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Siodłak D, Doboszewska U, Nowak G, Wlaź P, Mlyniec K. Investigating the role of GPR39 in treatment of stress-induced depression and anxiety. Psychopharmacology (Berl) 2025; 242:1377-1406. [PMID: 39775023 DOI: 10.1007/s00213-024-06736-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025]
Abstract
RATIONALE Chronic stress is one of the leading causes of depression. Yet, knowledge of the pathomechanism of this process still eludes us. Chronic unpredictable mild stress (CUMS) model of depression enables researchers to look for a root cause of the disease in mice by mimicking a stressful human environment. OBJECTIVE Since zinc has already been shown to impact the treatment of depression, in our study we aimed to shed light on the role of the zinc receptor GPR39 in stress-induced depression. We also aimed to highlight the role of GPR39 activation in monoamine-based antidepressant treatment. METHODS Using large battery of behavioural tests, we provided a detailed description of CUMS-induced phenotype in both - CD-1 and GPR39 knock-out mice. RESULTS Our experiments showed that combined treatment with TC-G 1008 (GPR39 agonist) and antidepressants produces stronger antidepressant-like effect of classic antidepressants. We also demonstrated the inter-strain differences in stress response and the greater stress susceptibility of GPR39 knock-out mice. The lack of GPR39 expression also either diminished or completely abolished the response to treatment with different antidepressants combined with TC-G 1008. CONCLUSIONS The results show that GPR39 KO mice are more susceptible to chronic stress and that they are non-responsive to SSRI treatment. Utilizing various behavioural tests gave us much broader understanding not only of the role of GPR39 in depression treatment, but also of the importance of detailed behavioural description in a proper interpretation of the results. Further research with known selective agonists and antagonists of GPR39 will be necessary to understand the full potential of this receptor as a pharmacological target.
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Affiliation(s)
- Dominika Siodłak
- Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland
| | - Urszula Doboszewska
- Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland
| | - Gabriel Nowak
- Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland
- Department of Neurobiology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smetna Street 12, 31-343, Krakow, Poland
| | - Piotr Wlaź
- Department of Animal Physiology and Pharmacology, Institute of Biological Sciences, Faculty of Biology and Biotechnology, Maria Curie-Sklodowska University, Akademicka 19, 20-033, Lublin, Poland
| | - Katarzyna Mlyniec
- Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
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Fatehfar S, Sameei P, Abdollahzade N, Chodari L, Saboory E, Roshan-Milani S. Maternal Treadmill Exercise and Zinc Supplementation Alleviate Prenatal Stress-Induced Cognitive Deficits and Restore Neurological Biomarkers in Offspring: A Study on Male Rats Aged 30 and 90 Days. Dev Neurobiol 2025; 85:e22964. [PMID: 40195087 DOI: 10.1002/dneu.22964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Revised: 02/25/2025] [Accepted: 03/04/2025] [Indexed: 04/09/2025]
Abstract
The detrimental effects of prenatal stress (PS) on offspring's neurological and behavioral outcomes are well documented. However, strategies to mitigate these effects are underexplored. This study examines whether prenatal zinc supplementation and treadmill exercise can modulate PS-induced cognitive impairments and neurobiological markers in young and adult male rat offspring, leveraging the established neuroprotective potential of both physical activity and zinc. Pregnant rats were divided into five groups: control, stress, stress + exercise, stress + zinc, and stress + exercise + zinc, with all rats except the control group subjected to restraint stress (gestational days 15-19). Pregnant rats in the exercise groups underwent forced exercise, whereas those in the zinc groups received oral zinc sulfate throughout the pregnancy. At postnatal days 30 and 90, the cognitive function of male offspring was evaluated using the Morris water maze (MWM) test, and the hippocampal gene expression levels of caspase-3, brain-derived neurotrophic factor (BDNF), and glial fibrillary acidic protein (GFAP) were measured using reverse transcription-polymerase chain reaction (RT-PCR). PS impaired cognitive functions, increased caspase-3 expression, and decreased BDNF and GFAP expression levels in adult rats. Prenatal exercise was found to mitigate PS-induced cognitive deficits primarily through enhancing GFAP expression, whereas prenatal zinc improved PS-induced cognitive impairments mainly through reduced caspase-3 and increased BDNF expression. The combined effect of exercise and zinc was not additive on cognitive functions and biomarkers. Physical activity may alleviate PS-induced cognitive deficits by modulating astrocytic factors, whereas zinc may exert its effects by inhibiting apoptosis via a BDNF-dependent pathway. Further targeted research is necessary to confirm these relationships.
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Affiliation(s)
- Sina Fatehfar
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- School of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran
| | - Parsa Sameei
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- School of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran
| | - Naseh Abdollahzade
- Neurophysiology Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
- Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Leila Chodari
- Neurophysiology Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
- Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Ehsan Saboory
- Zanjan Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Shiva Roshan-Milani
- Neurophysiology Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
- Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
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Tanaka T, Kojo K, Suetomi T, Nagumo Y, Midorikawa H, Matsuda T, Nakazono A, Shimizu T, Fujimoto S, Ikeda A, Kandori S, Negoro H, Takayama T, Nishiyama H. Distinct Clusters of Testosterone Levels, Symptoms, and Serum Trace Elements in Young Men: A Cross-Sectional Analysis. Nutrients 2025; 17:867. [PMID: 40077734 PMCID: PMC11901754 DOI: 10.3390/nu17050867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 02/21/2025] [Accepted: 02/24/2025] [Indexed: 03/14/2025] Open
Abstract
Background/Objectives: Modern societal stressors have been linked to declining testosterone levels among young men, contributing to somatic, psychological, and sexual health problems. Despite growing evidence suggesting a link between trace elements and testosterone-related symptoms, there are only a few comprehensive analyses on younger populations. This study's aim was to examine how serum trace elements modulate the relationship between testosterone levels and symptom severity. Methods: This cross-sectional study included 225 young men seeking infertility consultation in Japan. Serum total and free testosterone levels were measured, along with self-reported symptoms using the Aging Males' Symptoms scale (somatic, psychological, sexual) and the Erection Hardness Score. The serum concentrations of 20 trace elements were measured. We used unsupervised clustering to classify participants based on testosterone levels and symptom severity and then compared the distribution of trace elements among the resulting clusters. Results: Three distinct clusters emerged: (1) lowest testosterone with highest symptom severity, (2) intermediate, and (3) highest testosterone with minimal symptoms. Interestingly, the intermediate cluster displayed low testosterone levels but minimal symptoms. Eleven trace elements (phosphorus, sulfur, potassium, calcium, iron, zinc, arsenic, rubidium, strontium, molybdenum, and cesium) were identified as potential contributors to testosterone dynamics. Weighted quantile sum regression indicated that phosphorus, strontium, and molybdenum negatively influenced testosterone outcomes, whereas iron, sulfur, and zinc were beneficial. Conclusions: Serum trace element profiles are significantly associated with testosterone levels and symptom severity in young men. Targeted interventions may address testosterone decline and its implications. These findings may help develop tailored strategies for optimizing male health.
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Affiliation(s)
- Takazo Tanaka
- Department of Urology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan
| | - Kosuke Kojo
- Department of Urology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan
- Center for Human Reproduction, International University of Health and Welfare Hospital, 537-3, Iguchi, Nasushiobara 329-2763, Japan (T.T.)
- Tsukuba Clinical Research & Development Organization, University of Tsukuba, 2-1-1, Amakubo, Tsukuba 305-8576, Japan
| | - Takahiro Suetomi
- Department of Urology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan
- Department of Urology, Ibaraki Seinan Medical Center Hospital, 2190, Sakai-machi, Sashima-gun, Ibaraki 306-0433, Japan
| | - Yoshiyuki Nagumo
- Department of Urology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan
| | - Haruhiko Midorikawa
- Department of Psychiatry, University of Tsukuba Hospital, 2-1-1, Amakubo, Tsukuba 305-8576, Japan
| | - Takaaki Matsuda
- Tsukuba Clinical Research & Development Organization, University of Tsukuba, 2-1-1, Amakubo, Tsukuba 305-8576, Japan
- Department of Endocrinology and Metabolism, University of Tsukuba Hospital, 2-1-1 Amakubo, Tsukuba 305-8576, Japan
| | - Ayumi Nakazono
- Center for Human Reproduction, International University of Health and Welfare Hospital, 537-3, Iguchi, Nasushiobara 329-2763, Japan (T.T.)
| | - Takuya Shimizu
- Health Care Analysis Center, Renatech Co., Ltd., 4-19-15, Takamori, Isehara 259-1114, Japan
| | - Shunsuke Fujimoto
- Health Care Analysis Center, Renatech Co., Ltd., 4-19-15, Takamori, Isehara 259-1114, Japan
| | - Atsushi Ikeda
- Department of Urology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan
| | - Shuya Kandori
- Department of Urology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan
| | - Hiromitsu Negoro
- Department of Urology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan
| | - Tatsuya Takayama
- Center for Human Reproduction, International University of Health and Welfare Hospital, 537-3, Iguchi, Nasushiobara 329-2763, Japan (T.T.)
- Department of Urology, International University of Health and Welfare Hospital, 537-3, Iguchi, Nasushiobara 329-2763, Japan
| | - Hiroyuki Nishiyama
- Department of Urology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan
- Tsukuba Clinical Research & Development Organization, University of Tsukuba, 2-1-1, Amakubo, Tsukuba 305-8576, Japan
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Hepatic Homeostasis of Metal Ions Following Acute Repeated Stress Exposure in Rats. Antioxidants (Basel) 2021; 11:antiox11010085. [PMID: 35052588 PMCID: PMC8773239 DOI: 10.3390/antiox11010085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/22/2021] [Accepted: 12/28/2021] [Indexed: 01/25/2023] Open
Abstract
Essential metals such as copper, iron, and zinc are cofactors in various biological processes including oxygen utilisation, cell growth, and biomolecular synthesis. The homeostasis of these essential metals is carefully controlled through a system of protein transporters involved in the uptake, storage, and secretion. Some metal ions can be transformed by processes including reduction/oxidation (redox) reactions, and correspondingly, the breakdown of metal ion homeostasis can lead to formation of reactive oxygen and nitrogen species. We have previously demonstrated rapid biochemical responses to stress involving alterations in the redox state to generate free radicals and the resultant oxidative stress. However, the effects of stress on redox-active metals including iron and copper and redox-inert zinc have not been well characterised. Therefore, this study aims to examine the changes in these essential metals following exposure to short-term repeated stress, and to further elucidate the alterations in metal homeostasis through expression analysis of different metal transporters. Outbred male Wistar rats were exposed to unrestrained (control), 1 day, or 3 days of 6 h restraint stress (n = 8 per group). After the respective stress treatment, blood and liver samples were collected for the analysis of biometal concentrations and relative gene expression of metal transporter and binding proteins. Exposure to repeated restraint stress was highly effective in causing hepatic redox imbalance. Stress was also shown to induce hepatic metal redistribution, while modulating the mRNA levels of key metal transporters. Overall, this study is the first to characterise the gene expression profile of metal homeostasis following stress and provide insight into the changes occurring prior to the onset of chronic stress conditions.
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Kondrakhina IN, Verbenko DA, Zatevalov AM, Gatiatulina ER, Nikonorov AA, Deryabin DG, Kubanov AA. A Cross-sectional Study of Plasma Trace Elements and Vitamins Content in Androgenetic Alopecia in Men. Biol Trace Elem Res 2021; 199:3232-3241. [PMID: 33151470 DOI: 10.1007/s12011-020-02468-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 10/30/2020] [Indexed: 12/11/2022]
Abstract
Androgenetic alopecia (AGA) is the most common variant of male pattern baldness in which occurrence and development of multiple genetic, hormonal, and metabolic factors are involved. We aimed to estimate plasma element content (Mg, Ca, Zn, Cu, Se, Fe), vitamin status (B12, D, E, and folic acid) in patients with AGA using direct colorimetric tests or atomic absorption spectrometry, and the influence of these parameters in the formation of various hair loss patterns. The study included 50 patients with I-IV stages of AGA divided into two groups with normal and high levels of dihydrotestosterone compared with 25 healthy individuals. The presence of two patterns of pathological hair loss in the androgen-dependent (parietal) and androgen-independent (occipital) areas of the scalp was confirmed. It was shown that all patients with AGA have a deficiency of elements (Zn, Cu, Mg, Se) and vitamins (B12, E, D, folic acid). However, the hair loss rate was not due to their content. А positive interrelation between quantitative trichogram parameters in the occipital region and iron metabolism in pairs "hair density vs Fe" and "hair diameter vs ferritin" was shown. In turn, in the parietal region, an inverse correlation of hair diameter with plasma Cu level was found, the most pronouncing in patients with high levels of dihydrotestosterone. The obtained results indicate the importance of multiple micronutrient deficiencies in the AGA occurrence accompanied by the existence of two different hair loss patterns, differently related to the content of certain trace elements and androgens in the blood.
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Affiliation(s)
- Irina N Kondrakhina
- State Research Center of Dermatovenereology and Cosmetology, Korolenko St., 3, Bldg 6, Moscow, Russian Federation, 107076
| | - Dmitry A Verbenko
- State Research Center of Dermatovenereology and Cosmetology, Korolenko St., 3, Bldg 6, Moscow, Russian Federation, 107076
| | - Alexander M Zatevalov
- G.N. Gabrichevsky Research Institute for Epidemiology and Microbiology, Admiral Makarov St., 10, 125212, Moscow, Russian Federation
| | - Eugenia R Gatiatulina
- All-Russian Research Institute of Medicinal and Aromatic Plants (VILAR), Grina St., 7, Moscow, Russian Federation, 117216
| | - Alexander A Nikonorov
- State Research Center of Dermatovenereology and Cosmetology, Korolenko St., 3, Bldg 6, Moscow, Russian Federation, 107076.
| | - Dmitry G Deryabin
- State Research Center of Dermatovenereology and Cosmetology, Korolenko St., 3, Bldg 6, Moscow, Russian Federation, 107076
| | - Alexey A Kubanov
- State Research Center of Dermatovenereology and Cosmetology, Korolenko St., 3, Bldg 6, Moscow, Russian Federation, 107076
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Tsoukalas D, Zlatian O, Mitroi M, Renieri E, Tsatsakis A, Izotov BN, Burada F, Sosoi S, Burada E, Buga AM, Rogoveanu I, Docea AO, Calina D. A Novel Nutraceutical Formulation Can Improve Motor Activity and Decrease the Stress Level in a Murine Model of Middle-Age Animals. J Clin Med 2021; 10:624. [PMID: 33562115 PMCID: PMC7915416 DOI: 10.3390/jcm10040624] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/01/2021] [Accepted: 02/02/2021] [Indexed: 12/14/2022] Open
Abstract
Ageing is a genetically programmed physiological process that is modulated by numerous environmental factors, associated with decreasing physiological function, decreasing reproductive rate and increasing age-related mortality rate. Maintaining mobility performance and physical function in the elderly is the main objective of the successful ageing concept. In this study, we aimed to evaluate the beneficial effect of a novel nutraceutical formulation containing Centella asiatica L. extract, vitamin C, zinc and vitamin D3 (as cholecalciferol) on motor activity and anxiety with the use of a murine model of old animals, as a means of providing proof for clinical use in the elderly, for enhancing physical strength and improving life quality. Eighteen Sprague Dawley 18 months old male rats were divided into three groups and received corn oil (the control group) or 1 capsule/kg bw Reverse supplement (treatment group 1) or 2 capsules/kg bw Reverse supplement (treatment group 2), for a period of 3 months. The Reverse supplement (Natural Doctor S.A, Athens, Greece) contains 9 mg Centella asiatica L. extract, vitamin C (200 mg as magnesium ascorbate), zinc (5 mg as zinc citrate), vitamin D3 (50 µg as cholecalciferol) per capsule. Before and after the treatment, the motor function and behavioral changes for anxiety and depression were evaluated using the open-field test, elevated plus-maze test and rotarod test. The supplementation with Reverse (Natural Doctor S.A) supplement can improve the locomotor activity in old rats in a dose-dependent manner, as demonstrated by an increase in the latency to leave from the middle square, in the number of rearings in the open field test, in the time spent in the open arms and time spent in the center in the elevated plus-maze test and the latency to all in all three consecutive trials in the rotarod test. Stress also decreased significantly in a dose-dependent manner, following the treatment with Reverse supplement, as was demonstrated by the decrease in the number of groomings at the open field test and time spent in the dark and the number of groomings at the elevated plus-maze test.
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Affiliation(s)
- Dimitris Tsoukalas
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
- Metabolomic Medicine, Health Clinic for Autoimmune and Chronic Diseases, 10674 Athens, Greece
- European Institute of Nutritional Medicine (E.I.Nu.M.), 00198 Rome, Italy
| | - Ovidiu Zlatian
- Department of Microbiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Mihaela Mitroi
- ENT Department, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Elisavet Renieri
- Laboratory of Toxicology and Forensic Sciences, Medical School, University of Crete, 71003 Heraklion, Greece; (E.R.); (A.T.)
| | - Aristidis Tsatsakis
- Laboratory of Toxicology and Forensic Sciences, Medical School, University of Crete, 71003 Heraklion, Greece; (E.R.); (A.T.)
- Department of Analytical and Forensic Medical Toxicology, Sechenov University, 119991 Moscow, Russia;
| | - Boris Nikolaevich Izotov
- Department of Analytical and Forensic Medical Toxicology, Sechenov University, 119991 Moscow, Russia;
| | - Florin Burada
- Human Genomics Laboratory, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (F.B.); (S.S.)
| | - Simona Sosoi
- Human Genomics Laboratory, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (F.B.); (S.S.)
| | - Emilia Burada
- Department of Physiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Ana Maria Buga
- Department of Biochemistry, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Ion Rogoveanu
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Anca Oana Docea
- Department of Toxicology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
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Madireddy S, Madireddy S. Most Effective Combination of Nutraceuticals for Improved Memory and Cognitive Performance in the House Cricket, Acheta domesticus. Nutrients 2021; 13:nu13020362. [PMID: 33504066 PMCID: PMC7911739 DOI: 10.3390/nu13020362] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/22/2021] [Accepted: 01/22/2021] [Indexed: 12/22/2022] Open
Abstract
Background: Dietary intake of multivitamins, zinc, polyphenols, omega fatty acids, and probiotics have all shown benefits in learning, spatial memory, and cognitive function. It is important to determine the most effective combination of antioxidants and/or probiotics because regular ingestion of all nutraceuticals may not be practical. This study examined various combinations of nutrients to determine which may best enhance spatial memory and cognitive performance in the house cricket (Acheta domesticus (L.)). Methods: Based on the 31 possible combinations of multivitamins, zinc, polyphenols, omega-3 polyunsaturated fatty acids (PUFAs), and probiotics, 128 house crickets were divided into one control group and 31 experimental groups with four house crickets in each group. Over eight weeks, crickets were fed their respective nutrients, and an Alternation Test and Recognition Memory Test were conducted every week using a Y-maze to test spatial working memory. Results: The highest-scoring diets shared by both tests were the combination of multivitamins, zinc, and omega-3 fatty acids (VitZncPuf; Alternation: slope = 0.07226, Recognition Memory: slope = 0.07001), the combination of probiotics, polyphenols, multivitamins, zinc, and omega-3 PUFAs (ProPolVitZncPuf; Alternation: slope = 0.07182, Recognition Memory: slope = 0.07001), the combination of probiotics, multivitamins, zinc, and omega-3 PUFAs (ProVitZncPuf; Alternation: slope = 0.06999, Recognition Memory: slope = 0.07001), and the combination of polyphenols, multivitamins, zinc, and omega-3 PUFAs (PolVitZncPuf; Alternation: slope = 0.06873, Recognition Memory: slope = 0.06956). Conclusion: All of the nutrient combinations demonstrated a benefit over the control diet, but the most significant improvement compared to the control was found in the VitZncPuf, ProVitZncPuf, PolVitZncPuf, and ProPolVitZncPuf. Since this study found no significant difference between the performance and improvement of subjects within these four groups, the combination of multivitamins, zinc, and omega-3 fatty acids (VitZncPuf) was concluded to be the most effective option for improving memory and cognitive performance.
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Affiliation(s)
- Samskruthi Madireddy
- Independent Researcher, 1353 Tanaka Drive, San Jose, CA 95131, USA
- Correspondence:
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Fatima S, Zaidi SS, Alsharidah AS, Aljaser FS, Banu N. Possible Prophylactic Approach for SARS-CoV-2 Infection by Combination of Melatonin, Vitamin C and Zinc in Animals. Front Vet Sci 2020; 7:585789. [PMID: 33344529 PMCID: PMC7744567 DOI: 10.3389/fvets.2020.585789] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 11/02/2020] [Indexed: 11/15/2022] Open
Abstract
SARS-CoV-2, an epidemic, causes severe stress in both human and animals and may induce oxidative stress (OS) and increases susceptibility to infection. Domestic animals are found infected by their COVID-2 suffering owners. Chronic immobilization stress (CIS), a model of psychological and physical stress of confinement, can trigger depression and anxiety in animals. We evaluated the ameliorative effect of the proposed SARS-CoV-2 prophylactic drugs melatonin, vitamin C, and zinc on CIS-induced OS, inflammation, and DNA damage in rats. Forty male Swiss albino rats (200–250 g, 7–9 weeks old) were divided into five groups as controls, CIS, treated with melatonin (20 mg/kg), and vitamin C plus zinc [VitC+Zn (250 + 2.5 mg/kg)] alone or in combination (melatonin+VitC+zinc) subjected to CIS for 3 weeks. CIS was induced by immobilizing the whole body of the rats in wire mesh cages of their size with free movement of head. Exposure to CIS significantly compromised the circulatory activities of superoxide dismutase, catalase, and glutathione with enhanced malondialdehyde, inflammatory markers (IL-6, IL10, and TNFα), and lymphocyte DNA damage in comparison to controls. Treatment with melatonin and VitC+Zn alone or in combination significantly restored the altered biochemical parameters and DNA damage of stressed rats to their respective control values. However, the cumulative action of melatonin with VitC+Zn was more effective in alleviating the CIS-induced OS, inflammation, and DNA damage. The present study indicates that the antioxidant combination can be an effective preventive measure to combat severe psychological and confinement stress-induced biochemical changes in animals due to abnormal conditions such as SARS-CoV-2.
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Affiliation(s)
- Sabiha Fatima
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Syed Shams Zaidi
- Director of Pharmacy, Goulburn Valley Health, Shepparton, VIC, Australia
| | | | - Feda S Aljaser
- Chair of Medical and Molecular Genetics Research, Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Naheed Banu
- Department of Physical Therapy, College of Medical Rehabilitation, Qassim University, Buraidah, Saudi Arabia
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Guo S, Yang C, Jiang S, Ni Y, Zhao R, Ma W. Repeated Restraint Stress Enhances Hepatic TFR2 Expression and Induces Hepatic Iron Accumulation in Rats. Biol Trace Elem Res 2020; 196:590-596. [PMID: 31707638 DOI: 10.1007/s12011-019-01956-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 10/24/2019] [Indexed: 12/26/2022]
Abstract
Abnormal hepatic iron metabolism is detrimental to health. The objective of this study was to detect repeated restraint stress on liver iron metabolism in rats. Twenty-four male rats aged 7 weeks were randomly divided into 2 groups: control group (Con) and repeated restraint stress group (RS). Rats were subjected to 6 h of daily restraint stress for 14 consecutive days in the repeated restraint stress group. The results showed that repeated restraint stress exposure decreased growth performance including impaired final weight (P = 0.07), reducing average daily gain (P = 0.01), and average daily feed intake (P = 0.00) during the 14-day experimental period. Repeated restraint stress exposure did not affect hemoglobin content and plasma iron parameters except downregulated unsaturated iron-binding capacity (P = 0.04). Repeated restraint stress exposure inhibited liver development (P = 0.03) and induced liver iron accumulation (P = 0.05). In addition, repeated restraint stress downregulated the expression of transferrin (TF) and transferrin receptor 2 (TFR2) at the mRNA level (P < 0.01), but upregulated at the protein level (P = 0.03 for TF; P = 0.00 for TFR2). These results indicated that repeated restraint stress induces hepatic iron accumulation, which is closely related to higher expression of hepatic TFR2 protein in rats.
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Affiliation(s)
- Shihui Guo
- Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, No. 1 Weigang Road, Nanjing, 210095, Jiangsu, People's Republic of China
- MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China
| | - Chun Yang
- Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, No. 1 Weigang Road, Nanjing, 210095, Jiangsu, People's Republic of China
- MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China
| | - Shuxia Jiang
- Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, No. 1 Weigang Road, Nanjing, 210095, Jiangsu, People's Republic of China
- MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China
| | - Yingdong Ni
- Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, No. 1 Weigang Road, Nanjing, 210095, Jiangsu, People's Republic of China
- MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China
| | - Ruqian Zhao
- Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, No. 1 Weigang Road, Nanjing, 210095, Jiangsu, People's Republic of China
- MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China
| | - Wenqiang Ma
- Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, No. 1 Weigang Road, Nanjing, 210095, Jiangsu, People's Republic of China.
- MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China.
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10
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Trace elements differences in the depression sensitive and resilient rat models. Biochem Biophys Res Commun 2020; 529:204-209. [PMID: 32703412 DOI: 10.1016/j.bbrc.2020.05.228] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 05/31/2020] [Indexed: 11/21/2022]
Abstract
The etiology and pathophysiology of depressive disorders remain unclear. Increasing evidences have demonstrated that trace elements such as zinc, magnesium, iron, calcium, selenium, manganese and chromium play vital roles in depressive symptoms. We used a Chronic Unpredictable Mild Stress (CUMS) model to simulate social pressure in rat model and compared the levels of trace elements in the plasma and brain. The concentrations trace elements were evaluated using inductively coupled plasma mass spectrometry or inductively coupled plasma-atomic emission spectrometry. In the CUMS model, 57% (12/21) of rats showed no significant decrease in sucrose preference and were grouped as CUMS-resilient; otherwise, CUMS-sensitive. The resilient group had higher levels of iron, sodium, sulfur, manganese and cobalt than the sensitive group in the brain samples (P < 0.05). The sensitive group had lower levels of calcium, potassium, sulfur, selenium and cobalt than the resilient groups, in the plasma samples. The higher levels of iron, calcium, selenium, manganese and cobalt in the resilient group indicated these trace elements might be protective against the development of depressive symptoms in response to stress.
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11
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Yuan ZY, Li J, Zhou XJ, Wu MH, Li L, Pei G, Chen NH, Liu KL, Xie MZ, Huang HY. HS-GC-IMS-Based metabonomics study of Baihe Jizihuang Tang in a rat model of chronic unpredictable mild stress. J Chromatogr B Analyt Technol Biomed Life Sci 2020; 1148:122143. [PMID: 32417717 DOI: 10.1016/j.jchromb.2020.122143] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 04/02/2020] [Accepted: 05/01/2020] [Indexed: 12/17/2022]
Abstract
The aim of this study was to investigate the differences in volatile organic compounds (VOCs) obtained from the feces of a Baihe Jizihuang Tang (BHT)-treated rat depression model. Rats were subjected to chronic unpredictable mild stress (CUMS), and the differences in VOCs were analyzed by headspace-gas chromatography-ion mobility spectrometry (HS-GC-IMS), NIST software, principal component analysis, and orthogonal partial least squares discriminant analysis. Eleven biomarkers were identified on the basis of VOC migration time, and their relative peak intensities were analyzed. A metabonomic model was established using multivariate statistical analysis. The study demonstrated the metabonomics of CUMS rats and the intervention effect of BHT and also highlighted the potential therapeutic effects of the traditional Chinese medicine (TCM) Jingfang for the clinical treatment of complex diseases, which was in line with the holistic and systemic approaches of TCM. This study augments the use of metabonomics based on HS-GC-IMS in research studies. Using this method, there is no need to pre-process samples by extraction or derivatization, and the VOC component of the sample can be detected directly and rapidly. In conclusion, this study establishes a simple, convenient, and fast technique, which can help identify clinical biomarkers for rapid medical diagnosis.
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Affiliation(s)
- Zhi-Ying Yuan
- Hunan University of Chinese Medicine, Changsha 410208, China; Hunan Engineering Technology Center of Functional Food Homology of Medicine, Changsha 410208, China; Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha 410208, China
| | - Jing Li
- Hunan University of Chinese Medicine, Changsha 410208, China
| | - Xiao-Jiang Zhou
- Hunan University of Chinese Medicine, Changsha 410208, China; Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha 410208, China
| | - Min-Hui Wu
- Hunan University of Chinese Medicine, Changsha 410208, China
| | - Liang Li
- Hunan University of Chinese Medicine, Changsha 410208, China
| | - Gang Pei
- Hunan University of Chinese Medicine, Changsha 410208, China; Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha 410208, China
| | - Nai-Hong Chen
- Hunan University of Chinese Medicine, Changsha 410208, China; Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Kai-Li Liu
- Hunan University of Chinese Medicine, Changsha 410208, China
| | - Men-Zhou Xie
- Hunan University of Chinese Medicine, Changsha 410208, China; Hunan Engineering Technology Center of Functional Food Homology of Medicine, Changsha 410208, China.
| | - Hui-Yong Huang
- Hunan University of Chinese Medicine, Changsha 410208, China; Hunan Engineering Technology Center of Functional Food Homology of Medicine, Changsha 410208, China.
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12
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Lopresti AL. The Effects of Psychological and Environmental Stress on Micronutrient Concentrations in the Body: A Review of the Evidence. Adv Nutr 2020; 11:103-112. [PMID: 31504084 PMCID: PMC7442351 DOI: 10.1093/advances/nmz082] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 06/14/2019] [Accepted: 07/08/2019] [Indexed: 12/21/2022] Open
Abstract
Stress is the nonspecific response of the body to any demand for change. Excess or chronic psychological or environmental stress is associated with an increased risk of mental and physical diseases, with several mechanisms theorized to be associated with its detrimental effects. One underappreciated potential mechanism relates to the effects of psychological and environmental stress on micronutrient concentrations. Micronutrients (vitamins and minerals) are essential for optimal physical and mental function, with deficiencies associated with an array of diseases. In this article, animal and human studies investigating the effects of various psychological and environmental stressors on micronutrient concentrations are reviewed. In particular, the effects of psychological stress, sleep deprivation, and physical exercise on micronutrient concentrations and micronutrient excretion are summarized. Micronutrients identified in this review include magnesium, zinc, calcium, iron, and niacin. Overall, the bulk of evidence suggests stress can affect micronutrient concentrations, often leading to micronutrient depletion. However, before definitive conclusions about the effects of stress can be made, the impact of different stressors, stress severity, and acute versus chronic stress on micronutrient concentrations requires investigation. Moreover, the impact of stress on micronutrients in different populations varying in age, gender, and premorbid health status and the durability of changes after a stressor is resolved require examination. The medical, physical, and psychological implications of nutrient changes caused by a stressor also remain to be determined.
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Affiliation(s)
- Adrian L Lopresti
- School of Psychology and Exercise Science, Murdoch University, Perth, Australia; and Clinical Research Australia, Duncraig, Australia,Address correspondence to ALL (e-mail: )
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13
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McAllister BB, Wright DK, Wortman RC, Shultz SR, Dyck RH. Elimination of vesicular zinc alters the behavioural and neuroanatomical effects of social defeat stress in mice. Neurobiol Stress 2018; 9:199-213. [PMID: 30450385 PMCID: PMC6234281 DOI: 10.1016/j.ynstr.2018.10.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 09/26/2018] [Accepted: 10/19/2018] [Indexed: 12/12/2022] Open
Abstract
Chronic stress can have deleterious effects on mental health, increasing the risk of developing depression or anxiety. But not all individuals are equally affected by stress; some are susceptible while others are more resilient. Understanding the mechanisms that lead to these differing outcomes has been a focus of considerable research. One unexplored mechanism is vesicular zinc – zinc that is released by neurons as a neuromodulator. We examined how chronic stress, induced by repeated social defeat, affects mice that lack vesicular zinc due to genetic deletion of zinc transporter 3 (ZnT3). These mice, unlike wild type mice, did not become socially avoidant of a novel conspecific, suggesting resilience to stress. However, they showed enhanced sensitivity to the potentiating effect of stress on cued fear memory. Thus, the contribution of vesicular zinc to stress susceptibility is not straightforward. Stress also increased anxiety-like behaviour but produced no deficits in a spatial Y-maze test. We found no evidence that microglial activation or hippocampal neurogenesis accounted for the differences in behavioural outcome. Volumetric analysis revealed that ZnT3 KO mice have larger corpus callosum and parietal cortex volumes, and that corpus callosum volume was decreased by stress in ZnT3 KO, but not wild type, mice.
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Key Words
- BLA, Basolateral amygdala
- CC, Corpus callosum
- Chronic stress
- Depression
- EPM, Elevated plus-maze
- Fear memory
- LV, Lateral ventricles
- Magnetic resonance imaging (MRI)
- NAc, Nucleus accumbens
- NSF, Novelty-suppressed feeding
- PBS, Phosphate-buffered saline
- PFA, Paraformaldehyde
- PFC, Prefrontal cortex
- RSD, Repeated social defeat
- SLC30A3
- Synaptic zinc
- ZnT3, Zinc transporter 3
- dHPC, Dorsal hippocampus
- vHPC, Ventral hippocampus
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Affiliation(s)
- Brendan B McAllister
- Department of Psychology & Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
| | - David K Wright
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3052, Australia.,Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia
| | - Ryan C Wortman
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia
| | - Sandy R Shultz
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia.,Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Richard H Dyck
- Department of Psychology & Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
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14
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Abstract
Exposure to stress is known to cause hepatic iron dysregulation, but the relationship between prolonged stress and liver iron metabolism is not yet fully understood. Thirty 13-week-old female Sprague-Dawley rats were randomly divided into two groups, as follows: the control group (saline-injection) and the dexamethasone group (Dexamethasone (Dex)-injection 0.1 mg/kg/day). After the 21-day stress trial, the results showed that chronic Dex administration not only impaired serum corticosterone (p = 0.00) and interleukin-6 (IL-6) (p = 0.01) levels, but also decreased white blood cell counts (p = 0.00), and reduced blood lymphocyte counts (p = 0.00). The daily Dex-injection also significantly reduced body weight (p < 0.01) by inhibiting food intake. Consecutive Dex administration resulted in decreased iron intake (p = 0.00), enhanced serum iron levels (p = 0.01), and increased the serum souble transferrin receptor (sTfR) content (p = 0.00) in rats. Meanwhile, long-term Dex exposure down-regulated duodenal cytochrome b (DCYTB) (p = 0.00) and the divalent metal transporter 1 (DMT1) (p = 0.04) protein expression, but up-regulated ferroportin (FPN) protein expression (p = 0.04). Chronic Dex administration reduced liver iron concentration (p = 0.02) in rats. Hepatic transferrin receptor 1 (TFR1) expression was lowered at the protein level (p = 0.03), yet with uncoupled mRNA abundance in Dex-treated rats. Enhanced iron-regulatory protein (IRP)/iron-responsive element (IRE) binding activity was observed, but did not line up with lowered hepatic TFR1 protein expression. This study indicates that long-term Dex exposure reduces liver iron content, which is closely associated with down-regulated hepatic TFR1 protein expression.
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Sela H, Cohen H, Karpas Z, Zeiri Y. Distinctive hippocampal zinc distribution patterns following stress exposure in an animal model of PTSD. Metallomics 2017; 9:323-333. [PMID: 28252129 DOI: 10.1039/c6mt00207b] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Emerging evidence suggests that zinc (Zn) deficiency is associated with depression and anxiety in both human and animal studies. The present study sought to assess whether there is an association between the magnitude of behavioral responses to stress and patterns of Zn distribution. The work has focused on one case study, the association between an animal model of posttraumatic stress disorder (PTSD) and the Zn distribution in the rat hippocampus. Behaviors were assessed with the elevated plus-maze and acoustic startle response tests 7 days later. Preset cut-off criteria classified exposed animals according to their individual behavioral responses. To further characterize the distribution of Zn that occurs in the hippocampus 8 days after the exposure, laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging was used. It has been found that Zn distribution in the dentate gyrus (DG) sub-region in the hippocampus is clearly more widely spread for rats that belong to the extreme behavioral response (EBR) group as compared to the control group. Comparison of the Zn concentration changes in the cornu ammonis 1 (CA1) and the DG sub-regions of the hippocampus shows that the concentration changes are statistically significantly higher in the EBR rats compared to the rats in the control and minimal behavioral response (MBR) groups. In order to understand the mechanism of stress-induced hippocampal Zn dyshomeostasis, relative quantitative analyses of metallothionein (MT), B-cell lymphoma 2 (Bcl-2) and caspase 3 immunoreactivity were performed. Significant differences in the number of caspase-ir and Bcl-2 cells were found in the hippocampal DG sub-region between the EBR group and the control and MBR groups. The results of this study demonstrate a statistically significant association between the degree of behavioral disruption resulting from stress exposure and the patterns of Zn distribution and concentration changes in the various hippocampal regions. Taken together, these findings indicate that Zn distribution patterns play an active role in the neurobiological response to predator scent stress.
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Affiliation(s)
- Hagit Sela
- Biomedical Engineering, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel. and Department of Chemistry, NRCN, P.O. Box 9001, Beer-Sheva 8419001, Israel.
| | - Hagit Cohen
- Beer-Sheva Mental Health Center, The State of Israel Ministry of Health, Anxiety and Stress Research Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
| | - Zeev Karpas
- Department of Chemistry, NRCN, P.O. Box 9001, Beer-Sheva 8419001, Israel.
| | - Yehuda Zeiri
- Biomedical Engineering, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel. and Department of Chemistry, NRCN, P.O. Box 9001, Beer-Sheva 8419001, Israel.
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16
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Ding Q, Li H, Tian X, Shen Z, Wang X, Mo F, Huang J, Shen H. Zinc and imipramine reverse the depression-like behavior in mice induced by chronic restraint stress. J Affect Disord 2016; 197:100-6. [PMID: 26985741 DOI: 10.1016/j.jad.2016.03.017] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Revised: 02/19/2016] [Accepted: 03/07/2016] [Indexed: 12/25/2022]
Abstract
Depression is a common psychopathological disorders. Studies of depression have indicated that zinc play a role in the depression pathophysiology and treatment. In present study, we examined the effects of zinc and imipramine supplement alone or combination of zinc and imipramine in mice induced by chronic restraint stress (CRS). Moreover, the possible roles of zinc receptor (G protein-coupled receptor 39, GPR39)-related pathway was investigated. Decreased weight and increased corticosterone (CORT) were observed after 3 weeks CRS exposure. It was shown that CRS induced lower serum zinc, higher hippocampal zinc, increased immobility time in tail suspension test and decreased movement distance in spontaneous activity test, which could be normalized by zinc (30 mg/kg) and imipramine (20 mg/kg) supplement alone and combination of zinc (15 mg/kg) and imipramine (5 mg/kg) for 3 weeks after CRS exposure. Moreover, the changes in mRNA expressions of GPR39, cAMP-response element binding protein (CREB), brain-derived neurotropic factor (BDNF) and n-methytl-d-aspartate receptors (NMDAR) could be reversed by the same treatment mentioned above. These results suggested that zinc dyshomeostasis in serum and hippocampus and depression-like behavior in CRS exposure animals observed in present study could be normalized by zinc and imipramine. The combination of zinc and imipramine in low dose has synergetic effects. The possible mechanism might be correlated to GPR39 receptor-related pathway.
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Affiliation(s)
- Qin Ding
- Department of Naval Hygiene, Second Military Medical University, Shanghai, China
| | - Hongxia Li
- Department of Naval Hygiene, Second Military Medical University, Shanghai, China
| | - Xue Tian
- Department of Naval Hygiene, Second Military Medical University, Shanghai, China
| | - Zhilei Shen
- Department of Naval Hygiene, Second Military Medical University, Shanghai, China
| | - Xiaoli Wang
- Department of Naval Hygiene, Second Military Medical University, Shanghai, China
| | - Fengfeng Mo
- Department of Naval Hygiene, Second Military Medical University, Shanghai, China
| | - Junlong Huang
- Department of Naval Hygiene, Second Military Medical University, Shanghai, China.
| | - Hui Shen
- Department of Naval Hygiene, Second Military Medical University, Shanghai, China.
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Doboszewska U, Szewczyk B, Sowa-Kućma M, Noworyta-Sokołowska K, Misztak P, Gołębiowska J, Młyniec K, Ostachowicz B, Krośniak M, Wojtanowska-Krośniak A, Gołembiowska K, Lankosz M, Piekoszewski W, Nowak G. Alterations of Bio-elements, Oxidative, and Inflammatory Status in the Zinc Deficiency Model in Rats. Neurotox Res 2016; 29:143-54. [PMID: 26581375 PMCID: PMC4701762 DOI: 10.1007/s12640-015-9571-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2015] [Revised: 10/26/2015] [Accepted: 10/28/2015] [Indexed: 12/17/2022]
Abstract
Our previous study showed that dietary zinc restriction induces depression-like behavior with concomitant up-regulation of the N-methyl-D-aspartate receptor (NMDAR). Because metal ions, oxidative stress, and inflammation are involved in depression/NMDAR function, in the present study, bio-elements (zinc, copper, iron, magnesium, and calcium), oxidative (thiobarbituric acid-reactive substances; protein carbonyl content), and inflammatory (IL-1α, IL-1β) factors were measured in serum, hippocampus (Hp), and prefrontal cortex (PFC) of male Sprague-Dawley rats subjected to a zinc-adequate (ZnA) (50 mg Zn/kg) or a zinc-deficient (ZnD) (3 mg Zn/kg) diet for 4 or 6 weeks. Both periods of dietary zinc restriction reduced serum zinc and increased serum iron levels. At 4 weeks, lowered zinc level in the PFC and Hp as well as lowered iron level in the PFC of the ZnD rats was observed. At 6 weeks, however, iron level was increased in the PFC of these rats. Although at 6 weeks zinc level in the PFC did not differ between the ZnA and ZnD rats, extracellular zinc concentration after 100 mM KCl stimulation was reduced in the PFC of the ZnD rats and was accompanied by increased extracellular iron and glutamate levels (as measured by the in vivo microdialysis). The examined oxidative and inflammatory parameters were generally enhanced in the tissue of the ZnD animals. The obtained data suggest dynamic redistribution of bio-elements and enhancement of oxidative/inflammatory parameters after dietary zinc restriction, which may have a link with depression-like behavior/NMDAR function/neurodegeneration.
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Affiliation(s)
- Urszula Doboszewska
- Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland.
| | - Bernadeta Szewczyk
- Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland
| | - Magdalena Sowa-Kućma
- Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland
| | | | - Paulina Misztak
- Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland
- Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland
| | - Joanna Gołębiowska
- Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland
| | - Katarzyna Młyniec
- Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland
| | - Beata Ostachowicz
- Faculty of Physics and Applied Computer Sciences, AGH University of Science and Technology, Mickiewicza 30, 30-059, Kraków, Poland
| | - Mirosław Krośniak
- Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland
| | | | - Krystyna Gołembiowska
- Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland
| | - Marek Lankosz
- Faculty of Physics and Applied Computer Sciences, AGH University of Science and Technology, Mickiewicza 30, 30-059, Kraków, Poland
| | | | - Gabriel Nowak
- Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland
- Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland
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18
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Golbidi S, Frisbee JC, Laher I. Chronic stress impacts the cardiovascular system: animal models and clinical outcomes. Am J Physiol Heart Circ Physiol 2015; 308:H1476-98. [DOI: 10.1152/ajpheart.00859.2014] [Citation(s) in RCA: 109] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 04/03/2015] [Indexed: 01/01/2023]
Abstract
Psychological stresses are associated with cardiovascular diseases to the extent that cardiovascular diseases are among the most important group of psychosomatic diseases. The longstanding association between stress and cardiovascular disease exists despite a large ambiguity about the underlying mechanisms. An array of possibilities have been proposed including overactivity of the autonomic nervous system and humoral changes, which then converge on endothelial dysfunction that initiates unwanted cardiovascular consequences. We review some of the features of the two most important stress-activated systems, i.e., the humoral and nervous systems, and focus on alterations in endothelial function that could ensue as a result of these changes. Cardiac and hematologic consequences of stress are also addressed briefly. It is likely that activation of the inflammatory cascade in association with oxidative imbalance represents key pathophysiological components of stress-induced cardiovascular changes. We also review some of the commonly used animal models of stress and discuss the cardiovascular outcomes reported in these models of stress. The unique ability of animals for adaptation under stressful conditions lessens the extrapolation of laboratory findings to conditions of human stress. An animal model of unpredictable chronic stress, which applies various stress modules in a random fashion, might be a useful solution to this predicament. The use of stress markers as indicators of stress intensity is also discussed in various models of animal stress and in clinical studies.
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Affiliation(s)
- Saeid Golbidi
- Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada; and
| | - Jefferson C. Frisbee
- Center for Cardiovascular and Respiratory Sciences, West Virginia University Health Sciences Center, Morgantown, West Virginia
| | - Ismail Laher
- Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada; and
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19
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Zinc, future mono/adjunctive therapy for depression: Mechanisms of antidepressant action. Pharmacol Rep 2015; 67:659-62. [DOI: 10.1016/j.pharep.2015.01.015] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Revised: 01/18/2015] [Accepted: 01/27/2015] [Indexed: 11/23/2022]
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20
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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. [PMID: 25878905 PMCID: PMC4386645 DOI: 10.1155/2015/972791] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 03/05/2015] [Indexed: 12/27/2022] Open
Abstract
A growing amount of research indicates that abnormalities in the gastrointestinal (GI) system during development might be a common factor in multiple neurological disorders and might be responsible for some of the shared comorbidities seen among these diseases. For example, many patients with Autism Spectrum Disorder (ASD) have symptoms associated with GI disorders. Maternal zinc status may be an important factor given the multifaceted effect of zinc on gut development and morphology in the offspring. Zinc status influences and is influenced by multiple factors and an interdependence of prenatal and early life stress, immune system abnormalities, impaired GI functions, and zinc deficiency can be hypothesized. In line with this, systemic inflammatory events and prenatal stress have been reported to increase the risk for ASD. Thus, here, we will review the current literature on the role of zinc in gut formation, a possible link between gut and brain development in ASD and other neurological disorders with shared comorbidities, and tie in possible effects on the immune system. Based on these data, we present a novel model outlining how alterations in the maternal zinc status might pathologically impact the offspring leading to impairments in brain functions later in life.
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Affiliation(s)
- Guillermo Vela
- Zinpro Corporation, Eden Prairie, MN 55344, USA
- Autismo ABP, 64639 Monterrey, NL, Mexico
| | - Peter Stark
- Zinpro Corporation, Eden Prairie, MN 55344, USA
| | | | - Ann Katrin Sauer
- WG Molecular Analysis of Synaptopathies, Neurology Department, Neurocenter of Ulm University, 89081 Ulm, Germany
| | - Simone Hagmeyer
- WG Molecular Analysis of Synaptopathies, Neurology Department, Neurocenter of Ulm University, 89081 Ulm, Germany
| | - Andreas M. Grabrucker
- WG Molecular Analysis of Synaptopathies, Neurology Department, Neurocenter of Ulm University, 89081 Ulm, Germany
- Institute for Anatomy and Cell Biology, Ulm University, 89081 Ulm, Germany
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Soria M, González-Haro C, Ansón M, López-Colón JL, Escanero JF. Plasma levels of trace elements and exercise induced stress hormones in well-trained athletes. J Trace Elem Med Biol 2015; 31:113-9. [PMID: 26004901 DOI: 10.1016/j.jtemb.2015.04.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Revised: 03/27/2015] [Accepted: 04/13/2015] [Indexed: 01/04/2023]
Abstract
This study analyzed the variation and relationship of several trace elements, metabolic substrates and stress hormones activated by exercise during incremental exercise. Seventeen well-trained endurance athletes performed a cycle ergometer test: after a warm-up of 10 min at 2.0 W kg(-1), the workload was increased by 0.5 W kg(-1) every 10 min until exhaustion. Prior diet, activity patterns, and levels of exercise training were controlled, and tests timed to minimize variations due to the circadian rhythm. Oxygen uptake, blood lactate concentration, plasma ions (Zn, Se, Mn and Co), serum glucose, non-esterified fatty acids (NEFAs) and several hormones were measured at rest, at the end of each stage and 3, 5 and 7 min post-exercise. Urine specific gravity was measured before and after the test, and participants drank water ad libitum. Significant differences were found in plasma Zn and Se levels as a function of exercise intensity. Zn was significantly correlated with epinephrine, norepinephrine and cortisol (r = 0.884, P < 0.01; r = 0.871, P < 0.01; and r = 0.808, P = 0.05); and Se showed significant positive correlations whit epinephrine and cortisol (r = 0.743, P < 0.05; and r = 0.776, P < 0.05). Neither Zn nor Se levels were associated with insulin or glucagon, and neither Mn nor Co levels were associated with any of the hormones or substrate metabolites studied. Further, while Zn levels were found to be associated only with lactate, plasma Se was significantly correlated with lactate and glucose (respectively for Zn: r = 0.891, P < 0.01; and for Se: r = 0.743, P < 0.05; r = 0.831, P < 0.05). In conclusion, our data suggest that there is a positive correlation between the increases in plasma Zn or Se and stress hormones variations induced by exercise along different submaximal intensities in well-hydrated well-trained endurance athletes.
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Affiliation(s)
- Marisol Soria
- Department of Pharmacology and Physiology, Faculty of Medicine, University of Zaragoza, C/Domingo Miral, s/n, 50009 Zaragoza, Spain.
| | - Carlos González-Haro
- Department of Pharmacology and Physiology, Faculty of Medicine, University of Zaragoza, C/Domingo Miral, s/n, 50009 Zaragoza, Spain.
| | - Miguel Ansón
- Department of Pharmacology and Physiology, Faculty of Medicine, University of Zaragoza, C/Domingo Miral, s/n, 50009 Zaragoza, Spain
| | - José L López-Colón
- Toxicology Service, Hospital Central de la Defensa, Glorieta del Ejército, s/n, 28047 Madrid, Spain.
| | - Jesús F Escanero
- Department of Pharmacology and Physiology, Faculty of Medicine, University of Zaragoza, C/Domingo Miral, s/n, 50009 Zaragoza, Spain.
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22
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Dou X, Tian X, Zheng Y, Huang J, Shen Z, Li H, Wang X, Mo F, Wang W, Wang S, Shen H. Psychological stress induced hippocampus zinc dyshomeostasis and depression-like behavior in rats. Behav Brain Res 2014; 273:133-8. [PMID: 25092572 DOI: 10.1016/j.bbr.2014.07.040] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2014] [Revised: 07/19/2014] [Accepted: 07/24/2014] [Indexed: 12/20/2022]
Abstract
There are strong evidences showed that psychological stress (PS) could result in depression. Recently, many attentions were paid to the roles of corticosterone (CORT) and zinc dyshomeostasis in the development of depression. In this study, we investigated the zinc level in rat hippocampus after exposure to PS and accompanied behavior change. Male SD rats were randomly divided into the control and PS groups. Each group had two subgroups: 7-d group and 14-d group. A communication box was used to produce the PS model in rats. Compared to control group, the PS-treated group showed decreased total zinc levels and increased free zinc levels observed by TSQ staining in hippocampus. Meanwhile, there were significant decreases in mRNA expressions of zinc transporters including ZnT1, ZnT3 and ZIP1 and metallothionein (MT) contents in hippocampus. Moreover, the increased immobility time in forced swim test (FST), lower movement time and total movement distance and longer immobile time in spontaneous activity test were demonstrated in rats after PS exposure. These results suggested that the depression-like behavior in PS-treated rats might be correlated with zinc dyshomeostasis including decreased zinc contents and increased free zinc in hippocampus which was related to changes in zinc transporters and MT expressions.
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Affiliation(s)
- Xiao Dou
- Department of Naval Hygiene, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, PR China
| | - Xue Tian
- Department of Naval Hygiene, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, PR China
| | - Yuanyuan Zheng
- Department of Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, PR China
| | - Junlong Huang
- Department of Naval Hygiene, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, PR China
| | - Zhilei Shen
- Department of Naval Hygiene, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, PR China
| | - Hongxia Li
- Department of Naval Hygiene, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, PR China
| | - Xiaoli Wang
- Department of Naval Hygiene, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, PR China
| | - Fengfeng Mo
- Department of Naval Hygiene, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, PR China
| | - Wanyin Wang
- Department of Naval Hygiene, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, PR China
| | - Shi Wang
- Department of Neurology, No. 411 Hospital, 15 East Dongjiangwan Road, Shanghai 200081, PR China.
| | - Hui Shen
- Department of Naval Hygiene, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, PR China.
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