part in autocrine keratinocyte proliferation. The effect of Gö6976 and Gö6983 on MAPK activity could be explained by the inhibition of PKC-dependent MAPK-phosphatase expression. The effect of staurosporine could be explained by its paradoxical action (activation) on protein kinase C (PKC) in keratinocytes.

Cell Division↗
PubMed1983

Analysis of urinary steroid profiles of women with Cushing's syndrome by computerised gas chromatography-mass spectrometry.

Urinary steroidal profiles were studied in five women with Cushing's syndrome and in two normal women that were chosen as controls, by means of gas chromatography and gas chromatography-mass spectrometry. Four patients presented ACTH-dependent adrenal hyperplasia and the last patient had an adrenocortical carcinoma. Steroids were analyzed in urinary extracts, as their respective trimethylsilyloximes and/or trimethylsilylderivatives. Qualitative and quantitative data about 36 urinary steroids were obtained. Three pituitary patients showed a well defined picture of "5-ene pathway" in adrenal function. The fourth patient depicted some primary deficiencies of corticosteroid biosynthesis that overshadowed most biochemical expressions of Cushing's disease. The patient with adrenal carcinoma developed a steroidal pattern resembling autonomous functioning of adrenal cortex inner zones, showing both "5-ene pathway" and "4-ene pathway" increase. This patient also had an unexpected excretion of a major metabolite of 18-hydroxycorticosterone, that did not correlate with parameters of aldosterone production. Tetrahydro-6-hydroxy-cortisol was determined in urine of two patients and original data about urinary cortoic acids in Cushing's syndrome are given. Peripheral reductive metabolism played the most important role in almost all patients. In turn, some oxidative metabolic pathways for cortisol were not specifically favoured in the cases of Cushing's disease here reported.

18-Hydroxycorticosterone↗
PubMed2001

neuralized functions cell-autonomously to regulate a subset of notch-dependent processes during adult Drosophila development.

neuralized (neu) represents one of the strong neurogenic mutants in Drosophila. Mutants of this class display, among other phenotypes, a strong overcommitment to neural fates at the expense of epidermal fates. We analyzed the role of neu during adult development by using mutant clonal analysis, misexpression of wild-type and truncated forms of Neu, and examination of genetic interactions with N-pathway mutations. We find that neu is required cell-autonomously for lateral inhibition during peripheral neurogenesis and for multiple asymmetric cell divisions in the sensory lineage. In contrast, neu is apparently dispensable for other N-mediated processes, including lateral inhibition during wing vein development and wing margin induction. Misexpression of wild-type Neu causes defects in both peripheral neurogenesis and wing vein development, while a truncated form lacking the RING finger is further capable of inhibiting formation of the wing margin. In addition, the phenotypes produced by misexpression of wild-type and truncated Neu proteins are sensitive to the dosage of several N-pathway components. Finally, using epitope-tagged Neu proteins, we localize Neu to the plasma membrane and reveal a novel morphology to the sensory organ precursor cells of wing imaginal discs. Collectively, these data indicate a key role for neu in the reception of the lateral inhibitory signal during peripheral neurogenesis.

Animals↗
PubMed2006

Targeting of autonomous parvoviruses to colon cancer by insertion of Tcf sites in the P4 promoter.

The Wnt signaling pathway is activated by mutations in the adenomatous polyposis coli (APC) or beta-catenin genes in most colon cancers, leading to the transactivation of promoters containing binding sites for the Tcf/LEF family of transcription factors. We have previously shown that it is possible to confer colon cancer specificity on autonomous parvoviruses by inserting Tcf sites into the viral P4 promoter. The mutant Tcf promoters were responsive to activation of the Wnt pathway but the viruses replicated poorly. We show here that reduction of the number of Tcf sites from four to two leads to an increase in the efficiency of replication and toxicity of the viruses in Co115 colon cancer cells, with only a small reduction in selectivity for cells with an active Wnt signaling pathway. Despite this improvement, virus production by most colon cancer cells remained low. Analysis of parental phH1 virus infection of SW480 colon cancer cells showed that the nonstructural and capsid proteins were expressed, but single stranded DNA and progeny virus were not produced. This defect reflects the dependence of autonomous parvoviruses on host functions for many steps in their replication cycle and represents a major limitation to the use of selectively replicating parvoviruses for colon cancer therapy.

Adenomatous Polyposis Coli↗
PubMed2005

[The nuclear factor kappa B activation: the key step of cell proliferation in estrogen receptor-negative breast cancer cells].

OBJECTIVE: To investigate the way of nuclear factor kappa B (NF-kappaB) activation and the mechanism of NF-kappaB-promoted proliferation in estrogen receptor (ER)-negative breast cancer cells. METHODS: The protein of IkappaB kinase alpha (IKKalpha) was measured by Western blot and the influence on cell-cycle was assayed by flow cytometry (FCM). RESULTS: The IKKalpha was tested higher in three ER-negative breast cancer cell lines than in MCF-7. The influence caused by epidermal growth factor (EGF), tumor necrosis factor (TNF)-alpha and E(2) to tumor cells' proliferation was tested. EGF could remarkably enhance cyclin D(1) expression about 83% more in EGF group than that in control group and proliferation index from 0.22 to 0.31 (P < 0.01). On the other hand, TNF-alpha inhibited cyclin D(1) expression. Protein kinase C inhibitor, Go6976, could peculiarly prevent NF-kappaB over-expression caused by EGF. The cell-cycle was assayed by FCM in phase G(0)/G(1) 69.36% and in phase S 22.77% when adding EGF and in phase G(0)/G(1) 91.54% and in phase S 7.81% when adding EGF and Go6976. The proliferation index decreased from 0.31 to 0.09 (P < 0.01). CONCLUSIONS: EGF-EGFR pathway can provide ER-negative breast cancer cells the signal for the autonomous growth. This signal promoted tumor cells' proliferation is transmitted by activating NF-kappaB and expressing more cyclin D(1). In this pathway, NF-kappaB play an important role as signal transmitting. The strategy to NF-kappaB activating may provide new way to treat ER-negative breast cancers.

Breast Neoplasms↗
PubMed1987

Feline dysautonomia: an ultrastructural study of neurones in the XII nucleus.

A feline dysautonomia of unknown aetiology has been reported in numerous cats in the United Kingdom since 1981. The consistent histological lesion is a chromatolytic-type change within the neurones of the autonomic nervous system, which is also found less frequently in non-autonomic regions, such as the XII nucleus. This study describes the ultrastructural changes in the XII nucleus within the first 2 weeks of clinical disease. In the abnormal neurones there is a dispersion of the Nissl substance, progressing to dilation of individual cisternae by an electron-dense floccular material. Such cisternae have lost the majority of their ribosomes. Normal Golgi complexes can be seen in neurones where there is only slight dispersion of the Nissl substance, but no Golgi complexes, either normal or abnormal, can be identified in any cell in which the Nissl substance is markedly disrupted. There is proliferation of smooth endoplasmic reticulum in several neurones, and there may also be an increased number of morphologically normal mitochondria. The nuclei of affected neurones are eccentric with crenations of the nuclear envelope, and in some cases nucleolar changes are also observed. Autophagic vacuoles are present in small numbers. Other organelles appear normal. These findings compare closely to those for the autonomic neurones, suggesting that the primary effect of the causal agent(s) is on the protein synthetic pathway of specific neurones.

Animals↗
PubMed2006

Comparison of pramipexole and modafinil on arousal, autonomic, and endocrine functions in healthy volunteers.

The noradrenergic locus coeruleus is a major wakefulness-promoting nucleus of the brain, which is also involved in the regulation of autonomic and endocrine functions. The activity of the locus coeruleus is believed to be tonically enhanced by a mesocoerulear dopaminergic pathway arising from the ventral tegmental area of the midbrain. Both modafinil, a wakefulness-promoting drug, and pramipexole, a D(2)/D(3)receptor agonist with sedative properties, may act on this pathway, with modafinil increasing and pramipexole decreasing locus coeruleus activity. The aim of this study was to compare the two drugs on alertness, autonomic and endocrine functions in healthy volunteers. Pramipexole (0.5mg), modafinil (200mg), and their combination were administered to 16 healthy males in a double-blind, placebo-controlled design. Methods included tests of alertness (pupillographic sleepiness test, critical flicker fusion frequency, visual analogue scales), autonomic functions (resting pupil diameter, light and darkness reflex responses, heart rate, blood pressure, salivation, core temperature), and endocrine functions (blood concentrations of prolactin, growth hormone, and thyroid stimulating hormone). Data were analysed by ANOVA. Pramipexole reduced alertness, caused pupil dilatation, increased heart rate, reduced prolactin and thyroid stimulating hormone, and increased growth hormone level. Modafinil caused small increases in blood pressure and core temperature, and reduced prolactin levels. The sedative effect of pramipexole and the autonomic effects of modafinil are consistent with altered activity in the mesocoerulear pathway; the pupil dilatation following pramipexole suggests reduced dopaminergic excitation of the Edinger-Westphal nucleus.

Adolescent↗
PubMed2001

Cell-autonomous expression of barley Mla1 confers race-specific resistance to the powdery mildew fungus via a Rar1-independent signaling pathway.

The barley Mla locus encodes 28 characterized resistance specificities to the biotrophic fungal pathogen barley powdery mildew. We describe a single-cell transient expression assay using entire cosmid DNAs to pinpoint Mla1 within the complex 240-kb Mla locus. The MLA1 cDNA encodes a 108-kD protein containing an N-terminal coiled-coil structure, a central nucleotide binding domain, and a C-terminal leucine-rich repeat region; it also contains a second short open reading frame at the 5' end that has a possible regulatory function. Although most Mla-encoded resistance specificities require Rar1 for their function, we used the single-cell expression system to demonstrate that Mla1 triggers full resistance in the presence of the severely defective rar1-2 mutant allele. Wheat contains an ortholog of barley Mla, designated TaMla, that is tightly linked to (0.7 centimorgan) but distinct from a tested resistance specificity at the complex Pm3 locus to wheat powdery mildew. Thus, the most polymorphic powdery mildew resistance loci in barley and wheat may have evolved in parallel at two closely linked homeoloci. Barley Mla1 expressed in wheat using the single-cell transformation system failed to trigger a response to any of the wheat powdery mildew Avr genes tested, indicating that AvrMla1 is not genetically fixed in wheat mildew strains.

Alleles↗
PubMed2002

Atrioventricular nodal reentrant tachycardia in children: effect of slow pathway ablation on fast pathway function.

INTRODUCTION: Prior studies in adults have shown significant shortening of the fast pathway effective refractory period after successful slow pathway ablation. As differences between adults and children exist in other characteristics of AV nodal reentrant tachycardia (AVNRT), we sought to characterize the effect of slow pathway ablation or modification in a multicenter study of pediatric patients. METHODS AND RESULTS: Data from procedures in pediatric patients were gathered retrospectively from five institutions. Entry criteria were age <21 years, typical AVNRT inducible with/without isoproterenol infusion, and attempted slow pathway ablation or modification. Dual AV nodal pathways were defined as those with > or =50 msec jump in A2-H2 with a 10-msec decrease in A1-A2. Successful ablation was defined as elimination of AVNRT inducibility. A total of 159 patients (age 4.4 to 21 years, mean 13.1) were studied and had attempted slow pathway ablation. AVNRT was inducible in the baseline state in 74 (47%) of 159 patients and with isoproterenol in the remainder. Dual AV nodal pathways were noted in 98 (62%) of 159 patients in the baseline state. Ablation was successful in 154 (97%) of 159 patients. In patients with dual AV nodal pathways and successful slow pathway ablation, the mean fast pathway effective refractory period was 343+/-68 msec before ablation and 263+/-64 msec after ablation. Mean decrease in the fast pathway effective refractory period was 81+/-82 msec (P < 0.0001) and was not explained by changes in autonomic tone, as measured by changes in sinus cycle length during the ablation procedure. Electrophysiologic measurements were correlated with age. Fast pathway effective refractory period was related to age both before (P = 0.0044) and after ablation (P < 0.0001). AV block cycle length was related to age both before (P = 0.0005) and after ablation (P < 0.0001). However, in dual AV nodal pathway patients, the magnitude of change in the fast pathway effective refractory period after ablation was not related to age. CONCLUSION: Lack of clear dual AV node physiology is common in pediatric patients with inducible AVNRT (38%). Fast pathway effective refractory period shortens substantially in response to slow pathway ablation. The magnitude of change is large compared with adult reports and is not completely explained by changes in autonomic tone. Prospective studies in children using autonomic blockade are needed.

Adolescent↗
PubMed1994

Electrophysiologic and histologic effects of dissection of the connections between the atrium and posterior part of the atrioventricular node.

OBJECTIVES: This study was designed to examine the effects of destroying the posterior approaches to the atrioventricular (AV) node. BACKGROUND: Surgical and catheter ablation procedures have been developed for the cure of AV junctional reentrant tachycardia. Some of these destroy the posterior approaches to the AV node. METHODS: Atrioventricular node function and electrical excitation of Koch's triangle and the proximal coronary sinus were examined in 18 dogs. Dissection of the posterior atrionodal connections was performed in 10 dogs and a sham procedure in 8. After 28 to 35 days, repeat electrophysiologic and mapping studies were performed to assess changes in AV node function and the routes of AV and ventriculoatrial (VA) conduction. The AV junction was then examined with light microscopy. RESULTS: The compact AV node was undamaged in eight cases (80%). In two cases minor fibrosis occurred at the posterior limit of the compact node. The right-sided posterior atrionodal connections lying between the coronary sinus orifice and the tricuspid annulus were replaced by scar tissue in all cases, but the left-sided posterior connections and the anterior connections remained intact. Atrioventricular and VA conduction intervals and refractory periods were not altered. Atrioventricular junctional echoes were present in 10 dogs before and in 7 dogs after dissection (p = 0.06). Posterior (slow pathway) retrograde exists from the AV node were present in seven dogs before and in seven dogs after dissection. However, retrograde atrial excitation was altered in four of these seven dogs, so that the site of exit from the AV node was more leftward than it had been preoperatively. The node remained responsive to autonomic blocking drugs postoperatively. Double atrial electrograms similar to slow pathway potentials were found in all dogs. CONCLUSIONS: This procedure ablates the posterior atrionodal connections but rarely damages the compact AV node. Atrioventricular node function is not impaired and the node is not denervated. The mechanism of cure of AV junctional reentrant tachycardia is probably damage to the perinodal atrium. This suggests that part of the slow AV node pathway may lie outside the compact AV node. Dual AV node exits and double atrial electrograms are present in the normal canine heart.

Animals↗
PubMed1991

Retinoic acid-induced granulocytic differentiation of HL60 human promyelocytic leukemia cells is preceded by downregulation of autonomous generation of inositol lipid-derived second messengers.

Inositol phosphates (InsPs) and diacyglycerol (DAG) are second messengers derived via the breakdown of inositol phospholipids, and which play important signalling roles in the regulation of proliferation of some cell types. We have studied the operation of this pathway during the early stages of retionic acid (RA)-induced granulocytic differentiation of HL60 myeloid leukemia cells. The autonomous breakdown of inositol lipids that occurred in HL60 cells labeled with [3H] inositol was completely abolished following 48 hours of RA treatment. The rate of influx of 45Ca2+ was also significantly decreased at 48 hours, consistent with the role of inositol lipid-derived second messengers in regulating Ca2+ entry into cells. The downregulation of inositol lipid metabolism clearly preceded the onset of reduced proliferation induced by RA treatment, and was therefore not a consequence of decreased cell growth. The generation of InsPs in RA-treated cells was reactivated by the fluoroaluminate ion, a direct activator of guanine nucleotide-binding protein(s) (G proteins) that regulate the inositol lipid signalling pathway. Subtle alterations to a regulatory mechanism may therefore mediate the RA-induced downregulation of this pathway. The data are consistent with the hypothesis that the autonomous generation of inositol lipid-derived second messengers may contribute to the continuous proliferation of HL60 cells, and that the RA-induced downregulation of this pathway may, in turn, play a role in signalling the cessation of proliferation that preceedes granulocytic differentiation.

Aluminum↗
PubMed2002

Local and long-range signaling pathways regulating plant responses to nitrate.

Nitrate is the major source of nitrogen (N) for plants growing in aerobic soils. However, the NO3- ion is also used by plants as a signal to reprogram plant metabolism and to trigger changes in plant architecture. A striking example is the way that a root system can react to a localized source of NO3- by activating the NO3- uptake system and proliferating lateral roots preferentially within the NO3(-)-rich zone. That roots are able to respond autonomously in this fashion implies the existence of local signaling pathways that are sensitive to local changes in the external NO3- concentration. On the other hand, long-range signaling pathways are also needed to modulate these responses according to the plant's N status and to coordinate the allocation of resources between the root and the shoot. This review examines these signaling mechanisms and their interactions with sugar-sensing and hormonal response pathways.

Nitrates↗
PubMed2002

Cardiovascular effects associated with air pollution: potential mechanisms and methods of testing.

A recent series of epidemiologic reports have shown associations between fine particulate matter (PM) levels and increased cardiovascular morbidity and mortality. Elevated PM levels have been linked with cardiac events, including serious ventricular arrhythmias and myocardial infarction. A workshop brought together epidemiologists, cardiologists, and toxicologists from academia, government, and industry to examine plausible mechanisms that could be responsible for such effects, and to consider the armamentarium of noninvasive tests available to examine these relationships. Possible mechanisms considered by the participants include: (a) effects on the autonomic nervous system; (b) alterations on ion channel function in myocardial cells; (c) ischemic responses in the myocardium; and (d) inflammatory responses triggering endothelial dysfunction, atherosclerosis, and thrombosis. A large number of tests were identified to assess specific mechanistic pathways underlying the cardiovascular effects of air pollution and include: (a) autonomic control of the cardiovascular system assessed primarily by heart-rate variability; (b) myocardial substrate and vulnerability assessed by the electrocardiogram and estimations of ejection fraction and wall motion abnormalities in imaging studies; and (c) endothelial function, atherosclerosis, and thrombosis assessed by clotting parameters, cytokines, lipid profiles, and forearm blood flow. A variety of approaches ranging from molecular and genetic investigations to human clinical studies were recommended to further investigate the important epidemiologic associations.

Air Pollutants↗