scholarly journals Electrophysiological Correlates of Ionic and Osmotic Stress in an Osmoconforming Bivalve (Mytilus Edulis)

1978 ◽  
Vol 77 (1) ◽  
pp. 181-205 ◽  
Author(s):  
P. G. WILLMER
Keyword(s):  
Osmotic Stress ◽  
Mytilus Edulis ◽  
Sodium Concentration ◽  
Salinity Acclimation ◽  
Pharmacological Agents ◽  
Full Effect ◽  
Critical Salinity ◽  
In Trans ◽  
Time Courses ◽  
High Concentrations

Mytilus edulis suffered reductions in trans-membrane sodium concentration gradient during dilute salinity acclimation. Nevertheless the nerves of this osmoconformer had a conventional basis for their excitability, irrespective of the salinity to which they were adapted, and could produce full-sized spikes after acclimation to 25% media. 2. The connectives showed rapid and predictable responses to sodium and to potassium ions, and the time-courses of these effects were unrelated to the presence or absence of the neural sheath at either of the acclimation salinities tested. Neural adaptation was therefore not a consequence of restricted access after acclimation to dilute media. 3. Classic pharmacological agents (tetrodotoxin, tetra-ethyl ammonium ions, 2,4-dinitrophenol and ouabain) elicited the expected responses, but invariably required rather high concentrations and long exposures for full effect. 4. Acute exposures of the connectives to hyposmotic or isosmotic dilutions resulted in changes in polarization accompanying the decline of the action potential. These were attributed to losses of potassium and of chloride from the axons, with a net loss of anion (and hence depolarization) during naturally occurring hyposmotic stress. 5. Mytilus connectives exhibited a critical salinity, with hyposmotic exposure below this level producing irreversible impairment of function. This salinity occurred at 20% s.w. for 100%-adapted tissues, and at 3.25% s.w. (i.e. 15% initial concentration) for 25%-adapted nerves. Gross isosmotic dilutions produced no permanent decrements in axonal function. 6. The observed patterns of response to chronic and acute osmotic stress in Mytilus are contrasted with those reported in annelid and crustacean conformers, and possible adaptations which might underlie these responses are discussed.

scholarly journals Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 2. THR-687

2021 ◽  
Author(s):  
Marc Vanhove ◽  
Jean-Marc Wagner ◽  
Bernard Noppen ◽  
Bart Jonckx ◽  
Elke Vermassen ◽  
...  
Keyword(s):  
General Circulation ◽  
Pharmacokinetic Model ◽  
Systemic Exposure ◽  
Age Related Macular Degeneration ◽  
Whole Body ◽  
Pharmacological Agents ◽  
Age Related ◽  
Pharmacokinetic Properties ◽  
High Concentrations ◽  
Systemic Compartment

AbstractIntravitreal (IVT) injection remains the preferred administration route of pharmacological agents intended for the treatment of back of the eye diseases such as diabetic macular edema (DME) and neovascular age-related macular degeneration (nvAMD). The procedure enables drugs to be delivered locally at high concentrations whilst limiting whole body exposure and associated risk of systemic adverse events. Nevertheless, intravitreally-delivered drugs do enter the general circulation and achieving an accurate understanding of systemic exposure is pivotal for the evaluation and development of drugs administered in the eye. We report here the full pharmacokinetic properties of THR-687, a pan RGD integrin antagonist currently in clinical development for the treatment of DME, in both rabbit and minipig. Pharmacokinetic characterization included description of vitreal elimination, of systemic pharmacokinetics, and of systemic exposure following IVT administration. For the latter, we present a novel pharmacokinetic model that assumes clear partition between the vitreous humor compartment itself where the drug is administered and the central systemic compartment. We also propose an analytical solution to the system of differential equations that represent the pharmacokinetic model, thereby allowing data analysis with standard nonlinear regression analysis. The model accurately describes circulating levels of THR-687 following IVT administration in relevant animal models, and we suggest that this approach is relevant to a range of drugs and analysis of subsequent systemic exposure.

Accumulation of natural and synthetic betaines by a mammalian renal cell line

1996 ◽  
Vol 74 (2) ◽  
pp. 283-287 ◽  
Author(s):  
K. Randall ◽  
M. Lever ◽  
B. A. Peddie ◽  
S. T. Chambers
Keyword(s):  
Osmotic Stress ◽  
Glycine Betaine ◽  
Mdck Cells ◽  
Intracellular Accumulation ◽  
Madin Darby Canine Kidney ◽  
Renal Cell Line ◽  
High Concentrations ◽  
Inhibition Studies ◽  
Darby Canine Kidney ◽  
Canine Kidney

Intracellular accumulation of different betaines was compared in osmotically stressed Madin Darby canine kidney (MDCK) cells to model the betaine accumulation specificity of the mammalian inner medulla and to show how this accumulation differed from that of bacteria. All betaines accumulated less than glycine betaine. Arsenobetaine (the arsenic analogue of glycine betaine) accumulated to 12% of the glycine betaine levels and the sulphur analogue dimethylthetin accumulated to >80%. Most substituted glycine betaine analogues accumulated to 2–5% of intracellular glycine betaine concentrations, however, serine betaine accumulated to <0.5% of glycine betaine levels. Inhibition studies to distinguish the betaine ports were performed by the addition of proline. Butyrobetaine and carnitine accumulation was not proline sensitive, whereas that of omer betaines was. As with glycine betaine, the accumulation of propionobetaine and dimethylthetin was proline sensitive and osmoregulated. Pyridinium betaine was accumulated by both proline-sensitive and -insensitive systems, with a small increase under osmotic stress. High concentrations (10 times that of glycine betaine) of the dietary betaines proline betaine and trigonelline inhibited total betaine accumulation. Because α-substituted betaines are accumulated by bacteria and not by MDCK cells, these betaines may be the basis for design of antimicrobial agents.Key words: MDCK cells, betaine accumulation, osmolytes, betaine analogues.

scholarly journals Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 349
Author(s):  
Sepideh Mirzaei ◽  
Ali Zarrabi ◽  
Farid Hashemi ◽  
Amirhossein Zabolian ◽  
Hossein Saleki ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Adverse Effects ◽  
Cancer Progression ◽  
Related Factor ◽  
Pharmacological Agents ◽  
Nrf2 Signaling Pathway ◽  
High Concentrations ◽  
Genetic Interventions ◽  
Underlying Mechanisms ◽  
In Cells

Doxorubicin (DOX) is extensively applied in cancer therapy due to its efficacy in suppressing cancer progression and inducing apoptosis. After its discovery, this chemotherapeutic agent has been frequently used for cancer therapy, leading to chemoresistance. Due to dose-dependent toxicity, high concentrations of DOX cannot be administered to cancer patients. Therefore, experiments have been directed towards revealing underlying mechanisms responsible for DOX resistance and ameliorating its adverse effects. Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling is activated to increase levels of reactive oxygen species (ROS) in cells to protect them against oxidative stress. It has been reported that Nrf2 activation is associated with drug resistance. In cells exposed to DOX, stimulation of Nrf2 signaling protects cells against cell death. Various upstream mediators regulate Nrf2 in DOX resistance. Strategies, both pharmacological and genetic interventions, have been applied for reversing DOX resistance. However, Nrf2 induction is of importance for alleviating side effects of DOX. Pharmacological agents with naturally occurring compounds as the most common have been used for inducing Nrf2 signaling in DOX amelioration. Furthermore, signaling networks in which Nrf2 is a key player for protection against DOX adverse effects have been revealed and are discussed in the current review.

scholarly journals PP2A Methylation is Necessary for Broad Stress Tolerance

2021 ◽  
Author(s):  
Maria T. Creighton ◽  
Dugassa Nemie-Feyissa ◽  
Nabeela Zaman ◽  
Sverre S. Johansen ◽  
Hege Dysjaland ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Tolerance ◽  
Dry Weight ◽  
Sodium Concentration ◽  
Post Translational Modification ◽  
Iron Starvation ◽  
Methyl Transferase ◽  
High Concentrations ◽  
Fe Homeostasis ◽  
Rock Wool

Abstract Background: LEUCINE CARBOXYL METHYL TRANSFERASE 1 (LCMT1) transfers a methyl group from the methyl donor S-adenosylmethionine (SAM) to the catalytic subunit of PROTEIN PHOSPHATASE 2A (PP2A). This post-translational modification of PP2A is manifested throughout eukaryotes from yeast to plants and animals. Although highly conserved, the importance of the methylation is poorly understood. Since Arabidopsis plants with knocked out LCMT1 grow and develop fairly normally, we decided to search for conditions that may reveal the benefits of this regulation. We compared the effects of various stressful conditions on Arabidopsis wild type (WT) and a lcmt1 mutant possessing only non-methylated PP2A. Results: Seedlings were grown in Petri dishes for 5-12 days, or in rock wool and soil for up to 7 weeks. A significant increase in sodium concentration was found for lcmt1 relative to WT, but this was not linked with stressful conditions. Plants were exposed to variable levels of the chelator EDTA, iron, zinc, aluminium, heat, and hydrogen peroxide. The lcmt1 mutant was clearly more sensitive than WT to all the various stresses, as demonstrated by effects on seedling root growth and on shoots of rosette stage plants on rock wool. When omitting EDTA, expression of genes known as signature genes for iron deficiency, FIT1, bHLH100, IMA1, IRT1 was strongly enhanced in lcmt1. Although an iron starvation response was induced, Fe homeostasis was apparently maintained by slowed growth in lcmt1 and the Fe level related to tissue dry weight was not changed. Among genes induced in lcmt1 were also the Zn induced gene ZIF1, and heat shock protein HSP90-1. Concentrations of non-iron transition metals, Cu, Mn and Zn, increased significantly in response to lack of EDTA for both lcmt1 and WT tissue, and especially the growth of lcmt1 was strongly hampered. Conclusions: Presence of the LCMT1 gene was necessary to cope efficiently with an imbalance in the micronutrients, heat stress, and oxidative stress. Methylation of PP2A appears important to ameliorate the toxic effects of metals present in unfavourable high concentrations as well as heat or oxidative stress. The experiments establish LCMT1 as a key component in broad stress tolerance.

Effects of protamine and strophanthin on mitochondrial potassium, sodium and water

1960 ◽  
Vol 199 (4) ◽  
pp. 653-656
Author(s):  
Leonard Share
Keyword(s):  
Rat Liver ◽  
Sodium Concentration ◽  
Water Metabolism ◽  
Intact Cells ◽  
Kidney Mitochondria ◽  
Potassium Sodium ◽  
Isolated Mitochondria ◽  
Liver And Kidney ◽  
Uncoupling Of Oxidative Phosphorylation ◽  
High Concentrations

A study was made of the effects of certain agents, which inhibit potassium transport in intact cells, on the potassium, sodium and water metabolism of isolated mitochondria. Protamine (4 mg/100 ml) induced swelling in rat liver and kidney mitochondria and impaired the ability of these mitochondria to concentrate potassium. These actions appeared to be associated with the uncoupling of oxidative phosphorylation. Protamine was without effect on the mitochondrial sodium concentration. Strophanthin at extremely high concentrations (1 gm/100 ml) was also found to induce swelling of rat liver, kidney and heart mitochondria and to interfere with the ability of the mitochondria to concentrate potassium. There was a tendency for mitochondrial sodium concentration to be elevated. It is concluded that the actions of protamine and strophanthin on mitochondria are qualitatively and quantitatively different from the actions of these substances on intact cells and that there are basic differences between the potassium concentrating mechanisms in mitochondria and in intact cells.

scholarly journals The Effect of Bacterial Endotoxin LPS on Serotonergic Modulation of Glutamatergic Synaptic Transmission

Biology ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 210
Author(s):  
Jate Bernard ◽  
Abigail Greenhalgh ◽  
Oscar Istas ◽  
Nicole T. Marguerite ◽  
Robin L. Cooper
Keyword(s):  
Synaptic Transmission ◽  
Motor Neurons ◽  
Positive Outcome ◽  
The Body ◽  
Receptor Subtype ◽  
Pharmacological Agents ◽  
Enhanced Transmission ◽  
Glutamatergic Synaptic Transmission ◽  
The Central Nervous System ◽  
High Concentrations

The release of the endotoxin lipopolysaccharides (LPS) from gram-negative bacteria is key in the induction of the downstream cytokine release from cells targeting cells throughout the body. However, LPS itself has direct effects on cellular activity and can alter synaptic transmission. Animals experiencing septicemia are generally in a critical state and are often treated with various pharmacological agents. Since antidepressants related to the serotonergic system have been shown to have a positive outcome for septicemic conditions impacting the central nervous system, the actions of serotonin (5-HT) on neurons also exposed to LPS were investigated. At the model glutamatergic synapse of the crayfish neuromuscular junction (NMJ), 5-HT primarily acts through a 5-HT2A receptor subtype to enhance transmission to the motor neurons. LPS from Serratia marcescens also enhances transmission at the crayfish NMJ but by a currently unknown mechanism. LPS at 100 µg/mL had no significant effect on transmission or on altering the response to 5-HT. LPS at 500 µg/mL increased the amplitude of the evoked synaptic excitatory junction potential, and 5-HT in combination with 500 µg/mL LPS continued to promote enhanced transmission. The preparations maintained responsiveness to serotonin in the presence of low or high concentrations of LPS.

Ryanodine-Sensitive Stores Regulate the Excitability of AH Neurons in the Myenteric Plexus of Guinea-Pig Ileum

2000 ◽  
Vol 84 (6) ◽  
pp. 2777-2785 ◽  
Author(s):  
K. Hillsley ◽  
J. L. Kenyon ◽  
T. K. Smith
Keyword(s):  
Sensory Processing ◽  
Calcium Release ◽  
Excitatory Postsynaptic Potential ◽  
Similar Time ◽  
Intracellular Ca ◽  
Time Courses ◽  
High Concentrations ◽  
Calcium Induced Calcium Release ◽  
Activity Dependent

Myenteric afterhyperpolarizing (AH) neurons are primary afferent neurons within the gastrointestinal tract. Stimulation of the intestinal mucosa evokes action potentials (AP) that are followed by a slow afterhyperpolarization (AHPslow) in the soma. The role of intracellular Ca2+ ([Ca2+]i) and ryanodine-sensitive Ca2+ stores in modulating the electrical activity of myenteric AH neurons was investigated by recording membrane potential and bis-fura-2 fluorescence from 34 AH neurons. Mean resting [Ca2+]i was ∼200 nM. Depolarizing current pulses that elicited APs evoked AHPslow and an increase in [Ca2+]i, with similar time courses. The amplitudes and durations of AHPslow and the Ca2+ transient were proportional to the number of evoked APs, with each AP increasing [Ca2+]i by ∼50 nM. Ryanodine (10 μM) significantly reduced both the amplitude and duration (by 60%) of the evoked Ca2+ transient and AHPslow over the range of APs tested (1–15). Calcium-induced calcium release (CICR) was graded and proportional to the number of APs, with each AP triggering a rise in [Ca2+]i of ∼30 nM Ca2+ via CICR. This indicates that CICR amplifies Ca2+ influx. Similar changes in [Ca2+]i and AHPslow were evoked by two APs in control and six APs in ryanodine. Thus, the magnitude of the change in bulk [Ca2+]i and not the source of the Ca2+ is the determinant of the magnitude of AHPslow. Furthermore, lowering of free [Ca2+]i, either by reducing extracellular Ca2+ or injecting high concentrations of Ca2+buffer, induced depolarization, increased excitability, and abolition of AHPslow. In addition, activation of synaptic input to AH neurons elicited a slow excitatory postsynaptic potential (sEPSP) that was completely blocked in ryanodine. These results demonstrate the importance of [Ca2+]i and CICR in sensory processing in AH neurons. Activity-dependent CICR may be a mechanism to grade the output of AH neurons according to the intensity of sensory input.

Effects of long-term ionic and osmotic stress conditions on photosynthesis in the cyanobacterium Synechocystis sp. PCC 6803

2005 ◽  
Vol 32 (9) ◽  
pp. 807 ◽  
Author(s):  
Saowarath Jantaro ◽  
Paula Mulo ◽  
Tove Jansén ◽  
Aran Incharoensakdi ◽  
Pirkko Mäenpää
Keyword(s):  
Osmotic Stress ◽  
Stress Component ◽  
D1 Protein ◽  
Long Term Effects ◽  
High Concentration ◽  
High Concentrations ◽  
Synechocystis Sp ◽  
Halotolerant Cyanobacterium ◽  
Pcc 6803

Salinity is considered to be one of the most severe problems in worldwide agricultural production, but the published investigations give contradictory results of the effect of ionic and osmotic stresses on photosynthesis. In the present study, long-term effects of both ionic and osmotic stresses, especially on photosynthesis, were investigated using the moderately halotolerant cyanobacterium Synechocystis sp. PCC 6803. Our results show that the PSII activity and the photosynthetic capacity tolerated NaCl but a high concentration of sorbitol completely inhibited both activities. In line with these results, we show that the amount of the D1 protein of PSII was decreased under severe osmotic stress, whereas the levels of PsaA / B and NdhF3 proteins remained unchanged. However, high concentrations of sorbitol stress led to a drastic decrease of both psbA (encoding D1) and psaA (encoding PsaA) transcripts, suggesting that severe osmotic stress may abolish the tight coordination of transcription and translation normally present in bacteria, at least in the case of the psaA gene. Taken together, our results indicate that the osmotic stress component is more detrimental to photosynthesis than the ionic one and, furthermore, under osmotic stress, the D1 protein appears to be the target of this stress treatment.

scholarly journals The Effects of External Potassium and Long Duration Voltage Conditioning on the Amplitude of Sodium Currents in the Giant Axon of the Squid, Loligo pealei

1969 ◽  
Vol 54 (5) ◽  
pp. 589-606 ◽  
Author(s):  
William J. Adelman ◽  
Yoram Palti
Keyword(s):  
Steady State ◽  
Time Constant ◽  
State Level ◽  
Giant Axon ◽  
Sodium Concentration ◽  
Quasi Steady State ◽  
Steady State Level ◽  
Long Duration ◽  
Time Courses ◽  
Loligo Pealei

Giant axons were voltage-clamped in solutions of constant sodium concentration (230 mM) and variable potassium concentrations (from 0 to 210 mM). The values of the peak initial transient current, Ip, were measured as a function of conditioning prepulse duration over the range from less than 1 msec to over 3 min. Prepulse amplitudes were varied from Em = -20 mv to Em = -160 mv. The attenuation of the Ip values in high [Ko] was found to vary as a function of time when long duration conditioning potentials were applied. In both high and low [Ko], Ip values which had reached a quasi-steady—state level within a few milliseconds following a few milliseconds of hyperpolarization were found to increase following longer hyperpolarization. A second plateau was reached with a time constant of about 100–500 msec and a third with a time constant in the range of 30 to 200 sec. The intermediate quasi-steady—state level was absent in K-free ASW solutions. Sodium inactivation curves, normalized to Ipmax values obtained at either the first or second plateaus, were significantly different in different [Ko]. The inactivation curves, however, tended to superpose after about 1 min of hyperpolarizing conditioning. The time courses and magnitudes of the intermediate and very slow sodium conductance restorations induced by long hyperpolarizing pulses are in agreement with those predicted from the calculated rates and magnitudes of [K+] depletion in the space between the axolemma and the Schwann layer.

scholarly journals ABSCISIC ACID AND WATER RELATIONS MODELS OF SEED GERMINATION.

HortScience ◽  
1990 ◽  
Vol 25 (9) ◽  
pp. 1093e-1093
Author(s):  
Bing-Rui Ni ◽  
Kent J. Bradford
Keyword(s):  
Standard Deviation ◽  
Seed Germination ◽  
Osmotic Stress ◽  
Water Relations ◽  
Growth Models ◽  
Probit Analysis ◽  
Population Characteristics ◽  
Germination Time ◽  
The Mean ◽  
Time Courses

Cell growth models were applied to characterize the response of seed germination, based upon the timing of radicle emergence, to y and ABA. Using probit analysis, three basic parameters can be derived to describe the population characteristics of seed lots. In the response of seed germination to osmotic stress, these three parameters are the “hydrotime constant” (q H), the mean base water potential (y b), and the standard deviation (s b) population. In the response to ABA, they are the “ABA-time constant” (q ABA), the mean base ABA concentration (ABAb), and the standard deviation (s ABAb) of the seed population. Using only these three parameters, germination time courses can be predicted at any corresponding medium y or ABA concentration. In the presence of both ABA and osmotic stress, the same parameters can be used to predict seed germination time courses with any combination of y and ABA concentration. The water relations model and the ABA model were additive and it appeared that the two factors slowed down germination independently. Effects of osmotic stress and ABA on the parameters in Lockhart equation are also discussed.

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