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Wei HJ, Tan HY, Cao JP, He J, Zhang QL, Jiang L, Zhou GJ, Xiao F. Therapeutic importance of hydrogen sulfide in cognitive impairment diseases. Brain Res 2025; 1856:149547. [PMID: 40120710 DOI: 10.1016/j.brainres.2025.149547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 01/02/2025] [Accepted: 03/02/2025] [Indexed: 03/25/2025]
Abstract
The brain naturally synthesizes hydrogen sulfide (H2S) via enzymes such as cystathionine-β-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3-MST), cysteine aminotransferase (CAT), and cystathionine-γ-lyase (CSE). From a physiological point of view, H2S serves as a neuromodulator with antioxidant and neuroprotective properties. Recent research suggests that H2S is crucial in regulating learning and memory, as its downregulation is commonly observed in cognitive impairment diseases. Preclinical studies suggest that external supplementation, through donors like sodium hydrosulfide (NaHS), can improve cognitive impairment in various cognitive disorder models. Moreover, numerous molecular mechanisms have been proposed to explain the effects of these H2S donors. This review aims to detail the roles of H2S in various models of cognitive impairment and in human subjects, highlighting its potential mechanisms and providing experimental support for its use as a novel therapeutic approach in treating cognitive disorders. Overall, H2S plays a significant role in the treatment of cognitive impairment diseases, but further large-scale studies are still required to support the results of current research.
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Affiliation(s)
- Hai-Jun Wei
- Hunan Polytechnic of Environment and Biology, Hengyang, Hunan 421005 PR China
| | - Hui-Ying Tan
- The People's Hospital Dongkou, Shaoyang, Hunan 422300 PR China
| | - Jian-Ping Cao
- Hunan Polytechnic of Environment and Biology, Hengyang, Hunan 421005 PR China
| | - Juan He
- Hunan University of Medicine, Huaihua, Hunan 418000 PR China
| | - Qing-Li Zhang
- Hunan Polytechnic of Environment and Biology, Hengyang, Hunan 421005 PR China
| | - Li Jiang
- Department of Neurology, Nanhua Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001 Hunan, PR China
| | - Gui-Juan Zhou
- The First Affiliated Hospital, Department of Rehabilitation, Hengyang Medical School, University of South China, Hengyang 421001 Hunan, PR China
| | - Fan Xiao
- Clinical Research Institute, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001 PR China.
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Ling Z, Kong Q, He Z, Hao X, Liu R, Liu J, Wang Y, Liu J, Du W, Liu Y. Hydrogen sulfide improves depression-like behaviors in CUMS-induced mice by regulating autophagy. Psychoneuroendocrinology 2025; 175:107418. [PMID: 40023886 DOI: 10.1016/j.psyneuen.2025.107418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 02/18/2025] [Accepted: 02/27/2025] [Indexed: 03/04/2025]
Abstract
The pathogenesis of depression is associated with synaptic impairment and dysfunction in autophagy processes. Mendelian randomization (MR) analysis revealed that six GWAS IDs revealed a significant association between Beclin-1 levels and depression risk. Besides, all SNPs had a positive effect on depression risk. Analyzing neurons from depressed individuals using single-cell RNA sequencing (scRNA-seq) uncovered decreased expression of AKT, mTOR, and genes linked to synaptic plasticity. The activation of the PI3K/AKT/mTOR signaling has been demonstrated to control autophagy and have a protective effect on the nervous system. Hydrogen sulfide (H2S) is an endogenous gasotransmitter that can potentially treat various neurological disorders by improving neuronal synaptic plasticity. However, whether H2S regulates autophagy through PI3K/AKT/mTOR signaling, improves neuronal synaptic plasticity damage, and plays an antidepressant role is unclear. Our current research revealed that the reduction in the expression of p-PI3K, p-AKT, and p-mTOR proteins increase in neuronal autophagy activity and decline synaptic plasticity in mice with depression induced by chronic unpredictable mild stress (CUMS). Treatment with the exogenous hydrogen sulfide donor NaHS for one day and continuous treatment for one week improved the depression-like behaviors in the mice. Compared with those after one day of NaHS treatment, the above protein expression levels were restored and maintained, and the antidepressant effect was more significant after one week of continuous treatment with NaHS. Moreover, the PI3K inhibitor LY294002 was used to demonstrate that NaHS suppresses autophagy through activating the PI3K/AKT/mTOR signaling and ameliorates synaptic plasticity impairments. This study provides novel insights into the antidepressant mechanisms of H2S, highlighting its antidepressant therapeutic potential.
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Affiliation(s)
- Zhaoke Ling
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Qingqing Kong
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Zhiqiang He
- Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Xin Hao
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Ruiyao Liu
- Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China
| | - Jie Liu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Yushi Wang
- Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Jiao Liu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Wenlong Du
- Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
| | - Yi Liu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China; Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
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Duan P, Li X, Bi Y, Feng W, Jin Z, Zhang X, He G, An D, Wen Z, Zhang B. GYY4137 ameliorates blood brain barrier damage by inhibiting autophagy mediated occludin degradation in cardiac arrest and resuscitation. Sci Rep 2025; 15:905. [PMID: 39762518 PMCID: PMC11704213 DOI: 10.1038/s41598-024-84948-2] [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: 10/16/2024] [Accepted: 12/30/2024] [Indexed: 01/11/2025] Open
Abstract
Cardiopulmonary resuscitation (CPR) after cardiac arrest (CA) is an important cause of neurological impairment and leads to considerable morbidity and mortality. The stability of the blood-brain barrier (BBB) is crucial for minimizing secondary neurological damage and improving long-term prognosis. However, the precise mechanisms and regulatory pathways that contribute to BBB dysfunction after CPR remain elusive. GYY4137 is an innovative hydrogen sulfide slow-release agent with excellent properties as a hydrogen sulfide substitute. The aim of this study was to investigate the protective effects of GYY4137 on CA/CPR and the underlying mechanisms of BBB protection. The effects of GYY4137 on systemic inflammation, BBB integrity, and autophagy were evaluated using a mouse CA/CPR model. The underlying mechanisms of occludin changes associated with GYY4137 were investigated using oxygen-glucose deprivation / reoxygenation (OGD/R) model. ELISA, neurological function and other tests showed that GYY4137 ameliorates systemic inflammation and neurological prognosis. Western blotting, transwell migration and tube formation assays showed that GYY4137 improves BBB function both in vivo and in vitro. The detection of autophagy flow and protein degradation pathways showed the inhibition of occludin reduction by GYY4137 was mainly achieved by suppressing autophagy mediated degradation. Taken together, GYY4137 may improve BBB dysfunction following CPR by increasing occludin content. This effect was achieved by inhibiting autophagic degradation rather than promoting synthesis. GYY4137 also mitigated systemic inflammation and improved neurological outcomes after CA/CPR. In summary, our study provides valuable insights into protecting the integrity of BBB and improving neurological outcomes after CPR.
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Affiliation(s)
- Pengyu Duan
- Department of Anesthesiology, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang Province, China
- The Key Laboratory of Anesthesiology and Intensive Care Research of Heilongjiang Province, Harbin, China
| | - Xiaoyan Li
- Department of Anesthesiology, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang Province, China
- The Key Laboratory of Anesthesiology and Intensive Care Research of Heilongjiang Province, Harbin, China
| | - Yonghong Bi
- Department of Anesthesiology, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang Province, China
- The Key Laboratory of Anesthesiology and Intensive Care Research of Heilongjiang Province, Harbin, China
| | - Weiyu Feng
- Department of Anesthesiology, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang Province, China
- The Key Laboratory of Anesthesiology and Intensive Care Research of Heilongjiang Province, Harbin, China
| | - Zhehao Jin
- Department of Anesthesiology, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang Province, China
- The Key Laboratory of Anesthesiology and Intensive Care Research of Heilongjiang Province, Harbin, China
| | - Xiaoqian Zhang
- Department of Anesthesiology, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang Province, China
- The Key Laboratory of Anesthesiology and Intensive Care Research of Heilongjiang Province, Harbin, China
| | - Guanghui He
- Department of Anesthesiology, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang Province, China
- The Key Laboratory of Anesthesiology and Intensive Care Research of Heilongjiang Province, Harbin, China
| | - Da An
- Department of Anesthesiology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Zhibin Wen
- Department of Anesthesiology, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Bing Zhang
- Department of Anesthesiology, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang Province, China.
- The Key Laboratory of Anesthesiology and Intensive Care Research of Heilongjiang Province, Harbin, China.
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Lim CR, Ogawa S, Kumari Y. Exploring β-caryophyllene: a non-psychotropic cannabinoid's potential in mitigating cognitive impairment induced by sleep deprivation. Arch Pharm Res 2025; 48:1-42. [PMID: 39653971 DOI: 10.1007/s12272-024-01523-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 11/25/2024] [Indexed: 01/04/2025]
Abstract
Sleep deprivation or sleep loss, a prevalent issue in modern society, is linked to cognitive impairment, leading to heightened risks of errors and accidents. Chronic sleep deprivation affects various cognitive functions, including memory, attention, and decision-making, and is associated with an increased risk of neurodegenerative diseases, cardiovascular issues, and metabolic disorders. This review examines the potential of β-caryophyllene, a dietary non-psychotropic cannabinoid, and FDA-approved flavoring agent, as a therapeutic solution for sleep loss-induced cognitive impairment. It highlights β-caryophyllene's ability to mitigate key contributors to sleep loss-induced cognitive impairment, such as inflammation, oxidative stress, neuronal death, and reduced neuroplasticity, by modulating various signaling pathways, including TLR4/NF-κB/NLRP3, MAPK, Nrf2/HO-1, PI3K/Akt, and cAMP/PKA/CREB. As a naturally occurring, non-psychotropic compound with low toxicity, β-caryophyllene emerges as a promising candidate for further investigation. The review underscores the therapeutic potential of β-caryophyllene for sleep loss-induced cognitive impairment and provides mechanistic insights into its action on crucial pathways, suggesting that β-caryophyllene could be a valuable addition to strategies aimed at combating cognitive impairment and other health issues due to sleep loss.
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Affiliation(s)
- Cher Ryn Lim
- Neurological Disorder and Aging Research Group (NDA), Neuroscience Research Strength (NRS), Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, 47500, Selangor, Malaysia
| | - Satoshi Ogawa
- Neuroscience Research Strength (NRS), Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, 47500, Selangor, Malaysia
| | - Yatinesh Kumari
- Neurological Disorder and Aging Research Group (NDA), Neuroscience Research Strength (NRS), Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, 47500, Selangor, Malaysia.
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Xiong Y, Liang W, Wang X, Zhu H, Yi P, Wei G, Liu H, Lin Y, Zhang L, Ying J, Hua F. S100A8 knockdown activates the PI3K/AKT signaling pathway to inhibit microglial autophagy and improve cognitive impairment mediated by chronic sleep deprivation. Int Immunopharmacol 2024; 143:113375. [PMID: 39418730 DOI: 10.1016/j.intimp.2024.113375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 10/06/2024] [Accepted: 10/07/2024] [Indexed: 10/19/2024]
Abstract
OBJECTIVE Cognitive dysfunction is one of the major symptoms of chronic sleep deprivation (CSD). Abnormal autophagy and apoptosis are thought to be important mechanisms. S100 Calcium Binding Protein A8 (S100A8) plays a key role in autophagy and apoptosis of microglia. This study investigated whether S100A8 knockdown can effectively inhibit aberrant autophagy in microglia and improve cognitive function by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway under CSD conditions. METHODS CSD mouse models and BV2 cell autophagy models were established in vivo and in vitro. Transcriptome sequencing was used to determine the key regulator related to autophagy. The Morris water maze test was used to evaluate the cognitive behavior of the mice. RT-qPCR and western blot were conducted to examine S100A8 expression and autophagy signalling. HE, TUNEL, transmission electron microscopy, immunofluorescence, and histochemistry were performed to detect pathological changes, neuronal autophagy, apoptosis, or positive cells in hippocampal tissues, respectively. RESULTS Transcriptome sequencing showed that S100A8 was significantly elevated in CSD mice, and fluorescence colocalization results further suggested that S100A8 mainly colocalizes with microglia. In vivo studies revealed that knockdown of S100A8 alleviated CSD-induced cognitive impairment in mice. Through further mechanistic investigations employing both in vivo and in vitro models, we demonstrated that silencing S100A8 can activate the PI3K/AKT pathway, thereby reducing CSD-induced abnormal autophagy and apoptosis in microglia. Aberrant autophagy and apoptosis in microglia were reversed with the PI3K/AKT pathway inhibitor LY294002. CONCLUSION The S100A8/PI3K/AKT axis plays a crucial role in chronic sleep deprivation-mediated autophagy and apoptosis in microglia.
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Affiliation(s)
- Yanhong Xiong
- Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Province Key Laboratory of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Weidong Liang
- Department of Anesthesiology, the First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Xifeng Wang
- Jiangxi Province Key Laboratory of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Department of Anesthesiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Hong Zhu
- Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Province Key Laboratory of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Pengcheng Yi
- Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Province Key Laboratory of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Gen Wei
- Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Province Key Laboratory of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Hailin Liu
- Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Province Key Laboratory of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yue Lin
- Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Province Key Laboratory of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Lieliang Zhang
- Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Province Key Laboratory of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Jun Ying
- Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Province Key Laboratory of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
| | - Fuzhou Hua
- Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Province Key Laboratory of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
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Zhang Y, Zhang C, Dai Q, Ma R. Continuous Theta Burst Stimulation Inhibits Oxidative Stress-Induced Inflammation and Autophagy in Hippocampal Neurons by Activating Glutathione Synthesis Pathway, Improving Cognitive Impairment in Sleep-Deprived Mice. Neuromolecular Med 2024; 26:40. [PMID: 39388015 DOI: 10.1007/s12017-024-08807-z] [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: 05/08/2024] [Accepted: 09/29/2024] [Indexed: 10/12/2024]
Abstract
Sleep deprivation (SD) has been reported to have a negative impact on cognitive function. Continuous theta burst stimulation (cTBS) shows certain effects in improving sleep and neurological diseases, and its molecular or cellular role in SD-induced cognition impairment still need further exploration. In this study, C57BL/6 mice were subjected to 48 h of SD and cTBS treatment, and cTBS treatment significantly improved SD-triggered impairment of spatial learning and memory abilities in mice. Additionally, cTBS reduced malondialdehyde levels, increased superoxide dismutase activities, and inhibited the production of inflammatory cytokines, alleviating oxidative stress and inflammation levels in hippocampal tissues of SD model mice. cTBS decreased LC3II/LC3I ratio, Beclin1 protein levels, and LC3B puncta intensity, and elevated p62 protein levels to suppress excessive autophagy in hippocampal tissues of SD-stimulated mice. Then, we proved that inhibiting oxidative stress alleviated inflammation, autophagy, and death of hippocampal neuron cells through an in vitro cellular model for oxidative stress, and cTBS treatment promoted the production of glutathione (GSH), the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the mRNA expression of GSH synthesis-related genes to enhance antioxidant capacity in hippocampal tissues of SD mice. An Nrf2 inhibitor ML385 or a GSH synthesis inhibitor BSO reversed the alleviating effects of cTBS treatment on oxidative stress-associated damage of hippocampal tissues and cognitive impairment in SD model mice. Altogether, our study demonstrated that cTBS mitigates oxidative stress-associated inflammation and autophagy through activating the Nrf2-mediated GSH synthesis pathway, improving cognitive impairment in SD mice.
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Affiliation(s)
- Yi Zhang
- Clinical Psychology Department, the People's Hospital of Xinjiang Uygur Autonomous Region, 91 Tianchi Road, Urumqi, 830001, China
| | - Cheng Zhang
- Clinical Psychology Department, the People's Hospital of Xinjiang Uygur Autonomous Region, 91 Tianchi Road, Urumqi, 830001, China
| | - Qing Dai
- Anesthesiology Department, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China
| | - Rui Ma
- Clinical Psychology Department, the People's Hospital of Xinjiang Uygur Autonomous Region, 91 Tianchi Road, Urumqi, 830001, China.
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Wang B, Chen SM, Yang SQ, Jiang JM, Zhang P, Zou W, Tang XQ. GDF11 mediates H 2S to prevent chronic stress-induced cognitive impairment by reducing hippocampal NLRP3/caspase-1-dependent pyroptosis. J Affect Disord 2024; 344:600-611. [PMID: 37827256 DOI: 10.1016/j.jad.2023.10.040] [Citation(s) in RCA: 1] [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: 05/21/2023] [Revised: 09/17/2023] [Accepted: 10/08/2023] [Indexed: 10/14/2023]
Abstract
BACKGROUND We previously revealed that hydrogen sulfide (H2S) attenuates chronic stress-induced cognitive impairment, but the underlying mechanism needs to be further clarified. Growth differentiation factor 11 (GDF11) plays an important regulatory role in cognitive function and that hippocampal NLRP3/caspase-1-mediated pyroptosis contributes to the pathogenesis of cognitive impairment. Hence, this research aimed to explore whether promoting GDF11 levels and suppressing hippocampal NLRP3/caspase-1-mediated pyroptosis mediate H2S to alleviate chronic stress-induced cognitive impairment. METHODS Sprague-Dawley rats were subjected to unpredictable chronic mild stress lasting four weeks to establish an animal model of chronic stress-induced cognitive impairment. Behavioral performance was assessed by the Y-maze test and the novel object recognition test. The expression levels of proteins were analyzed by Western blot analysis. The levels of IL-1β and IL-18 in the hippocampus were measured by ELISA. RESULTS NaHS upregulated the expression of GDF11 in the hippocampus of chronic unpredictable mild stress (CUMS)-exposed rats. Silencing GDF11 blocked NaHS-improved cognitive impairment in CUMS-exposed rats, according to the Y-maze test and the novel object recognition test. Furthermore, NaHS mitigated NLRP3/caspase-1-mediated pyroptosis in the hippocampus of CUMS-exposed rats and this effect was reversed by silencing GDF11. Moreover, overexpression of GDF11 alleviated CUMS-induced cognitive impairment and NLRP3/caspase-1-mediated hippocampal pyroptosis. CONCLUSIONS GDF11 mediates H2S to attenuate chronic stress-induced cognitive impairment via inhibiting hippocampal NLRP3/caspase-1-mediated pyroptosis.
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Affiliation(s)
- Bo Wang
- The First Affiliated Hospital, Institute of Neurology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, PR China; The First Affiliated Hospital, Institute of Anesthesiology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, PR China
| | - Si-Min Chen
- The First Affiliated Hospital, Institute of Neurology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, PR China
| | - San-Qiao Yang
- The First Affiliated Hospital, Institute of Neurology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, PR China
| | - Jia-Mei Jiang
- The First Affiliated Hospital, Institute of Neurology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, PR China
| | - Ping Zhang
- The Affiliated Nanhua Hospital, Department of Neurology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, PR China
| | - Wei Zou
- The Affiliated Nanhua Hospital, Department of Neurology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, PR China.
| | - Xiao-Qing Tang
- The First Affiliated Hospital, Institute of Neurology, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, PR China; Hengyang Key Laboratory of Neurodegeneration and Cognitive Impairment, Institute of Neuroscience, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, PR China; The Second Affiliated Hospital, Institute of Cerebral Disease, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, PR China.
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Jin YM, Huang AR, Yu MQ, Ye WD, Hu XG, Wang HM, Xu ZW, Liang DS. Protective Effects of NaHS/miR-133a-3p on Lipopolysaccharide-Induced Cardiomyocytes Injury. J Toxicol 2023; 2023:2566754. [PMID: 38106638 PMCID: PMC10723929 DOI: 10.1155/2023/2566754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 11/20/2023] [Accepted: 11/27/2023] [Indexed: 12/19/2023] Open
Abstract
Objective The aim of this study was to investigate the effects of sodium hydrosulfide (NaHS) on Lipopolysaccharide (LPS)-induced cardiomyocyte injury in H9c2 cells. Methods H9c2 cardiomyocytes cultivated with medium containing 10 μg/mL LPS were used to recapitulate the phenotypes of those in sepsis. Two sequential experiments were performed. The first contained a control group, a LPS group, and a LPS + NaHS group, with the aim to assure the protective effects of NaHS on LPS-treated cardiomyocytes. The second experiment added a fourth group, the LPS + NaHS + miR-133a-3p inhibition group, with the aim to preliminarily explore whether miR-133-3p exerts a protective function downstream of NaHS. The adenosine triphosphate (ATP) kit was used to detect ATP content; real-time quantitative polynucleotide chain reaction (qPCR) was used to measure the levels of mammalian targets of rapamycin (mTOR), AMP-dependent protein kinase (AMPK), and miR-133a-3p, and Western blot (WB) was used to detect protein levels of mTOR, AMPK, myosin-like Bcl2 interacting protein (Beclin-1), microtubule-associated protein 1 light chain 3 (LC3I/II), and P62 (sequestosome-1, sqstm-1/P62). Results Compared with the control group, the expressions of miR-133a-3p (P < 0.001), P62 (P < 0.001), and the content of ATP (P < 0.001) decreased, while the expressions of Beclin-1 (P = 0.023) and LC3I/II (P = 0.048) increased in the LPS group. Compared with the LPS group, the expressions of miR-133a-3p (P < 0.001), P62 (P < 0.001), and the content of ATP (P < 0.001) in the NaHS + LPS group increased, while the expressions of Beclin-1 (P = 0.023) and LC3I/II (P = 0.022) decreased. Compared with the NaHS + LPS group, the expression levels of miR-133a-3p (P < 0.001), P62 (P = 0.001), and the content of ATP (P < 0.001) in the LPS + NaHS + miR-133a-3p inhibition group were downregulated, and the expression levels of Beclin-1 (P = 0.012) and LC3I/II (P = 0.010) were upregulated. The difference was statistically significant. There was no significant difference in the expression of AMPK and mTOR between groups. Conclusion Our research demonstrated that NaHS relieved LPS-induced myocardial injury in H9c2 by promoting the expression of miR-133a-3p, inhibiting autophagy in cardiomyocytes, and restoring cellular ATP levels.
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Affiliation(s)
- Yi-Mei Jin
- Department of Pediatrics, Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Ai-Rong Huang
- Department of Pediatrics, Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Mei-qian Yu
- Department of Pediatrics, Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Wan-Ding Ye
- Department of Pediatrics, Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Xiao-guang Hu
- Department of Pediatrics, Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Hua-min Wang
- Department of Pediatrics, Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Zhi-wei Xu
- Department of Pediatrics, Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Dong-shi Liang
- Department of Pediatrics, Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
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Yang K, Hou R, Zhao J, Wang X, Wei J, Pan X, Zhu X. Lifestyle effects on aging and CVD: A spotlight on the nutrient-sensing network. Ageing Res Rev 2023; 92:102121. [PMID: 37944707 DOI: 10.1016/j.arr.2023.102121] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 10/12/2023] [Accepted: 11/04/2023] [Indexed: 11/12/2023]
Abstract
Aging is widespread worldwide and a significant risk factor for cardiovascular disease (CVD). Mechanisms underlying aging have attracted considerable attention in recent years. Remarkably, aging and CVD overlap in numerous ways, with deregulated nutrient sensing as a common mechanism and lifestyle as a communal modifier. Interestingly, lifestyle triggers or suppresses multiple nutrient-related signaling pathways. In this review, we first present the composition of the nutrient-sensing network (NSN) and its metabolic impact on aging and CVD. Secondly, we review how risk factors closely associated with CVD, including adverse life states such as sedentary behavior, sleep disorders, high-fat diet, and psychosocial stress, contribute to aging and CVD, with a focus on the bridging role of the NSN. Finally, we focus on the positive effects of beneficial dietary interventions, specifically dietary restriction and the Mediterranean diet, on the regulation of nutrient metabolism and the delayed effects of aging and CVD that depend on the balance of the NSN. In summary, we expound on the interaction between lifestyle, NSN, aging, and CVD.
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Affiliation(s)
- Kaiying Yang
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Rongyao Hou
- Department of Neurology, The Affiliated Hiser Hospital of Qingdao University, Qingdao 266000, China
| | - Jie Zhao
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Xia Wang
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Jin Wei
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Xudong Pan
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China.
| | - Xiaoyan Zhu
- Department of Critical Care Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266000, China.
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10
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Sethi P, Mehan S, Khan Z, Chhabra S. Acetyl-11-keto-beta boswellic acid(AKBA) modulates CSTC-pathway by activating SIRT-1/Nrf2-HO-1 signalling in experimental rat model of obsessive-compulsive disorder: Evidenced by CSF, blood plasma and histopathological alterations. Neurotoxicology 2023; 98:61-85. [PMID: 37549874 DOI: 10.1016/j.neuro.2023.08.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 07/23/2023] [Accepted: 08/03/2023] [Indexed: 08/09/2023]
Abstract
Obsessive-Compulsive disorder (OCD) is a long-term and persistent mental illness characterised by obsessive thoughts and compulsive behaviours. Numerous factors can contribute to the development or progression of OCD. These factors may result from the dysregulation of multiple intrinsic cellular pathways, including SIRT-1, Nrf2, and HO-1. Inhibitors of selective serotonin reuptake (SSRIs) are effective first-line treatments for OCD. In our ongoing research, we have investigated the role of SIRT-1, Nrf2, and HO-1, as well as the neuroprotective potential of Acetyl-11-keto-beta boswellic acid (AKBA) against behavioural and neurochemical changes in rodents treated with 8-OH-DPAT. In addition, the effects of AKBA were compared to those of fluvoxamine (FLX), a standard OCD medication. Injections of 8-OH-DPAT into the intra-dorso raphe nuclei (IDRN) of rats for seven days induced repetitive and compulsive behaviour accompanied by elevated oxidative stress, inflammatory processes, apoptosis, and neurotransmitter imbalances in CSF, blood plasma, and brain samples. Chronic administration of AKBA at 50 mg/kg and 100 mg/kg p.o. restored histopathological alterations in the cortico-striatal-thalamo-cortical (CSTC) pathway, including the cerebral cortex, striatum, and hippocampal regions. Our investigation revealed that when AKBA and fluvoxamine were administered together, the alterations were restored to a greater degree than when administered separately. These findings demonstrate that the neuroprotective effect of AKBA can serve as an effective basis for developing a novel OCD treatment.
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Affiliation(s)
- Pranshul Sethi
- Division of Neuroscience, Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Sidharth Mehan
- Division of Neuroscience, Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India.
| | - Zuber Khan
- Division of Neuroscience, Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Swesha Chhabra
- Division of Neuroscience, Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
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11
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Li Y, Xie Z, Luo X, Wang X, Wang Y, Guo M, Zhou Z, Sun R, Hua D, Luo A, Li S. Farnesol Exerts Protective Effects against Chronic Sleep Deprivation-Induced Cognitive Impairment via Activation SIRT1/Nrf2 Pathway in the Hippocampi of Adult Mice. Mol Nutr Food Res 2023; 67:e2200735. [PMID: 36989169 DOI: 10.1002/mnfr.202200735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 03/19/2023] [Indexed: 03/30/2023]
Abstract
SCOPE Sleep deprivation (SD) negatively affects all aspects of health, with one serious consequence being impaired cognition. Farnesol (FOL) is a sesquiterpene synthesized by plants and mammals that has antioxidant, anti-inflammatory, and neuroprotective properties. This study investigates the mechanism underlying the neuroprotective effect of FOL on SD-induced cognitive impairment. METHODS AND RESULTS Administration of FOL dramatically ameliorates chronic sleep deprivation (CSD)-induced cognitive impairment. In addition, FOL notably attenuates oxidative stress damage, pro-inflammatory cytokines activation, and microglial activation in the hippocampi of the CSD-exposed mice. Further examination indicates that administration of FOL after the CSD significantly increases the protein expressions of silent information regulator factor 2-related enzyme 1 (Sirt1), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (Gpx4) in the hippocampi. Sirt1 agonist resveratrol (RES) has a similar neuroprotective effect, indicating that FOL could exert neuroprotective effects through the activation of the Sirt1/Nrf2 signaling pathway. CONCLUSION The results reveal that FOL could protect against CSD-induced cognitive impairment by activating the Sirt1/Nrf2 signaling pathway.
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Affiliation(s)
- Yujuan Li
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 027-430030, China
| | - Zheng Xie
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 027-430030, China
| | - Xiaoxiao Luo
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuan Wang
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 027-430030, China
| | - Yue Wang
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 027-430030, China
| | - Mingke Guo
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 027-430030, China
| | - Zhiqiang Zhou
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 027-430030, China
| | - Rao Sun
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 027-430030, China
| | - Dongyu Hua
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 027-430030, China
| | - Ailin Luo
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 027-430030, China
| | - Shiyong Li
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 027-430030, China
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12
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Chen J, Xiao L, Chen Y, Li W, Liu Y, Zhou Y, Tan H. YT521-B homology domain containing 1 ameliorates mitochondrial damage and ferroptosis in sleep deprivation by activating the sirtuin 1/nuclear factor erythroid-derived 2-like 2/heme oxygenase 1 pathway. Brain Res Bull 2023; 197:1-12. [PMID: 36935054 DOI: 10.1016/j.brainresbull.2023.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 03/01/2023] [Accepted: 03/16/2023] [Indexed: 03/19/2023]
Abstract
In sleep deprivation (SD) models, ferroptosis is increased. SIRT1 alleviates cognitive impairment in SD, and SIRT1/NRF2/HO1 pathway depresses ferroptosis in different diseases. Moreover, YTHDC1 can regulate SIRT1 mRNA stability. Therefore, our study explored effects of the YTHDC1/SIRT1/NRF2/HO1 axis on neuronal damage and ferroptosis in SD. The SD mouse model was established through a modified multi-platform water environment method and a cell model of ferroptosis was constructed with Erastin, followed by gain- and loss-of-function assays. In mice, the cognitive impairment and CLOCK and BMAL1 levels in hippocampal tissues were assessed. In cells, viability was measured. In mice and cells, mitochondrial ultrastructure, the content of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and iron, and the expression of GPX4 and ACSL4 were detected. The potential relationships among YTHDC1, SIRT1, and NRF2 were analyzed. SD mice had downregulated YTHDC1, SIRT1, NRF2, and HO1 protein expression in hippocampal tissues and increased ferroptosis. Mechanically, SIRT1 activated the NRF2/HO1 pathway through deacetylation, and YTHDC1 increased SIRT1 mRNA stability. YTHDC1 overexpression diminished mitochondrial damage, the content of ROS, iron, and MDA, and the expression of ACSL4 while enhancing GSH contents and GPX4 expression in hippocampal tissues of SD mice and Erastin-induced HT22 cells. Additionally, YTHDC1 overexpression elevated viability in Erastin-induced HT22 cells. SIRT1 or NRF2 overexpression ameliorated Erastin-induced mitochondrial damage and ferroptosis in HT22 cells. Silencing SIRT1 abolished the impact of YTHDC1 overexpression on SD mice and Erastin-induced HT22 cells. Collectively, YTHDC1 ameliorates mitochondrial damage and ferroptosis after SD by activating the SIRT1/NRF2/HO1 pathway.
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Affiliation(s)
- Juan Chen
- Department of Neurology, the First Hospital of Changsha, Changsha, Hunan 410005, P.R. China.
| | - Lijun Xiao
- Department of Neurology, the First Hospital of Changsha, Changsha, Hunan 410005, P.R. China
| | - Ying Chen
- Department of Neurology, the First Hospital of Changsha, Changsha, Hunan 410005, P.R. China
| | - Wei Li
- Department of Neurology, the First Hospital of Changsha, Changsha, Hunan 410005, P.R. China
| | - Yinan Liu
- Department of Neurology, the First Hospital of Changsha, Changsha, Hunan 410005, P.R. China
| | - Ying Zhou
- Department of Neurology, the First Hospital of Changsha, Changsha, Hunan 410005, P.R. China
| | - Hong Tan
- Department of Neurology, the First Hospital of Changsha, Changsha, Hunan 410005, P.R. China
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13
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Zhu H, Wang C, Cheng Y, Guo Y, Qian H, Liu Y. Brassica rapa L. (Tibetan turnip) prevents sleep-deprivation induced cognitive deficits via the inhibition of neuroinflammation and mitochondrial depolarization. Food Funct 2022; 13:10610-10622. [PMID: 36168843 DOI: 10.1039/d2fo02649j] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Brassica rapa L., an edible, feeding and medicinal plant cultivated on the Tibetan plateau with altitudes above 3800 m, has several pharmacological effects. However, its therapeutic effects against memory impairment and central fatigue have yet to be conclusively established. In this study, the Y-maze and Morris water maze tasks revealed that Brassica rapa L. aqueous extract (BE) significantly ameliorated cognitive deficits of sleep deprivation (SD)-treated mice. Moreover, BE treatment partially alleviated SD-induced reductions in the levels of peripheral energy metabolism, and significantly decreased inflammatory factor levels in serum and hippocampus. In addition, BE treatment significantly relieved central fatigue and stabilized the excitability as well as activities of neurons by regulating the levels of hypothalamus tryptophan metabolites and striatum neurotransmitters. The neuroprotective effects of BE were also confirmed using glutamate-treated HT22 cells, whereby BE pretreatment significantly attenuated intracellular ROS production and mitochondrial depolarization via adenosine 5'-monophosphate activated protein kinase/peroxisome proliferators-activated receptors (AMPK/PPAR-γ) signaling pathways. Thus, BE might probably prevent SD-induced learning and memory deficits by inhibiting neuroinflammation and restoring mitochondrial energy metabolism in the hippocampus. These findings imply that BE is a potential complementary therapy for those suffering from deficient sleep or neurometabolic disorders, although this needs verification by prospective clinical studies.
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Affiliation(s)
- Hongkang Zhu
- State Key Laboratory of Food Science and Technology, Jiangnan University, China. .,Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, China.,School of Food Science and Technology, Jiangnan University, No. 1800 Lihu Avenue, Wuxi, Jiangsu Province, 214122, China
| | - Cheng Wang
- State Key Laboratory of Food Science and Technology, Jiangnan University, China. .,Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, China.,School of Food Science and Technology, Jiangnan University, No. 1800 Lihu Avenue, Wuxi, Jiangsu Province, 214122, China
| | - Yuliang Cheng
- State Key Laboratory of Food Science and Technology, Jiangnan University, China. .,Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, China.,School of Food Science and Technology, Jiangnan University, No. 1800 Lihu Avenue, Wuxi, Jiangsu Province, 214122, China
| | - Yahui Guo
- State Key Laboratory of Food Science and Technology, Jiangnan University, China. .,Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, China.,School of Food Science and Technology, Jiangnan University, No. 1800 Lihu Avenue, Wuxi, Jiangsu Province, 214122, China
| | - He Qian
- State Key Laboratory of Food Science and Technology, Jiangnan University, China. .,Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, Jiangnan University, China.,School of Food Science and Technology, Jiangnan University, No. 1800 Lihu Avenue, Wuxi, Jiangsu Province, 214122, China
| | - Yu Liu
- Wuxi 9th People's Hospital Affiliated to Soochow University, China.
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14
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The Role of Hydrogen Sulfide Targeting Autophagy in the Pathological Processes of the Nervous System. Metabolites 2022; 12:metabo12090879. [PMID: 36144282 PMCID: PMC9502065 DOI: 10.3390/metabo12090879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/13/2022] [Accepted: 09/15/2022] [Indexed: 11/16/2022] Open
Abstract
Autophagy is an important cellular process, involving the transportation of cytoplasmic contents in the double membrane vesicles to lysosomes for degradation. Autophagy disorder contributes to many diseases, such as immune dysfunction, cancers and nervous system diseases. Hydrogen sulfide (H2S) is a volatile and toxic gas with a rotten egg odor. For a long time, it was considered as an environmental pollution gas. In recent years, H2S is regarded as the third most important gas signal molecule after NO and CO. H2S has a variety of biological functions and can play an important role in a variety of physiological and pathological processes. Increasingly more evidences show that H2S can regulate autophagy to play a protective role in the nervous system, but the mechanism is not fully understood. In this review, we summarize the recent literatures on the role of H2S in the pathological process of the nervous system by regulating autophagy, and analyze the mechanism in detail, hoping to provide the reference for future related research.
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15
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Fagerli E, Escobar I, Ferrier FJ, Jackson CW, Perez-Lao EJ, Perez-Pinzon MA. Sirtuins and cognition: implications for learning and memory in neurological disorders. Front Physiol 2022; 13:908689. [PMID: 35936890 PMCID: PMC9355297 DOI: 10.3389/fphys.2022.908689] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 06/30/2022] [Indexed: 11/18/2022] Open
Abstract
Sirtuins are an evolutionarily conserved family of regulatory proteins that function in an NAD+ -dependent manner. The mammalian family of sirtuins is composed of seven histone deacetylase and ADP-ribosyltransferase proteins (SIRT1-SIRT7) that are found throughout the different cellular compartments of the cell. Sirtuins in the brain have received considerable attention in cognition due to their role in a plethora of metabolic and age-related diseases and their ability to induce neuroprotection. More recently, sirtuins have been shown to play a role in normal physiological cognitive function, and aberrant sirtuin function is seen in pathological cellular states. Sirtuins are believed to play a role in cognition through enhancing synaptic plasticity, influencing epigenetic regulation, and playing key roles in molecular pathways involved with oxidative stress affecting mitochondrial function. This review aims to discuss recent advances in the understanding of the role of mammalian sirtuins in cognitive function and the therapeutic potential of targeting sirtuins to ameliorate cognitive deficits in neurological disorders.
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Affiliation(s)
| | | | | | | | | | - Miguel A. Perez-Pinzon
- Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, United States
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16
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Zatsepina OG, Chuvakova LN, Nikitina EA, Rezvykh AP, Zakluta AS, Sarantseva SV, Surina NV, Ksenofontov AL, Baratova LA, Shilova VY, Evgen’ev MB. Genes Responsible for H 2S Production and Metabolism Are Involved in Learning and Memory in Drosophila melanogaster. Biomolecules 2022; 12:751. [PMID: 35740876 PMCID: PMC9221306 DOI: 10.3390/biom12060751] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 12/13/2022] Open
Abstract
The gasotransmitter hydrogen sulfide (H2S) produced by the transsulfuration pathway (TSP) is an important biological mediator, involved in many physiological and pathological processes in multiple higher organisms, including humans. Cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) enzymes play a central role in H2S production and metabolism. Here, we investigated the role of H2S in learning and memory processes by exploring several Drosophila melanogaster strains with single and double deletions of CBS and CSE developed by the CRISPR/Cas9 technique. We monitored the learning and memory parameters of these strains using the mating rejection courtship paradigm and demonstrated that the deletion of the CBS gene, which is expressed predominantly in the central nervous system, and double deletions completely block short- and long-term memory formation in fruit flies. On the other hand, the flies with CSE deletion preserve short- and long-term memory but fail to exhibit long-term memory retention. Transcriptome profiling of the heads of the males from the strains with deletions in Gene Ontology terms revealed a strong down-regulation of many genes involved in learning and memory, reproductive behavior, cognition, and the oxidation-reduction process in all strains with CBS deletion, indicating an important role of the hydrogen sulfide production in these vital processes.
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Affiliation(s)
- Olga G. Zatsepina
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (O.G.Z.); (L.N.C.); (A.P.R.); (A.S.Z.); (V.Y.S.)
| | - Lyubov N. Chuvakova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (O.G.Z.); (L.N.C.); (A.P.R.); (A.S.Z.); (V.Y.S.)
| | - Ekaterina A. Nikitina
- Department of Neurogenetics, Pavlov Institute of Physiology, 199034 Saint Petersburg, Russia;
- Department of Human and Animal Anatomy and Physiology, Herzen State Pedagogical University, 191186 Saint Petersburg, Russia
| | - Alexander P. Rezvykh
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (O.G.Z.); (L.N.C.); (A.P.R.); (A.S.Z.); (V.Y.S.)
| | - Alexey S. Zakluta
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (O.G.Z.); (L.N.C.); (A.P.R.); (A.S.Z.); (V.Y.S.)
| | - Svetlana V. Sarantseva
- Petersburg Institute of Nuclear Physics, Russian Academy of Sciences, 188300 Gatchina, Russia; (S.V.S.); (N.V.S.)
| | - Nina V. Surina
- Petersburg Institute of Nuclear Physics, Russian Academy of Sciences, 188300 Gatchina, Russia; (S.V.S.); (N.V.S.)
| | - Alexander L. Ksenofontov
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; (A.L.K.); (L.A.B.)
| | - Ludmila A. Baratova
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; (A.L.K.); (L.A.B.)
| | - Viktoria Y. Shilova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (O.G.Z.); (L.N.C.); (A.P.R.); (A.S.Z.); (V.Y.S.)
| | - Michael B. Evgen’ev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia; (O.G.Z.); (L.N.C.); (A.P.R.); (A.S.Z.); (V.Y.S.)
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17
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Interaction of lithium and sleep deprivation on memory performance and anxiety-like behavior in male Wistar rats. Behav Brain Res 2022; 428:113890. [DOI: 10.1016/j.bbr.2022.113890] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 03/12/2022] [Accepted: 04/07/2022] [Indexed: 12/28/2022]
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18
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Protective Effects of Novel Substituted Triazinoindole Inhibitors of Aldose Reductase and Epalrestat in Neuron-like PC12 Cells and BV2 Rodent Microglial Cells Exposed to Toxic Models of Oxidative Stress: Comparison with the Pyridoindole Antioxidant Stobadine. Neurotox Res 2021; 39:588-597. [PMID: 33713301 DOI: 10.1007/s12640-021-00349-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 03/01/2021] [Accepted: 03/04/2021] [Indexed: 12/29/2022]
Abstract
Aldose reductase (AR) catalyzes the conversion of glucose to sorbitol in a NADPH-dependent reaction, thereby increasing the production of reactive oxygen species (ROS). Since AR activation is linked to redox dysregulation and cell damage in neurodegenerative diseases, AR inhibitors (ARIs) constitute promising therapeutic tools for the treatment of these disorders. Among these compounds, the novel substituted triazinoindole derivatives cemtirestat (CMTI) and COTI, as well as the clinically employed epalrestat (EPA) and the pyridoindole-antioxidant stobadine (STB), were tested in both PC12 cells and BV2 microglia exposed to four different neurotoxic models. These include (1) oxidative stress with hydrogen peroxide (H2O2), (2) mitochondrial complex IV inhibition with NaN3, (3) endoplasmic reticulum-stress and lipotoxicity induced by palmitic acid/bovine serum albumin (PAM/BSA), and (4) advanced carbonyl compound lipotoxicity by 4-hydroxynonenal (4-HNE). All toxic compounds decreased cell viability and increased ROS formation in both PC12 and BV2 cells in a concentration-dependent manner (1-1000 μM; NaN3 < H2O2≈PAM/BSA < 4-HNE). In PC12 cells, EPA increased cell viability in all toxic models only at 1 μM, whereas CMTI restored baseline viability in all toxic models. COTI afforded protection against lipotoxicity, while STB only prevented H2O2-induced toxicity. Except for the 4-HNE model, EPA prevented ROS generation in all other toxic models, whereas CMTI, COTI, and STB prevented ROS production in all toxic models. In BV2 cells, EPA and CMTI restored baseline cell viability in all toxic models tested, while COTI and STB did not prevent the loss of viability in the NaN3 model. All ARIs and STB efficiently prevented ROS formation in all toxic models in a concentration-independent manner. The differential protective effects evoked by the novel ARIs and STB on the toxic models tested herein provide novel and relevant comparative evidence for the design of specific therapeutic strategies against neurodegenerative events associated with neurological disorders.
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