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At least 289 records · Page 16Linked to original sources
PubMed1997

Postsynaptic action potentials do not alter short-term potentiation in the dentate gyrus.

The dendrites of neocortical neurons have been shown to support active action potentials which back-propagate from the soma after an output spike has been initiated. This observation has led to speculation that dendritic action potentials may participate in various forms of synaptic plasticity. The contribution of dendritic spikes to paired-pulse facilitation (PPF), a form of short-term plasticity, was investigated in the dentate gyrus of hippocampal slices. Paired orthodromic stimulation of the perforant path produced an average facilitation of the test population spike (PS) amplitude of 167% (n = 16, conditioning response = 100%). There was also a small but significant increase in slope of the field EPSP (fEPSP) of 108%. To determine whether increased presynaptic drive could account for this facilitation, the relationship between fEPSP slope and spike amplitude (I-O) was determined for a range of stimulus intensities. An increase in fEPSP slope of 171% was associated with an increase in PS amplitude equal to the facilitation produced by paired-pulse stimulation (167%), suggesting a postsynaptic component in PPF. Electric field effects were then used as a tool to alter the excitability of granule cells during the conditioning response without changing synaptic drive. Any change in the test response associated with manipulation of the conditioning population spike amplitude would suggest that dendritic spikes may contribute to the postsynaptic component of PPF. Surprisingly, altering the number of neurons responding to the conditioning stimulus with an action potential had no effect on the test response, suggesting that dendritic action potentials do not participate in this form of short-term synaptic plasticity.

Action Potentials↗
PubMed1987

Fasting-mediated alteration studies in insulin action on lipolysis and lipogenesis in obese women.

The effects of fasting on insulin-induced antilipolysis and lipogenesis were investigated in vitro in isolated human fat cells of 11 obese females. Glycerol release and lipogenesis were determined simultaneously in the same test tube and related to methylglucose transport and specific insulin binding. Insulin binding and sensitivity and the responsiveness (maximum effect) of insulin-induced antilipolysis were enhanced by fasting. The latter was strongly correlated with an enhancement in the lipolysis rate. The effects of fasting on antilipolysis were not dependent on the glucose concentration, unlike insulin-stimulated lipogenesis. At 1 mumol/l of glucose, where hexose transport is rate limiting, sensitivity and responsiveness of insulin-induced lipogenesis were inhibited by fasting. Similar results were obtained with methylglucose transport. At 1-10 mmol/l of glucose, where hexose metabolism is rate limiting, insulin stimulated lipogenesis before fasting but was totally ineffective after fasting. In conclusion, fasting induces multiple alterations in insulin action on lipolysis and lipogenesis in adipocytes. Antilipolysis is enhanced because of stimulation at the receptor and postreceptor levels, which may be associated with an enhanced rate of lipolysis. Fasting inhibits the lipogenic effect of insulin due to postreceptor changes involving both transport and metabolism of glucose, making lipogenesis unresponsive to insulin at physiological glucose concentrations.

Adipose Tissue↗
PubMedDate not supplied

Effect of subminimal inhibitory concentrations of mecillinam on the synthesis of DNA, RNA, and protein of Salmonella typhimurium: a proposed mechanism of action.

Salmonellae alter their rod-like morphology to become large ovals within 3-5 hr after being exposed to concentrations of mecillinam below the minimal inhibitory concentration. Before this overt morphologic change occurs, synthesis of DNA increases, with a concomitant decrease in total protein synthesis. Incorporation of [3H]leucine into cell wall protein is markedly inhibited by mecillinam, whereas incorporation of leucine into soluble intracellular proteins is enchanced by the drug. Electrophoretic separation of stained, soluble intracellular proteins of salmonellae exposed to mecillinam indicates that as many as 15-20 individual groups of protein occur at higher concentrations in mecillinam-exposed salmonellae than in unexposed control organisms. These results suggest that, at low concentrations, mecillinam binds selectively to cell wall components, thereby interfering with the assembly of the cell wall during growth. This interference causes a buildup of newly synthesized soluble proteins that are normally involved in cell wall assembly. The weakening of the cell wall, combined with this buildup, causes the cell to assume a three-dimensional oval structure that is the result of equal hydrostatic pressure exerted by the medium.

Amdinocillin↗
PubMed2005

Anti-cancer drugs: molecular mechanisms of action.

Genetic alterations are responsible for all cancers. These mutations produce, in turn, alterations in key proteins of certain signaling pathways. Amongst the best known and studied alterations related to malignant transformations are those which occur in Ras protein and p53. In most cases mutations in Ras and p53 lead to the appearance of practically most malignant transformations. Mutated Ras genes exist in approximately 20 to 30% of all human cancers. Ras proteins are switches that regulate diverse functions such as cell proliferation, differentiation and apoptosis. Normal p53 expression, also known as the "genome guardian", is a key molecule for suppressing cell proliferation. The great importance of these proteins rests on their intimacy with the events leading to cell proliferation or death. The comprehension of the extent of transformation on Ras and p53, and of the diverse biochemical pathways of intracellular signaling, activated by them, is of extreme importance for the understanding of malignant transformation, as well as its control, through the creation, for example, of new drugs which contribute to the elimination of these cells. To clarify the consequences originated by transformed Ras, p53 and their biochemical interlinks in the different intracellular pathways, besides the possible intervening points and pharmacological controls presently used in combating cancer, are the aims of this review.

Alkyl and Aryl Transferases↗
PubMedDate not supplied

[Changes in the pulsatility index (Gosling) under drug action].

The alterations in cerebral hemodynamics induced by drugs (papaverine, Cavinton, magnesium sulphate, piracetam, histamine) in a series of 152 patients compared with a control series were analysed. The response of each basal cerebral artery to these drugs is assessed through the pulsatility index value.

Blood Flow Velocity↗
PubMedDate not supplied

[Dynamics of thyroxine and triiodothyronine concentration in the rat blood at early times after subtotal removal of the thyroid gland or under effects of different I-131 action].

The alterations of amount of thyroid hormones have the characteristic dynamics that manifest itself by initial reduction with following partial or complete restoration of T3 and T4 concentration in rat blood after surgical or radioactive injuries of thyroid gland. Through presence of threshold of several dozens Gy for early dose-dependent hypothyroidism, the thyroid gland seems to be relatively radioresistant organ. Thyroid hormones concentration in blood has restored to normal level after experimental injuries which shows high restoration potential of thyroid gland function.

Animals↗
PubMed1986

Systemic hypertension induces disparate localized left ventricular action potential lengthening and altered sensitivity to verapamil in left ventricular myocardium.

Previously, we demonstrated that acute exposure to superfusate containing verapamil suppresses action potential plateau to a greater degree in cells at the tip of the anterior papillary muscle compared to those at its base in normal cat left ventricle (LV) studied in tissue bath. To determine the effects of chronic pressure overload brought about by renal hypertension on papillary muscle electrophysiology and regional sensitivity to verapamil, LV were isolated from cats subjected to unilateral nephrectomy and contralateral kidney wrapping. After 3 months, systemic hypertension (mean increase = 60.2 +/- 1.4 mmHg) was associated with moderate LV hypertrophy of approximately equal to 18% (LV weight/body weight). Transmembrane action potentials recorded from the endocardial surface (including anterior papillary muscle) in pressure overloaded LV in vitro (800 ms stimulus cycle length) showed increased action potential duration at 25, 75 and 90% of repolarization (APD25, APD75 and APD90, respectively) relative to controls (LV from normal and sham operated cats). With respect to the anterior papillary muscle in pressure overloaded LV, APD25, APD75 and APD90 were increased to a greater extent in cells at the base of the muscle compared to those increases observed at the tip (P less than 0.05). In contrast to its effects in controls, verapamil (2 micrograms/ml) significantly reduced APD25 at both the base and the tip of the papillary muscle in pressure overloaded preparations, but particularly at the base; also, the disparities between the APD75 or APD90 at tip and base were decreased. Thus, regional electrophysiologic disparities were induced in systemic hypertension, and these differences were subsequently reduced by verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed2003

Transforming growth factor-alpha changes firing properties of developing neocortical GABAergic neurons by down-regulation of voltage-gated potassium currents.

Transforming growth factor-alpha (TGFalpha), a member of the epidermal growth factor family, has neurotrophic actions on postmitotic neurons. We examined the chronic effects of TGFalpha on the electrophysiological properties of one type of GABAergic neuron, identified by its bipolar morphology, in neocortical primary culture. Approximately 85% of the bipolar neurons were GABA-immunoreactive. In response to depolarizing current injection, the bipolar neurons usually showed tonic firing of action potential under control conditions. After treatment with TGFalpha (20 ng/ml) for 2 days, these neurons failed to generate trains of action potentials. Furthermore, the treatment altered the action potential waveforms of the bipolar neurons, including the duration and amplitude of the fast after-hyperpolarization, which implies a reduction in voltage-gated potassium currents. In contrast, TGFalpha did not affect the firing properties of pyramidal-shaped non-GABAergic neurons. Voltage-clamp recordings from the bipolar neurons indicated that chronic treatment with TGFalpha markedly decreased the current densities of slow delayed rectifier (IK) and transient voltage-gated potassium currents, whereas the treatment had no effect on voltage-gated sodium current and fast delayed rectifier potassium current densities. Reverse transcription-polymerase chain reaction analysis of potassium channel mRNA in the bipolar neurons revealed that the reduction in the IK current density was caused by Kv2.2 mRNA down-regulation. Thus, chronic treatment with TGFalpha down-regulated slow delayed rectifier and transient voltage-gated potassium currents, and in parallel, suppressed repetitive generation of action potentials in the cortical GABAergic neurons.

4-Aminopyridine↗
PubMed1999

Reduction in atherosclerotic lesion size in pigs by alphaVbeta3 inhibitors is associated with inhibition of insulin-like growth factor-I-mediated signaling.

Insulin-like growth factor-I (IGF-I) is a potent stimulant of smooth muscle cell (SMC) migration and proliferation and has been implicated in the development of experimental atherosclerotic lesions. Because optimal stimulation of SMC in vitro by IGF-I requires ligand occupancy of alphaVbeta3, these studies were conducted to determine whether alphaVbeta3 antagonists would result in a change in lesion size and whether they could alter IGF-I-mediated actions. Clamps were placed on the carotid and femoral arteries of normal pigs that had been fed a high-cholesterol diet for 4 weeks. alphaVbeta3 inhibitors (SC-69000, SC-65811) (10(-6) mol/L) or saline were infused for 2 weeks into the peristenotic area. Lesion area, the number of SMC layers, and proliferating cell nuclear antigen positive cells were determined in a 1.2-mm segment of each artery. Lesion areas were 304 788+/-113 453 micron(2) (saline), compared with 149 799+/-35 456 micron(2) (SC-69000) (P<0.01). Lesion areas in arteries treated with SC-64258, a compound that does not bind to alphaVbeta3, were 310 284+/-160 467 micron(2), P=not significant. In a second experiment, lesion areas were 110 391+/-17 347 micron(2) (saline) and 59 533+/-17 568 micron(2) (SC-65811, P<0.001). Neointimal SMC layers were reduced by SC-65811 from 7.4+/-4.5 to 3.0+/-0.4 (P<0.001). To determine whether IGF-I action was altered, IGF binding protein-5, which is synthesized in response to IGF-I, was analyzed. IGF-I binding protein-5 mRNA abundance was reduced by 67+/-8% in the 6 lesions treated with SRL-69000 compared with saline controls (P<0.001). We conclude that alphaVbeta3 antagonists block the development of lesions in pigs that have been induced by a high-cholesterol diet and stenosis, and the effect of these compounds is associated with their ability to inhibit IGF-I-mediated signaling.

Aniline Compounds↗
PubMed1990

Elevated potassium shortens action potential duration by altering outward currents in chick dorsal root ganglia neurons.

Dissociated embryonic chick dorsal root ganglion (DRG) neurons maintained in culture exhibit a mixed Na+/Ca2+ action potential. The characteristic "shoulder" on the repolarizing phase is due to the relatively prolonged inward Ca2+ current. DRG neurons grown in an elevated K+ medium (25 versus. 5 mM) lack the plateau phase of the action potential. Voltage-clamp analysis showed that this plastic change in action potential duration is not due to the loss of the inward Ca2+ current but is partly due to the appearance of a Ca2(+)-dependent, 4-aminopyridine-(4-AP)-sensitive transient outward current. Faster activation of the purely voltage-dependent delayed rectifier outward current also contributes to the rapid repolarization observed in neurons cultured in elevated K+ medium.

4-Aminopyridine↗
PubMed1988

Mechanisms of altered hormone and neurotransmitter action during aging: the role of impaired calcium mobilization.

Age-related changes in hormone and neurotransmitter regulation of physiological functions result from various mechanistic alterations. In many cases changes in the receptors for these agents appear to be closely linked to altered responsiveness. In other instances, receptors are unaffected by aging, and various post-receptor changes result in functional deterioration. Examples of the latter situation include stimulation of cyclic AMP production and high-affinity association of steroid receptor-hormone complexes with nuclear acceptor sites in various cell and tissue types. One of the most noteworthy post-receptor changes appears to be an impaired ability to stimulate calcium mobilization in many aged systems resulting in reductions in various biological responses. Although the processes which govern regulation of calcium fluxes vary with cell type, many such dysfunctions can be at least partially reversed if sufficient calcium can be transported to appropriate cellular sites. Thus, elucidation of the molecular mechanisms involved in impaired calcium mobilization may provide the basis for new therapeutic strategies.

Aging↗
PubMed2006

Protoporphyrin IX generation from delta-aminolevulinic acid elicits pulmonary artery relaxation and soluble guanylate cyclase activation.

Protoporphyrin IX is an activator of soluble guanylate cyclase (sGC), but its role as an endogenous regulator of vascular function through cGMP has not been previously reported. In this study we examined whether the heme precursor delta-aminolevulinic acid (ALA) could regulate vascular force through promoting protoporphyrin IX-elicited activation of sGC. Exposure of endothelium-denuded bovine pulmonary arteries (BPA) in organoid culture to increasing concentrations of the heme precursor ALA caused a concentration-dependent increase in BPA epifluorescence, consistent with increased tissue protoporphyrin IX levels, associated with decreased force generation to increasing concentrations of serotonin. The force-depressing actions of 0.1 mM ALA were associated with increased cGMP-associated vasodilator-stimulated phosphoprotein (VASP) phosphorylation and increased sGC activity in homogenates of BPA cultured with ALA. Increasing iron availability with 0.1 mM FeSO(4) inhibited the decrease in contraction to serotonin and increase in sGC activity caused by ALA, associated with decreased protoporphyrin IX and increased heme. Chelating endogenous iron with 0.1 mM deferoxamine increased the detection of protoporphyrin IX and force depressing activity of 10 microM ALA. The inhibition of sGC activation with the heme oxidant 10 muM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) attenuated the force depressing actions of an NO donor without altering the actions of ALA. Thus control of endogenous formation of protoporphyrin IX from ALA by the availability of iron is potentially a novel physiological mechanism of controlling vascular function through regulating the activity of sGC.

Aminolevulinic Acid↗
PubMed1981

Adriamycin induced alterations in canine Purkinje fiber action potential.

To study the electrophysiologic effects of adriamycin, transmembrane action potential characteristics of canine purkinje fibers were analyzed. Adriamycin significantly (p less than 0.05) prolonged action potential duration and refractory period but did not significantly alter resting membrane potential, action potential amplitude, dV/dt max and threshold for stimulation. Furthermore adriamycin effects were not reversible 20 minutes after the drug had been 'washed out'. These data indicate that adriamycin has significant cardiac electrophysiology effects that may account for its toxicity in man and that these effects are not quickly reversible.

Action Potentials↗
PubMedDate not supplied

In heme catabolism C2 and C4 vinyl groups reduction of cobalt protoporphyrin forms cobalt mesoporphyrin and alters the nature of action of the metalloporphyrin in vivo.

Heme is a tetrapyrrolic ring with iron as the central metal atom and acts as a prosthetic group for a number of enzymes, e.g. cytochromes and globins. It also plays an important role in the regulation of transcription, translation, protein translocation and erythroid differentiation. Thus, heme regulation is under strict control in the body. Our studies on the regulatory enzymes of heme anabolism, aminolevulinic acid synthetase (ALA-S), and of catabolism, heme oxygenase (HMOX), in the spleen has revealed that cobalt protoporphyrin acts as an inducer of HMOX. It is revealed that by alteration of side groups at C2 and C4 changes the nature of action of Co-protoporphyrin from an inducer to a strong inhibitor of HMOX activity. All the three analogues Co-protoporphyrin, Co-mesoporphyrin and Co-hematoporphyrin have been shown to induce the ALA-S activity to the similar extent. NADPH-cytochrome c reductase, a microsomal membrane bound enzyme, is required by HMOX for the enzymatic conversion of heme into biliverdin IXc and is also required for NADPH-dependent lipid peroxidation in the microsomes. It has been observed that Co-mesoporphyrin causes an inhibition of HMOX activity and consequently leads to an induced level of microsomal NADPH-dependent lipid peroxidation.

5-Aminolevulinate Synthetase↗
PubMed1992

In vivo kindling does not alter afterhyperpolarizations (AHPs) following action potential firing in vitro in basolateral amygdala neurons.

Kindling in vivo results in enhanced glutamatergic synaptic transmission and epileptiform bursting in vitro in neurons of the basolateral amygdala (BLA). We tested the hypothesis that reduction of intrinsic inhibitory mechanisms, such as the slow- and medium-afterhyperpolarizations (s-AHPs, m-AHPs), contributes to the enhanced neuronal excitability observed in kindling-induced epileptogenesis using intracellular recording methodology. In these studies, neurons were recorded from the BLA contralateral to the kindling site. AHPs following depolarizing current-induced (100 ms, 1 nA) action potentials were recorded from BLA neurons of control and kindled animals. We found no difference in the amplitude of the s-AHP and m-AHP, or the duration of the s-AHP between control and kindled neurons. In addition, kindling did not alter the distribution of accommodating/non-accommodating BLA neurons (as assessed from neuronal responses during long (500 ms) depolarizing current injection). It is concluded that an alteration in the neuronal network within the BLA rather than a blockade of an intrinsic inhibitory mechanism underlies the enhanced excitability recorded in BLA neurons following kindling.

Action Potentials↗
PubMed2005

Endocrine disrupting compounds and prostate cancer.

Prostate cancer is a major health concern and is treated based on its hormone dependence. Agents that alter hormone action can have substantial biological effects on prostate cancer development and progression. As such, there is significant interest in uncovering the potential effects of endocrine disrupting compound (EDC) exposure on prostate cancer. The present review is focused on agents that alter hormone action in the prostate and how they may impact cancer growth or treatment.

Androgens↗
PubMed2006

Macrophages block insulin action in adipocytes by altering expression of signaling and glucose transport proteins.

Obesity leads to a proinflammatory state with immune responses that include infiltration of adipose tissue with macrophages. These macrophages are believed to alter insulin sensitivity in adipocytes, but the mechanisms that underlie this effect have not been characterized. We have explored the interaction between macrophages and adipocytes in the context of both indirect and direct coculture. Macrophage-secreted factors blocked insulin action in adipocytes via downregulation of GLUT4 and IRS-1, leading to a decrease in Akt phosphorylation and impaired insulin-stimulated GLUT4 translocation to the plasma membrane. GLUT1 was upregulated with a concomitant increase in basal glucose uptake. These changes recapitulate those seen in adipose tissue from insulin-resistant humans and animal models. TNF-alpha-neutralizing antibodies partially reversed the insulin resistance produced by macrophage-conditioned media. Peritoneal macrophages and macrophage-enriched stromal vascular cells from adipose tissue also attenuated responsiveness to insulin in a manner correlating with inflammatory cytokine secretion. Adipose tissue macrophages from obese mice have an F4/80(+)CD11b(+)CD68(+)CD14(-) phenotype and form long cellular extensions in culture. Peritoneal macrophages take on similar characteristics in direct coculture with adipocytes and induce proinflammatory cytokines, suggesting that macrophage activation state is influenced by contact with adipocytes. Thus both indirect/secreted and direct/cell contact-mediated factors derived from macrophages influence insulin sensitivity in adipocytes.

3T3-L1 Cells↗
PubMed2026

Molecular Profiling Across 80,000 Patients With Lung Cancer.

INTRODUCTION: Biomarker testing is an essential component of optimal therapeutic management in NSCLC, enabling the use of both Food and Drug Administration-approved and emerging targeted therapies. Despite well-established biomarker testing guidelines and the availability of many approved targeted therapies, a substantial proportion of patients with advanced NSCLC are not benefiting from precision oncology. In this study, we analyze the distribution of actionable genomic alterations across histologic subtypes and clinicodemographic subgroups of NSCLC using data in 82,328 samples profiled with a single comprehensive genomic profiling assay, aiming to support universal molecular testing across all NSCLC subtypes to ensure equitable access to available therapeutics. METHODS: This is an observational retrospective analysis on histologically confirmed NSCLC cases tested with comprehensive genomic profiling by next-generation sequencing between 2014 and 2022 using Foundation One/Foundation CDx. All cases were centrally reviewed by board-certified anatomic pathologist to determine histologic type and subtype. RESULTS: A total of 82,328 patients with NSCLC were included. An actionable genomic alteration (GA) was found in 35.1% of the cases. Lung adenocarcinoma (LUAD) and adenosquamous carcinoma were more frequently associated with actionable GA (45.8% and 40.9%, respectively) as compared with sarcomatoid (29.1%), not otherwise specified (27.6%), large cell (21.1%), and squamous cell (6.5%) histologies. Sarcomatoid histology had the highest METex14 skipping mutation (mut) frequency (9.95% versus 2.43% in LUAD). Tumor mutation burden more than or equal to 10 mut/Mb was associated with histology (50.91% in large cell, 40.79% in not otherwise specified, 39.08% in squamous cell, and 36.30% in sarcomatoid versus 31.22% in LUAD and 29.22% in adenosquamous carcinoma). Patients with actionable GA had usually a low tumor mutation burden (80.88%). A significant correlation (p < 0.005) between age and actionable GA was reported for BRAF/ERBB2 muts, ALK/RET/ROS1 rearrangements, and MET amplification. EGFR actionable muts and KRAS G12C were more frequently observed in females, whereas no significant correlation between sex and other GA was observed. Finally, genetic ancestry analyses revealed a strong correlation for EGFR actionable muts and South/East Asia and America, but not for other GA. CONCLUSIONS: This is the largest NSCLC data set analyzed for biomarker distribution across histologies, age, sex, and genetic ancestry. This data set confirms sufficient enough biomarker prevalence across many histologic subtypes of NSCLC, providing reassurance that all NSCLC cases should be considered for biomarker workup.

Humans↗