Regulatory aspects of coenzyme Q metabolism

A number of factors are involved in the regulation of the amount and distribution of coenzyme Q in cells and tissues. These factors modify preferentially the biosynthetic mechanism in order to keep up an optimal tissue concentration of the lipid. The amount of substrate provided by the mevalonate pathway is able to both up- and down-regulate the velocity of synthesis. At the translation level, regulation occurs by receptor-mediated ligand binding and appears most clearly upon treatment with hormones and peroxisomal inducers. There are a number of pathophysiological conditions when these mechanisms of regulation are modified and explain the decreased coenzyme Q tissue concentrations. It is of considerable interest to establish appropriate physiological, hormonal and drug-mediated conditions in order to counteract disturbed cellular functions caused by coenzyme Q deficiency.     

The Endothelin/Sarafotoxin‐Induced Increase of the Proliferation of Undifferentiated and DMSO‐Differentiated GEM‐81 Goldfish Erythrophoroma Cells is Mediated by ETB Receptors

Endothelins (ETs) and sarafotoxins (SRTXs) have been reported to exert ET_B‐mediated effects on vertebrate pigment cells. GEM‐81 cell line, a red pigment cell‐derived cutaneous tumor of the teleost Carassius auratus, expresses ET_B receptors and can be differentiated with 1.5% DMSO treatment, thus constituting an useful model to investigate ET and SRTX effects on cultured fish pigment cells. Our aim was to characterize the pharmacology and biological effects mediated by ET receptors in DMSO‐differentiated and undifferentiated cells. ET subtype receptors and their respective Ki values in both cell types were determined by competitive binding assays using ¹²⁵I ET‐1 and BQ‐485 (an ET_A antagonist) or BQ‐788 (an ET_B antagonist). BQ‐788, but not BQ‐485, significantly reduced ¹²⁵I‐ET‐1 binding in both cell types, with similar low (Ki > nM) affinities. To determine the proliferation effects of ETs/SRTXs, cells were treated for 72 h with the hormones, and counted in a hemocytometer. The proliferation assays were repeated for SRTX S6c in the presence or absence of BQ‐788. The results demonstrated that, with the exception of ET‐1 (biphasic effect) and ET‐3 (no significant effect) in undifferentiated GEM‐81 cells, all the tested hormones induced increases in the proliferation of both types of cells. The hormones were equipotent in DMSO‐differentiated cells, which exhibited increased sensitivity to ETs, but not to SRTXs, as compared with undifferentiated cells. The BQ‐788 antagonistic effect was also exerted on the proliferation responses to SRTX S6c. These results corroborate the long and important evolutionary history of the ET/SRTX receptor system in vertebrate pigment cells.     

Women's interest in visual sexual stimuli varies with menstrual cycle phase at first exposure and predicts later interest

This study investigated whether women's interest in visual sexual stimuli varied with their hormonal state. Viewing times of 30 women, 15 normal cycling (NC) and 15 oral contracepting (OC), to sexually explicit photos were measured at three different times. NC women were tested during their menstrual, periovulatory, and luteal phases, and OC women were tested at equivalent temporal intervals. Subjects viewed stimuli as long as desired, thus viewing time measured subject interest. Subjective ratings of stimulus sexual attractiveness were obtained on each test. There was no overall relationship between menstrual cycle phase and viewing time. However the participant's menstrual cycle phase during first exposure to sexual stimuli predicted subsequent interest in sexual stimuli during the next two tests. NC women who first viewed stimuli during their periovulatory phase looked longer at the sexual stimuli across all sessions than did women first tested in their luteal phase. OC women first exposed to the sexual stimuli during menstruation looked longer at the stimuli across all sessions than did OC women first exposed at other test phases. Neither current test phase nor initial cycle phase influenced subjective ratings. Women had increased interest in sexual stimuli across all sessions if first exposed to sexual stimuli when endogenous estrogens were most likely highest. These data suggest that women's interest in visual sexual stimuli is modulated by hormones such that the hormonal condition at first exposure possibly determines the stimuli's emotional valence, markedly affecting subsequent interest in sexual stimuli.     

Agonist-regulated Cleavage of the Extracellular Domain of Parathyroid Hormone Receptor Type 1

The receptor for parathyroid hormone (PTHR) is a main regulator of calcium homeostasis and bone maintenance. As a member of class B of G protein-coupled receptors, it harbors a large extracellular domain, which is required for ligand binding. Here, we demonstrate that the PTHR extracellular domain is cleaved by a protease belonging to the family of extracellular metalloproteinases. We show that the cleavage takes place in a region of the extracellular domain that belongs to an unstructured loop connecting the ligand-binding parts and that the N-terminal 10-kDa fragment is connected to the receptor core by a disulfide bond. Cleaved receptor revealed reduced protein stability compared with noncleaved receptor, suggesting degradation of the whole receptor. In the presence of the agonistic peptides PTH(1–34), PTH(1–14), or PTH(1–31), the processing of the PTHR extracellular domain was inhibited, and receptor protein levels were stabilized. A processed form of the PTHR was also detected in human kidney. These findings suggest a new model of PTHR processing and regulation of its stability.     

Secretion Stimulates Intramembrane Proteolysis of a Secretory Granule Membrane Enzyme

Regulated intramembrane proteolysis, a highly conserved process employed by diverse regulatory pathways, can release soluble fragments that directly or indirectly modulate gene expression. In this study we used pharmacological tools to identify peptidylglycine α-amidating monooxygenase (PAM), a type I secretory granule membrane protein, as a γ-secretase substrate. PAM, an essential enzyme, catalyzes the final step in the synthesis of the majority of neuropeptides that control metabolic homeostasis. Mass spectroscopy was most consistent with the presence of multiple closely spaced NH₂ termini, suggesting that cleavage occurred near the middle of the PAM transmembrane domain. The luminal domains of PAM must undergo a series of prohormone convertase or α-secretase-mediated cleavages before the remaining transmembrane domain/cytosolic domain fragment can undergo a γ-secretase-like cleavage. Cleavage by γ-secretase generates a soluble fragment of the cytosolic domain (sf-CD) that is known to localize to the nucleus. Although PAM sf-CD is unstable in AtT-20 corticotroph tumor cells, it is readily detected in primary rat anterior pituitary cells. PAM isoform expression, which is tissue-specific and developmentally regulated, affects the efficiency with which sf-CD is produced. sf-CD levels are also modulated by the phosphorylation status of the cytosolic domain and by the ability of the cytosolic domain to interact with cytosolic proteins. sf-CD is produced by primary rat anterior pituitary cells in response to secretogogue, suggesting that sf-CD acts as a signaling molecule relaying information about secretion from the secretory granule to the nucleus.     

Relationship between change in core temperature and change in cortisol and TNFα during exercise

The combined thermal load created by exercise and a hot environment is associated with an exaggerated core temperature response. The elevated core temperature is believed to increase the total stress of the exercise. Increased stress during exercise has been associated with increased levels of cortisol. The association of cortisol with increased inflammatory responses following exercise in the heat is equivocal. Thus, the purpose of the current investigation was to explore the relationship between increases in rectal temperature (T_re) and TNFα and cortisol. To induce T_re changes, 8 male subjects (mean±SD, age=23.6±2 yr, VO₂max=52.8±3.7 mL/kg/min, BMI=24.2±1.9) participated in two 40 min trials of cycle ergometry at 65% of VO₂peak immersed to chest level in cool (25 °C) and warm (38.5 °C) water. T_re was monitored throughout each trial, with blood samples taken immediately pre and post of each trial. Neither cortisol nor TNFα changed significantly during exercise in the cool water; however, in the warm trial, both cortisol and TNFα significantly increased (p<0.004). Concordance correlations (R_c) between Δ cortisol and Δ TNFα indicated a strong but non-significant correlation (R_c=0.833, p=0.135). In conclusion, changes in core temperature may be impacting the relationship between exercise induced changes in cortisol and TNFα. Therefore, acute moderate-intensity exercise (40 min or less) in warm water impacts the stress and inflammatory response. Understanding this is important because exercise load may need to be adjusted in warm and hot environments to avoid the negative effects of elevated stress and inflammation response.     

Anatomy, function and regulation of neuropeptide EI (NEI)

This review is focused on the anatomy, role and behavior of neuropeptide-glutamic acid-isoleucine (NEI), providing a general report on the neuropeptide. In addition to hormone release, this peptide also takes part in the regulation of grooming behavior and locomotor activity. NEI is produced by cleavage of prepro-MCH that probably takes place at the Lys(129)-Arg(130) and Arg(145)-Arg(146) sites (the glycine residue on the C-terminus of NEI strongly suggests that this peptide is amidated). This same prohormone is also the precursor of MCH, widely studied in relation to food and water intake, and NGE, of which little is known. NEI and MCH are extensively colocalized throughout the central nervous system (CNS), and NEI is also present in peripheral tissues. The latter is also effective in stimulating luteinizing hormone (LH) release and, to a lesser extent, FSH from primary pituitary cell cultures. In addition to releasing LH from the medial eminence, NEI also acts directly on gonadotropes. Lastly, this neuropeptide also acts at the CNS level on gonadotropin-releasing hormone (GnRH) neurons.     

Effect of Boron as an Antidote on Dry Matter Intake,Nutrient Utilization and Fluorine Balance in Buffalo (<Emphasis Type="Italic">Bubalus bubalis</Emphasis>) Exposed to High Fluoride Ration

Twenty male buffalo calves (8–9 months, 112.1 ± 7.69 kg) were divided into four groups of five animals in each and fed diets without (T1) or supplemented with 0.3 ppm selenium (Se) (T2), 0.3 ppm Se + 10 ppm copper (Cu) (T3), and 10 ppm Cu (T4) for 120 days during which blood samples were collected on day 0, 40, 80, and 120. Concentrations of glucose, total protein, urea, uric acid, and creatinine were similar in all the four groups, but the level of globulin was significantly (P < 0.01) increased in groups T2 and T3, leading to reduced levels of albumin and A:G ratio (P < 0.01) in these groups. The level of different serum enzymes viz. lactate dehydrogenase (LDH), alkaline phosphatase (ALP), glutamate pyruvate transaminase (SGPT), and glutamate oxaloacetate transaminase (SGOT) and hormones viz. T₃, T₄, testosterone and insulin and T₄:T₃ ratio were similar (P > 0.05) among the four groups. It was deduced that supplementation of 0.3 ppm Se and/or 10.0 ppm of Cu had no effect on blood metabolic profile in buffalo calves, except for an increased globulin level, indicating improved immunity status of these animals.