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PubMed1994

Differential expression of nuclear retinoid receptors in normal, premalignant, and malignant head and neck tissues.

Retinoids reverse premalignant lesions and inhibit the development of second primary cancers in patients with upper aerodigestive tract cancers. It is thought that these effects result from the ability of retinoids to restore normal cell growth and differentiation. Since nuclear retinoid receptors (RARs and RXRs) are the ultimate mediators of retinoid actions, alterations in their expression could lead to cancer development. To determine whether the expression of the mRNAs of the receptors is related to the development of head and neck squamous cell carcinoma (HNSCC), we used digoxigenin-labeled antisense riboprobes of RAR-alpha, RAR-beta, RAR-gamma, RXR-alpha, and RXR-beta for in situ hybridization to histological sections of specimens from 7 normal volunteers and 31 HNSCC patients. All 31 tissue specimens contained carcinomas, 16 also contained dysplastic lesions, 22 also contained hyperplastic lesions, 17 also contained adjacent normal tissue, and 6 contained all 4 types of tissue. All specimens from normal volunteers expressed the 5 receptors. Similar levels of RAR-gamma and RXR-alpha and RXR-beta mRNAs were detected in most of the adjacent normal, hyperplastic, dysplastic, and malignant tissues. RAR-alpha mRNA was detected in 94% of adjacent normal tissues and hyperplastic tissues, in 87% of dysplasias, and in 77% of HNSCCs. In contrast, RAR-beta mRNA was detected in about 70% of adjacent normal and hyperplastic lesions, and its expression decreased further to 56% of dysplastic lesions and to 35% of HNSCCs. The difference in RAR-beta level in carcinoma and adjacent normal tissues was significant (P < 0.05). These results indicate that the decreased expression of RAR-beta may be associated with HNSCC development.

Carcinoma, Squamous Cell↗
PubMed1993

Follicle-stimulating hormone regulation of A-kinase anchoring proteins in granulosa cells.

It has been well established that the biochemical and morphological changes during maturation of granulosa cells that are induced by follicle-stimulating hormone (FSH) occur through the elevation of intracellular cAMP and consequent activation of the cAMP-dependent protein kinase (PKA). In this report we show that FSH action alters the expression of A-Kinase Anchoring Proteins (AKAPs), which function to target the subcellular distribution of the type II PKA. Exposure of granulosa cells grown in primary culture with FSH and estradiol for 72 h resulted in the up-regulation of an 80-kDa AKAP and the RII beta subunit of PKA, whereas cells grown in control medium containing only estradiol produced a time-dependent increase of a 140-kDa AKAP. RII overlays performed with [32P]RII alpha preferentially detected RII-binding bands of 80 and 95 kDa compared to blots probed with [32P]RII beta, suggesting that FSH may alter the subcellular location of PKA in an isoform-specific manner. FSH treatment causes a translocation of RII alpha from the particulate to the cytosolic fraction coincident with the induction of the 80-kDa AKAP, which is also predominately cytosolic. These data suggest that FSH promotes a redistribution of the type II PKA holoenzyme through the selective induction of an RII isoform-specific AKAP.

A Kinase Anchor Proteins↗
PubMedDate not supplied

Abnormalities in measures of liver function and injury in thyroid disorders.

Thyroid hormones exert their effect on all tissue and modulate the rate of metabolic activity appropriate for each situation. As a result of their actions, alterations in thyroid function can affect the liver and perturb measures of hepatic function and injury in the absence of liver disease. These alterations in the measure of hepatic function and injury may be difficult to recognize as being caused by thyroid dysfunction rather than hepatic disease. As a result, they may be quite troublesome for patients and physicians if their cause is not properly identified. Importantly, abnormalities in liver function tests return to normal once the primary thyroid pathology is recognized and treated.

Animals↗
PubMed1998

Effects of fetal and neonatal environment on sympathetic nervous system development.

The sympathoadrenal system plays an important role in the regulation of metabolic and cardiovascular activity. With respect to carbohydrate metabolism, specifically, catecholamines affect both insulin secretion and insulin action. Alterations in sympathoadrenal system function have been suggested to contribute to the constellation of disorders referred to as syndrome X (obesity, hypertension, NIDDM, and dyslipoproteinemia). The origin of any such abnormalities in sympathoadrenal function is unknown. The sympathoadrenal system, like other parts of the mammalian nervous system, is susceptible to environmental influences during development. Although these neurological alterations in rats are particularly prominent during the postpartum period, they are also apparent during intrauterine life. Moreover, the effects of these early environmental factors last well into adulthood and may represent permanent alterations in sympathetic nervous system behavior. Although the impact of maternal diabetes on sympathetic neural development has not been examined extensively, limited data available indicate that maternal diabetes may affect sympathetic nervous system development in the offspring. Although the full impact of maternal diabetes on neurological development in the offspring is unknown, given the myriad effects of the sympathoadrenal system on mammalian physiology, lasting changes in autonomic nervous system function may have potentially profound consequences for metabolic and cardiovascular regulation in adulthood.

Animals↗
PubMed1998

Differential electrophysiologic effects of global and regional ischemia and reperfusion in perfused rat hearts. Effects of Mg2+ concentration.

The effects of regional and global ischemia on cellular electrical activity and on arrhythmias induced by reperfusion were studied at different Mg2+ concentrations (Mg2+o, 0, 1.2, and 4.8 mM) in perfused rat hearts. Surface electrograms and transmembrane potentials were recorded during control, 10 min of ischemia (perfusion arrest or coronary ligation), and reperfusion. Increasing Mg2+o from 0-4.8 mM decreased heart rate, did not alter action potential morphology, and had a strong antiarrhythmic action on reperfusion following coronary ligation. At low and normal Mg2+o, the incidence of tachyarrhythmias was between 70 and 80%. Global ischemia led to progressive atrioventricular block and the final ventricular beating rate was similar at all Mg2+o despite unequal initial values. The severity of arrhythmias was similar to that found after regional ischemia in Mg2+o = 0, but much lower at normal and high Mg2+o. The resting depolarization induced by coronary ligation decreased as Mg2+o was raised, but such a relation was not seen during global ischemia where the depolarization was less marked. The action potential duration did not vary with the ventricular rate between 160 and 380 beats per min but increased considerably when sinus rate was markedly slowed (40 to 80 bpm) by raising Mg2+o to 9.6 mM. Our data show that a high Mg2+o exerts a strong protection against reperfusion arrhythmias regardless of the type of ischemia. Modulation of the sinus rhythm by Mg2+ may contribute to its protective effect by decreasing K+o accumulation and Na+i loading during ischemia.

Action Potentials↗
PubMed1995

Lead and nickel alter the cardiorenal actions of endothelin in the rat.

In the current study, we have determined to what extent lead and nickel alter the cardiorenal actions of endothelin in pentobarbital anesthetized female rats. One hour following surgery, 3 x 15-min renal clearances were collected and endothelin (ET)-1 was infused iv at 110 ng/kg/min for 30 min during which time an additional two clearances were collected. Lead (infused as lead acetate throughout the experiment) at 4.8 nmoles/min and 24 nmoles/min significantly attenuated the ET-induced increase in mean arterial pressure (MAP); lead infused at 0.48 nmoles/min had no effect. An ET-induced decrease in the glomerular filtration rate (GFR) in control rats was completely blocked by the higher doses of Pb2+. By contrast, Pb2+ had no effect on angiotensin II or norepinephrine induced increases in MAP. In additional experiments, calcium chloride was infused at 500 nmoles/min for 105 min, then Ca2+ + Pb2+ (4.8 nmoles/min) were infused for another 105 min; in these experiments, there was no Pb(2+)-induced inhibition of the MAP response to endothelin; the GFR response to the peptide remained blocked. NiCl2 reduced the ET-induced increase in MAP only at 24 nmoles/min; at 4.8 and 24 nmoles/min, nickel attenuated the decrease in GFR induced by ET. Finally, Ca2+ infusion had no effect on the inhibition by Ni2+ of the GFR response to ET. These data illustrate that (i) lead inhibits the cardiorenal actions of endothelin; (ii) a Ca(2+)-related process is involved the systemic but not the renal component of this inhibition; (iii) since the heavy metal does not affect angiotensin II or norepinephrine-induced increases in MAP, the inhibition by lead of the systemic response is relatively specific for endothelin; and (iv) nickel also inhibits the renal response to the peptide but higher doses are required to inhibit the systemic response.

Angiotensin II↗
PubMed2003

Wheel-running exercise alters rat diaphragm action potentials and their regulation by K+ channels.

Endurance exercise modifies regulatory systems that control skeletal muscle Na+ and K+ fluxes, in particular Na+-K+-ATPase-mediated transport of these ions. Na+ and K+ ion channels also play important roles in the regulation of ionic movements, specifically mediating Na+ influx and K+ efflux that occur during contractions resulting from action potential depolarization and repolarization. Whether exercise alters skeletal muscle electrophysiological properties controlled by these ion channels is unclear. The present study tested the hypothesis that endurance exercise modifies diaphragm action potential properties. Exercised rats spent 8 wk with free access to running wheels, and they were compared with sedentary rats living in conventional rodent housing. Diaphragm muscle was subsequently removed under anesthesia and studied in vitro. Resting membrane potential was not affected by endurance exercise. Muscle from exercised rats had a slower rate of action potential repolarization than that of sedentary animals (P = 0.0098), whereas rate of depolarization was similar in the two groups. The K+ channel blocker 3,4-diaminopyridine slowed action potential repolarization and increased action potential area of both exercised and sedentary muscle. However, these effects were significantly smaller in diaphragm from exercised than sedentary rats. These data indicate that voluntary running slows diaphragm action potential repolarization, most likely by modulating K+ channel number or function.

4-Aminopyridine↗
PubMed1995

Alterations in the action potential of Aplysia neurons evoked by a phorbolester are mediated by protein kinase C.

Alterations in the parameters of action potentials upon changes in protein kinase C (PKC) activity were studied on neurons of the visceral ganglion of Aplysia californica. The amplitude and maximum speed of the up-and downstroke of the action potentials (APs) were measured. Intracellularly injected PKC and intra- and extracellularly applied phorbol-12,13-diacetate (PDAc) had similar effects on the Aplysia neurons, the most prominent being an increase of the upstroke speed of the AP in every neuron. The non-PKC-activating 4 alpha-phorbol didecanoate had no effect, and the effects of the PKC blocker H-7 were opposite to those of PDAc. It was concluded that the changes of the AP evoked by PDAc are mediated through PKC activation.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMedDate not supplied

Sex-related differences in cadmium-induced alteration of drug action in the rat.

3 days after pretreatment of rats of both sexes with cadmium (2 mg/kg, 1.p.) the duration of hypnosis induced by hexobarbital (75 mg/kg, 1.p.) was potentiated in males but not females. Likewise similar treatment with cadmium leads to significant inhibition of the metabolism of hexobarbital by hepatic microsomal enzymes obtained from male but not female animals. These data suggest that there is a sex-related difference in the ability of cadmium to alter drug action in rats.

Animals↗
PubMed1989

Sex-related alteration of drug action in carrageenan-induced inflammation in the rat.

Twenty-four hours after treatment with carrageenan the duration of hexobarbital-induced hypnosis was prolonged in males but not females in Wistar rats bearing carrageenan-induced paw edema. Similar treatment with carrageenan led to significant inhibition of the metabolism of hexobarbital by hepatic enzymes obtained from male but not female animals. These data suggest that there is a sex-related difference in the ability of carrageenan to alter drug actions in rats.

Animals↗
PubMed2005

Severe impairment in liver insulin signaling fails to alter hepatic insulin action in conscious mice.

Insulin exerts its potent effects on hepatic glucose fluxes via direct and indirect mechanisms. Whereas a liver-specific insulin receptor (IR) knockout (LIRKO) mouse exhibits glucose intolerance as well as insulin resistance, it is unclear whether a more acute decrease in the expression of hepatic IR would be sufficient to induce hepatic insulin resistance. Here we report that the downregulation of hepatic IR expression by up to 95% does not modify hepatic insulin action. The i.p. administration (2 injections over 1 week) of an antisense oligodeoxynucleotide (ASO) directed to reduce insulin expression downregulated hepatic IR expression in C57BL6J mice. A high dose of IR-ASO decreased IR protein approximately 95%, while a control-ASO failed to modify IR expression. At this dose, the IR-ASO also decreased IR expression in adipose tissue but did not significantly decrease IR expression in hypothalamus or skeletal muscle. Insulin action was assessed with insulin clamp studies in conscious mice. The rate of glucose infusion during the clamp studies was comparable in control-ASO- and IR-ASO-treated mice. Importantly, the depletion of liver IR protein markedly impaired downstream insulin signaling in the liver, but it failed to modify the rate of glucose production. Thus, near ablation of liver IR does not alter insulin action on glucose production.

Animals↗
PubMed2026

Tumor Mutational Landscape and Its Correlation With Histopathological Characteristics in Breast Cancer.

BACKGROUND/AIM: In breast cancer, knowledge of the associations between clinicopathologic characteristics, genetic changes, and subtype-specific patterns is expanding. This study investigated how pathological and clinical variables affect the actionability of Next Generation Sequencing (NGS)-based tumor molecular data. MATERIALS AND METHODS: 227 breast cancer patients referred to Genekor's laboratory for tumor molecular profile analysis were included in the study. Pathology records were used to assess critical clinicopathological features, including HER2, ER, PR, Ki67, grade, metastatic site, and age. A 1021-gene NGS-based multigene panel was utilized to assess tumor biology alongside tumor mutational burden (TMB) and microsatellite instability (MSI). RESULTS: Comprehensive genomic profiling revealed that 95.6% of the patients harbored at least one oncogenic or likely oncogenic alteration, highlighting the high diagnostic yield of NGS-based testing. Distinct subtype-specific patterns were observed: HR+/HER2- tumors were enriched for PIK3CA and ESR1 gene alterations, whereas triple-negative breast cancer (TNBC) was dominated by TP53 alterations. Clinically actionable alterations were most common in HR+/HER2- tumors (~60% on-label), whereas TNBC more often harbored off-label or trial-associated targets. The inclusion of tumor-agnostic biomarkers (TMB/MSI) increased on-label actionability up to 64.5% in HR+/HER2- tumors, primarily driven by TMB-high cases. Median TMB values were low, and age was the only independent predictor. Furthermore, the presence of actionable alterations was significantly higher in metastatic tumors, and TP53 alterations were associated with aggressive tumor characteristics. CONCLUSION: Comprehensive NGS-based genomic profiling identifies clinically actionable alterations in over half of breast cancer patients, with substantial variability across molecular subtypes. The HR+/HER2- subtype demonstrates the highest prevalence of on-label actionable biomarkers. These findings support the routine implementation of comprehensive genomic profiling, especially in metastatic HER2-negative breast cancer, to guide precision oncology strategies and enable enrollment in biomarker-driven clinical trials.

Humans↗
PubMed1981

Alteration of the action potential of tissue cultured neuronal cells by growth in the presence of a polyunsaturated fatty acid.

The effects of alterations in membrane phospholipid fatty acid composition on the excitability of neuroblastoma X glioma hybrid cells, clone NG108-15, were examined using intracellular recording techniques. Cells were grown in the presence of arachidonate (20:4) added to the culture medium as a complex with bovine serum albumin. Exposure of the cells to 20:4 for 3-21 days produced a 40% decrease in the maximum rate of rise of the action potential (dV/dt) with a small change in its amplitude. The resting membrane potential and passive properties of the cells were unaffected. An effect of 20:4 was not observed until 24 hr after treatment and increased over the next 2 days. The phospholipid content of 20:4 and its metabolite 22:4 increased from 6.9% to 25.3% of total fatty acids during approximately the same time span. It is concluded that the action potential dV/dt can be altered by changes in membrane lipid composition.

Action Potentials↗
PubMed1978

Zinc-induced protection against cadmium alteration of drug action.

Pretreatment of male rats with cadmium acetate potentiates the duration of hexobarbital hypnosis and inhibits the rate of hepatic microsomal drug metabolism. Pretreatment of rats with zinc acetate protects against these alterations in drug action elicited by cadmium.

Animals↗
PubMed1998

The action of local anaesthetics on the compound action potential is altered by the nature of the permeant ion in frog nerve.

Compound action potentials were recorded from the isolated frog sciatic nerve using either sodium or lithium as the permeant ion, and an assessment of the action of local anaesthetics was made. The compound action potentials evoked from the nerve were not different in terms of their mean amplitude or time to peak whether recorded with sodium or lithium as the permeant ion. The local anaesthetics tested, procaine, lignocaine and benzocaine, were more potent, as measured by their IC50 values, by 2.3, 2.1 and 1.8 times, respectively, when lithium rather than sodium was used as the permeant ion. The sensitivity of the nerves to tetrodotoxin was not significantly different whether sodium or lithium was used as the permeant ion. The slope of the concentration inhibition curves was not significantly altered in the presence of sodium or lithium for any of the compounds tested. These results are consistent with the idea that the binding site for local anaesthetics is intimately associated with the pore region of the channel and that the nature of the permeant ion can alter the interaction of the drugs with the sodium channel. However, since this is not a common feature of all compounds which block sodium channels by interacting at the pore, it may help refine the existing structural models of sodium channels.

Action Potentials↗
PubMed1995

Nitric oxide and prostacyclin modulate the alterations in cardiac action potential duration mediated by platelets during ischaemia.

OBJECTIVE: To investigate the effects of alterations of nitric oxide (NO) and prostacyclin (PGI2) availability on platelet-mediated electrophysiological effects during myocardial ischaemia. METHODS: Transmembrane action potentials and electrograms were recorded from isolated, Langendorff-perfused guinea-pig hearts during normal perfusion, global myocardial ischaemia and reperfusion during infusion of washed human platelets. Experiments were performed in the presence of 100 microM NG-nitro-L-arginine methyl ester (L-NAME), 30 microM L-arginine, 10 microM haemoglobin, 100 microM sodium nitroprusside and 2.3 nM iloprost, or using hearts obtained from DL-lysine monoacetylsalicylate (Aspisol, 50 mg.kg-1 i.p.)-treated animals. RESULTS: Perfusion with L-NAME and haemoglobin increased perfusion pressure by 33% (P = 0.0017) and 23% (P = 0.0026) while sodium nitroprusside and iloprost reduced it (17%, P = 0.0004, and 24%, P = 0.0006). In the absence of platelets, these compounds had no effect on arrhythmogenesis, but in the presence of platelets L-NAME reduced the onset time of ventricular tachycardia during ischaemia from 19.4 (s.e.m. 2.0) min to 12.9 (2.1) min, P = 0.04 and accentuated the ischaemia-induced reduction of action potential duration at 95% repolarization (APD95): 95(6) vs. 115(5) ms, P < 0.05 at 25 min. Sodium nitroprusside in the presence of platelets attenuated the ischaemia-induced reduction in APD95, while iloprost in the presence of platelets was antiarrhythmic (ventricular fibrillation 25 vs. 75%, P = 0.04) and attenuated the reduction in APD95 during ischaemia 115(4) vs. 94(4) ms, P < 0.05 at 20 min. Infusion of platelets into hearts obtained from DL-lysine-monoacetylsalicylate-treated guinea-pigs accentuated the ischaemia-induced reduction in APD95 (94(4) vs. 119(7) ms, P < 0.05 at 20 min) and this was reversed by sodium nitroprusside (117(7) ms, P < 0.05 at 20 min). L-NAME and haemoglobin had no effect on the aggregatory responses of the platelets to 5 microM ADP and 4 micrograms.ml-1 collagen, while sodium nitroprusside and iloprost ablated the responses to ADP and reduced the responses to collagen (maximum height of the aggregatory response reduced by 75 and 84%, respectively, both P = 0.03.) CONCLUSIONS: Inhibition of NO and PGI2 synthesis exacerbates the reduction in cardiac action potential duration associated with platelet activation during ischaemia, while provision of exogenous NO and PGI2 attenuates the reduction in cardiac action potential duration. Provision of exogenous NO and PGI2 (as iloprost) was associated with inhibition of platelet reactivity.

Action Potentials↗
PubMed1988

Anoxic contractile failure in rat heart myocytes is caused by failure of intracellular calcium release due to alteration of the action potential.

Anoxia of the heart causes failure of contraction before any irreversible injury occurs; the mechanism by which anoxia blocks cardiac excitation-contraction coupling is unknown. Studies in whole muscle are confounded by heterogeneity; however, achieving the low oxygen tensions required to study anoxia in a single myocyte during electrophysiological recording has been a barrier in experimental design. Guided by calculations of oxygen transport, we developed a system to insulate myocytes in an open dish from oxygen by a laminar counterflowing argon column, permitting free access to the cell by microelectrodes while maintaining a PO2 less than 0.02 torr (1 torr = 133 Pa). In the absence of glucose, the amplitude of stimulated contraction of anoxic ventricular myocytes fell to zero over 2 min after a lag period attributable to the consumption of endogenous glycogen. The cytosolic calcium concentration transient, measured by indo-1 fluorescence, fell to zero simultaneously with contraction. After the twitch had failed, microinjection of caffeine around the cell still caused a large calcium release and contraction, indicating that sarcoplasmic reticular calcium stores were not depleted. Twitch failure was accompanied by shortening and then failure of the action potential; under voltage clamp, large outward currents, reversing at the resting potential, developed during contractile failure. After failure of action potential-mediated contraction, voltage-clamp depolarization, with a large command voltage to compensate for the series-resistance error due to outward currents, restored normal twitch contraction. We conclude that anoxic contractile failure in the rat myocyte is due to alteration of the action potential and the distal pathways of excitation-contraction coupling remain essentially intact.

Action Potentials↗
PubMed1995

Mutant mice lacking the gamma isoform of protein kinase C show decreased behavioral actions of ethanol and altered function of gamma-aminobutyrate type A receptors.

Calcium/phospholipid-dependent protein kinase (protein kinase C, PKC) has been suggested to play a role in the sensitivity of gamma-aminobutyrate type A (GABAA) receptors to ethanol. We tested a line of null mutant mice that lacks the gamma isoform of PKC (PKC gamma) to determine the role of this brain-specific isoenzyme in ethanol sensitivity. We found that the mutation reduced the amount of PKC gamma immunoreactivity in cerebellum to undetectable levels without altering the levels of the alpha, beta I, or beta II isoforms of PKC. The mutant mice display reduced sensitivity to the effects of ethanol on loss of righting reflex and hypothermia but show normal responses to flunitrazepam or pentobarbital. Likewise, GABAA receptor function of isolated brain membranes showed that the mutation abolished the action of ethanol but did not alter actions of flunitrazepam or pentobarbital. These studies show the unique interactions of ethanol with GABAA receptors and suggest protein kinase isoenzymes as possible determinants of genetic differences in response to ethanol.

Animals↗