Balance between hypertrophic and hypoxic stimulus in caspase-3 activation during rat heart development

Summary During heart development, cell hyperplasia and hypertrophy are the main mechanisms by which cardiac mass grows. Both these processes along with programmed cell death lead to complete growth and function. In addition, since the establishment of cardiac function depends on the relationship between oxygen supply and demand, we investigated some of the molecular mechanisms at the basis of rat myocardial cell response to hypoxic stress at different times of neonatal life. In particular, the role played by hypertrophic and survival factors like NF-kB and IAP-1 (Inhibiting Apoptosis Protein) and by death factors ASK-1 (Apoptosis Signal Regulating Kinase), JNK/SAPK (Jun-N-Terminal-Kinase/Stress-Activated Protein Kinase) pathways in regulating caspase-3 expression and activity has been evaluated by immunohistochemical and Western blotting analyses, respectively. Level of phosphorylation of IkB and IAP-1 expression were substantial in 8-day-old hypoxic hearts, suggesting the persistence of NF-kB driven hypertrophic signal along with a rescue attempt against hypoxic stress. In contrast, ASK-1 mediated JNK/SAPK activation, regulating Bcl₂ levels, allows Bax homodimerization and caspase-3 activation in the same experimental conditions. Thus, a regulation carried out by NF-kB and JNK/SAPK pathways on caspase-3 activation at day 8 of neonatal life can be suggested as the main factor for the heart adaptive response to hypoxia.     

Effect of rest deprivation on motor activity of fish

Summary The rest-activity behavior of two fish species,Cichlosoma nigrofasciatum andCarassius auratus kept under 12-h light-12-h dim condition was investigated. Rest and activity were determined from continuous time-lapse video recordings. Three states were discriminated based on the degree of motor activity. Both species exhibited a clear rest-activity rhythm with activity predominating during the light period (Figs. 1, 2). Rest deprivation was carried out in perch during the habitual dim period by exposing the animals to either 12 h continuous light or to 6 h intermittent light (1 h light — 1 h dim for 12 h). Both light schedules enhanced activity and reduced rest (Fig. 3). Light-induced activation was followed by an increase in low activity and rest behavior which prevailed for 12 h following continuous light, and for 6 h following intermittent light (Figs. 3, 4). The results indicate that homeostatic mechanisms are involved in the regulation of rest and activity in fish. These mechanisms may be similar to those underlying sleep regulation in mammals.Abbreviations Ldim light-dim - EEG electroencephalogram - REM rapid eye movements     

Neuroendocrine and neurochemical mechanisms of the domestication of animals

A review of experimental data documenting that domestication of animals is associated with hereditary reorganization of neuro-endocrine mechanisms, responsible for basic processes of ontogeny, is presented. The data demonstrated changes in gonadal and pituitary-adrenal systems in domesticated animals. Analysis of evidence that selection for low aggressiveness towards man is, in fact, the selection for definite activity of brain neurotransmitters regulating aggressive behaviour and emotional stress response has been carried out. Supposed role of modifications in the mechanisms of domestication is discussed.     

ENaC at the Cutting Edge: Regulation of Epithelial Sodium Channels by Proteases

Epithelial Na⁺ channels facilitate the transport of Na⁺ across high resistance epithelia. Proteolytic cleavage has an important role in regulating the activity of these channels by increasing their open probability. Specific proteases have been shown to activate epithelial Na⁺ channels by cleaving channel subunits at defined sites within their extracellular domains. This minireview addresses the mechanisms by which proteases activate this channel and the question of why proteolysis has evolved as a mechanism of channel activation.Many ion channels are silent at rest and are activated in response to a variety of factors, including membrane potential, external ligands, and intracellular signaling processes. The ENaC² has evolved as a channel that is thought to reside primarily in an active state, facilitating the bulk movement of Na⁺ out of renal tubular or airway lumens. The regulated insertion and retrieval of channels at the plasma membrane have important roles in modulating ENaC-dependent Na⁺ transport (1). A number of factors also have a role in regulating ENaC activity via changes in channel P_o or gating. In this regard, it has become increasingly apparent that proteolysis of ENaC subunits has a key role in this process (2). This minireview addresses several questions regarding the role of ENaC subunit proteolysis in regulating channel gating. (i) Where are ENaC subunits cleaved? (ii) Which proteases mediate ENaC cleavage? (iii) Why are channels activated by proteolysis? (iv) Is proteolysis responsible, in part, for the highly variable channel P_o that has been noted for ENaC? (v) Why have ENaCs evolved as channels that require proteolysis for activation?     

The enzymatic activities of the Escherichia coli basic aliphatic amino acid decarboxylases exhibit a pH zone of inhibition

The stringent response regulator ppGpp has recently been shown by our group to inhibit the Escherichia coli inducible lysine decarboxylase, LdcI. As a follow-up to this observation, we examined the mechanisms that regulate the activities of the other four E. coli enzymes paralogous to LdcI: the constitutive lysine decarboxylase LdcC, the inducible arginine decarboxylase AdiA, the inducible ornithine decarboxylase SpeF, and the constitutive ornithine decarboxylase SpeC. LdcC and SpeC are involved in cellular polyamine biosynthesis, while LdcI, AdiA, and SpeF are involved in the acid stress response. Multiple mechanisms of regulation were found for these enzymes. In addition to LdcI, LdcC and SpeC were found to be inhibited by ppGpp; AdiA activity was found to be regulated by changes in oligomerization, while SpeF and SpeC activities were regulated by GTP. These findings indicate the presence of multiple mechanisms regulating the activity of this important family of decarboxylases. When the enzyme inhibition profiles are analyzed in parallel, a "zone of inhibition" between pH 6 and pH 8 is observed. Hence, the data suggest that E. coli utilizes multiple mechanisms to ensure that these decarboxylases remain inactive around neutral pH possibly to reduce the consumption of amino acids at this pH.     

Calcium is the switch in the moonlighting dual function of the ligand-activated receptor kinase phytosulfokine receptor 1

Background

A number of receptor kinases contain guanylate cyclase (GC) catalytic centres encapsulated in the cytosolic kinase domain. A prototypical example is the phytosulfokine receptor 1 (PSKR1) that is involved in regulating growth responses in plants. PSKR1 contains both kinase and GC activities however the underlying mechanisms regulating the dual functions have remained elusive.

Findings

Here, we confirm the dual activity of the cytoplasmic domain of the PSKR1 receptor. We show that mutations within the guanylate cyclase centre modulate the GC activity while not affecting the kinase catalytic activity. Using physiologically relevant Ca²⁺ levels, we demonstrate that its GC activity is enhanced over two-fold by Ca²⁺ in a concentration-dependent manner. Conversely, increasing Ca²⁺ levels inhibits kinase activity up to 500-fold at 100 nM Ca²⁺.

Conclusions

Changes in calcium at physiological levels can regulate the kinase and GC activities of PSKR1. We therefore propose a functional model of how calcium acts as a bimodal switch between kinase and GC activity in PSKR1 that could be relevant to other members of this novel class of ligand-activated receptor kinases.

     

The lymphocyte acetylcholinesterase activity in rats poisoned by pesticides

The experiments carried out present the evidence of acetylcholinesterase activity of Wistar rat lymphocytes. It was shown that splenocytes and thymocytes had significantly different levels of the enzyme activity. Peroral administration of phosphor-organic pesticide antio (phormothion) 1/100 and 1/20 LD50 induced the dose-dependent inhibition of splenocyte acetylcholine-esterase activity after 2 months of treatment. It suggests the relation of the immunosuppressive action of pesticide with the interference into the neuromediator mechanisms regulating the lymphoid cell function.     

Mechanisms regulating proteostasis are involved in sympatric speciation of the blind mole rat,Spalax galili

Genome-wide analysis demonstrates extensive genomic adaptive complexes involved in sympatric speciation between blind mole rats (Spalax galili) in abutting populations living in basalt and chalk soils. Among the gene ontology (GO) enrichment, musculature and metabolism stood out in basalt dwellers while nutrition and neurogenetics were highlighted in chalk residents. Measurements of mechanisms regulating protein homeostasis inspired by these GO terms suggest that at the proteomic level there is also a habitat/soil-type driven divergence with the basalt residents exhibiting higher proteasome activity whereas elevated levels of markers of autophagy are evident in the chalk inhabitants.     

Genetic basis of time perception in athletes

The association between the subjective time perception and polymorphism of some genes, regulating activity of serotonin and dopamine, was studied in 89 synchronized swimmers. COMT gene, responsible for dopamine destruction, influences on reproduction of short time intervals (1-2 s). 5-HT2A and MAOA genes, regulating activity of serotonin, influence on subjective time flow. 5-HTT and COMT genes, regulating activity of serotonin and dopamine respectively, are related with accuracy of orientation in time. Association of time perception with different genes and mediators suggests different perception mechanisms, in different time ranges, in concordance with the previous physiological studies. The current study reveals that these physiological mechanisms have different molecular-neurochemical basis that helps to overcome the gap between the investigation on systemic and molecular levels.     

Effect of erythropoiesis, size of iron accumulation and oxygen saturation of tissues on iron resorption

The volume of iron resorption is altered by numerous factors. To a wide extent, the exact regulating mechanisms have not been elucidated to the present day. The present paper deals with representing the influence of iron resorption by erythropoiesis, filling condition of iron stores and oxygen saturation of the tissue as well as with main aspects which are relevant for future research.     

Underlying mechanisms mediating the antidepressant effects of estrogens

Background

There is an increased risk for depressive symptoms and affective disorders in individuals who experience drastic drops or fluctuations of gonadal hormones. Moreover, clinical studies indicate that estrogens have the potential to be effective in treating depression.

Scope of the review

Possible underlying mechanisms for the antidepressant activity of estrogens are reviewed and discussed.

Major conclusions

Estrogens exert their antidepressant activity via a multimodal mechanism of action by regulating several pathways and functions associated with antidepressive effects. Estrogens increase serotonergic activity by regulating the synthesis and degradation of serotonin, as well as spontaneous firing of the serotonergic neurons in the raphe nuclei. Both pre- and postsynaptic serotonin receptors are shown to be regulated by estrogens. In addition, estrogens are neurotrophic and promote neuroplasticity and neurogenesis. Similar effects are also observed after treatment with current antidepressant therapies. However in stark contrast to current therapies which must be administered chronically to produce an effect, the responses to estrogens are often observed after a single dose. Many of these estrogenic effects, including antidepressant and anxiolytic responses in behavioral models in rodents, appear to be mediated via the estrogen receptor β subtype.

General significance

The rapid onset of action combined with the multifactorial mechanism of action of estrogens indicates that estrogen treatment could complement currently available therapies for depression. Considering safety aspects, selective estrogen receptor β agonists would probably be the optimal estrogenic therapy.     

Psycho-physiological monitoring in real and simulated space flight conditions

Earlier in simulating experiments from long isolation of small group in hermetic cabin we were found out the significant interrelation between changes physiological parameters and subjective appraisal of a condition, activity regulating systems of organism, individual variability of a colour choice, and also quality of operator's activity. On the basis of these results we develop a method of psychophysiological monitoring. The important component of a method is study of the variational characteristics of registered parameters, with the purpose of reception of the information about character of transients in organism. The present research is carried out in conditions of 135-daily isolation in a breadboard model MIR station (experiment HUBES). Its PURPOSE was study of dynamic psycho-emotional condition, simultaneously with study physiological and biochemical parameters, describing process of adaptation to complex conditions of ability to live. Besides were analyzed the results of circadian rhythm's researches during space flights of 6 Russian cosmonauts (duration from 70 till 182 days) on orbital MIR station.     

Endothelial Nitric Oxide Synthase Dimerization Is Regulated by Heat Shock Protein 90 Rather than by Phosphorylation

Endothelial nitric oxide synthase (eNOS) is a multifunctional enzyme with roles in diverse cellular processes including angiogenesis, tissue remodeling, and the maintenance of vascular tone. Monomeric and dimeric forms of eNOS exist in various tissues. The dimeric form of eNOS is considered the active form and the monomeric form is considered inactive. The activity of eNOS is also regulated by many other mechanisms, including amino acid phosphorylation and interactions with other proteins. However, the precise mechanisms regulating eNOS dimerization, phosphorylation, and activity remain incompletely characterized. We utilized purified eNOS and bovine aorta endothelial cells (BAECs) to investigate the mechanisms regulating eNOS degradation. Both eNOS monomer and dimer existed in purified bovine eNOS. Incubation of purified bovine eNOS with protein phosphatase 2A (PP2A) resulted in dephosphorylation at Serine 1179 (Ser1179) in both dimer and monomer and decrease in eNOS activity. However, the eNOS dimer∶monomer ratio was unchanged. Similarly, protein phosphatase 1 (PP1) induced dephosphorylation of eNOS at Threonine 497 (Thr497), without altering the eNOS dimer∶monomer ratio. Different from purified eNOS, in cultured BAECs eNOS existed predominantly as dimers. However, eNOS monomers accumulated following treatment with the proteasome inhibitor lactacystin. Additionally, treatment of BAECs with vascular endothelial growth factor (VEGF) resulted in phosphorylation of Ser1179 in eNOS dimers without altering the phosphorylation status of Thr497 in either form. Inhibition of heat shock protein 90 (Hsp90) or Hsp90 silencing destabilized eNOS dimers and was accompanied by dephosphorylation both of Ser1179 and Thr497. In conclusion, our study demonstrates that eNOS monomers, but not eNOS dimers, are degraded by ubiquitination. Additionally, the dimeric eNOS structure is the predominant condition for eNOS amino acid modification and activity regulation. Finally, destabilization of eNOS dimers not only results in eNOS degradation, but also causes changes in eNOS amino acid modifications that further affect eNOS activity.     

Genetics and phenogenetics of the hormonal characteristics of animals. II. Changes in the reactivity of the pituitary-adrenal system and influence of the sex glands in selection of silver-black foxes by behavior]

Seasonal changes in the reactivity of adrenal cortex to ACTH and of the pituitary-adrenal system to psychic stress in intact and castrated domesticated (tame) and non-domesticated (non-tame) silver foxes of both sexes were studied. It is demonstrated that in tame foxes there are differences among the intact and castrated animal in their reaction to ACTH and psychic stress. These differences are maifested especially in autumn (September, October) which is the period of extra-seasonal sexual activity for domesticated animals. This points to the fact that the sex glands exert a great influence on the condition of central regulating mechanisms of the pituitary-adrenal complex and that the selection of silver foxes for tame behaviour changes the functional state of these mechanisms through the change of the functional state of the sex glands.