Chamaecyparis lawsoniana and Its Active Compound Quercetin as Ca2+ Inhibitors in the Contraction of Airway Smooth Muscle.

The Cupressaceae family includes species considered to be medicinal. Their essential oil is used for headaches, colds, cough, and bronchitis. Cedar trees like Chamaecyparis lawsoniana (C. lawsoniana) are commonly found in urban areas. We investigated whether C. lawsoniana exerts some of its effects by modifying airway smooth muscle (ASM) contractility. The leaves of C. lawsoniana (363 g) were pulverized mechanically, and extracts were obtained by successive maceration 1:10 (w:w) with methanol/CHCl3. Guinea pig tracheal rings were contracted with KCl, tetraethylammonium (TEA), histamine (HIS), or carbachol (Cch) in organ baths. In the Cch experiments, tissues were pre-incubated with D-600, an antagonist of L-type voltage-dependent Ca2+ channels (L-VDCC) before the addition of C. lawsoniana. Interestingly, at different concentrations, C. lawsoniana diminished the tracheal contractions induced by KCl, TEA, HIS, and Cch. In ASM cells, C. lawsoniana significantly diminished L-type Ca2+ currents. ASM cells stimulated with Cch produced a transient Ca2+ peak followed by a sustained plateau maintained by L-VDCC and store-operated Ca2+ channels (SOCC). C. lawsoniana almost abolished this last response. These results show that C. lawsoniana, and its active metabolite quercetin, relax the ASM by inhibiting the L-VDCC and SOCC; further studies must be performed to obtain the complete set of metabolites of the extract and study at length their pharmacological properties.

Phytoestrogen-Based Hormonal Replacement Therapy Could Benefit Women Suffering Late-Onset Asthma.

It has been observed that plasmatic concentrations of estrogens, progesterone, or both correlate with symptoms in asthmatic women. Fluctuations in female sex steroid concentrations during menstrual periods are closely related to asthma symptoms, while menopause induces severe physiological changes that might require hormonal replacement therapy (HRT), that could influence asthma symptoms in these women. Late-onset asthma (LOA) has been categorized as a specific asthmatic phenotype that includes menopausal women and novel research regarding therapeutic alternatives that might provide relief to asthmatic women suffering LOA warrants more thorough and comprehensive analysis. Therefore, the present review proposes phytoestrogens as a promising HRT that might provide these females with relief for both their menopause and asthma symptoms. Besides their well-recognized anti-inflammatory and antioxidant capacities, phytoestrogens activate estrogen receptors and promote mild hormone-like responses that benefit postmenopausal women, particularly asthmatics, constituting therefore a very attractive potential therapy largely due to their low toxicity and scarce side effects.

Estrogenic Modulation of Ionic Channels, Pumps and Exchangers in Airway Smooth Muscle.

To preserve ionic homeostasis (primarily Ca2+, K+, Na+, and Cl-), in the airway smooth muscle (ASM) numerous transporters (channels, exchangers, and pumps) regulate the influx and efflux of these ions. Many of intracellular processes depend on continuous ionic permeation, including exocytosis, contraction, metabolism, transcription, fecundation, proliferation, and apoptosis. These mechanisms are precisely regulated, for instance, through hormonal activity. The lipophilic nature of steroidal hormones allows their free transit into the cell where, in most cases, they occupy their cognate receptor to generate genomic actions. In the sense, estrogens can stimulate development, proliferation, migration, and survival of target cells, including in lung physiology. Non-genomic actions on the other hand do not imply estrogen's intracellular receptor occupation, nor do they initiate transcription and are mostly immediate to the stimulus. Among estrogen's non genomic responses regulation of calcium homeostasis and contraction and relaxation processes play paramount roles in ASM. On the other hand, disruption of calcium homeostasis has been closely associated with some ASM pathological mechanism. Thus, this paper intends to summarize the effects of estrogen on ionic handling proteins in ASM. The considerable diversity, range and power of estrogens regulates ionic homeostasis through genomic and non-genomic mechanisms.

Further Evidence of the Melatonin Calmodulin Interaction: Effect on CaMKII Activity.

Melatonin (MEL) is a pleiotropic indolamine that reaches multiple intracellular targets. Among these, MEL binds to calmodulin (CaM) with high affinity. In presence of Ca2+, CaM binds to CaM-dependent kinase II (CaMKII). The Ca2+-CaM/CaMKII pathway regulates a myriad of brain functions in different cellular compartments. Evidence showing the regulation of this cellular pathway by MEL is scarce. Thus, our main objective was to study the interaction of MEL with CaM and its effects on CaMKII activity in two microenvironments (aqueous and lipidic) naturally occurring within the cell. In addition, colocalization of MEL with CaM in vivo was explored in mice brain hippocampus. In vitro CaM-MEL interaction and the structural conformations of CaM in the presence of this indoleamine were assessed through electrophoretic mobility and isoelectric point. The functional consequence of this interaction was evaluated by measuring CaMKII activity. Ca2+-CaM-MEL increased the activity of CaMKII in aqueous buffer but reduced the kinase activity in lipid buffer. Importantly, MEL colocalizes in vivo with Ca2+-CaM in the hippocampus. Our evidence suggests that MEL regulates the key cellular Ca2+-CaM/CaMKII pathway and might explain why physiological MEL concentrations reduce CaMKII activity in some experimental conditions, while in others it drives biological processes through activation of this kinase.

Could Lower Testosterone in Older Men Explain Higher COVID-19 Morbidity and Mortalities?

The health scourge imposed on humanity by the COVID-19 pandemic seems not to recede. This fact warrants refined and novel ideas analyzing different aspects of the illness. One such aspect is related to the observation that most COVID-19 casualties were older males, a tendency also noticed in the epidemics of SARS-CoV in 2003 and the Middle East respiratory syndrome in 2012. This gender-related difference in the COVID-19 death toll might be directly involved with testosterone (TEST) and its plasmatic concentration in men. TEST has been demonstrated to provide men with anti-inflammatory and immunological advantages. As the plasmatic concentration of this androgen decreases with age, the health benefit it confers also diminishes. Low plasmatic levels of TEST can be determinant in the infection's outcome and might be related to a dysfunctional cell Ca2+ homeostasis. Not only does TEST modulate the activity of diverse proteins that regulate cellular calcium concentrations, but these proteins have also been proven to be necessary for the replication of many viruses. Therefore, we discuss herein how TEST regulates different Ca2+-handling proteins in healthy tissues and propose how low TEST concentrations might facilitate the replication of the SARS-CoV-2 virus through the lack of modulation of the mechanisms that regulate intracellular Ca2+ concentrations.

Theophylline: Old Drug in a New Light, Application in COVID-19 through Computational Studies.

Theophylline (3-methyxanthine) is a historically prominent drug used to treat respiratory diseases, alone or in combination with other drugs. The rapid onset of the COVID-19 pandemic urged the development of effective pharmacological treatments to directly attack the development of new variants of the SARS-CoV-2 virus and possess a therapeutical battery of compounds that could improve the current management of the disease worldwide. In this context, theophylline, through bronchodilatory, immunomodulatory, and potentially antiviral mechanisms, is an interesting proposal as an adjuvant in the treatment of COVID-19 patients. Nevertheless, it is essential to understand how this compound could behave against such a disease, not only at a pharmacodynamic but also at a pharmacokinetic level. In this sense, the quickest approach in drug discovery is through different computational methods, either from network pharmacology or from quantitative systems pharmacology approaches. In the present review, we explore the possibility of using theophylline in the treatment of COVID-19 patients since it seems to be a relevant candidate by aiming at several immunological targets involved in the pathophysiology of the disease. Theophylline down-regulates the inflammatory processes activated by SARS-CoV-2 through various mechanisms, and herein, they are discussed by reviewing computational simulation studies and their different applications and effects.

Possible Beneficial Actions of Caffeine in SARS-CoV-2.

The COVID-19 pandemic has established an unparalleled necessity to rapidly find effective treatments for the illness; unfortunately, no specific treatment has been found yet. As this is a new emerging chaotic situation, already existing drugs have been suggested to ameliorate the infection of SARS-CoV-2. The consumption of caffeine has been suggested primarily because it improves exercise performance, reduces fatigue, and increases wakefulness and awareness. Caffeine has been proven to be an effective anti-inflammatory and immunomodulator. In airway smooth muscle, it has bronchodilator effects mainly due to its activity as a phosphodiesterase inhibitor and adenosine receptor antagonist. In addition, a recent published document has suggested the potential antiviral activity of this drug using in silico molecular dynamics and molecular docking; in this regard, caffeine might block the viral entrance into host cells by inhibiting the formation of a receptor-binding domain and the angiotensin-converting enzyme complex and, additionally, might reduce viral replication by the inhibition of the activity of 3-chymotrypsin-like proteases. Here, we discuss how caffeine through certain mechanisms of action could be beneficial in SARS-CoV-2. Nevertheless, further studies are required for validation through in vitro and in vivo models.

Melatonin Rescues the Dendrite Collapse Induced by the Pro-Oxidant Toxin Okadaic Acid in Organotypic Cultures of Rat Hilar Hippocampus.

The pro-oxidant compound okadaic acid (OKA) mimics alterations found in Alzheimer's disease (AD) as oxidative stress and tau hyperphosphorylation, leading to neurodegeneration and cognitive decline. Although loss of dendrite complexity occurs in AD, the study of this post-synaptic domain in chemical-induced models remains unexplored. Moreover, there is a growing expectation for therapeutic adjuvants to counteract these brain dysfunctions. Melatonin, a free-radical scavenger, inhibits tau hyperphosphorylation, modulates phosphatases, and strengthens dendritic arbors. Thus, we determined if OKA alters the dendritic arbors of hilar hippocampal neurons and whether melatonin prevents, counteracts, or reverses these damages. Rat organotypic cultures were incubated with vehicle, OKA, melatonin, and combined treatments with melatonin either before, simultaneously, or after OKA. DNA breaks were assessed by TUNEL assay and nuclei were counterstained with DAPI. Additionally, MAP2 was immunostained to assess the dendritic arbor properties by the Sholl method. In hippocampal hilus, OKA increased DNA fragmentation and reduced the number of MAP2(+) cells, whereas melatonin protected against oxidation and apoptosis. Additionally, OKA decreased the dendritic arbor complexity and melatonin not only counteracted, but also prevented and reversed the dendritic arbor retraction, highlighting its role in post-synaptic domain integrity preservation against neurodegenerative events in hippocampal neurons.

Dysregulated expression of hypoxia-inducible factors augments myofibroblasts differentiation in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an age-related, progressive and lethal disease, whose pathogenesis is associated with fibroblasts/myofibroblasts foci that produce excessive extracellular matrix accumulation in lung parenchyma. Hypoxia has been described as a determinant factor in its development and progression. However, the role of distinct members of this pathway is not completely described. METHODS: By western blot, quantitative PCR, Immunohistochemistry and Immunocitochemistry were evaluated, the expression HIF alpha subunit isoforms 1, 2 & 3 as well, as their role in myofibroblast differentiation in lung tissue and fibroblast cell lines derived from IPF patients. RESULTS: Hypoxia signaling pathway was found very active in lungs and fibroblasts from IPF patients, as demonstrated by the abundance of alpha subunits 1 and 2, which further correlated with the increased expression of myofibroblast marker αSMA. In contrast, HIF-3α showed reduced expression associated with its promoter hypermethylation. CONCLUSIONS: This study lends further support to the involvement of hypoxia in the pathogenesis of IPF, and poses HIF-3α expression as a potential negative regulator of these phenomena.

The Timing of Melatonin Administration Is Crucial for Its Antidepressant-Like Effect in Mice.

Melatonin is synthesized by the pineal gland with a circadian rhythm in synchrony with the environmental light/dark cycle. A gradual increase in circulating levels of melatonin occur after lights off, reaching its maximum around the middle of the dark phase. Agonists of melatonin receptors have proved effectiveness as antidepressants in clinical trials. However, there is contradictory evidence about the potential antidepressant effect of melatonin itself. Herein we studied melatonin administration in mice at two zeitgeber times (ZT; ZT = 0 lights on; 12:12 L/D), one hour before the beginning (ZT11) and at the middle (ZT18) of the dark phase after either a single or a three-dose protocol. Behavioral despair was assessed through a forced-swimming test (FST) or a tail suspension test (TST), at ZT18.5. A single dose of 4 mg/kg melatonin at ZT11 was effective to reduce the immobility time in both tests. However, acute administration of melatonin at ZT18 was not effective in mice subjected to FST, and a higher dose (16 mg/kg) was required to reduce immobility time in the TST. A three-dose administration protocol of 16 mg/kg melatonin (ZT18, ZT11, and ZT18) significantly reduced immobility time in FST. Data indicate that the timely administration of melatonin could improve its antidepressant-like effect.

Involvement of Melatonin in the Regulation of the Circadian System in Crayfish.

Melatonin (MEL) is an ancient molecule, broadly distributed in nature from unicellular to multicellular species. MEL is an indoleamine that acts on a wide variety of cellular targets regulating different physiological functions. This review is focused on the role played by this molecule in the regulation of the circadian rhythms in crayfish. In these species, information about internal and external time progression might be transmitted by the periodical release of MEL and other endocrine signals acting through the pacemaker. We describe documented and original evidence in support of this hypothesis that also suggests that the rhythmic release of MEL contributes to the reinforcement of the temporal organization of nocturnal or diurnal circadian oscillators. Finally, we discuss how MEL might coordinate functions that converge in the performance of complex behaviors, such as the agonistic responses to establish social dominance status in Procambarus clarkii and the burrowing behavior in the secondary digging crayfish P. acanthophorus.

Abnormally Increased Secretion in Olfactory Neuronal Precursors from a Case of Schizophrenia Is Modulated by Melatonin: A Pilot Study.

The alterations that underlie the pathophysiology of schizophrenia (SCZ) include the dysregulation of structural and functional properties of neurons. Among these, the secretion of neurotransmitters and hormones, which plays a key role for neuronal communication and development, is altered. Neuronal precursors from the human olfactory epithelium have been recently characterized as a reliable model for studying the etiopathogenesis of neuropsychiatric diseases. Our previous work has shown that melatonin enhances the development of morphological and functional features of cloned olfactory neuronal precursors (ONPs) from a healthy subject. In this work we found that primary cultures of ONPs obtained from a schizophrenic patient display an increased potassium-evoked secretion, when compared with ONPs from an age- and gender-matched healthy control subject (HCS). Secretion was evaluated by FM1-43 fluorescence cumulative changes in response to depolarization. Interestingly, a 12 h-melatonin treatment modulated the abnormally increased secretion in SCZ ONPs and brought it to levels similar to those found in the HCS ONPs. Our results suggest that the actin cytoskeleton might be a target for melatonin effects, since it induces the thickening of actin microfilament bundles. Further research will address the mechanisms by which melatonin modulates neurochemical secretion from ONPs.

Tumor Necrosis Factor Alpha Inhibits L-Type Ca(2+) Channels in Sensitized Guinea Pig Airway Smooth Muscle through ERK 1/2 Pathway.

Tumor necrosis factor alpha (TNF-α) is a potent proinflammatory cytokine that plays a significant role in the pathogenesis of asthma by inducing hyperresponsiveness and airway remodeling. TNF-α diminishes the L-type voltage dependent Ca(2+) channel (L-VDCC) current in cardiac myocytes, an observation that seems paradoxical. In guinea pig sensitized tracheas KCl responses were lower than in control tissues. Serum from sensitized animals (Ser-S) induced the same phenomenon. In tracheal myocytes from nonsensitized (NS) and sensitized (S) guinea pigs, an L-VDCC current (ICa) was observed and diminished by Ser-S. The same decrease was detected in NS myocytes incubated with TNF-α, pointing out that this cytokine might be present in Ser-S. We observed that a small-molecule inhibitor of TNF-α (SMI-TNF) and a TNF-α receptor 1 (TNFR1) antagonist (WP9QY) reversed ICa decrease induced by Ser-S in NS myocytes, confirming the former hypothesis. U0126 (a blocker of ERK 1/2 kinase) also reverted the decrease in ICa. Neither cycloheximide (a protein synthesis inhibitor) nor actinomycin D (a transcription inhibitor) showed any effect on the TNF-α-induced ICa reduction. We found that CaV1.2 and CaV1.3 mRNA and proteins were expressed in tracheal myocytes and that sensitization did not modify them. In cardiac myocytes, ERK 1/2 phosphorylates two sites of the L-VDCC, augmenting or decreasing ICa; we postulate that, in guinea pig tracheal smooth muscle, TNF-α diminishes ICa probably by phosphorylating the L-VDCC site that reduces its activity through the ERK1/2 MAP kinase pathway.

Voltage-Activated Calcium Channels as Functional Markers of Mature Neurons in Human Olfactory Neuroepithelial Cells: Implications for the Study of Neurodevelopment in Neuropsychiatric Disorders.

In adulthood, differentiation of precursor cells into neurons continues in several brain structures as well as in the olfactory neuroepithelium. Isolated precursors allow the study of the neurodevelopmental process in vitro. The aim of this work was to determine whether the expression of functional Voltage-Activated Ca(2+) Channels (VACC) is dependent on the neurodevelopmental stage in neuronal cells obtained from the human olfactory epithelium of a single healthy donor. The presence of channel-forming proteins in Olfactory Sensory Neurons (OSN) was demonstrated by immunofluorescent labeling, and VACC functioning was assessed by microfluorometry and the patch-clamp technique. VACC were immunodetected only in OSN. Mature neurons responded to forskolin with a five-fold increase in Ca(2+). By contrast, in precursor cells, a subtle response was observed. The involvement of VACC in the precursors' response was discarded for the absence of transmembrane inward Ca(2+) movement evoked by step depolarizations. Data suggest differential expression of VACC in neuronal cells depending on their developmental stage and also that the expression of these channels is acquired by OSN during maturation, to enable specialized functions such as ion movement triggered by membrane depolarization. The results support that VACC in OSN could be considered as a functional marker to study neurodevelopment.

Melatonin stimulates dendrite formation and complexity in the hilar zone of the rat hippocampus: participation of the Ca++/Calmodulin complex.

Melatonin (MEL), the main product synthesized by the pineal gland, stimulates early and late stages of neurodevelopment in the adult brain. MEL increases dendrite length, thickness and complexity in the hilar and mossy neurons of hippocampus. Dendrite formation involves activation of Ca2+/Calmodulin (CaM)-dependent kinase II (CaMKII) by CaM. Previous work showed that MEL increased the synthesis and translocation of CaM, suggesting that MEL activates CaM-dependent enzymes by this pathway. In this work we investigated whether MEL stimulates dendrite formation by CaMKII activation in organotypic cultures from adult rat hippocampus. We found that the CaMKII inhibitor, KN-62, abolished the MEL stimulatory effects on dendritogenesis and that MEL increased the relative amount of CaM in the soluble fraction of hippocampal slices. Also, PKC inhibition abolished dendritogenesis, while luzindole, an antagonist of MEL receptors (MT1/2), partially blocked the effects of MEL. Moreover, autophosphorylation of CaMKII and PKC was increased in presence of MEL, as well as phosphorylation of ERK1/2. Our results indicate that MEL stimulates dendrite formation through CaMKII and the translocation of CaM to the soluble fraction. Dendritogenesis elicited by MEL also required PKC activation, and signaling through MT1/2 receptors was partially involved. Data strongly suggest that MEL could repair the loss of hippocampal dendrites that occur in neuropsychiatric disorders by increasing CaM levels and activation of CaMKII.

Potential of olfactory neuroepithelial cells as a model to study schizophrenia: A focus on GPCRs (Review).

Schizophrenia (SZ) is a multifactorial disorder characterized by volume reduction in gray and white matter, oxidative stress, neuroinflammation, altered neurotransmission, as well as molecular deficiencies such as punctual mutation in Disrupted­in­Schizophrenia 1 protein. In this regard, it is essential to understand the underlying molecular disturbances to determine the pathophysiological mechanisms of the disease. The signaling pathways activated by G protein­coupled receptors (GPCRs) are key molecular signaling pathways altered in SZ. Convenient models need to be designed and validated to study these processes and mechanisms at the cellular level. Cultured olfactory stem cells are used to investigate neural molecular and cellular alterations related to the pathophysiology of SZ. Multipotent human olfactory stem cells are undifferentiated and express GPCRs involved in numerous physiological functions such as proliferation, differentiation and bioenergetics. The use of olfactory stem cells obtained from patients with SZ may identify alterations in GPCR signaling that underlie dysfunctional processes in both undifferentiated and specialized neurons or derived neuroglia. The present review aimed to analyze the role of GPCRs and their signaling in the pathophysiology of SZ. Culture of olfactory epithelial cells constitutes a suitable model to study SZ and other psychiatric disorders at the cellular level.

17ß-estradiol induces hyperresponsiveness in guinea pig airway smooth muscle by inhibiting the plasma membrane Ca2+-ATPase.

High serum estrogen concentrations are associated with asthma development and severity, suggesting a link between estradiol and airway hyperresponsiveness (AHR). 17ß-estradiol (E2) has non-genomic effects via Ca2+ regulatory mechanisms; however, its effect on the plasma membrane Ca2+-ATPases (PMCA1 and 4) and sarcoplasmic reticulum Ca2+-ATPase (SERCA) is unknown. Hence, in the present study, we aim to demonstrate if E2 favors AHR by increasing intracellular Ca2+ concentrations in guinea pig airway smooth muscle (ASM) through a mechanism involving Ca2+-ATPases. In guinea pig ASM, Ca2+ microfluorometry, muscle contraction, and Western blot were evaluated. Then, we performed molecular docking analysis between the estrogens and Ca2+ ATPases. In tracheal rings, E2 produced AHR to carbachol. In guinea pig myocytes, acute exposure to physiological levels of E2 modified the transient Ca2+ peak induced by caffeine to a Ca2+ plateau. The incubation with PMCA inhibitors (lanthanum and carboxyeosin, CE) partially reversed the E2-induced sustained plateau in the caffeine response. In contrast, cyclopiazonic acid (SERCA inhibitor), U-0126 (an inhibitor of ERK 1/2), and choline chloride did not modify the Ca2+ plateau produced by E2. The mitochondrial uniporter activity and the capacitative Ca2+ entry were unaffected by E2. In guinea pig ASM, Western blot analysis demonstrated PMCA1 and PMCA4 expression. The results from the docking modeling demonstrate that E2 binds to both plasma membrane ATPases. In guinea pig tracheal smooth muscle, inhibiting the PMCA with CE, induced hyperresponsiveness to carbachol. 17ß-estradiol produces hyperresponsiveness by inhibiting the PMCA in the ASM and could be one of the mechanisms responsible for the increase in asthmatic crisis in women.

Hypoxia Induces Alterations in the Circadian Rhythm in Patients with Chronic Respiratory Diseases.

The function of the circadian cycle is to determine the natural 24 h biological rhythm, which includes physiological, metabolic, and hormonal changes that occur daily in the body. This cycle is controlled by an internal biological clock that is present in the body's tissues and helps regulate various processes such as sleeping, eating, and others. Interestingly, animal models have provided enough evidence to assume that the alteration in the circadian system leads to the appearance of numerous diseases. Alterations in breathing patterns in lung diseases can modify oxygenation and the circadian cycles; however, the response mechanisms to hypoxia and their relationship with the clock genes are not fully understood. Hypoxia is a condition in which the lack of adequate oxygenation promotes adaptation mechanisms and is related to several genes that regulate the circadian cycles, the latter because hypoxia alters the production of melatonin and brain physiology. Additionally, the lack of oxygen alters the expression of clock genes, leading to an alteration in the regularity and precision of the circadian cycle. In this sense, hypoxia is a hallmark of a wide variety of lung diseases. In the present work, we intended to review the functional repercussions of hypoxia in the presence of asthma, chronic obstructive sleep apnea, lung cancer, idiopathic pulmonary fibrosis, obstructive sleep apnea, influenza, and COVID-19 and its repercussions on the circadian cycles.

Pigment dispersing hormone modulates spontaneous electrical activity of the cerebroid ganglion and synchronizes electroretinogram circadian rhythm in crayfish Procambarus clarkii.

In crayfish, one very well-studied circadian rhythm is that of electroretinogram (ERG) amplitude. The cerebroid ganglion has been considered a plausible site for the circadian pacemaker of this rhythm and for the retinular photoreceptors, as the corresponding effectors. The pigment dispersing hormone (PDH) appears to synchronize ERG rhythm, but its characterization as a synchronizer cue remains incomplete. The main purposes of this work were a) to determine whether PDH acts on the cerebroid ganglion, and b) to complete its characterization as a non-photic synchronizer. Here we show that PDH increases the number of the spontaneous potentials of the cerebroid ganglion, reaching 149.92±6.42% of the activity recorded in the controls, and that daily application of PDH for 15 consecutive days adjusts the ERG circadian rhythm period to 24.0±0.2h and the end of the activity period of the rhythm coincides with the injection of the hormone. In this work, we hypothesized that in crayfish, PDH transmits the "day" signal to the ERG circadian system and acts upon both the presumptive circadian pacemaker and the corresponding effectors to reinforce the synchronization of the system.

Insights into myelin dysfunction in schizophrenia and bipolar disorder.

Schizophrenia and bipolar disorder are disabling psychiatric disorders with a worldwide prevalence of approximately 1%. Both disorders present chronic and deteriorating prognoses that impose a large burden, not only on patients but also on society and health systems. These mental illnesses share several clinical and neurobiological traits; of these traits, oligodendroglial dysfunction and alterations to white matter (WM) tracts could underlie the disconnection between brain regions related to their symptomatic domains. WM is mainly composed of heavily myelinated axons and glial cells. Myelin internodes are discrete axon-wrapping membrane sheaths formed by oligodendrocyte processes. Myelin ensheathment allows fast and efficient conduction of nerve impulses through the nodes of Ranvier, improving the overall function of neuronal circuits. Rapid and precisely synchronized nerve impulse conduction through fibers that connect distant brain structures is crucial for higher-level functions, such as cognition, memory, mood, and language. Several cellular and subcellular anomalies related to myelin and oligodendrocytes have been found in postmortem samples from patients with schizophrenia or bipolar disorder, and neuroimaging techniques have revealed consistent alterations at the macroscale connectomic level in both disorders. In this work, evidence regarding these multilevel alterations in oligodendrocytes and myelinated tracts is discussed, and the involvement of proteins in key functions of the oligodendroglial lineage, such as oligodendrogenesis and myelination, is highlighted. The molecular components of the axo-myelin unit could be important targets for novel therapeutic approaches to schizophrenia and bipolar disorder.