Molecular mechanisms defining application of glycine and zinc combination in correction of stress and anxiety main manifestations
- 作者: Shishkova V.N.1,2, Nartcissov Y.R.3,4, Titova V.Y.3, Sheshegova E.V.3
-
隶属关系:
- National Medical Research Center for Therapy and Preventive Medicine
- Evdokimov Moscow State Medical and Dental University
- Institute of Cytochemistry and Molecular Pharmacology
- Biomedical Research Group, BiDiPharma GmbH
- 期: 卷 10, 编号 5 (2022)
- 页面: 404-415
- 栏目: REVIEWS
- URL: https://journals.eco-vector.com/2307-9266/article/view/375282
- DOI: https://doi.org/10.19163/2307-9266-2022-10-5-404-415
- ID: 375282
如何引用文章
详细
The aim of the work was to carry out a systematic analysis of the molecular mechanisms that determine the possibility of a combined use of amino acid glycine and zinc compounds for the treatment of patients with manifestations of stress and anxiety.
Materials and methods. Information retrieval (Scopus, PubMed) and library (eLibrary) databases were used as research tools. In some cases, the ResearchGate application was applied for a semantic search. The analysis and generalization of references was carried out on the research topic, covering the period from 2000 to the present time.
Results. It has been shown that amino acid glycine, along with gamma-aminobutyric acid (GABA), is a key neurotransmitter that regulates physiological inhibition processes in the central nervous system (CNS) by increasing transmembrane conductance in specific pentameric ligand-gated ion channels. The introduction of zinc ions can potentiate the opening of these receptors by increasing their affinity for glycine, resulting in an inhibitory processes increase in CNS neurons. The replenishment of the glycine and zinc combined deficiency is an important element in the correction of a post-stress dysfunction of the central nervous system. A balanced intake of zinc and glycine is essential for most people who experience daily effects of multiple stresses and anxiety. This combination is especially useful for the people experiencing a state of chronic psycho-emotional stress and maladaptation, including those who have a difficulty in falling asleep.
Conclusion. A balanced maintenance of the zinc and glycine concentration in the body of a healthy person leads to the development of a stable anti-anxiety effect, which is accompanied by the normalization of the sleep-wake rhythm, which makes it possible to have a good rest without any loss of working efficiency after waking up.
全文:
Abbreviations: GABA – gamma-aminobutyric acid; pLGICs – pentameric ligand-gated ion channels; CNS – central nervous system; GlyR – glycine receptor; MT – metallothioneins; ROS – reactive oxygen species; RNS – reactive nitrogen species; SHMT – serine hydroxymethyltransferase; GCS – glycine cleavage system; VIAAT – vesicular inhibitory amino acid transporter; BBB – blood-brain barrier.
INTRODUCTION
A negative impact of stress and anxiety is experienced by an increasing number of people in the modern world, regardless of age and gender [1]. It is known that stress is also called a state of acute or chronic psycho-emotional tension. It should be also notified that anxiety disorders are significant psychosocial risk factors for the development of many chronic noncommunicable diseases [2]. Taking into account the growing need for timely therapy and prevention of disorders associated with the development of stress and anxiety, the search and development of safe and effective means for their correction are becoming increasingly important.
Treatment regimens for anxiety states of various origins are based on the use of a number of anxiolytic psychotropic drugs [3]. The molecular mechanism of their anti-anxiety action is based on a long-term increase in the activity of subclass A gamma-aminobutyric acid (GABA) receptors [4]. This class of membrane receptors responsible for the inhibition in neurons belongs to the family of pentameric ligand-gated ion channels (pLGICs) [5, 6]. The interaction of the agonist with the receptor, leading to the opening of a selective anion channel on the surface of the excitable membrane, leads to an increase in the Cl- flux, which causes hyperpolarization of the neuron [7]. This activation of the transmembrane anionic current through the GABA receptors makes it possible to consider GABA as the main inhibitory neurotransmitter in the central nervous system (CNS) in the classical approach to neurophysiological processes [8]. Along with this, the second most physiologically important mediator that causes inhibition in the neurons of the spinal cord and brainstem is amino acid glycine [9]. This neurotransmitter, along with GABA, is present both in specific glycinergic and mixed synapses and is widely distributed in different parts of the brain. It also activates the transmembrane conductivity of chloride ions in the glycine receptor (GlyR), which belongs to the already mentioned pLGICs family [10, 11] (Fig. 1).
Figure 1 – Pentamers activation of pLGICs family by CNS inhibitory neurotransmitters. Note: Structural images of membrane proteins are presented based on the Protein Data Bank (PDB) (https://www.rcsb.org) in parallel planes (GABAA receptor, 7PBZ, [12]; glycine receptor, 6VM3, [23]) and perpendicular (glycine receptor, 5VDI, [13]) plane of the membrane.
It is noteworthy that the structures of transmembrane proteins are isolated together with zinc ions, which are present in the analyzed recombinant proteins [12, 13]. Zinc belongs to the group of the most significant trace elements in the body along with iron, magnesium, and iodine. A decrease in the content of this divalent cation leads to significant problems for patients in both developing and developed countries [14, 15].
Zinc is the second most common micronutrient in the body after iron. On average, the body of an adult contains 2–3 grams of zinc [16]. In the body, it is distributed according to the skeletal type – 63% in the skeletal muscles, 22% in the skeletal system. The maximum concentration of zinc is also observed in the muscles and bones, as well as in the prostate gland in men. The concentration of zinc in the brain is estimated at 150 µmol/l, which, in turn, is 10 times higher than the content of zinc in blood serum [17]. Zinc is involved in all types of metabolism: it is assumed that it binds to about 3000 enzymes in vivo, which corresponds to about 10% of the human proteome [18]; regulates the cell stability and permeability and participates in membrane transport [19]; it has a pronounced immunomodulatory effect on hematopoiesis, osteogenesis, respiration processes and programmed cell death (apoptosis) [16, 20]. The role of Zn2+ as a neurotransmitter and modulator of the neurons state has been experimentally proven, since this ion is able to accumulate in presynaptic vesicles with a subsequent release into the synaptic cleft [21]. In addition, the level of zinc affects the susceptibility to learning and memory [22]. These results show that zinc ions, along with well-known neurotransmitters, can directly affect the state of neurons and participate in the regulation processes of CNS excitation and inhibition.
THE AIM of the work was to carry out a possible combined application of glycine and zinc compounds to change the metabolism and correct the conditions of patients with anxiety disorders and manifestations of stress.
MATERIALS AND METHODS
Information retrieval (Scopus, PubMed) and library (eLibrary) databases were used as research tools. In some cases, the ResearchGate application was used for a semantic search.
The analysis and synthesis of the scientific literature on the research topic, was carried out covering the period from 2000 to September 2022.
The following keywords and word combinations were used in the search: anxiety, anxiolytic properties, neuron metabolism, a synaptic cleft, inhibitory mediators, glycine metabolism, glycine receptor, GABA, GABA receptors, glycine transporters, chloride ion properties, chloride connectivity, zinc metabolism, tissue zinc levels, zinc levels, zinc transport, zinc effects, allosteric regulation, reactive oxygen species, antioxidant effects, metabolic levels of glycine, metabolic level of zinc, blood-brain barrier, vasodilatation, cerebral blood flow, anti-anxiety effects of glycine, glycine effects on stress, clinical trials of glycine.
Visualization of membrane receptors was carried out using the data from the Protein Data Bank (PDB) (https://www.rcsb.org/). To make up chemical formulas and illustrations, the libraries of the ACD/ChemSketch 2020.2.0 software package were used.
RESULTS AND DISCUSSION
A feature of the molecular mechanisms underlying the therapeutic effect of glycine and zinc ions on patients suffering from anxiety disorders is the combined effect of these metabolites on various biochemical and signaling systems. In fact, it is necessary to discuss a complex effect touching upon several systems at once.
In the context of accumulation and transformation, in neurons and other types of human cells, there are fundamental differences between glycine and zinc due to their chemical nature. Glycine is a non-essential amino acid that is actively involved in many metabolic processes, while Zn2+ is a part of the trace elements, the level of which is always regulated by an influx from an external source.
Processes of zinc transport and storage in human cells and tissues
In enterocytes of the small intestine, zinc buffer proteins determine the process of this ion transfer into the bloodstream. Further, Zn2+ is redistributed between albumin (the main zinc carrier, binds up to 80% in blood), α-microglobulin and transferrin [22, 24]. The protein content of food, as well as the condition of the mucosal layer of the small intestine, determine the absorption of zinc. Only 10% of zinc is excreted from the body with sweat and urine, the rest – with fecal masses [25].
At the cellular level, 30–40% of zinc is localized in the nucleus, 50% in the cytoplasm and organelles, and the rest – in the cell membrane. Cellular zinc homeostasis is mediated by three main mechanisms [26]. First, this is transport across the plasma membrane by importer proteins from the ZIP and ZnT families (Fig. 2). Second, this is due to the sequestration mediated by the transporter into intracellular organelles, including endoplasmic reticulum, a Golgi complex and lysosomes. To maintain the cell viability, a strict control of zinc homeostasis is necessary, since dysregulation leads to the cell death. The third mechanism for maintaining homeostasis is the metallothionein/thionein system [18]. Metallothioneins (MTs) form complexes with about 20% of intracellular zinc. MTs are ubiquitous proteins characterized by a low molecular weight, a high cysteine content and the ability to form complexes with metal ions.
Figure 2 – Main ways of zinc ions transport and deposition in human cells. Note: Intracellular compartments are: endoplasmic reticulum (ZnT1, ZIP7), Golgi apparatus (ZnT5-7, ZIP13), endosomes (ZnT4), lysosomes (ZnT2), insulin granules (ZnT5, ZnT8) and synaptic vesicles (ZnT3).
One MT molecule can bind up to seven zinc ions. Due to the different affinity of metal ion binding sites, Zn can act as a powerful cellular zinc buffer. Free and weakly bound zinc ions interact with the apoprotein thionein (Tred) to form MTs [27]. An increase in the level of free zinc ions triggers the transcription factor-1 (MTF), thus inducing the expression of thionein [18]. In addition, oxidation of thiols by reactive oxygen species (ROS) or nitrogen (RNS) triggers the formation of oxidized protein thionine (Tox) with a concomitant zinc release [28].
Since there is no zinc storage system in the body, its level in cells must be constantly maintained. Both vegetable (mushrooms, nuts, cereals, legumes) and animal (meat, liver, seafood, cheese) products can be used as sources to maintain the normal level of this ion [25, 29].
In accordance with the norms of physiological needs for energy and nutrients for various population groups in the Russian Federation (Methodological recommendations MP 2.3.1.0253-21), the recommended daily allowance is from 3 to 12 mg of zinc for children and 12 mg for adults. In the US, the daily allowance of zinc for men is 11 mg, for women – 8 mg. In Germany, it is 10 mg for men and 7 mg for women [26].
Glycine metabolism in human cells
As mentioned above, unlike zinc, amino acid glycine, being both a substrate and a product of enzymatic reactions, is actively involved in the metabolic processes of human cells. In most cases, glycine is synthesized by serine hydroxymethyltransferase (SHMT), which uses serine supplied with food or obtained as a product of anabolic reactions from glucose and glutamate, as a substrate [30]. SHMT is a pyridoxal phosphate and a tetrahydrofolate dependent protein that is present in both the cytoplasm (SHMT1) and mitochondria (SHMT2), with the mitochondrial enzyme being more active [31]. Alternative metabolic pathways are the synthesis of glycine from threonine (with the participation of threonine aldolase and threonine dehydrogenase), choline (initiated by choline oxidase), and glyoxylate (catalyzed by alanine glyoxylate aminotransferase) [32, 33]. In general, the balance and dominance of these anabolic pathways is highly dependent on conditions, diet, and a body state. As catabolic reactions, one can consider the reversibility of the SHMT reaction, as well as the mitochondrial glycine cleavage system (GCS), which is a combination of four proteins (glycine decarboxylase (P-protein), aminomethyltransferase (T-protein), dihydrolipoamide dehydrogenase (L-protein) and a protein containing lipoic acid (H-protein) [34]. It should be notified that despite the complexity of the process, GCS is considered as a reversible system and its activity is unevenly distributed in human tissues: the glycine cleavage system is more represented in the liver and kidneys and, to a lesser extent, in the brain, testicles, and the small intestine [30].
Role of glycine as neurotransmitter in neurons
Synthesized glycine is pumped into vesicles via the vesicular inhibitory amino acid transporter (VIAAT), which is associated with the transport of chloride ions into synaptic particles [35]. Such an activity is typical for both glycinergic and GABAergic neurons, as well as for terminal endings of a mixed type [36]. Exocytosis of synaptic vesicles leads to the diffusion of glycine into the postsynaptic membrane with a subsequent activation of GlyR, which, in turn, leads to the depletion of the chloride ion gradient [37, 38]. For most mature CNS neurons, the intracellular concentration of chloride ions is maintained at a low level (about 5 mM) [39], which is achieved due to the activity of K+/Cl- carriers known as KCC2 [40, 41], which function along with Na+/K+/Cl- transporter (NKCC1), as well as glycine transporters – GlyT1 and GlyT2 [42] (Fig. 3).
Figure 3 – Schematic representation of glycinergic synapse. Note: A neurotransmitter release from synaptic vesicles is accompanied by a subsequent diffusion into the synaptic cleft and the activation of structured GlyR and gephyrin clusters on the postsynaptic membrane. The increasing concentration of chloride ions in the postsynaptic terminal is regulated by transport through the KCC2 transporter. Structural plasticity of the synapse is mediated by the interaction of α-neurexin (presynaptic membrane) and the neuroligin-2 complex with the structural network of gephyrin trimers in the postsynaptic terminal [43].
It should be emphasized that a distinctive structure feature of the postsynaptic region containing glycine and GABAA receptors is their cluster organization on the membrane surface. A similar effect is achieved due to the interaction of GlyR with a specific protein, gephyrin [44], which consists of three subunits [43] and forms trimers associated with cytoskeleton (Fig. 3). This protein is a part of a multistage system that ensures the formation and development of neuroplasticity of the neurons postsynaptic membrane containing receptors activated by inhibitory neurotransmitters (glycine and GABA) [45]. This process is dynamic and can be regulated in various ways, in particular, by the level of a specific brain-derived neurotrophic factor [46]. Glycine released into the synaptic cleft is subsequently captured back into neurons and glial cells through the already mentioned GlyT carriers, and some of the neurotransmitter molecules are carried away by convection diffusion into the interstitial fluid. This process is important for the formation of spatial heterogeneity in the distribution of glycine and the explanation of the molecular mechanisms of its effects in neurons [33].
Other concomitant and metabolic effects of glycine
The considered molecular activation mechanism of chlorine ions transmembrane currents indicates the direct participation of glycine in the formation of inhibitory processes in CNS neurons and is the basis for the formation of various treatment regimens aimed at reducing anxiety and reducing the manifestation of stress. Thus, it has been experimentally shown that high doses of glycine when taken orally (3 g once before falling asleep) improve the subjective and objective assessment of the quality of sleep in the group of patients under consideration [47]. The oral intake of glycine reduces metabolic disorders in patients with cardiovascular diseases, inflammation of various origins in a number of cancers, as well as in obesity and diabetes [48]. Glycine protects against oxidative stress caused by a wide range of toxic compounds (including drugs) at the level of cells or an entire organ in the liver, kidneys, intestines, and a vascular system [49]. It is noteworthy that glycine has a direct effect on the arteriole dilatation [50, 51], which is the most important aspect of this amino acid overall effect on the CNS state [52]. The impact on the blood flow system in microvessels and capillaries leads to a theoretically substantiated [53–55] and experimentally confirmed increase in the glucose content in tissues [56].
Allosteric regulation of GlyR by zinc ions
A number of experimental works have shown the allosteric regulation of GlyR by zinc ions [57, 58]. The effect of zinc on the activity of glycine receptors depends on the level of the ion content and has a biphasic form. At low concentrations of Zn2+ (<10 μM), the receptor is activated, while at high concentrations (>10 μM), it is inhibited. These multidirectional processes involve different sites on the receptor and have different molecular mechanisms. Potentiation is achieved by increasing the affinity of the receptor for glycine, while inhibition is achieved by decreasing its efficiency [57]. These effects should be considered as a consequence of zinc physicochemical properties; zinc is the only ion among transition metals that does not have a biological redox activity. It is the lack of the zinc redox activity, along with its relatively strong affinity for proteins that has made zinc a suitable ion to play the role of a structural cofactor that modulates the activity of the glycine receptor.
Antioxidant effects of glycine and zinc
In addition to the immediate direct combined effect on the state of the neuron membrane polarization, glycine and Zn2+ have many effects on metabolic processes that directly affect the condition of patients with anxiety disorders. In particular, it has been experimentally shown that an increase in the concentration of glycine has a protective effect on the oxidative phosphorylation system in the mitochondria of neurons under anoxia and hypoxia conditions [59–61], which is a part of the global regulatory mechanism of the metabolism switching state depending on the level of the tissue amino acids [62]. In addition, a direct increase in the content of glycine reduces the generation level of reactive oxygen species initiated by glutamate excitotoxicity [63]. The antioxidant effect is supported by the mediated participation of glycine in the glutathione tripeptide in the system of protection against the oxidative stress, which is the basis of this amino acid protective effect in various ischemic conditions and acute cerebrovascular accidents [64]. Under normal physiological conditions, Zn2+ is redox-inactive; therefore, it takes part in the processes of receiving and transmitting electrons indirectly. The antioxidant properties of zinc are the result of several indirect mechanisms, i.e. the inhibition of ROS formation by transition metals and sulfhydryl stabilization [65, 66].
The above-mentioned molecular mechanisms of the glycine and zinc effect on the cellular and subcellular systems of the brain tissue indicate the need for the combined use of these metabolites to achieve a more pronounced effect in patients suffering from anxiety disorders. At the same time, both the ability to maintain the concentration of the amino acid and microelement in question, as well as their effectiveness and bioavailability, are important.
Bioavailability and maintenance of glycine and zinc levels in human body
Despite the fact that glycine is a non-essential amino acid, Melendes-Hevia E. et al. point at the need for its supply from outside as a source to meet the biological needs of the cells [67]. It should be notified that to date, the ability of glycine to penetrate the BBB with the help of nonspecific amino acid carriers when administered orally has been experimentally proven [47]. Nevertheless, the doses used in this method of administration are quite high [68] and, therefore, it is necessary to take into account the specificity of local changes in the concentration of glycine, which is achieved by an effective choice of this metabolite route of delivery.
To maintain full zinc homeostasis, a sufficient daily intake is necessary, because the systems of the intracellular zinc ions localization discussed above, are rather dynamically filled compartments and traps, which ultimately can lead to the absence of a deposition system for this microelement in the body.
Unfortunately, zinc deficiency does not show any specific symptoms. With its deficiency, such nonspecific conditions as sleep disturbances, deterioration of the skin, hair and nails, decreased appetite, increased hair loss, impaired night vision, decreased mood, increased duration of wound healing, and others can be observed [69].
Zinc deficiency is more common among people on the diet high in phytates [15]. Most often, they are residents of developing countries. Phytates are found in grains, seeds, nuts, legumes, cocoa beans and cocoa powder, and coffee beans. Phytates bind to zinc, thereby reducing its bioavailability [25, 26]. It is worth noting that zinc derived from animal products has a higher bioavailability compared to plant foods. Therefore, vegetarians are usually recommended to increase the zinc norm by 1.5 times [26].
To increase its bioavailability in vegetarian diets, legumes should be used in the sprouted form, or grains and legumes should be soaked in water for several hours before cooking.
According to the unified sanitary-epidemiological and hygienic requirements for goods subject to sanitary-epidemiological supervision (control), the recommended adequate level of the daily zinc intake for an adult is 12 mg; the upper allowable intake level is 25 mg [70]. The physiological need for children is from 3 to 12 mg/day (depending on age). Breastfeeding until at least 6 months of age provides an adequate level of zinc intake in the child’s body [71].
Interestingly, some authors point at the need for sublingual zinc in the treatment of colds [14]. A slow drug dissolution in the mouth will allow zinc ions to be released, absorbed and transported to the nose – the source of infection. The chemical composition of the preparation is also important so that zinc can be ionized in the oral cavity at pH 7.4: citric acid, glycine and tartrate prevent zinc ionization [14].
In biologically active food supplements, zinc can be present in the form of compounds: acetate, sulfate, chloride, citrate, gluconate, lactate, oxide, carbonate, L-ascorbate, L-aspartate, bisglycinate, L-lysinate, malate, mono-L-methionine sulfate, picolinate, L-pyroglutamate, as well as amino acid complexes (in accordance with the Unified Sanitary-Epidemiological and Hygienic Requirements). Biological zinc supplements have a varying bioavailability. Zinc bound to amino acids such as aspartate, cysteine and histidine, has the highest absorption concentration, followed by zinc chloride, sulfate and acetate, while zinc oxide has the lowest bioavailability [14, 26, 72]. A comparison of various saccharides and their combinations effect on the zinc uptake by vesicles with brush border membranes showed that the addition of maltose and a mixture of galactose with glucose did not significantly reduce the level of the zinc uptake compared with the control. The addition of a glucose polymer or lactose significantly increased the bioavailability of zinc [73]. The addition of glucose to lactose or mannitol to the glucose polymer had the same effect as lactose or polymer alone, respectively. The galactose-only buffer had no effect on zinc binding. In another study, a low molecular weight lactose-zinc complex was found out to have a higher bioavailability in vitro [74].
The use of Zn2+ together with glycine will allow the formation of chelated forms of zinc, the undeniable advantages of which include a maximum bioavailability even under the conditions where the assimilation of the components is impaired (the lack of interaction with food, other minerals and gastric hydrochloric acid, the absence of adverse reactions) [75].
It has been established that zinc, as one of the most important trace elements, plays an important role in various pathological conditions. Various diseases of the gastrointestinal tract, such as malabsorption, cirrhosis of the liver, a celiac disease, Crohn’s disease and chronic diarrhea, can also lead to zinc deficiency, due to the impaired absorption [19, 26].
Low zinc levels have been shown to be associated with metabolic syndrome and diabetes [76, 77], as well as decreased immunity [26, 78, 79]. Large amounts of iron from supplements can interfere with the zinc absorption. Disruption of zinc homeostasis, leading to either depletion or excess zinc, causes severe damage to neurons [80]. Zinc-induced cell death and changes in brain zinc status are associated with a wide range of diseases, including many neurodegenerative disorders, such as Alzheimer’s disease, and mood disorders, including depression, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and prion diseases, as well as autism spectrum disorders. [66, 81–83].
The considered molecular mechanisms of the metabolites action are reflected in the clinical practice of the anxiety states treatment. In particular, it was shown that such anxiety symptoms as anxious mood, tension, and sleep disturbances were subjected to the greatest reverse dynamics during glycine therapy [85]. In addition, a randomized placebo-controlled study demonstrated the effectiveness of glycine in the treatment of mild anxiety in patients with an adjustment disorder with a predominance of disturbance of other emotions [86].
All major metabolic pathways are regulated by zinc metalloenzymes. The functions of these enzymes include catalytic, structural and regulatory roles. The status of zinc, whether deficient or abundant, is able of influencing each of this element’s diverse roles in human biology.
CONCLUSION
Thus, deficiencies of certain essential trace elements and amino acids, such as glycine and zinc, especially their combined deficiencies, are one of the frequent causes of various adverse effects, including post-stress CNS dysfunctions. Given the accumulated experience of these micronutrients positive impact on the processes of recovery and maintenance of the central nervous system normal functioning, an adequate intake of zinc and glycine may be important for most people who experience the consequences of numerous stresses and anxiety on a daily basis. This combination can be especially useful for the people experiencing a state of chronic psycho-emotional stress and maladaptation, including those who have difficulty in falling asleep. Replenishment of zinc and glycine deficiency in the body of a healthy person is manifested by the development of a persistent anti-anxiety effect, which is accompanied by the normalization of the sleep-wake rhythm, which makes it possible to have a good rest without any loss of working efficiency after waking up.
FUNDING
The work was carried out with the financial support of LLC "MNPK "BIOTIKI". The sponsor had no influence on the choice of material for publication, analysis and interpretation of the data.
CONFLICT OF INTERESTS
The authors declare no conflict of interest.
AUTHORS’ CONTRIBUTION
VNS – writing and editing the text, analyzing literary sources and interpreting the results, analyzing glycine and zinc clinical effects, approval of the text; YRN – writing and editing the text, analyzing literary sources and interpreting the results, conducting a database search in the Protein Data Bank (PDB) (https://www.rcsb.org/), selecting material on the glycine action, developing design and making illustrations using graphic tools and the library of the ACD/ChemSketch 2020.2.0 software package, approval of the article final version for publication; VYT – writing and editing the text, analyzing literary sources and interpreting the results, selecting material on the metabolic zinc action; EVS – writing and editing the text, analyzing literary sources and interpreting the results, analyzing pharmaceutically acceptable zinc compounds and bioavailability of combinations, approval of the text.
作者简介
Veronika Shishkova
National Medical Research Center for Therapy and Preventive Medicine; Evdokimov Moscow State Medical and Dental University
编辑信件的主要联系方式.
Email: veronika-1306@mail.ru
ORCID iD: 0000-0002-1042-4275
Doctor of Sciences (Medicine), Leading Researcher, Head of the Department for the Prevention of Cognitive and Psychoemotional Disorders, Associate Professor of the Department of Therapy and Preventive Medicine
俄罗斯联邦, Bld. 3, 10, Petroverigsky Ln., Moscow, 101990; Bld. 1, 20, Delegatskaya St., Moscow, 127473Yaroslav Nartcissov
Institute of Cytochemistry and Molecular Pharmacology; Biomedical Research Group, BiDiPharma GmbH
Email: yarosl@biotic.dol.ru
ORCID iD: 0000-0001-9020-7686
Candidate of Sciences (Physics and Mathematics), Associate Professor in Biophysics, Head of the Department of Mathematical Modeling and Statistical Processing of Results, Head of Biomedical Research Group
俄罗斯联邦, Bldg 14, 24, 6th Radial’naya St., Moscow, 115404; 5, Bültbek, Siek, Germany, 22962Victoria Titova
Institute of Cytochemistry and Molecular Pharmacology
Email: victorinchik@gmail.com
ORCID iD: 0000-0002-4741-2331
Junior Researcher, Department of Mathematical Modeling and Statistical Processing of Results
俄罗斯联邦, Bldg 14, 24, 6th Radial’naya St., Moscow, 115404Elena Sheshegova
Institute of Cytochemistry and Molecular Pharmacology
Email: elshesh@yandex.ru
ORCID iD: 0000-0003-1796-3017
Candidate of Sciences (Pharmacy), Head of the Department of Experimental Pharmacology
俄罗斯联邦, Bldg 14, 24, 6th Radial’naya St., Moscow, 115404参考
- GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018 Nov 10;392(10159):1789–1858. doi: 10.1016/S0140-6736(18)32279-7
- Drapkina OM, Kontsevaya AV, Kalinina AM, Avdeev SM, Agaltsov MV, Alexandrova LM, Antsiferova AA, Aronov DM, Akhmedzhanov NM, Balanova YuA, Balakhonova TV, Berns SA, Bochkarev MV, Bochkareva EV, Bubnova MV, Budnevsky AV, Gambaryan MG, Gorbunov VM, Gorny BE, Gorshkov AYu, Gumanova NG, Dadaeva VA, Drozdova LYu, Egorov VA, Eliashevich SO, Ershova AI, Ivanova ES, Imaeva AE, Ipatov PV, Kaprin AD, Karamnova NS, Kobalava ZD, Konradi AO, Kopylova OV, Korostovtseva LS, Kotova MB, Kulikova MS, Lavrenova EA, Lischenko OV, Lopatina MV, Lukina YuV, Lukyanov MM, Mayev IV, Mamedov MN, Markelova SV, Martsevich SYu, Metelskaya VA, Meshkov AN, Milushkina OYu, Mukaneeva DK, Myrzamatova AO, Nebieridze DV, Orlov DO, Poddubskaya EA, Popovich MV, Popovkina OE, Potievskaya VI, Prozorova GG, Rakovskaya YuS, Rotar OP, Rybakov IA, Sviryaev YuV, Skripnikova IA, Skoblina NA, Smirnova MI, Starinsky VV, Tolpygina SN, Usova EV, Khailova ZV, Shalnova SA, Shepel RN, Shishkova VN, Yavelov IS, Mardanov BU. 2022 Prevention of chronic non-communicable diseases in the Russian Federation. National guidelines. Cardiovascular Therapy and Prevention. 2022;21(4):3235. doi: 10.15829/1728-8800-2022-3235. Russian
- Beune T, Absalom A. Anxiolytics, sedatives and hypnotics. Anaesthesia & Intensive Care Medicine. 2022;23(8):481–6. doi: 10.1016/j.mpaic.2022.04.013
- Sinclair L, Nutt D. Anxiolytics. Psychiatry. 2007;6(7):284–8. doi: 10.1016/j.mppsy.2007.04.007
- Amundarain MJ, Ribeiro RP, Costabel MD, Giorgetti A. GABAA receptor family: overview on structural characterization. Future Med Chem. 2019 Feb 25. doi: 10.4155/fmc-2018-0336
- Kim JJ, Hibbs RE. Direct Structural Insights into GABAA Receptor Pharmacology. Trends Biochem Sci. 2021 Jun;46(6):502–17. doi: 10.1016/j.tibs.2021.01.011
- Knoflach F, Bertrand D. Pharmacological modulation of GABAA receptors. Curr Opin Pharmacol. 2021;59:3–10. doi: 10.1016/j.coph.2021.04.003
- Avoli M, Krnjević K. The Long and Winding Road to Gamma-Amino-Butyric Acid as Neurotransmitter. Can J Neurol Sci. 2016 Mar;43(2):219–26. doi: 10.1017/cjn.2015.333
- Benarroch EE. Glycine and its synaptic interactions: functional and clinical implications. Neurology. 2011 Aug 16;77(7):677–83. doi: 10.1212/WNL.0b013e31822a2791
- Betz H, Laube B. Glycine receptors: recent insights into their structural organization and functional diversity. J Neurochem. 2006 Jun;97(6):1600–10. doi: 10.1111/j.1471-4159.2006.03908.x
- Beato M. The time course of transmitter at glycinergic synapses onto motoneurons. J Neurosci. 2008 Jul 16;28(29):7412–25. doi: 10.1523/JNEUROSCI.0581-08.2008
- Kasaragod VB, Mortensen M, Hardwick SW, Wahid AA, Dorovykh V, Chirgadze DY, Smart TG, Miller PS. Mechanisms of inhibition and activation of extrasynaptic αβ GABAA receptors. Nature. 2022;602(7897):529–33. doi: 10.1038/s41586-022-04402-z
- Huang X, Chen H, Shaffer PL. Crystal Structures of Human GlyRα3 Bound to Ivermectin. Structure. 2017 Jun 6;25(6):945-950.e2. doi: 10.1016/j.str.2017.04.007
- Prasad AS. Discovery of human zinc deficiency: its impact on human health and disease. Adv Nutr. 2013 Mar 1;4(2):176–90. doi: 10.3945/an.112.003210
- Wessells KR, Brown KH. Estimating the global prevalence of zinc deficiency: results based on zinc availability in national food supplies and the prevalence of stunting. PLoS One. 2012;7(11):e50568. doi: 10.1371/journal.pone.0050568
- Asl SH, Nikfarjam S, Majidi Zolbanin N, Nassiri R, Jafari R. Immunopharmacological perspective on zinc in SARS-CoV-2 infection. Int Immunopharmacol. 2021 Jul;96:107630. doi: 10.1016/j.intimp.2021.107630
- Portbury SD, Adlard PA. Zinc Signal in Brain Diseases. Int J Mol Sci. 2017 Nov 23;18(12):2506. doi: 10.3390/ijms18122506
- Kimura T, Kambe T. The Functions of Metallothionein and ZIP and ZnT Transporters: An Overview and Perspective. Int J Mol Sci. 2016 Mar 4;17(3):336. doi: 10.3390/ijms17030336
- Wang S, Liu GC, Wintergerst KA, Cai L. Chapter 14 – Metals in Diabetes: Zinc Homeostasis in the Metabolic Syndrome and Diabetes. In: Mauricio D, editor. Molecular Nutrition and Diabetes. Academic Press; 2016. p. 169–182. doi: 10.1016/B978-0-12-801585-8.00014-2
- Daaboul D, Rosenkranz E, Uciechowski P, Rink L. Repletion of zinc in zinc-deficient cells strongly up-regulates IL-1β-induced IL-2 production in T-cells. Metallomics. 2012 Oct;4(10):1088–97. doi: 10.1039/c2mt20118f
- Li Y, Hough CJ, Suh SW, Sarvey JM, Frederickson CJ. Rapid translocation of Zn(2+) from presynaptic terminals into postsynaptic hippocampal neurons after physiological stimulation. J Neurophysiol. 2001 Nov;86(5):2597–604. doi: 10.1152/jn.2001.86.5.2597
- Tamano H, Koike Y, Nakada H, Shakushi Y, Takeda A. Significance of synaptic Zn2+ signaling in zincergic and non-zincergic synapses in the hippocampus in cognition. J Trace Element Medic Biolog. 2016;38:93–8. doi: 10.1016/j.jtemb.2016.03.003
- Kumar A, Basak S, Rao S, Gicheru Y, Mayer ML, Sansom MSP, Chakrapani S. Mechanisms of activation and desensitization of full-length glycine receptor in lipid nanodiscs. Nat Commun. 2020 Jul 27;11(1):3752. doi: 10.1038/s41467-020-17364-5
- Lu J, Stewart AJ, Sadler PJ, Pinheiro TJ, Blindauer CA. Albumin as a zinc carrier: properties of its high-affinity zinc-binding site. Biochem Soc Trans. 2008 Dec;36 (Pt 6):1317–21. doi: 10.1042/BST0361317
- Sandstead HH, Freeland-Graves JH. Dietary phytate, zinc and hidden zinc deficiency. J Trace Elem Med Biol. 2014 Oct;28(4):414–7. doi: 10.1016/j.jtemb.2014.08.011
- Gammoh NZ, Rink L. Zinc in Infection and Inflammation. Nutrients. 2017 Jun 17;9(6):624. doi: 10.3390/nu9060624
- Maret W. The function of zinc metallothionein: a link between cellular zinc and redox state. J Nutr. 2000 May;130(5S Suppl):1455S–8S. doi: 10.1093/jn/130.5.1455S
- Plum LM, Rink L, Haase H. The essential toxin: impact of zinc on human health. Int J Environ Res Public Health. 2010 Apr;7(4):1342–65. doi: 10.3390/ijerph7041342
- Drapkina OM, Karamnova NS, Kontsevaya AV, Gorny BE, Dadaeva VA, Drozdova LYu, Yeganyan RA, Eliashevich SO, Izmailova OV, Lavrenova EA, Lischenko OV, Skripnikova IA, Shvabskaya OB, Shishkova VN. Russian Society for the Prevention of Noncommunicable Diseases (ROPNIZ). Alimentary-dependent risk factors for chronic non-communicable diseases and eating habits: dietary correction within the framework of preventive counseling. Methodological Guidelines. Cardiovascular Therapy and Prevention. 2021;20(5):2952. doi: 10.15829/1728-8800-2021-2952. Russian
- Wu G. Amino Acids: Biochemistry and Nutrition, 2nd Edition. CRC Print: Boca Raton; 2021. 816 p. doi: 10.1201/9781003092742
- Wang W, Wu Z, Dai Z, Yang Y, Wang J, Wu G. Glycine metabolism in animals and humans: implications for nutrition and health. Amino Acids. 2013 Sep;45(3):463–77. doi: 10.1007/s00726-013-1493-1
- Wu G. Functional amino acids in growth, reproduction, and health. Adv Nutr. 2010 Nov;1(1):31–7. doi: 10.3945/an.110.1008
- Nartsissov YR. Amino Acids as Neurotransmitters. The Balance between Excitation and Inhibition as a Background for Future Clinical Applications. COVID-19, Neuroimmunology and Neural Function, edited by Thomas Heinbockel, Robert Weissert, IntechOpen; 2022. doi: 10.5772/intechopen.103760
- Kikuchi G, Motokawa Y, Yoshida T, Hiraga K. Glycine cleavage system: reaction mechanism, physiological significance, and hyperglycinemia. Proc Jpn Acad Ser B Phys Biol Sci. 2008;84(7):246–63. doi: 10.2183/pjab.84.246
- Juge N, Muroyama A, Hiasa M, Omote H, Moriyama Y. Vesicular inhibitory amino acid transporter is a Cl-/gamma-aminobutyrate Co-transporter. J Biol Chem. 2009 Dec 11;284(50):35073–8. doi: 10.1074/jbc.M109.062414
- Ito T, Bishop DC, Oliver DL. Expression of glutamate and inhibitory amino acid vesicular transporters in the rodent auditory brainstem. J Comp Neurol. 2011 Feb 1;519(2):316–40. doi: 10.1002/cne.22521
- Berndt N, Hoffmann S, Benda J, Holzhutter HG. The influence of the chloride currents on action potential firing and volume regulation of excitable cells studied by a kinetic model. J Theor Biol. 2011;276(1):42–9. doi: 10.1016/j.jtbi.2011.01.022
- Doyon N, Prescott SA, Castonguay A, Godin AG, Kröger H, De Koninck Y. Efficacy of synaptic inhibition depends on multiple, dynamically interacting mechanisms implicated in chloride homeostasis. PLoS Comput Biol. 2011 Sep;7(9):e1002149. doi: 10.1371/journal.pcbi.1002149
- Raimondo JV, Richards BA, Woodin MA. Neuronal chloride and excitability – the big impact of small changes. Curr Opin Neurobiol. 2017 Apr;43:35–42. doi: 10.1016/j.conb.2016.11.012
- Chamma I, Chevy Q, Poncer JC, Lévi S. Role of the neuronal K-Cl co-transporter KCC2 in inhibitory and excitatory neurotransmission. Front Cell Neurosci. 2012 Feb 21;6:5. doi: 10.3389/fncel.2012.00005
- Kaila K, Price TJ, Payne JA, Puskarjov M, Voipio J. Cation-chloride cotransporters in neuronal development, plasticity and disease. Nat Rev Neurosci. 2014 Oct;15(10):637–54. doi: 10.1038/nrn3819
- Zaytsev KS, Mashkovtseva EV, Nartsissov YR. [Membrane Transporters of Glycine Amino Acid in Nervous Tissue: Structure, Localization, Functions and Regulation]. Uspekhi sovremennoj biologii. 2012;132(4):391–400. Russian
- Choii G, Ko J. Gephyrin: a central GABAergic synapse organizer. Exp Mol Med. 2015 Apr 17;47:e158. doi: 10.1038/emm.2015.5
- Baer K, Waldvogel HJ, During MJ, Snell RG, Faull RL, Rees MI. Association of gephyrin and glycine receptors in the human brainstem and spinal cord: an immunohistochemical analysis. Neuroscience. 2003;122(3):773–84. doi: 10.1016/s0306-4522(03)00543-8
- Luscher B, Fuchs T, Kilpatrick CL. GABAA receptor trafficking-mediated plasticity of inhibitory synapses. Neuron. 2011 May 12;70(3):385–409. doi: 10.1016/j.neuron.2011.03.024
- González MI. Brain-derived neurotrophic factor promotes gephyrin protein expression and GABAA receptor clustering in immature cultured hippocampal cells. Neurochem Int. 2014 Jun;72:14–21. doi: 10.1016/j.neuint.2014.04.006
- Bannai M, Kawai N. New therapeutic strategy for amino acid medicine: glycine improves the quality of sleep. J Pharmacol Sci. 2012;118(2):145–8. doi: 10.1254/jphs.11r04fm
- Razak MA, Begum PS, Viswanath B, Rajagopal S. Multifarious Beneficial Effect of Nonessential Amino Acid, Glycine: A Review. Oxid Med Cell Longev. 2017;2017:1716701. doi: 10.1155/2017/1716701
- Pérez-Torres I, Zuniga-Munoz AM, Guarner-Lans V. Beneficial Effects of the Amino Acid Glycine. Mini Rev Med Chem. 2017;17(1):15–32. doi: 10.2174/1389557516666160609081602
- Podoprigora GI, Nartsissov YR, Aleksandrov PN. Effect of glycine on microcirculation in pial vessels of rat brain. Bull Experiment Biol Med. 2005;139(6):675–7. doi: 10.1007/s10517-005-0375-2
- Podoprigora GI, Nartsissov YR. Effect of glycine on the microcirculation in rat mesenteric vessels. Bull Experiment Biol Med. 2009;147(3):308–11. doi: 10.1007/s10517-009-0498-y
- Podoprigora GI, Blagosklonov O, Angoué O, Boulahdour H, Nartsissov YR. Assessment of microcirculatory effects of glycine by intravital microscopy in rats. Annu Int Conf IEEE Eng Med Biol Soc. 2012;2012:2651–4. doi: 10.1109/EMBC.2012.6346509
- Nartsissov YR, Tyukina ES, Boronovsky SE, Sheshegova EV. Computer modeling of spatial-time distribution of metabolite concentrations in phantoms of biological objects by example of rat brain pial. Biophysics. 2013;58(5):703–11. doi: 10.1134/S0006350913050102
- Nartsissov YR. The Effect of Flux Dysconnectivity Functions on Concentration Gradients Changes in a Multicomponent Model of Convectional Reaction-Diffusion by the Example of a Neurovascular Unit. Defect and Diffusion Forum. 2021;413:19–28. doi: 10.4028/ href='www.scientific.net/DDF.413.19' target='_blank'>www.scientific.net/DDF.413.19
- Nartsissov YR. Application of a multicomponent model of convectional reaction-diffusion to description of glucose gradients in a neurovascular unit. Front Physiol. 2022 Aug 22;13:843473. doi: 10.3389/fphys.2022.843473
- Blagosklonov O, Podoprigora GI, Davani S, Nartsissov YR, Comas L., Boulahdour H, Cardot JC. FDG-PET scan shows increased cerebral blood flow in rat after sublingual glycine application. Nuclear Instruments and Methods in Physics Research, Section A: Accelerators, Spectrometers, Detectors and Associated Equipment. 2007;571(1–2):30–2. doi: 10.1016/j.nima.2006.10.022
- Yevenes GE, Zeilhofer HU. Allosteric modulation of glycine receptors. Br J Pharmacol. 2011 Sep;164(2): 224-36. doi: 10.1111/j.1476–5381.2011.01471.x
- Burgos CF, Yévenes GE, Aguayo LG. Structure and Pharmacologic Modulation of Inhibitory Glycine Receptors. Mol Pharmacol. 2016 Sep;90(3):318–25. doi: 10.1124/mol.116.105726
- Tonshin AA, Lobysheva NV, Yaguzhinsky LS, Bezgina EN, Moshkov DA, Nartsissov YR. Effect of the inhibitory neurotransmitter glycine on slow destructive processes in brain cortex slices under anoxic conditions. Biochemistry (Mosc). 2007 May;72(5):509–17. doi: 10.1134/s0006297907050070
- Lobysheva NV, Tonshin AA, Selin AA, Yaguzhinsky LS, Nartsissov YR. Diversity of neurodegenerative processes in the model of brain cortex tissue ischemia. Neurochem Int. 2009 May–Jun;54(5–6):322–9. doi: 10.1016/j.neuint.2008.12.015
- Selin AA, Lobysheva NV, Vorontsova ON, Tonshin AA, Yaguzhinsky LS, Narcissov YR. [The mechanism of action of glycine as a protector of brain tissue energy disorders in hypoxia]. Bulletin of Experimental Biology and Medicine. 2012;48(1):91–6. Russian
- Nesterov SV, Yaguzhinsky LS, Podoprigora GI, Nartsissov YR. Amino Acids as Regulators of Cell Metabolism. Biochemistry (Mosc). 2020 Apr;85(4):393–408. doi: 10.1134/S000629792004001X
- Lobysheva NV, Selin AA, Vangeli IM, Byvshev IM, Yaguzhinsky LS, Nartsissov YR. Glutamate induces H2O2 synthesis in nonsynaptic brain mitochondria. Free Radic Biol Med. 2013 Dec;65:428–435. doi: 10.1016/j.freeradbiomed.2013.07.030
- Skvortsova VI, Nartsissov YR, Bodykhov MK, Kichuk IV, Prianikova NA, Gudkova IuV, Sodatenkova TD, Kondrashova TT, Kalinina EV, Novichkova MD, Shut’eva AB, Kerbikov OB. [Oxidative stress and oxygen status in ischemic stroke]. Zh Nevrol Psikhiatr Im SS Korsakova. 2007;107(1):30–6. Russian
- Singh TA, Sharma A, Tejwan N, Ghosh N, Das J, Sil PC. A state of the art review on the synthesis, antibacterial, antioxidant, antidiabetic and tissue regeneration activities of zinc oxide nanoparticles. Advan Colloid Interface Sci. 2021;295:102495. doi: 10.1016/j.cis.2021.102495
- Faghfouri AH, Zarezadeh M, Aghapour B, Izadi A, Rostamkhani H, Majnouni A, Abu-Zaid A, Kord Varkaneh H, Ghoreishi Z, Ostadrahimi A. Clinical efficacy of zinc supplementation in improving antioxidant defense system: A comprehensive systematic review and time-response meta-analysis of controlled clinical trials. Europ J Pharmacol. 2021;907:174243. doi: 10.1016/j.ejphar.2021.174243
- Meléndez-Hevia E, De Paz-Lugo P, Cornish-Bowden A, Cárdenas ML. A weak link in metabolism: the metabolic capacity for glycine biosynthesis does not satisfy the need for collagen synthesis. J Biosci. 2009 Dec;34(6):853–72. doi: 10.1007/s12038-009-0100-9
- Leung S, Croft RJ, O’Neill BV, Nathan PJ. Acute high-dose glycine attenuates mismatch negativity (MMN) in healthy human controls. Psychopharmacology (Berl). 2008 Feb;196(3):451–60. doi: 10.1007/s00213-007-0976-8
- Rebrov VG, Gromova OA. [Vitamins, macro- and microelements]. Moscow: GEOTAR-Media; 2008, 960 p. Russian
- Popova AY, Tutelyan VA, Nikityuk DB. [On the new (2021) Norms of physiological requirements in energy and nutrients of various groups of the population of the Russian Federation]. Problems of Nutrition. 2021; 90(4): 6-19. doi: 10.33029/0042-8833-2021-90-4-6-19. Russian
- Salgueiro MJ, Zubillaga MB, Lysionek AE, Caro RA, Weill R, Boccio JR. The role of zinc in the growth and development of children. Nutrition. 2002 Jun;18(6):510-9. doi: 10.1016/s0899-9007(01)00812-7
- Reiber C, Brieger A, Engelhardt G, Hebel S, Rink L, Haase H. Zinc chelation decreases IFN-β-induced STAT1 upregulation and iNOS expression in RAW 264.7 macrophages. J Trace Elem Med Biol. 2017 Dec;44:76–82. doi: 10.1016/j.jtemb.2017.05.011
- Bertolo RF, Bettger WJ, Atkinson SA. Divalent metals inhibit and lactose stimulates zinc transport across brush border membrane vesicles from piglets. J Nutr Biochem. 2001 Feb;12(2):73–80. doi: 10.1016/s0955-2863(00)00126-1
- Sharma A, Shilpa Shree BG, Arora S, Tomar SK. Lactose–Zinc complex preparation and evaluation of acceptability of complex in milk. LWT – Food Science and Technology. 2015;64(Issue 1):275–81. doi: 10.1016/j.lwt.2015.05.056
- Beketova H, Horiacheva I. [Zinc and its impact on human health in conditions of COVID-19 pandemic: what’s new?] Pediatrics. Eastern Europe. 2021;9(1):8–20. doi: 10.34883/PI.2021.9.1.001. Russian
- Fathi M, Alavinejad P, Haidari Z, Amani R. The effects of zinc supplementation on metabolic profile and oxidative stress in overweight/obese patients with non-alcoholic fatty liver disease: A randomized, double-blind, placebo-controlled trial. J Trace Elem Med Biol. 2020 Dec;62:126635. doi: 10.1016/j.jtemb.2020.126635
- Barbara M, Mindikoglu AL. The role of zinc in the prevention and treatment of nonalcoholic fatty liver disease. Metabol Open. 2021 Jun 29;11:100105. doi: 10.1016/j.metop.2021.100105
- Osuna-Padilla IA, Briceño O, Aguilar-Vargas A, Rodríguez-Moguel NC, Villazon-De la Rosa A, Pinto-Cardoso S, Flores-Murrieta FJ, Perichart-Perera O, Tolentino-Dolores M, Vargas-Infante Y, Reyes-Terán G. Zinc and selenium indicators and their relation to immunologic and metabolic parameters in male patients with human immunodeficiency virus. Nutrition. 2020 Feb;70:110585. doi: 10.1016/j.nut.2019.110585
- Koo SI, Turk DE. Effect of zinc deficiency on the ultrastructure of the pancreatic acinar cell and intestinal epithelium in the rat. J Nutr. 1977 May;107(5):896–908. doi: 10.1093/jn/107.5.896
- Pang W, Leng X, Lu H, Yang H, Song N, Tan L, Jiang Y, Guo C. Depletion of intracellular zinc induces apoptosis of cultured hippocampal neurons through suppression of ERK signaling pathway and activation of caspase-3. Neurosci Lett. 2013 Sep 27;552:140–5. doi: 10.1016/j.neulet.2013.07.057
- Faber S, Zinn GM, Kern JC 2nd, Kingston HM. The plasma zinc/serum copper ratio as a biomarker in children with autism spectrum disorders. Biomarkers. 2009 May;14(3):171–80. doi: 10.1080/13547500902783747
- Vela G, Stark P, Socha M, Sauer AK, Hagmeyer S, Grabrucker AM. Zinc in gut-brain interaction in autism and neurological disorders. Neural Plast. 2015;2015:972791. doi: 10.1155/2015/972791
- Grabrucker S, Jannetti L, Eckert M, Gaub S, Chhabra R, Pfaender S, Mangus K, Reddy PP, Rankovic V, Schmeisser MJ, Kreutz MR, Ehret G, Boeckers TM, Grabrucker AM. Zinc deficiency dysregulates the synaptic ProSAP/Shank scaffold and might contribute to autism spectrum disorders. Brain. 2014 Jan;137(Pt 1):137–52. doi: 10.1093/brain/awt303
- Gromova OA, Pronin AV, Torshin IYu, Kalacheva AG, Grishina TR. Neurotrophic and antioxidant potential of neuropeptides and trace elements. Neurology, Neuropsychiatry, Psychosomatics. – 2015. – Vol. 7, No. 4. – P. 92–100. doi: 10.14412/2074-2711-2015-4-92-100. Russian
- Grigorova OV, Romasenko LV, Vazagaeva T., Maksimova LN, Nartsissov YR. [Therapy efficiency of anxiety at patients with adjustment disorder, on glycine therapy model with placebosensibility]. Russ J Psychiatry. 2012;(4):45–52. Russian
- Grigorova OV, Romasenko LV, Faizulloev AZ, Vazagaeva TI, Maksimova LN, Nartsissov YR. [The use of glycine in the treatment of patients suffering from adjustment disorder]. Practical Medicine J. 2012;57(2):178–82. Russian
补充文件
![](/img/style/loading.gif)