COVID-19: from the structure and replication cycle of SARS-CoV-2 to its disease symptoms and treatment.

In December 2019, a small number of cases of pneumonia of unknown origin were recognized in the city of Wuhan, China. Soon, the disease, whose etiological factor was recognized as a coronavirus SARS-CoV-2, had spread across the world. The resulting CoV-associated diseases were classified by the WHO as COVID-19, and a pandemic was declared in March 2020. By 25 November 2021, there have been nearly 256.8 million of confirmed cases of COVID-19 around the world, including 5.17 million deaths. This review focuses on basal characteristics of the SARS-CoV-2 virus - its structure, replication cycle, variants and course of infection. It also briefly characterizes the currently recommended drugs and vaccines. Coronaviruses (CoVs) are a group of RNA viruses with a characteristic solar corona image observable on electron micrographs. SARS-CoV-2 possesses high affinity to human angiotensin converting enzyme 2 (ACE2) which serves as a cellular entry receptor. Its replication in human cells is accompanied by a high mutation rate. Six variants of SARS-CoV-2 have been found to be associated with essential changes of global public health significance; they are referred to as 'variants of concern' (VOC). The main route of transmission is through respiratory droplets. Although COVID-19 presents primarily as a respiratory disease, it can affect various other organs and systems that present the ACE2 protein to which the virus binds, including the heart, kidneys, intestines, liver, muscular and nervous system. COVID-19 infection can result in uncontrolled systemic hyperinflammation caused by release of a large amount of pro-inflammatory cytokines (a 'cytokine storm'), which can lead to multi-organ failure, rapid clinical deterioration and even death. Around 30% of those infected with SARS-CoV-2 remain asymptomatic, with the majority of patients demonstrating only mild or moderate symptoms; however, about 20% develop severe or critical disease. Three main groups of medications are currently recommended for therapy of COVID-19: monoclonal antibodies against the S protein of SARS-CoV-2, antiviral drugs and immunosuppressants which inhibit the cytokine storm. At present, the safest and most cost-effective way to prevent COVID-19 illness is a preventative vaccination.

Photoperiod-dependent changes in melatonin synthesis in the turkey pineal gland and retina.

The effect of photoperiod on melatonin content and the activity of the melatonin-synthesizing enzymes, namely, serotonin N-acetyltransferase (AANAT) and hydroxyindole-O-methyltransferase, were investigated in the pineal gland and retina of turkeys. The birds were adapted to 3 different lighting conditions: 16L:8D (long photoperiod), 12L:12D (regular photoperiod), and 8L:16D (short photoperiod). Pineal, retinal, and plasma melatonin concentrations oscillated with a robust diurnal rhythm, with high values during darkness. The duration of elevated nocturnal melatonin levels in the turkey pineal gland, retina, and plasma changed markedly in response to the length of the dark phase, being longest during the short photoperiod with 16 h of darkness. These photoperiodic variations in melatonin synthesis appear to be driven by AANAT, because changes in the activity of this enzyme were closely correlated with changes in melatonin. By contrast, pineal and retinal hydroxyindole-O-methyltransferase activities failed to exhibit any significant 24-h variation in the different photoperiods. A marked effect of photoperiod on the level of melatonin production was also observed. Peak values of melatonin and AANAT activity in the pineal gland (but not in the retina) were highest during the long photoperiod. During the light phase, mean melatonin concentrations in the pineal gland and retina of turkeys kept under the long photoperiod were significantly higher compared with those from birds maintained under the regular and short photoperiods. In addition, mean circulating melatonin levels were lowest in the short photoperiod. Finally, the magnitude of the light-evoked suppression of nighttime pineal AANAT activity was also influenced by photoperiod, with suppression being smallest under the long photoperiod. These findings show that in the turkey, photoperiod plays an important role in regulating the melatonin signal.

L-745,870 suppresses the nighttime serotonin N-acetyltransferase activity in chick retina: in vivo evidence for agonist activity at D4-dopamine receptors.

This study examined the in vivo activity of L-745,870 at dopamine (DA) D(4) receptors, using the chick retina as a model system. In dark-adapted retinas of various vertebrates, including hen, DA acting via D(4) receptors suppresses melatonin content and activity of serotonin N-acetyltransferase (AA-NAT, a key regulatory enzyme in melatonin synthesis). Systemic administration to chicks of quinpirole (0.1 mg/kg), a high affinity agonist of D(3)/D(4)-DA receptors, potently decreased the nighttime AA-NAT activity of the retina. The quinpirole-evoked decline in the enzyme activity was attenuated by L-745,870 (0.1-10 nmol/eye). In addition to this action, L-745,870 given to chicks either directly into the eye (0.03-10 nmol/eye) or intraperitoneally (0.5-5 mg/kg) decreased the nighttime AA-NAT activity of the retina in a dose-dependent manner. The suppressive effect of L-745,870 on retinal AA-NAT activity was blocked by 2-chloro-11-(4-methylpiperazino)dibenz[ b, f]oxepin, an antagonist of D(4)-DA receptors, but was not affected by raclopride, an antagonist of D(2)/D(3)-DA receptors. Altogether these results indicate that in chicks L-745,870, the potent putative D(4)-DA receptor antagonist, behaves in vivo as a partial D(4) agonist.

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) activate protein kinase C in chick cerebral cortex.

Pituitary adenylate cyclase-activating polypeptide (PACAP38) and vasoactive intestinal peptide (VIP) were tested for their ability to influence protein kinase C (PKC) activity in the chick cerebral cortical slices. Thirty minutes incubation of the chick tissue with PACAP38 (0.1-1 microM) or VIP (0.3-3 microM) produced significant and concentration-dependent changes in PKC activity. Both peptides enhanced the enzyme activity in cell membrane preparation, and decreased it in cytosol preparation obtained from cerebral cortical slices. These changes in PKC activity suggest that PACAP and VIP are capable of activating this enzyme in cerebral cortex of chick.

Effect of glucocorticoid dexamethasone on cyclic AMP formation stimulated by pituitary adenylate cyclase-activating polypeptide (PACAP) in the cerebral cortex and hypothalamus of chick.

In this study we tested in chicks the effects of acute and chronic in vivo treatment with a glucocorticoid dexamethasone (4 mg/kg, i.p.) on PACAP-stimulated cyclic AMP formation in [3H]adenine-prelabeled slices of the hypothalamus and cerebral cortex. PACAP (1-100 nM) concentration-dependently stimulated cyclic AMP formation in both brain regions of chick. In acute experiments, dexamethasone (single dose)-injected chicks were killed after 2, 24 and 48 h; while in chronic experiment the glucocorticoid was given once daily for 12 days and the animals were killed 48 h after the last injection. The ability of PACAP to stimulate cyclic AMP formation in the hypothalamus and cerebral cortex was similar in vehicle-treated (control) and dexamethasone-treated animals, with the exception of the nucleotide response to 100 nM of the peptide in both brain regions, which was significantly larger in the group of chicks killed 48 h after the administration of the single steroid dose.

Effects of cycloheximide and aminophylline on 5-methoxytryptophol and melatonin contents in the chick pineal gland.

The chick pineal gland rhythmically synthesizes two 5-methoxyindoles, melatonin and 5-methoxytryptophol. These rhythms are circadian in nature and have opposite phases. The aim of this study was to determine the effects of cycloheximide, a protein synthesis inhibitor, and aminophylline, an inhibitor of phosphodiesterase, on 5-methoxytryptophol content in the chick pineal gland and to compare this with the drugs' action on pineal melatonin production. Inhibition of melatonin biosynthesis by cycloheximide (1 mg/kg, i.p. ), revealed by a marked reduction in the nighttime activity of serotonin N-acetyltransferase (AA-NAT; a key regulatory enzyme in melatonin synthesis) and melatonin concentrations, was accompanied by a significant increase in 5-methoxytryptophol content. In contrast, administration of aminophylline (100 mg/kg, i.p.) to light-exposed chicks significantly increased pineal AA-NAT activity and melatonin levels and decreased 5-methoxytryptophol concentrations. It is concluded that in the chick the production of pineal 5-methoxytryptophol and melatonin is inversely correlated.

Near-ultraviolet radiation suppresses melatonin synthesis in the chicken retina: a role of dopamine.

Effects of near-ultraviolet radiation (UV-A; 325-390 nm, peak at 365 nm) on melatonin content and activity of serotonin N-acetyltransferase (AA-NAT; a key regulatory enzyme in melatonin biosynthesis) were examined in the retina of chickens. Acute exposure of dark-adapted animals to UV-A light produced a marked decline in melatonin content and AA-NAT activity of the retina. The magnitude of the observed changes was dependent upon duration of the light pulse and age of chickens, with 1-2-week old birds being more sensitive to UV-A action than 6-7-week old ones. The decrease in the nocturnal AA-NAT activity evoked by a 5-min UV-A pulse gradually deepened during the first 30 min after the return of chickens to constant darkness, then the enzyme activity began to rise, reaching nearly complete restoration within 2.5 hr. Systemic administration to chickens of alpha-methyl-p-tyrosine (an inhibitor of catecholamine synthesis; 0.3 g/kg) blocked the suppressive effect of UV-A light on retinal AA-NAT activity. Haloperidol, sulpiride (blockers of D2-family of dopamine (DA) receptors) and 2-chloro-11-(4-methylpiperazino)dibenz[b,f]oxepin (an antagonist of D4-DA receptors), given intraocularly (1-100 nmol/eye) prevented the UV-A light-evoked decrease in AA-NAT activity in the chicken retina in a dose-dependent manner, while raclopride (300 nmol/eye), an antagonist of D2/D3-DA receptors, was ineffective. In dark-adapted chickens exposure to UV-A light increased the DA content of the retina. It is concluded that UV-A radiation, similar to visible light, potently suppresses melatonin biosynthesis in the retina of chicken, with a D4-dopaminergic signal playing the role of an intermediate in this action.

Characterization of beta-adrenergic receptors in duck cerebral cortex.

beta-adrenoceptor binding sites were characterized in duck cerebral cortex by an in vitro binding technique, using [3H]dihydroalprenolol ([3H]DHA) as a receptor-specific radioligand. The specific binding of [3H]DHA to duck cerebral cortical membranes was found to be rapid, stable, saturable, reversible, and of high affinity. Saturation analysis resulted in a linear Scatchard plot suggesting binding to a single class of receptor binding sites with high affinity (Kd = 1.18 nM) and high capacity (Bmax = 162 fmol/mg protein). Competition studies showed the following relative rank order of potency of various compounds to inhibit the [3H]DHA binding: antagonists--ICI 118,551 > S(-)-propranolol >> betaxolol, yohimbine, WB-4101, prazosin, mianserine; agonists--isoprenaline approximately equal to fenoterol > salbutamol >> clonidine, phenylephrine. The obtained data suggest that in duck cerebral cortex beta-adrenergic receptors (like those described in brains of chick and pigeon) are of the beta 2 subtype. This is in contrast to what has been reported for the mammalian brain, where--among beta-adrenoceptors--the beta 1 subtype is predominant.

Phase-shifting effects of light on the circadian rhythms of 5-methoxytryptophol and melatonin in the chick pineal gland.

In the chick pineal gland, 5-methoxytryptophol and melatonin concentrations fluctuate in a rhythmic manner. These rhythms are circadian in nature persisting in constant darkness and have opposite phases. Acute exposure of chicks to white light (30 lux for 5, 10, 20, and 30 min) at night increased the amount of pineal 5-methoxytryptophol and decreased pineal melatonin content. A 6 hr pulse of light (100 lux) applied early in the subjective night (CT12-CT18) caused a delay in the phase of the circadian rhythms of 5-methoxytryptophol and melatonin by 3.7 and 4.5 h, respectively, compared to untreated controls. When the 6 hr light pulse was given during the late subjective night (C18 CT24) it advanced the phase of the 5-methoxytryptophol and melatonin rhythms by 8.1 and 11.9 h, respectively. In the chick pineal the phase-advancing effects of light on the circadian rhythms of 5-methoxytryptophol and melatonin were more pronounced than the phase-delaying effects. Our results provide the first evidence that light is capable of phase shifting the 5-methoxytryptophol rhythm in a manner similar to its action on the melatonin rhythm.

Effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on cyclic AMP formation in the duck and goose brain.

Two molecular forms of pituitary adenylate cyclase-activating polypeptide (PACAP), i.e., PACAP27 and PACAP38 (0.0001-1 microM), as well as vasoactive intestinal polypeptide (VIP; 0.1-3 microM), have been studied for their effects on cyclic AMP formation in the hypothalamus and cerebral cortex of duck and goose. All three peptides concentration-dependently stimulated cyclic AMP production in the tested brain regions of 2-3-weeks-old (young) ducks, with VIP showing at least one order of magnitude weaker activity than PACAP. This characteristics suggests the existence in the duck's brain of adenylyl cyclase-linked PAC1 receptors. Both forms of PACAP also stimulated the nucleotide formation in the cerebral cortex and hypothalamus of 5-6-months-old (adult) ducks or geese grown under natural environment. The peptides-evoked effects in adult and young ducks were comparable, and clearly greater than those found in adult geese. The present data extend our recent observations made on chicks, and suggest PACAP to be a potent stimulator of the cyclic AMP generation in the avian central nervous system.

Effects of neuropeptides of the secretin/VIP/PACAP family on cyclic AMP formation in the chick hypothalamus and cerebral cortex.

Six neuropeptides: short and long form of the pituitary adenylate cyclase activating polypeptide (PACAP), i.e. PACAP27 and PACAP38, vasoactive intestinal peptide (VIP), peptide histidine-isoleucine (PHI), secretin and glucagon, members of the secretin/VIP/PACAP superfamily ofpolypeptides, were tested for their ability to stimulate cyclic AMP formation in [3H]adenine-prelabeled slices of the chick hypothalamus and cerebral cortex. Of the tested peptides, only PACAP evoked pronounced and significant responses in the two analyzed brain structures. Although magnitude of the responses varied in different experiments, the effects of both forms of PACAP were usually larger in the cerebral cortex than in the hypothalamus. Glucagon, PHI (both used at concentrations 0.01-1 microM) and VIP (0.1-3 microM) induced concentration-dependent yet comparatively small effects that did not reach statistical significance, while secretin (0.1-3 microM) had no effect.

[Melatonin and its role the circadian function]. / Melatonina i jej rola w funkcji systemu okolodobowego.

Melatonin is a principal hormone of the vertebrate pineal gland. Its production, being under control of a circadian oscillator, follows circadian rhythmicity with high values at night and low values during day-hours. As the nocturnal production of melatonin is proportional to the length of the night (or dark phase of an imposed light-dark illumination cycle), the hormone conveys an important chronobiological message to the whole body, playing the role of a biochemical clock and calendar. This article surveys a current knowledge on regulation of melatonin biosynthesis, receptors and function, and particularly provides a comprehensive view of the role the hormone may play in the vertebrate circadian system.

Melatonin: from biochemistry to therapeutic applications.

Melatonin (N-acetyl-5-methoxytryptamine) is an evolutionary highly conserved molecule that plays an important role in conveying the clock and calendar information to all living organisms, including man. The hormone is synthesized mainly by the pineal gland, and, to a lesser extent, by extrapineal tissues--such as the retina, Harderian gland, and gastrointestinal tract. The melatonin-generating system is characterized by three basic features: (1) photosensitivity, (2) diurnal (or circadian) rhythmicity (with highest levels of the hormone production occurring at night in darkness), and (3) age-related decrease in its activity. This review surveys data on the regulation of rhythmic melatonin biosynthesis by an array of factors, such as circadian pacemaker, light, neurotransmitters, second and third messenger molecules. Recent developments in the field of melatonin receptors are also presented. Finally, physiological and therapeutic properties of melatonin, with a special emphasis given to possible applications of this compound in the treatment of circadian rhythm sleep disorders, are discussed.

Stimulatory effect of pituitary adenylate cyclase-activating polypeptide (PACAP) on cyclic AMP formation in the hypothalamus and cerebral cortex of four avians and rat.

PACAP38 and PACAP27, tested at 0.0001-1 microM, potently stimulated synthesis of cyclic AMP in the hypothalamus and cerebral cortex of chicks; the effects of vasoactive intestinal polypeptide (VIP) in the two brain regions were much weaker, reaching statistical significance only at 3 microM concentration. This characteristics suggests the existence in the bird's brain of adenylyl cyclase-linked PAC1 receptors. PACAP27 (0.001-1 microM) concentration-dependently stimulated cyclic AMP production in the hypothalamus and cerebral cortex of three other birds: duck, goose and turkey; the effects were, however, somewhat lower than those in chicks, but comparable to those found in rats. These data demonstrate PACAP to be capable of potently stimulating cyclic AMP generating system in the avian central nervous system.

[Adenylyl cyclase--isoforms, regulation and function]. / Cyklaza adenylanowa--izoformy, regulacja aktywnosci i funkcja.

Since its discovery in 1956, cyclic AMP (cAMP) has been shown to be a ubiquitous second messenger. It functions as one of many signaling molecules enabling cells to respond to external signals. cAMP is synthesized by adenylyl cyclases (ACs), enzymes that convert adenosine triphosphate (ATP) to cAMP. Three classes of ACs have been cloned based on the conservation of their catalytic domains; they include: class I-ACs from Enterobacteria, including Escherichia coli; class II-"toxic" ACs, including calmodulin-activated enzymes from Bordetella pertussis and Bacillus anthracis; class III-ACs homologues from bacteria to human; they include nine isoformes found in mammals, and designated AC-1 to AC-9. Although ACs can exist in particulate and soluble forms, the former form predominates-at least in mammals. Nine (AC-1-AC-9) mammalian enzymes are stimulated by an "alpha" subunit of Gs-protein (Gs alpha) and by the diterpene forskolin, albeit to varying degrees (with AC-9 being least sensitive to forskolin). In addition to their core signaling capability in response to signals from Gs alpha, the different ACs are capable of receiving signals from a variety of sources, including other G-protein subunits, such as Gi alpha (inhibitory) or G beta gamma (stimulatory or inhibitory, depending on the enzyme), protein kinases (protein kinase A, PKA; protein kinase C, PKC; and calmodulin kinase, Ca(2+)-CaM), and Ca2+ by itself. The effects of activators are often highly synergistic or conditional, suggesting function of ACs as coincidence detectors. The plethora of G-protein-coupled receptors, together with functional differentiation among G-protein subunits and many AC isoforms, permits assembly of a very complex signaling systems with a wide variety of integrative characteristics. This survey presents basic facts on ACs classification and characteristics, and gives a brief review of the recent developments in this important and rapidly growing field of cyclic AMP research.

[Cascade of biochemical events triggered by stimulation of adrenergic receptors in the rat pineal gland--from cell membrane to nucleus]. / Kaskada procesów biochemicznych uruchamiana przez pobudzenie receptorów adrenergicznych w szyszynce szczura--przeplyw sygnalu od blony komórkowej do jadra komórkowego.

Pineal glands of various vertebrate species synthesize melatonin in a circadian rhythm generated by an endogenous pacemaker. The levels of melatonin and activity of serotonin N-acetyltransferase (AA-NAT: a penultimate and key regulatory enzyme in melatonin biosynthesis) are low during the light phase and high during the dark phase of any natural or imposed light-dark illumination cycle. The expression of AA-NAT gene in rat pineal gland is regulated by a photoneural system that acts through the adrenergic-cAMP-related mechanisms in pinealocytes. Concomitant stimulation by noradrenaline of beta 1- and alpha 1-adrenergic receptors, in a mechanism of "AND gate" activation, results in a large, 60-100-fold increase in intrapinealocyte cAMP level. The role of cAMP-dependent transcription factors CREB, ICER and Fra-2 in turning on and off the AA-NAT gene expression is discussed.

PACAP-induced formation of cyclic AMP in the chicken brain: regional variations and the effect of melatonin.

We have studied the effects of pituitary adenylate cyclase-activating polypeptide (PACAP27 and PACAP38) on cyclic AMP formation in chick brain, and the action of melatonin upon the PACAP-evoked effects. PACAP stimulated cyclic AMP production in the hypothalamus>cerebral cortex>pineal gland>optic lobes. In the hypothalamus and cerebral cortex, the rank-order of both PACAP forms and VIP in evoking the cyclic AMP response was: PACAP38 approximately PACAP27>>VIP, suggesting the presence in the tested tissues of PAC1 receptors. Melatonin suppressed (IC50=19.8 nM) the PACAP27 (0.1 microM)-induced cyclic AMP response in the hypothalamus, but not in the cerebral cortex. Melatonin also suppressed the hypothalamal cyclic AMP synthesis stimulated by forskolin, but not that evoked by histamine or isoprenaline. Our observations show that PACAP is capable of potently stimulating cyclic AMP formation in some regions of the chick brain, and suggest that the hypothalamus may be a site for a functional interaction between PACAP and the pineal hormone melatonin.

The effects of near-ultraviolet light on serotonin N-acetyltransferase activity in the chick pineal gland.

Effects of near-ultraviolet light (UV-A; 325-390 nm, peak at 365 nm) on the activity of the pineal serotonin N-acetyltransferase (NAT; a key regulatory enzyme in melatonin biosynthesis) were examined in chicks. Acute exposure of dark-adapted animals to UV-A radiation produced a marked decline in NAT activity of the pineal gland. The magnitude of this suppression was dependent upon duration of the light pulse and the age of the animals. The decrease in the nighttime NAT activity evoked by a 5 min pulse of UV-A light applied during the fourth hour of the dark phase of the 12 hr light:12 hr dark cycle (LD) gradually deepened during the first 40 min after the return of animals to constant darkness, then the enzyme activity began to rise, reaching control values by 2 hr. Exposure of chicks to a 5 min pulse of UV-A light during the ninth hour of the dark phase produced a marked decline in pineal NAT activity, which was reversible after 15 min of darkness. Pretreatment of animals with an inhibitor of catecholamine synthesis, alpha-methyl-p-tyrosine (300 mg/kg, i.p.), or with a blocker of alpha2-adrenergic receptors, yohimbine (2 mg/kg, i.p.), antagonized the suppressive effect of UV-A light on nighttime NAT activity of the chick pineal gland. It is concluded that UV-A irradiation, similar to visible light, potently suppresses melatonin biosynthesis in the chick pineal gland, with an alpha2-noradrenergic signal playing the role of an intermediate in this action.

Effects of near-ultraviolet (UV-A) light on melatonin biosynthesis in vertebrate pineal gland.

The effects of near-ultraviolet (UV-A) irradiation on nocturnal activity of serotonin N-acetyltransferase (NAT; a key regulatory enzyme in melatonin biosynthesis) in the pineal gland of the rat and chick were investigated. Exposure of the animals to UV-A during the 4th or 5th hour of the dark phase of the 12:12 h light-dark (LD) cycle suppressed the night-driven NAT activity in a time-dependent manner, the effects being generally more pronounced in rats than in chicks. The UV-A-evoked suppression of the nocturnal NAT activity was completely restored within 2 h (chicks) or 3 h (rats) in animals which, after irradiation, were returned to darkness. When a short UV-A pulse was applied to the animals after midnight, it induced a decrease in the enzyme activity in both species; yet, the effect was readily reversible only in chicks. The results presented here, as well as other data, demonstrate that UV-A light is a powerful signal affecting the pineal melatonin-generating system both in mammals and avians, and that the involved mechanisms may differ in the tested species.