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PubMed1998

Cytoprotective properties of melatonin: presumed association with oxidative damage and aging.

For years melatonin, a molecule widely produced in both the plant and animal kingdom, was thought to function exclusively as a synchronizer of seasonal reproduction, adjuster of the biological clock, sleep-inducing agent, and immune system stimulator. More recently melatonin has also been found to be a free-radical scavenger and antioxidant. Although pharmacologic levels (higher than those normally present endogenously) of melatonin possess substantial protective activity against molecular damage inflicted by free radicals, its role as a physiologic antioxidant is currently under active investigation. Toxic free radicals have been implicated in a variety of age-associated degenerative diseases, as well as in aging itself. Because melatonin production falls substantially during aging, the loss of this antioxidant is theorized to be instrumental in the degenerative processes associated with advanced age. The exogenous administration of melatonin has been found to be effective in reducing macromolecular damage that is normally seen in experimental models of age-related disease. How effective melatonin will be in terms of deferring aging, however, must await the outcome on subsequent studies.

Aging↗
PubMed1997

Mechanisms of cellular senescence.

Aging is a near universal process, yet the molecular mechanisms that underlie cellular senescence have remained elusive. Recent progress in determining the roles of various genetic influences in controlling the rate of cellular aging has made this an exciting time in aging research. Genetic screens designed to isolate long-lived mutants in Saccharomyces cerevisiae and Caenorhabditis elegans have implicated factors involved in transcriptional silencing and the dauer pathway in the control of aging. The gene responsible for Werner's syndrome, a disease with symptoms of premature aging, was isolated and found to be a member of the RecQ subfamily of DNA helicases. The regulation of telomere length and its role in senescence and cellular immortalization has been found to be more complex than expected. In C. elegans, mutations have been isolated in maternal-effect genes that presumably control its biological clocks and can dramatically extend its lifespan. Indeed, aging research within the past year has implicated a variety of mechanisms ranging from the control of gene expression, stress resistance, and DNA metabolism to the overall 'rate of living'.

Animals↗
PubMed1998

Adaptive significance of circadian programs in cyanobacteria.

Prokaryotic cyanobacteria express robust circadian (daily) rhythms, even when growing with doubling times that are considerably faster than once every 24 h. This biological clock orchestrates cellular events to occur in an optimal temporal program. Competition experiments demonstrate that fitness is enhanced when the circadian period resonates with the period of the environmental cycle.

Adaptation, Physiological↗
PubMed1996

Telomerase activity in hematopoietic cells is associated with self-renewal potential.

It has been proposed that the biological clock underlying the limited division potential of eukaryotic cells is telomere length. We assayed telomerase activity in single cells of the hematopoietic and immune systems. We examined hematopoietic stem cells at four stages of differentiation, lineage-committed progenitors, and mature myeloid and lymphoid cells. The frequency of telomerase-expressing cells within each population was proportional to the frequency of cells thought to have self-renewal potential. Among bone marrow hematopoietic stem cells, 70% exhibited detectable telomerase activity. The telomerase-expressing somatic cells observed in this study are not thought to be immortal, and expression was not correlated with cell cycle distribution or differentiation state. This study demonstrates that the developmental characteristic most consistently associated with telomerase expression is self-renewal potential.

Animals↗
PubMed2001

Regulation of gonadotropin-releasing hormone release by cyclic AMP signalling pathways.

The frequency and amplitude of gonadotropin-releasing hormone (GnRH) pulses are tightly regulated for the maintenance of reproductive cycles. Pulsatile GnRH release was shown to be an intrinsic property of murine GT1 GnRH neurons, and primate placodal GnRH neurons. GT1 neurons show spontaneous action potentials that are associated with Ca2+ oscillations and hormone secretion. Increased cyclic AMP (cAMP) levels in GT1 neurons appear to stimulate GnRH release by activation of cAMP-gated cation (CNG) channels. Activation of the CNG channels correlated with increased neuron excitability and Ca2+ oscillations. Activation of protein kinase A is not necessary for cAMP-induced stimulation of GnRH secretion, but appears to activate negative feedback pathways. Potential negative feedback pathways may decrease cAMP levels by inhibiting adenylyl cyclase V, and activating the phosphodiesterase, PDE4D3. These stimulatory and inhibitory cAMP-signalling pathways appear to regulate the excitability of the GT1 neurons, and may constitute a biological clock timing the pulsatile release of GnRH.

Adenylyl Cyclases↗
PubMed2001

Targeting protein ubiquitination for drug discovery. What is in the drug discovery toolbox?

Protein ubiquitination regulates the half-lives of many proteins by targeting them for degradation. Ubiquitination is a specific process associated with several highly regulated biological outcomes including cell cycle progression, differentiation, antigen presentation, retrovirus assembly, apoptosis, signal transduction, transcriptional activation, biological clocks, receptor downregulation and endocytosis. Newly discovered families of ubiquitination and deubiquitination enzymes participate in these processes. These enzymes could provide new families of drug targets and new ways of intervention in many human diseases; however, much work is required to validate this approach. This review will discuss what is in the drug discovery toolbox to assist in the validation of ubiquitination enzymes as therapeutic targets.

Journal Article↗
PubMedDate not supplied

Apoptosis in the human ovary.

Programmed cell death or apoptosis is an essential component of human ovarian function and development. During early fetal life approximately 7 x 10(6) oocytes are formed in the human ovary. However, the number of oocytes is dramatically reduced already before birth through apoptotic cell death. In reproductive life, a number of primordial follicles start growing during each menstrual cycle. Usually only one will ovulate and the fate of the rest of the follicles is atresia through the mechanism of apoptosis. Ultimately, only around 400 follicles will ovulate during a woman's reproductive life. After ovulation, the dominant follicle forms the corpus luteum, a novel endocrine gland that is responsible for the production of progesterone and maintenance of endometrium during early pregnancy. If pregnancy does not occur, corpus luteum action must cease so that new follicles can resume growing during the next menstrual cycle. Apoptosis is also responsible for corpus luteum regression in the human ovary. In recent years, new knowledge of the role and regulation of apoptosis in the ovary has been acquired through the use of knockout and transgenic animals. Apoptosis seems to be the mechanism that makes the female biological clock tick. The following review will discuss the role of apoptosis and its regulation of human ovarian function.

Animals↗
PubMed2002

Neurohypophyseal peptides in aging and Alzheimer's disease.

The neurohypophyseal hormones arginine-vasopressin (AVP) and oxytocin (OT) are produced in the neurons of the hypothalamic supraoptic (SON) and paraventricular (PVN) nucleus and in the much smaller cells of the suprachiasmatic (SCN) nucleus. The SON is the main source of plasma AVP. Part of the AVP and OT neurons of the PVN join the hypothalamo-neurohypophyseal tract, whereas others send projections to the median eminence or various brain areas, where AVP and OT are involved in a number of central functions as neurotransmitters/neuromodulators. AVP and OT from the PVN can also regulate via the autonomous innervation endocrine glands and fat tissue. OT is produced for a major part in the PVN but some OT neurons are present in the SON. Moreover, both AVP and OT containing neurons are observed in the "accessory nuclei", i.e. islands situated between the SON and PVN. The SCN is the biological clock, and the number of AVP expressing neurons in the SCN shows both diurnal and seasonal rhythms. In addition to these hypothalamic areas, AVP and OT may be found to a lesser extent in some other brain areas, such as the bed nucleus of the stria terminalis, diagonal band of Broca, nucleus basalis of Meynert, lateral septal nucleus, globus pallidus and the anterior amygdaloid nucleus, as well as in the peripheral tissues. The AVP and OT containing neurons should not be considered as one system. Prominent functional differences exist between the different nuclei. The heterogeneity also becomes clear from the marked differences in the neurohypophyseal peptides containing neurons of the SON, PVN and SCN during aging, and in the most prevalent age-related neurodegenerative diseases, i.e. Alzheimer's disease (AD). For those reasons, we will discuss the SON, PVN and SCN separately.

Aging↗
PubMed2002

Cluster headache: evidence for a disorder of circadian rhythm and hypothalamic function.

This article reviews the literature for evidence of a disorder of circadian rhythm and hypothalamic function in cluster headache. Cluster headache exhibits diurnal and seasonal rhythmicity. While cluster headache has traditionally been thought of as a vascular headache disorder, its periodicity suggests involvement of the suprachiasmatic nucleus of the hypothalamus, the biological clock. Normal circadian function and seasonal changes occurring in the suprachiasmatic nucleus and pineal gland are correlated to the clinical features and abnormalities of circadian rhythm seen in cluster headache. Abnormalities in the secretion of melatonin and cortisol in patients with cluster headache, neuroimaging of cluster headache attacks, and the use of melatonin as preventative therapy in cluster headache are discussed in this review. While the majority of studies exploring the relationship between circadian rhythms and cluster headache are not new, we have entered a new diagnostic and therapeutic era in primary headache disorders. The time has come to use the evidence for a disorder of circadian rhythm in cluster headache to further development of chronobiotics in the treatment of this disorder.

Circadian Rhythm↗
PubMed2004

The thalamic paraventricular nucleus relays information from the suprachiasmatic nucleus to the amygdala: a combined anterograde and retrograde tracing study in the rat at the light and electron microscopic levels.

The relationship between efferents of the hypothalamic suprachiasmatic nucleus (SCN) and neurons of the thalamic paraventricular nucleus (PVT) projecting to the amygdala was investigated in the rat using tract tracing in light and electron microscopy. Biotinylated dextran amine was used to label anterogradely SCN efferents. These fibers were found to reach the thalamic midline, terminating in PVT, through three pathways: anterodorsally through the preoptic region, dorsally through the periventricular hypothalamus, and through the contralateral medial hypothalamic and preoptic areas after crossing the midline in the optic chiasm. Preterminal and terminal-like elements labeled from the SCN were distributed throughout the rostrocaudal extent of PVT, with an anteroposterior gradient of density. Labeled terminal elements were densest in the dorsal portion of PVT beneath the ependymal lining and some of them entered the ependyma. Anterograde tracing of SCN fibers was combined with injections of retrograde tracers in the amygdala. Numerous retrogradely labeled cell bodies were seen throughout PVT, with a prevalence in its anterodorsal portion. Overlap was detected between puncta labeled from the SCN and retrogradely labeled neurons, especially in the anterodorsal sector of PVT, where numerous puncta were in close apposition to thalamo-amygdaloid cells. Electron microscopy revealed that boutons labeled from the SCN established synaptic contacts with dendritic profiles of PVT neurons labeled from the amygdala. The findings demonstrate that information processed in the biological clock is conveyed to the amygdala through PVT, indicating that this nucleus plays a role in the transfer of circadian timing information to the limbic system.

Amygdala↗
PubMed2002

[Circadian rhythm of cardiovascular emergencies].

Many cardiovascular emergencies occur predominantly in the morning hours. This diurnal distribution is due to synchronized exogenous and endogenous rhythms, the latter being controlled by a biological clock. In the morning, these rhythms raise blood pressure, heart rate, platelet aggregability, coronary vascular tone and thus, increase the risk of cardiovascular events.

Arousal↗
PubMed2000

Circadian rhythm of mt1 melatonin receptor expression in the suprachiasmatic nucleus of the C3H/HeN mouse.

This report studied the diurnal and circadian rhythms of mt1 melatonin receptor expression in the SCN of C3H/HeN mice maintained in either a light:dark (LD) cycle or in constant dark for a minimum of 6 wk. Diurnal times (ZT) were assessed with reference to the onset of the light period (ZT0) and circadian times (CT) were established by determining the phase of wheel running activity of each mouse before sacrifice. 2-[125I]-Iodomelatonin binding in the SCN revealed low amplitude diurnal and circadian rhythms with highest levels of binding 2 hr after lights on (41.3+/-1.7 fmol/mg protein, n = 5, at ZT2) or at the beginning of the subjective day (48.6+/-2.1 fmol/mg protein, n = 6, CT2), respectively. The expression of mt1 mRNA, determined by in situ hybridization with a 35S-labeled mouse mt1 riboprobe, showed robust diurnal and circadian rhythms. In animals housed under a LD cycle, low levels of expression were observed during the day, with a rapid rise in mt1 melatonin receptor expression at the beginning of the dark period (ZT14), coincident with an abrupt increase in levels of circulating melatonin measured by radioimmunoassay. In animals housed under constant dark conditions, a robust peak of mt1 mRNA expression occurred in the middle of the subjective night (CT18), 8 hr before the peak of protein expression, while the lowest levels of mt1 mRNA expression were observed during the day (CTI10). Results suggest that mt1 melatonin receptor rhythm in the C3H/HeN mouse SCN is regulated both by light and by the biological clock as distinct rhythms of both mRNA and protein are differentially expressed under a LD cycle and constant dark conditions.

Animals↗
PubMed2003

Perfusion of melatonin into the prefrontal cortex disrupts the circadian rhythm of acetylcholine but not of locomotor activity.

Extracellular concentrations of acetylcholine (ACh) in the prefrontal cortex displayed a circadian rhythm, with a maximum increase in the dark phase of the light:dark cycle. The increase in ACh related well to the circadian rhythm of the same rats in which a maximal increase of locomotor activity in the dark phase also was observed. Local perfusion of melatonin (200-500 microm), in a dose-dependent manner, disrupted the ACh rhythm in the prefrontal cortex but did not affect the circadian rhythm of locomotor activity. It is suggested that the change in the cholinergic transmission during a circadian period in the prefrontal cortex may be under the control of the biological clock through the action of melatonin; however, the prefrontal cortical ACh cycle seems not to be related to the regulation of locomotor activity.

Acetylcholine↗
PubMedDate not supplied

Restoration of circadian behavioural rhythms by gene transfer in Drosophila.

The per locus of Drosophila melanogaster has a fundamental role in the construction or maintenance of a biological clock. Three classes of per mutations have been identified: per mutants have circadian behavioural rhythms with a 29-h rather than a 24-h period, pers mutants have short-period rhythms of 19 h, and per mutants have no detectable circadian rhythms. Each of these mutations has a corresponding influence on the 55-s periodicity of male courtship song. Long- and short-period circadian rhythm phenotypes can also be obtained by altering the dosage of the wild-type gene: for example, females carrying only one dose of this X-linked gene have circadian rhythms with periodicities about 1 h longer than those carrying two doses. In a previous report, cloned DNA was used to localize several chromosomal rearrangement breakpoints that alter per locus function. The rearrangements all affected a 7-kilobase (kb) interval that encodes a 4.5-kb poly(A)+ RNA. We report here that when a 7.1-kb fragment from a per+ fly, including the sequences encoding the 4.5-kb transcript, is introduced into the genome of a per (arrhythmic) fly by P element-mediated transformation, circadian rhythmicity of behaviour such as eclosion and locomotor activity is restored. The transforming DNA complements per locus deletions and is transcribed, forming a single 4.5-kb poly(A)+ RNA comparable to that produced by wild-type flies.

Animals↗
PubMed1999

A suprachiasmatic nucleus generated rhythm in basal glucose concentrations.

The daily rhythm in feeding activity in mammals, as driven by the biological clock, largely determines the daily fluctuations in basal concentrations of glucose and insulin. To investigate a possible direct impact of the suprachiasmatic nucleus (SCN) on these parameters, we subjected intact rats and SCN-lesioned rats to a fasting regimen of 36 h, or to a scheduled feeding regimen of six identical meals equally distributed over the light:dark-cycle. Plasma profiles of glucose and insulin in rats during the final 24 h of the 36 h of fasting, and in rats subjected to the scheduled feeding regimen were compared to profiles in rats fed ad libitum. In rats fed ad libitum, in fasted rats and in rats subjected to a scheduled feeding regimen basal glucose concentrations showed a pronounced 24-h rhythm that was not found in rats that had been SCN-lesioned. Basal insulin levels showed a 24-h rhythm in 50% of the rats fed ad libitum and in 50% of the rats subjected to a scheduled feeding regimen; neither rhythms were present in SCN-lesioned rats. However, none of the fasted rats showed a 24-h rhythm in basal insulin concentrations. These data provide clear evidence that the SCN directly controls basal glucose concentrations independent of its influence on feeding activity. At the same time, we found no consistent evidence for a strong impact of the SCN on basal insulin concentrations.

Animals↗
PubMed2003

Daily rhythms in glucose metabolism: suprachiasmatic nucleus output to peripheral tissue.

The body has developed several control mechanisms to maintain plasma glucose concentrations within strict boundaries. Within those physiological boundaries, a clear daily rhythm in plasma glucose concentrations is present; this rhythm depends on the biological clock, which is located in the hypothalamic suprachiasmatic nucleus (SCN), and is independent of the daily rhythm in food intake. Interestingly, there is also a daily rhythm in glucose uptake, which also depends on the SCN and follows the same pattern as the daily rhythm in plasma glucose concentrations; both rise before the onset of activity. Thus, the SCN prepares the individual for the upcoming activity period in two different ways: by increasing plasma glucose concentrations and by facilitating tissue glucose uptake. In addition to this anticipation of glucose metabolism to expected glucose demands, the SCN also influences, depending on the time of the day, the responses of pancreas and liver to abrupt glucose changes (such as a glucose rise after a meal or hypoglycaemia). This review presents the view that the SCN uses different routes to (i) maintain daily glucose balance and (ii) set the level of the endocrine response to abrupt blood glucose changes.

Animals↗
PubMed2001

Chronobiological variations of indomethacin pharmacokinetic parameters in sheep.

A two-phase study to investigate the influence of administration time on pharmacokinetics of indomethacin in sheep was performed. In phase I, 12 animals were allocated to four groups, each corresponding to a different time: 08:00, 14:00, 20:00, 02:00 h. Sheep received an intravenous administration of 1 mg/kg indomethacin. In phase II, each group was administered indomethacin with a 12-h difference compared to Phase I. The trial was performed in autumn, and animals were subjected to a natural light:dark cycle of 10:14 h. Blood samples were taken and processed by high performance liquid chromatography (HPLC) with ultraviolet detection. For each pharmacokinetic parameter, an analysis of variance was performed to outline the existence of chronobiological variations. Concentration at zero time (C0), hybrid constant for distribution and its half life, hybrid constant for elimination and its half-life, volume of distribution (V(d)), area under the curve (AUC(infinity)) and clearance rate (Cl), presented chronobiological variations (P < 0.05) and were fitted to a cosine equation. The following parameters adjusted to circadian rhythms: C(0) (acrophase: 13.9788 h); AUC(infinity) (acrophase: 13.4377 h); V(d) (acrophase: 0.8245 h) and Cl (acrophase: 1.4965 h). It was concluded that pharmacokinetic parameters of intravenously injected indomethacin in sheep would behave in a different, though predictable, manner according to the animal's biological clock.

Animals↗
PubMed2002

The FtsH protease is involved in development, stress response and heat shock control in Caulobacter crescentus.

The ftsH gene of Caulobacter crescentus has been isolated and identified as a component of the general stress response of this organism. In C. crescentus, ftsH expression is transiently induced after temperature upshift and in stationary phase. Consistent with this, mutants deprived of the FtsH protease are viable at normal growth conditions, but are highly sensitive to elevated temperature, increased salt concentration or the presence of antibiotics. Overexpression of ftsH resulted in an increased salt but not thermotolerance, emphasizing the importance of the FtsH protease in stress response. Mutants lacking FtsH were unable to undergo morphological and physiological adaptation in stationary phase and, upon starvation, experienced a more pronounced loss of viability than cells containing FtsH. In addition, cells lacking FtsH had an increased cellular concentration of the heat shock sigma factor sigma32, indicating that, as in Escherichia coli, the FtsH protease is involved in the control of the C. crescentus heat shock response. In agreement with this, transcription of the heat-induced sigma32-dependent gene dnaK was derepressed at normal temperature when FtsH was absent. In contrast, the groEL gene, which is controlled in response to heat stress by both sigma32 and a HcrA/CIRCE mechanism, was not derepressed in an ftsH mutant. Finally, FtsH is involved in C. crescentus development and cell cycle control. ftsH mutants were unable to synthesize stalks efficiently and had a severe cell division phenotype. In the absence of FtsH, swarmer cells differentiated into stalked cells faster than when FtsH was present, even though the entire cell cycle was longer under these conditions. Thus, directly or indirectly, the FtsH protease is involved in the inherent biological clock mechanism, which controls the timing of cell differentiation in C. crescentus.

ATP-Dependent Proteases↗