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García-Cruz VM, Coria R, Arias C. Role of saturated fatty acid metabolism in posttranslational modifications of the Tau protein. Mol Cell Biochem 2025:10.1007/s11010-025-05275-2. [PMID: 40208460 DOI: 10.1007/s11010-025-05275-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 03/28/2025] [Indexed: 04/11/2025]
Abstract
The relationship between metabolic alterations induced by the consumption of a high-fat diet (HFD) and the risk of developing neurodegenerative diseases such as Alzheimer's disease (AD) has been extensively studied. In particular, the induction of neuronal insulin resistance, endoplasmic reticulum stress, and the production of reactive oxygen species by chronic exposure to high concentrations of saturated fatty acids (sFAs), such as palmitic acid (PA), have been proposed as the cellular and molecular mechanisms underlying cognitive decline. Lipid metabolism affects many processes critical for cellular homeostasis. However, questions remain as to whether neuronal exposure to high sFA levels contributes to the onset and progression of AD features, and how their metabolism plays a role in this process. Therefore, the aim of this work is to review the accumulated evidence for the potential mechanisms by which the neuronal metabolism of sFAs affects signaling pathways that may induce biochemical changes in the AD hallmark protein Tau, ultimately promoting its aggregation and the subsequent generation of neurofibrillary tangles. In particular, the data presented here provide evidence that PA-dependent metabolic stress results in an imbalance in the activities of protein kinases and deacetylases that potentially contribute to the post-translational modifications (PTMs) of Tau.
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Affiliation(s)
- Valeria Melissa García-Cruz
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico
| | - Roberto Coria
- Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico
| | - Clorinda Arias
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico.
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Zhong Z, Fan F, Lv J, Wang Z, Wang B, Deng C, Sun L. Changes of potential shorty-chain fatty acids producing bacteria in the gut of patients with spinal cord injury: a systematic review and meta-analysis. Front Microbiol 2025; 16:1483794. [PMID: 40083777 PMCID: PMC11905530 DOI: 10.3389/fmicb.2025.1483794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 01/22/2025] [Indexed: 03/16/2025] Open
Abstract
Gut bacteria that potential produce short-chain fatty acids (SCFAs) influences the recovery of motor function in the host in patients with spinal cord injury (SCI). We aimed to conduct a review and meta-analysis of the literature on gut microbiota in SCI patients. Following the Preferred Reporting Project for Systematic Review and Meta-Analysis (PRISMA), we searched Embase, PubMed, Cochrane Library, Web of Science (WOS) and ClinicalTrials.gov. The search period was from inception to March 31, 2024. We reported standardized mean differences (d) with 95% confidence intervals (CI) and used funnel plots and Egger tests to assess publication bias. The subacute of SCI data set revealed the microflora changes in the subacute phase, and meta-analysis summarized the changes in the chronic phase. Eleven studies (720 participants) were included, 2 phyla, 1 order, and 14 genus meta-analyses performed. No substantial heterogeneity was observed, and significant publication bias was not found among the studies included. In the subacute phase of spinal cord injury, the relative abundance of Bacteroidetes, Clostridiales, Faecalbacterium, Ruminococcus, Coprococcus, Lachnospira, Dorea, Prevotella, Roseburia, Atopobium, Bifidobacterium, Bacteroides, and Blautia increased. Firmicutes and Lactobacillus decreased. In the chronic phase, Firmicutes decreased in the SCI group. Bifidobacterium, Bacteroides, Blautia, and Eubacterium were found to have a higher average proportion of abundance in patients with SCI compared to non-SCI persons, and Clostridiales, Ruminococcus, Faecalbacterium, Coprococcus, and Lachnospira showed a lower relative abundance in SCI. The genus of potential SCFAs-producing bacteria is lower in the chronic phase of spinal cord injury than in the subacute phase, and gut dysbiosis is present in both the subacute and chronic phases.
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Affiliation(s)
- Zaowei Zhong
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Fei Fan
- Department of Orthopedics, The Third People’s Hospital of Datong, Datong, China
| | - Junqiao Lv
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Zhiqiang Wang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Beiyang Wang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Chen Deng
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Lin Sun
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
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Tomaszek N, Urbaniak AD, Bałdyga D, Chwesiuk K, Modzelewski S, Waszkiewicz N. Unraveling the Connections: Eating Issues, Microbiome, and Gastrointestinal Symptoms in Autism Spectrum Disorder. Nutrients 2025; 17:486. [PMID: 39940343 PMCID: PMC11819948 DOI: 10.3390/nu17030486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 01/27/2025] [Accepted: 01/28/2025] [Indexed: 02/16/2025] Open
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by challenges in social communication, restricted interests, and repetitive behaviors. It is also associated with a high prevalence of eating disorders, gastrointestinal (GI) symptoms, and alterations in gut microbiota composition. One of the most pressing concerns is food selectivity. Various eating disorders, such as food neophobia, avoidant/restrictive food intake disorder (ARFID), specific dietary patterns, and poor-quality diets, are commonly observed in this population, often leading to nutrient deficiencies. Additionally, gastrointestinal problems in children with ASD are linked to imbalances in gut microbiota and immune system dysregulation. The aim of this narrative review is to identify previous associations between the gut-brain axis and gastrointestinal problems in ASD. We discuss the impact of the "microbiome-gut-brain axis", a bidirectional connection between gut microbiota and brain function, on the development and symptoms of ASD. In gastrointestinal problems associated with ASD, a 'vicious cycle' may play a significant role: ASD symptoms contribute to the prevalence of ARFID, which in turn leads to microbiota degradation, ultimately worsening ASD symptoms. Current data suggest a link between gastrointestinal problems in ASD and the microbiota, but the amount of evidence is limited. Further research is needed, targeting the correlation of a patient's microbiota status, dietary habits, and disease course.
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Affiliation(s)
| | | | | | | | - Stefan Modzelewski
- Department of Psychiatry, Medical University of Bialystok, pl. Wołodyjowskiego 2, 15-272 Białystok, Poland; (N.T.); (A.D.U.); (D.B.); (K.C.); (N.W.)
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Cao Y, Zhao LW, Chen ZX, Li SH. New insights in lipid metabolism: potential therapeutic targets for the treatment of Alzheimer's disease. Front Neurosci 2024; 18:1430465. [PMID: 39323915 PMCID: PMC11422391 DOI: 10.3389/fnins.2024.1430465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 08/14/2024] [Indexed: 09/27/2024] Open
Abstract
Alzheimer's disease (AD) is increasingly recognized as being intertwined with the dysregulation of lipid metabolism. Lipids are a significant class of nutrients vital to all organisms, playing crucial roles in cellular structure, energy storage, and signaling. Alterations in the levels of various lipids in AD brains and dysregulation of lipid pathways and transportation have been implicated in AD pathogenesis. Clinically, evidence for a high-fat diet firmly links disrupted lipid metabolism to the pathogenesis and progression of AD, although contradictory findings warrant further exploration. In view of the significance of various lipids in brain physiology, the discovery of complex and diverse mechanisms that connect lipid metabolism with AD-related pathophysiology will bring new hope for patients with AD, underscoring the importance of lipid metabolism in AD pathophysiology, and promising targets for therapeutic intervention. Specifically, cholesterol, sphingolipids, and fatty acids have been shown to influence amyloid-beta (Aβ) accumulation and tau hyperphosphorylation, which are hallmarks of AD pathology. Recent studies have highlighted the potential therapeutic targets within lipid metabolism, such as enhancing apolipoprotein E lipidation, activating liver X receptors and retinoid X receptors, and modulating peroxisome proliferator-activated receptors. Ongoing clinical trials are investigating the efficacy of these strategies, including the use of ketogenic diets, statin therapy, and novel compounds like NE3107. The implications of these findings suggest that targeting lipid metabolism could offer new avenues for the treatment and management of AD. By concentrating on alterations in lipid metabolism within the central nervous system and their contribution to AD development, this review aims to shed light on novel research directions and treatment approaches for combating AD, offering hope for the development of more effective management strategies.
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Affiliation(s)
- Yuan Cao
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- NHC Key Laboratory of Prevention and Treatment of Cerebrovascular Diseases, Zhengzhou, China
- Clinical Systems Biology Laboratories, Translation Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Lin-Wei Zhao
- Department of Cardiology, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou University Central China Fuwai Hospital, Zhengzhou, China
| | - Zi-Xin Chen
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- NHC Key Laboratory of Prevention and Treatment of Cerebrovascular Diseases, Zhengzhou, China
- Clinical Systems Biology Laboratories, Translation Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Shao-Hua Li
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- NHC Key Laboratory of Prevention and Treatment of Cerebrovascular Diseases, Zhengzhou, China
- Clinical Systems Biology Laboratories, Translation Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
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Rodríguez-Vázquez E, Aranda-Torrecillas Á, López-Sancho M, Castellano JM, Tena-Sempere M. Emerging roles of lipid and metabolic sensing in the neuroendocrine control of body weight and reproduction. Front Endocrinol (Lausanne) 2024; 15:1454874. [PMID: 39290326 PMCID: PMC11405246 DOI: 10.3389/fendo.2024.1454874] [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: 06/25/2024] [Accepted: 08/19/2024] [Indexed: 09/19/2024] Open
Abstract
The hypothalamus lies at the intersection of brain and hormonal mechanisms governing essential bodily functions, including metabolic/body weight homeostasis and reproduction. While metabolism and fertility are precisely regulated by independent neuroendocrine axes, these are tightly connected, as reflection of the bidirectional interplay between the energy status of the organisms and their capacity to reproduce; a connection with important pathophysiological implications in disorders affecting these two crucial systems. Beyond the well-characterized roles of key hormones (e.g., leptin, insulin, ghrelin) and neuropeptides (e.g., melanocortins, kisspeptins) in the integral control of metabolism and reproduction, mounting evidence has pointed out a relevant function of cell energy sensors and lipid sensing mechanisms in the hypothalamic control of metabolism, with prominent roles also for metabolic sensors, such as mTOR, AMPK and SIRT1, in the nutritional regulation of key aspects of reproduction, such as pubertal maturation. We provide herein a synoptic overview of these novel regulatory pathways, with a particular focus on their putative function in the metabolic control of puberty, and delineate new avenues for further exploration of the intricate mechanisms whereby metabolism and reproduction are tightly connected.
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Affiliation(s)
- Elvira Rodríguez-Vázquez
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
| | - Álvaro Aranda-Torrecillas
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
| | - María López-Sancho
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
| | - Juan M Castellano
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
- Hospital Universitario Reina Sofia, Córdoba, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Córdoba, Spain
| | - Manuel Tena-Sempere
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
- Hospital Universitario Reina Sofia, Córdoba, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Córdoba, Spain
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Guerra-Cantera S, Frago LM, Espinoza-Chavarria Y, Collado-Pérez R, Jiménez-Hernaiz M, Torrecilla-Parra M, Barrios V, Belsham DD, Laursen LS, Oxvig C, Argente J, Chowen JA. Palmitic Acid Modulation of the Insulin-Like Growth Factor System in Hypothalamic Astrocytes and Neurons. Neuroendocrinology 2024; 114:958-974. [PMID: 39043147 DOI: 10.1159/000540442] [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: 11/24/2023] [Accepted: 07/17/2024] [Indexed: 07/25/2024]
Abstract
INTRODUCTION Insulin-like growth factor (IGF)1 and IGF2 have neuroprotective effects, but less is known regarding how other members of the IGF system, including IGF binding proteins (IGFBPs) and the regulatory proteinase pappalysin-1 (PAPP-A) and its endogenous inhibitor stanniocalcin-2 (STC2) participate in this process. Here, we analyzed whether these members of the IGF system are modified in neurons and astrocytes in response to palmitic acid (PA), a fatty acid that induces cell stress when increased centrally. METHODS Primary hypothalamic astrocyte cultures from male and female PND2 rats and the pro-opiomelanocortin (POMC) neuronal cell line, mHypoA-POMC/GFP-2, were treated with PA, IGF1 or both. To analyze the role of STC2 in astrocytes, siRNA assays were employed. RESULTS In astrocytes of both sexes, PA rapidly increased cell stress factors followed by increased Pappa and Stc2 mRNA levels and then a decrease in Igf1, Igf2, and Igfbp2 expression and cell number. Exogenous IGF1 did not revert these effects. In mHypoA-POMC/GFP-2 neurons, PA reduced cell number and Pomc and Igf1 mRNA levels, and increased Igfbp2 and Stc2, again with no effect of exogenous IGF1. PA increased STC2 expression, but no effects of decreasing its levels by interference assays or exogenous STC2 treatment in astrocytes were found. CONCLUSIONS The response of the IGF system to PA was cell and sex specific, but no protective effects of the IGFs were found. However, the modifications in hypothalamic PAPP-A and STC2 indicate that further studies are required to determine their role in the response to fatty acids and possibly in metabolic control.
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Affiliation(s)
- Santiago Guerra-Cantera
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
- Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Laura M Frago
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
- Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Yesenia Espinoza-Chavarria
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
| | - Roberto Collado-Pérez
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
- Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
| | - María Jiménez-Hernaiz
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Marta Torrecilla-Parra
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
| | - Vicente Barrios
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Denise D Belsham
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Lisbeth S Laursen
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Claus Oxvig
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Jesús Argente
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
- Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain
| | - Julie A Chowen
- Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain
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Petakh P, Duve K, Oksenych V, Behzadi P, Kamyshnyi O. Molecular mechanisms and therapeutic possibilities of short-chain fatty acids in posttraumatic stress disorder patients: a mini-review. Front Neurosci 2024; 18:1394953. [PMID: 38887367 PMCID: PMC11182003 DOI: 10.3389/fnins.2024.1394953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Accepted: 05/21/2024] [Indexed: 06/20/2024] Open
Abstract
This mini-review explores the role of short-chain fatty acids (SCFAs) in posttraumatic stress disorder (PTSD). Highlighting the microbiota-gut-brain axis, this study investigated the bidirectional communication between the gut microbiome and mental health. SCFAs, byproducts of gut microbial fermentation, have been examined for their potential impact on PTSD, with a focus on molecular mechanisms and therapeutic interventions. This review discusses changes in SCFA levels and bacterial profiles in individuals with PTSD, emphasizing the need for further research. Promising outcomes from clinical trials using probiotics and fermented formulations suggest potential avenues for PTSD management. Future directions involve establishing comprehensive human cohorts, integrating multiomics data, and employing advanced computational methods, with the goal of deepening our understanding of the role of SCFAs in PTSD and exploring microbiota-targeted interventions.
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Affiliation(s)
- Pavlo Petakh
- Department of Biochemistry and Pharmacology, Uzhhorod National University, Uzhhorod, Ukraine
- Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | - Khrystyna Duve
- Department of Neurology, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | - Valentyn Oksenych
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Payam Behzadi
- Department of Microbiology, Shahr-e-Qods Branch, Islamic Azad University, Tehran, Iran
| | - Oleksandr Kamyshnyi
- Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
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Elford JD, Becht N, Garssen J, Kraneveld AD, Perez-Pardo P. Buty and the beast: the complex role of butyrate in Parkinson's disease. Front Pharmacol 2024; 15:1388401. [PMID: 38694925 PMCID: PMC11061429 DOI: 10.3389/fphar.2024.1388401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 04/02/2024] [Indexed: 05/04/2024] Open
Abstract
Parkinson's disease (PD) is a complex neurodegenerative disease which is often associated with gastrointestinal (GI) dysfunction. The GI tract is home to a wide range of microorganisms, among which bacteria, that can influence the host through various mechanisms. Products produced by these bacteria can act in the gut but can also exert effects in the brain via what is now well established to be the microbiota-gut-brain axis. In those with PD the gut-bacteria composition is often found to be different to that of non-PD individuals. In addition to compositional changes, the metabolic activity of the gut-microbiota is also changed in PD. Specifically, it is often reported that key producers of short chain fatty acids (SCFAs) as well as the concentration of SCFAs themselves are altered in the stool and blood of those with PD. These SCFAs, among which butyrate, are essential nutrients for the host and are a major energy source for epithelial cells of the GI tract. Additionally, butyrate plays a key role in regulating various host responses particularly in relation to inflammation. Studies have demonstrated that a reduction in butyrate levels can have a critical role in the onset and progression of PD. Furthermore, it has been shown that restoring butyrate levels in those with PD through methods such as probiotics, prebiotics, sodium butyrate supplementation, and fecal transplantation can have a beneficial effect on both motor and non-motor outcomes of the disease. This review presents an overview of evidence for the altered gut-bacteria composition and corresponding metabolite production in those with PD, with a particular focus on the SCFA butyrate. In addition to presenting current studies regarding SCFA in clinical and preclinical reports, evidence for the possibility to target butyrate production using microbiome based approaches in a therapeutic context is discussed.
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Affiliation(s)
- Joshua D. Elford
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
| | - Nanette Becht
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
- Danone Nutricia Research, Utrecht, Netherlands
| | - Aletta D. Kraneveld
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
- Department of Neuroscience, Faculty of Science, Vrije Universiteit, Amsterdam, Netherlands
| | - Paula Perez-Pardo
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
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Puris E, Saveleva L, Auriola S, Gynther M, Kanninen KM, Fricker G. Sex-specific changes in protein expression of membrane transporters in the brain cortex of 5xFAD mouse model of Alzheimer's disease. Front Pharmacol 2024; 15:1365051. [PMID: 38572427 PMCID: PMC10989684 DOI: 10.3389/fphar.2024.1365051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 02/27/2024] [Indexed: 04/05/2024] Open
Abstract
Membrane transporters playing an important role in the passage of drugs, metabolites and nutrients across the membranes of the brain cells have been shown to be involved in pathogenesis of Alzheimer's disease (AD). However, little is known about sex-specific changes in transporter protein expression at the brain in AD. Here, we investigated sex-specific alterations in protein expression of three ATP-binding cassette (ABC) and five solute carriers (SLC) transporters in the prefrontal cortex of a commonly used model of familial AD (FAD), 5xFAD mice. Sensitive liquid chromatography tandem mass spectrometry-based quantitative targeted absolute proteomic analysis was applied for absolute quantification of transporter protein expression. We compared the changes in transporter protein expressions in 7-month-old male and female 5xFAD mice versus sex-matched wild-type mice. The study revealed a significant sex-specific increase in protein expression of ABCC1 (p = 0.007) only in male 5xFAD mice as compared to sex-matched wild-type animals. In addition, the increased protein expression of glucose transporter 1 (p = 0.01), 4F2 cell-surface antigen heavy chain (p = 0.01) and long-chain fatty acid transport protein 1 (p = 0.02) were found only in female 5xFAD mice as compared to sex-matched wild-type animals. Finally, protein expression of alanine/serine/cysteine/threonine transporter 1 was upregulated in both male (p = 0.02) and female (p = 0.002) 5xFAD mice. The study provides important information about sex-specific changes in brain cortical transporter expression in 5xFAD mice, which will facilitate drug development of therapeutic strategies for AD targeting these transporters and drug delivery research.
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Affiliation(s)
- Elena Puris
- Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls-University, Heidelberg, Germany
| | - Liudmila Saveleva
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Seppo Auriola
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Mikko Gynther
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Katja M. Kanninen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Gert Fricker
- Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls-University, Heidelberg, Germany
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Wen X, Dong H, Zou W. The role of gut microorganisms and metabolites in intracerebral hemorrhagic stroke: a comprehensive review. Front Neurosci 2024; 18:1346184. [PMID: 38449739 PMCID: PMC10915040 DOI: 10.3389/fnins.2024.1346184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 02/09/2024] [Indexed: 03/08/2024] Open
Abstract
Intracerebral hemorrhagic stroke, characterized by acute hemorrhage in the brain, has a significant clinical prevalence and poses a substantial threat to individuals' well-being and productivity. Recent research has elucidated the role of gut microorganisms and their metabolites in influencing brain function through the microbiota-gut-brain axis (MGBA). This article provides a comprehensive review of the current literature on the common metabolites, short-chain fatty acids (SCFAs) and trimethylamine-N-oxide (TMAO), produced by gut microbiota. These metabolites have demonstrated the potential to traverse the blood-brain barrier (BBB) and directly impact brain tissue. Additionally, these compounds have the potential to modulate the parasympathetic nervous system, thereby facilitating the release of pertinent substances, impeding the buildup of inflammatory agents within the brain, and manifesting anti-inflammatory properties. Furthermore, this scholarly analysis delves into the existing dearth of investigations concerning the influence of gut microorganisms and their metabolites on cerebral functions, while also highlighting prospective avenues for future research.
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Affiliation(s)
- Xin Wen
- The First Clinical Medical College, Heilongjiang University Of Chinese Medicine, Harbin, China
| | - Hao Dong
- The First Clinical Medical College, Heilongjiang University Of Chinese Medicine, Harbin, China
| | - Wei Zou
- The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
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11
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Cheng J, Hu H, Ju Y, Liu J, Wang M, Liu B, Zhang Y. Gut microbiota-derived short-chain fatty acids and depression: deep insight into biological mechanisms and potential applications. Gen Psychiatr 2024; 37:e101374. [PMID: 38390241 PMCID: PMC10882305 DOI: 10.1136/gpsych-2023-101374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 12/25/2023] [Indexed: 02/24/2024] Open
Abstract
The gut microbiota is a complex and dynamic ecosystem known as the 'second brain'. Composing the microbiota-gut-brain axis, the gut microbiota and its metabolites regulate the central nervous system through neural, endocrine and immune pathways to ensure the normal functioning of the organism, tuning individuals' health and disease status. Short-chain fatty acids (SCFAs), the main bioactive metabolites of the gut microbiota, are involved in several neuropsychiatric disorders, including depression. SCFAs have essential effects on each component of the microbiota-gut-brain axis in depression. In the present review, the roles of major SCFAs (acetate, propionate and butyrate) in the pathophysiology of depression are summarised with respect to chronic cerebral hypoperfusion, neuroinflammation, host epigenome and neuroendocrine alterations. Concluding remarks on the biological mechanisms related to gut microbiota will hopefully address the clinical value of microbiota-related treatments for depression.
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Affiliation(s)
- Junzhe Cheng
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Hongkun Hu
- Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Yumeng Ju
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Mental Health Institute of Central South University, China National Technology Institute on Mental Disorders, Hunan Key Laboratory of Psychiatry and Mental Health, Hunan Medical Center for Mental Health, Changsha, Hunan, China
| | - Jin Liu
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Mental Health Institute of Central South University, China National Technology Institute on Mental Disorders, Hunan Key Laboratory of Psychiatry and Mental Health, Hunan Medical Center for Mental Health, Changsha, Hunan, China
| | - Mi Wang
- Department of Mental Health Center, Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Bangshan Liu
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Mental Health Institute of Central South University, China National Technology Institute on Mental Disorders, Hunan Key Laboratory of Psychiatry and Mental Health, Hunan Medical Center for Mental Health, Changsha, Hunan, China
| | - Yan Zhang
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Mental Health Institute of Central South University, China National Technology Institute on Mental Disorders, Hunan Key Laboratory of Psychiatry and Mental Health, Hunan Medical Center for Mental Health, Changsha, Hunan, China
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12
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White CJ, Gausepohl AM, Wilkins HN, Eberhard CD, Orsburn BC, Williams DW. Spatial Heterogeneity of Brain Lipids in SIV-Infected Macaques Treated with Antiretroviral Therapy. JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY 2024; 35:185-196. [PMID: 38288997 DOI: 10.1021/jasms.3c00276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2024]
Abstract
Human immunodeficiency virus (HIV) infection continues to promote neurocognitive impairment, mood disorders, and brain atrophy, even in the modern era of viral suppression. Brain lipids are vulnerable to HIV-associated energetic strain and may contribute to HIV-associated neurologic dysfunction due to alterations in lipid breakdown and structural lipid composition. HIV neuropathology is region dependent, yet there has not been comprehensive characterization of the spatial heterogeneity of brain lipids during infection that possibly impacts neurologic function. To address this gap, we evaluated the spatial lipid distribution using matrix laser desorption/ionization imaging mass spectrometry (MALDI-IMS) across four brain regions (parietal cortex, midbrain, thalamus, and temporal cortex), as well as the kidney for a peripheral tissue control, in a simian immunodeficiency virus (SIV)-infected rhesus macaque treated with a course of antiretroviral therapies (ARTs). We assessed lipids indicative of fat breakdown [acylcarnitines (CARs)] and critical structural lipids [phosphatidylcholines (PCs) and phosphatidylethanolamines (PEs)] across fatty acid chain lengths and degrees of unsaturation. CARs with very long-chain, polyunsaturated fatty acids (PUFAs) were more abundant across all brain regions than shorter chain, saturated, or monounsaturated species. We observed distinct brain lipid distribution patterns for the CARs and PCs. However, no clear expression patterns emerged for PEs. Surprisingly, the kidney was nearly devoid of ions corresponding to PUFAs common in brain. PEs and PCs with PUFAs had little intensity and less density than other species, and only one CAR species was observed in kidney at high intensity. Overall, our study demonstrates the stark variation in structural phospholipids and lipid-energetic intermediates present in the virally suppressed SIV-macaque brain. These findings may be useful for identifying regional vulnerabilities to damage due to brain lipid changes in people with HIV.
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Affiliation(s)
- Cory J White
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
| | - Andrew M Gausepohl
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
| | - Hannah N Wilkins
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
| | - Colten D Eberhard
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
| | - Benjamin C Orsburn
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
| | - Dionna W Williams
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
- Department of Medicine, Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
- Department of Molecular Microbiology & Immunology, Johns Hopkins University School of Public Health, Baltimore, Maryland 21205, United States
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia 30322, United States
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13
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Satheesan A, Sharma S, Basu A. Sodium Butyrate Induced Neural Stem/Progenitor Cell Death in an Experimental Model of Japanese Encephalitis. Metab Brain Dis 2023; 38:2831-2847. [PMID: 37650987 DOI: 10.1007/s11011-023-01279-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 08/21/2023] [Indexed: 09/01/2023]
Abstract
The anti-inflammatory and neuroprotective effects of short chain fatty acid (SCFA) butyrate have been explored in a wide array of neurological pathologies. It is a 4-carbon SCFA produced from the fermentation of dietary fibers by the gut-microbiota. As evident from previous literature, butyrate plays a wide array of functions in CNS and interestingly enhances the differentiation potential of Neural stem/Progenitor Cells (NSPCs). Japanese encephalitis virus (JEV) is a well-known member of the Flaviviridae family and has been shown to alter neural stem cell pool of the brain, causing devastating consequences. In this study, we administered sodium butyrate (NaB) post JEV infection in BALB/c mouse model to examine any possible amelioration of the viral infection in NSPCs. In addition, ex vivo neurospheres and in vitro model of NSPCs were also used to study the effect of sodium butyrate in JEV infection. As an unprecedented finding, butyrate treated infected animals presented early onset of symptoms, as compared to their respective JEV infected groups. Alongside, we observed an increased viral load in NSPCs isolated from these animals as well as in cell culture models upon sodium butyrate treatment. Cytometric bead array analysis also revealed an increase in inflammatory cytokines, particularly, MCP-1 and IL-6. Further, increased expression of the key members of the canonical NF-κB pathway, viz-a-viz p-NF-κB, p-Iκ-Bα and p-IKK was observed. Overall, the increased inflammation and cell death caused early symptom progression in NaB-treated JEV infected animal model, which is contradictory to the well documented protective nature of NaB and therefore a better understanding of SCFA-based modulation of the gut-brain axis in viral infections is required.
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Affiliation(s)
| | - Shivangi Sharma
- National Brain Research Centre, Manesar, Haryana, 122052, India
| | - Anirban Basu
- National Brain Research Centre, Manesar, Haryana, 122052, India.
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Nápoles-Medina AY, Aguilar-Uscanga BR, Solís-Pacheco JR, Tejeda-Martínez AR, Ramírez-Jirano LJ, Urmeneta-Ortiz MF, Chaparro-Huerta V, Flores-Soto ME. Oral Administration of Lactobacillus Inhibits the Permeability of Blood-Brain and Gut Barriers in a Parkinsonism Model. Behav Neurol 2023; 2023:6686037. [PMID: 38025189 PMCID: PMC10653970 DOI: 10.1155/2023/6686037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 09/26/2023] [Accepted: 10/16/2023] [Indexed: 12/01/2023] Open
Abstract
It has recently been shown that the administration of probiotics can modulate the microbiota-gut-brain axis and may have favorable effects in models of Parkinson's disease. In this study, we used a hemiparkinsonism model induced by the neurotoxin 6-OHDA to evaluate the efficacy of the administration of a four-week administration of a mixture containing the microorganisms Lactobacillus fermentum LH01, Lactobacillus reuteri LH03, and Lactobacillus plantarum LH05. The hemiparkinsonism model induced an increase in rotations in the apomorphine test, along with a decrease in the latency time to fall in the rotarod test on days 14 and 21 after surgery, respectively. The administration of probiotics was sufficient to improve this condition. The model also showed a decrease in tyrosine hydroxylase immunoreactivity in the striatum and the number of labeled cells in the substantia nigra, both of which were counteracted by the administration of probiotics. The permeability of the blood-brain barrier was increased in the model, but this effect was reversed by the probiotics for both brain regions. The gut barrier was permeated with the model, and this effect was reversed and dropped to lower levels than the control group after the administration of probiotics. Finally, lipid peroxidation showed a pattern of differences similar to that of permeabilities. The inhibition of the permeability of the blood-brain and gut barriers mediated by the administration of probiotics will likely provide protection by downregulating oxidative stress, thus affecting the rotarod test performance.
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Affiliation(s)
- Angélica Y. Nápoles-Medina
- Laboratorio de Neurobiología Celular y Molecular, División de Neurociencias, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social, Sierra Mojada #800, Independencia Oriente, C.P. 44340 Guadalajara, Jalisco, Mexico
- Departamento de Farmacobiología, Laboratorio de Microbiología Industrial, Centro Universitario de Ciencias Exactas e Ingenierías, Universidad de Guadalajara, Blvd. Marcelino García Barragán # 1421, Olímpica, C.P. 44430 Guadalajara, Jalisco, Mexico
| | - Blanca R. Aguilar-Uscanga
- Departamento de Farmacobiología, Laboratorio de Microbiología Industrial, Centro Universitario de Ciencias Exactas e Ingenierías, Universidad de Guadalajara, Blvd. Marcelino García Barragán # 1421, Olímpica, C.P. 44430 Guadalajara, Jalisco, Mexico
| | - Josué R. Solís-Pacheco
- Departamento de Farmacobiología, Laboratorio de Microbiología Industrial, Centro Universitario de Ciencias Exactas e Ingenierías, Universidad de Guadalajara, Blvd. Marcelino García Barragán # 1421, Olímpica, C.P. 44430 Guadalajara, Jalisco, Mexico
| | - Aldo R. Tejeda-Martínez
- Laboratorio de Neurobiología Celular y Molecular, División de Neurociencias, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social, Sierra Mojada #800, Independencia Oriente, C.P. 44340 Guadalajara, Jalisco, Mexico
| | - Luis J. Ramírez-Jirano
- División de Neurociencias, Centro de Investigación Biomédica Occidente (IMSS), Guadalajara, Mexico
| | - María F. Urmeneta-Ortiz
- Laboratorio de Neurobiología Celular y Molecular, División de Neurociencias, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social, Sierra Mojada #800, Independencia Oriente, C.P. 44340 Guadalajara, Jalisco, Mexico
| | - Veronica Chaparro-Huerta
- Laboratorio de Neurobiología Celular y Molecular, División de Neurociencias, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social, Sierra Mojada #800, Independencia Oriente, C.P. 44340 Guadalajara, Jalisco, Mexico
| | - Mario E. Flores-Soto
- Laboratorio de Neurobiología Celular y Molecular, División de Neurociencias, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social, Sierra Mojada #800, Independencia Oriente, C.P. 44340 Guadalajara, Jalisco, Mexico
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15
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Lin B, Ye Z, Ye Z, Wang M, Cao Z, Gao R, Zhang Y. Gut microbiota in brain tumors: An emerging crucial player. CNS Neurosci Ther 2023; 29 Suppl 1:84-97. [PMID: 36627748 PMCID: PMC10314108 DOI: 10.1111/cns.14081] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 12/18/2022] [Accepted: 12/21/2022] [Indexed: 01/12/2023] Open
Abstract
In recent decades, various roles of the gut microbiota in physiological and pathological conditions have been uncovered. Among the many interacting pathways between the host and gut flora, the gut-brain axis has drawn increasing attention and is generally considered a promising way to understand and treat brain tumors, one of the most lethal neoplasms. In this narrative review, we aimed to unveil and dissect the sophisticated mechanisms by which the gut-brain axis exerts its influence on brain tumors. Furthermore, we summarized the latest research regarding the gastrointestinal microbial landscape and the effect of gut-brain axis malfunction on different brain tumors. Finally, we outlined the ongoing developing approaches of microbial manipulation and their corresponding research related to neuro-malignancies. Collectively, we recapitulated the advances in gut microbial alterations along with their potential interactive mechanisms in brain tumors and encouraged increased efforts in this area.
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Affiliation(s)
- Ben Lin
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical CollegeFudan UniversityShanghaiChina
- National Center for Neurological DisordersShanghaiChina
- Shanghai Key Laboratory of Brain Function and Restoration and Neural RegenerationShanghaiChina
- Neurosurgical Institute of Fudan UniversityShanghaiChina
- Shanghai Clinical Medical Center of NeurosurgeryShanghaiChina
| | - Zhen Ye
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical CollegeFudan UniversityShanghaiChina
- National Center for Neurological DisordersShanghaiChina
- Shanghai Key Laboratory of Brain Function and Restoration and Neural RegenerationShanghaiChina
- Neurosurgical Institute of Fudan UniversityShanghaiChina
- Shanghai Clinical Medical Center of NeurosurgeryShanghaiChina
| | - Zhao Ye
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical CollegeFudan UniversityShanghaiChina
- National Center for Neurological DisordersShanghaiChina
- Shanghai Key Laboratory of Brain Function and Restoration and Neural RegenerationShanghaiChina
- Neurosurgical Institute of Fudan UniversityShanghaiChina
- Shanghai Clinical Medical Center of NeurosurgeryShanghaiChina
| | - Meng Wang
- Department of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Zhan Cao
- Department of General Surgery, Shanghai Tenth People's Hospital, School of MedicineTongji UniversityShanghaiChina
| | - Renyuan Gao
- Department of General Surgery, Shanghai Tenth People's Hospital, School of MedicineTongji UniversityShanghaiChina
| | - Yichao Zhang
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical CollegeFudan UniversityShanghaiChina
- National Center for Neurological DisordersShanghaiChina
- Shanghai Key Laboratory of Brain Function and Restoration and Neural RegenerationShanghaiChina
- Neurosurgical Institute of Fudan UniversityShanghaiChina
- Shanghai Clinical Medical Center of NeurosurgeryShanghaiChina
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16
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Li Z, Zhang F, Sun M, Liu J, Zhao L, Liu S, Li S, Wang B. The modulatory effects of gut microbes and metabolites on blood–brain barrier integrity and brain function in sepsis-associated encephalopathy. PeerJ 2023; 11:e15122. [PMID: 37009158 PMCID: PMC10064995 DOI: 10.7717/peerj.15122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 03/03/2023] [Indexed: 03/30/2023] Open
Abstract
Background
Intestinal microbiota homeostasis and the gut-brain axis are key players associated with host health and alterations in metabolic, inflammatory, and neurodegenerative disorders. Sepsis-associated encephalopathy (SAE), which is closely associated with bacterial translocation, is a common secondary organ dysfunction and an urgent, unsolved problem affecting patient quality of life. Our study examined the neuroprotective effects of the gut microbiome and short-chain fatty acid (SCFA) metabolites on SAE.
Methods
Male C57BL/6 mice were administered SCFAs in drinking water, then subjected to cecal ligation and puncture (CLP) surgery to induce SAE. 16S rRNA sequencing was used to investigate gut microbiome changes. The open field test (OFT) and Y-maze were performed to evaluate brain function. The permeability of the blood–brain barrier (BBB) was assessed by Evans blue (EB) staining. Hematoxylin and eosin (HE) staining was used to examine intestinal tissue morphology. The expression levels of tight junction (TJ) proteins and inflammatory cytokines was assessed by western blots and immunohistochemistry. In vitro, bEND.3 cells were incubated with SCFAs and then with lipopolysaccharide (LPS). Immunofluorescence was used to examine the expression of TJ proteins.
Results
The composition of the gut microbiota was altered in SAE mice; this change may be related to SCFA metabolism. SCFA treatment significantly alleviated behavioral dysfunction and neuroinflammation in SAE mice. SCFAs upregulated occludin and ZO-1 expression in the intestine and brain in SAE mice and LPS-treated cerebromicrovascular cells.
Conclusions
These findings suggested that disturbances in the gut microbiota and SCFA metabolites play key roles in SAE. SCFA supplementation could exert neuroprotective effects against SAE by preserving BBB integrity.
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Affiliation(s)
- Zhaoying Li
- Department of Anesthesiology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province, China
- Institute of Anesthesiology, Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Fangxiang Zhang
- Department of Anesthesiology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province, China
| | - Meisha Sun
- Department of Anesthesiology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province, China
| | - Jia Liu
- Department of Anesthesiology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province, China
| | - Li Zhao
- Department of Anesthesiology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province, China
| | - Shuchun Liu
- Department of Anesthesiology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province, China
| | - Shanshan Li
- Department of Anesthesiology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province, China
| | - Bin Wang
- Department of Anesthesiology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province, China
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Yang J, Wang P, Jiang X, Xu J, Zhang M, Liu F, Lin Y, Tao J, He J, Zhou X, Zhang M. A Nanotherapy of Octanoic Acid Ameliorates Cardiac Arrest/Cardiopulmonary Resuscitation-Induced Brain Injury via RVG29- and Neutrophil Membrane-Mediated Injury Relay Targeting. ACS NANO 2023; 17:3528-3548. [PMID: 36758159 DOI: 10.1021/acsnano.2c09931] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
Treatment of cardiac arrest/cardiopulmonary resuscitation (CA/CPR)-induced brain injury remains a challenging issue without viable therapeutic options. Octanoic acid (OA), a lipid oil that is mainly metabolized in the astrocytes of the brain, is a promising treatment for this type of injury owing to its potential functions against oxidative stress, apoptosis, inflammation, and ability to stabilize mitochondria. However, the application of OA is strictly limited by its short half-life and low available concentration in the target organ. Herein, based on our previous research, an OA-based nanotherapy coated with a neutrophil membrane highly expressing RVG29, RVG29-H-NPOA, was successfully constructed by computer simulation-guided supramolecular assembly of polyethylenimine and OA. The in vitro and in vivo experiments showed that RVG29-H-NPOA could target and be distributed in the injured brain focus via the relay-targeted delivery mediated by RVG29-induced blood-brain barrier (BBB) penetration and neutrophil membrane protein-induced BBB binding and injury targeting. This results in enhancements of the antioxidant, antiapoptotic, mitochondrial stability-promoting and anti-inflammatory effects of OA and exhibited systematic alleviation of astrocyte injury, neuronal damage, and inflammatory response in the brain. Due to their systematic intervention in multiple pathological processes, RVG29-H-NPOA significantly increased the 24 h survival rate of CA/CPR model rats from 40% to 100% and significantly improved their neurological functions. Thus, RVG29-H-NPOA are expected to be a promising therapeutic for the treatment of CA/CPR-induced brain injury.
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Affiliation(s)
- Jingyuan Yang
- Department of Emergency Medicine, Second Affiliated Hospital of Zhejiang University, Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burns of Zhejiang Province, Clinical Research Center for Emergency and Critical Care Medicine of Zhejiang Province, Hangzhou 310009, China
| | - Pan Wang
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Xiangkang Jiang
- Department of Emergency Medicine, Second Affiliated Hospital of Zhejiang University, Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burns of Zhejiang Province, Clinical Research Center for Emergency and Critical Care Medicine of Zhejiang Province, Hangzhou 310009, China
| | - Jiefeng Xu
- Department of Emergency Medicine, Second Affiliated Hospital of Zhejiang University, Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burns of Zhejiang Province, Clinical Research Center for Emergency and Critical Care Medicine of Zhejiang Province, Hangzhou 310009, China
| | - Minhai Zhang
- Department of Emergency Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Fei Liu
- Department of Emergency Medicine, Second Affiliated Hospital of Zhejiang University, Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burns of Zhejiang Province, Clinical Research Center for Emergency and Critical Care Medicine of Zhejiang Province, Hangzhou 310009, China
| | - Yao Lin
- Department of Emergency Medicine, Second Affiliated Hospital of Zhejiang University, Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burns of Zhejiang Province, Clinical Research Center for Emergency and Critical Care Medicine of Zhejiang Province, Hangzhou 310009, China
| | - Jiawei Tao
- Department of Emergency Medicine, Second Affiliated Hospital of Zhejiang University, Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burns of Zhejiang Province, Clinical Research Center for Emergency and Critical Care Medicine of Zhejiang Province, Hangzhou 310009, China
| | - Jiantao He
- Department of Emergency Medicine, Second Affiliated Hospital of Zhejiang University, Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burns of Zhejiang Province, Clinical Research Center for Emergency and Critical Care Medicine of Zhejiang Province, Hangzhou 310009, China
| | - Xing Zhou
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Mao Zhang
- Department of Emergency Medicine, Second Affiliated Hospital of Zhejiang University, Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burns of Zhejiang Province, Clinical Research Center for Emergency and Critical Care Medicine of Zhejiang Province, Hangzhou 310009, China
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18
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Sun Y, Ho CT, Zhang X. Neuroprotection of Food Bioactives in Neurodegenerative Diseases: Role of the Gut Microbiota and Innate Immune Receptors. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:2718-2733. [PMID: 36700657 DOI: 10.1021/acs.jafc.2c07742] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Gut-brain connections may be mediated by an assortment of microbial molecules, which can subsequently traverse intestinal and blood-brain barriers and impact neurological function. Pattern recognition receptors (PRRs) are important innate immune proteins in the gut. Gut microbiota act in concert with the PRRs is a novel target for regulating host-microbe signaling and immune homeostasis, which may involve the pathogenesis of neurodegenerative diseases. Natural food bioactives bestow a protective advantage on neurodegenerative diseases through immunomodulatory effects of the modified gut microbiota or alterations in the landscape of microbiota-produced metabolites via PRRs modulation. In this review, we discuss the effect of natural food bioactives on the gut microbiota and the role of PRRs in the gut-brain crosstalk. We focused on the neuroprotective mechanisms of natural bioactive compounds behind the action of the gut microbiota and PRRs. Research advances in natural food bioactives as antineurodegeneration agents were also presented.
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Affiliation(s)
- Ying Sun
- Department of Food Science and Engineering, Ningbo University, Ningbo 315211, P.R. China
| | - Chi-Tang Ho
- Department of Food Science, Rutgers University, New Brunswick, New Jersey 08901, United States
| | - Xin Zhang
- Department of Food Science and Engineering, Ningbo University, Ningbo 315211, P.R. China
- State Key Laboratory for Quality and Safety of Agro-products, Ningbo University, Ningbo 315211, P.R. China
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19
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Ghazimoradi MM, Ghoushi E, Ghobadi Pour M, Karimi Ahmadabadi H, Rafieian-Kopaei M. A Review on Garlic as a Supplement for Alzheimer’s Disease: A Mechanistic Insight into its Direct and Indirect Effects. Curr Pharm Des 2023; 29:519-526. [PMID: 36809972 DOI: 10.2174/1381612829666230222093016] [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: 07/29/2022] [Revised: 12/19/2022] [Accepted: 12/29/2022] [Indexed: 02/24/2023]
Abstract
Alzheimer’s disease (AD) is one of the most complicated neurodegenerative diseases causing dementia in human beings. Aside from that, the incidence of AD is increasing and its treatment is very complicated. There are several known hypotheses regarding the pathology of Alzheimer’s disease, including the amyloid beta hypothesis, tau hypothesis, inflammation hypothesis, and cholinergic hypothesis, which are investigated in different researches to completely elucidate the pathology of AD. Besides, some new mechanisms, such as immune, endocrine, and vagus pathways, as well as bacteria metabolite secretions, are being explained as other causes to be somehow related to AD pathogenesis. There is still no definite treatment for Alzheimer’s disease that can completely cure and eradicate AD. Garlic (Allium sativum) is a traditional herb used as a spice in different cultures, and due to the organosulfur compounds, like allicin, it possesses highly anti-oxidant properties; the benefits of garlic in cardiovascular diseases, like hypertension and atherosclerosis, have been examined and reviewed, although its beneficiary effects in neurodegenerative diseases, such as AD, are not completely understood. In this review, we discuss the effects of garlic based on its components, such as allicin and S-allyl cysteine, on Alzheimer’s disease and the mechanisms of garlic components that can be beneficiary for AD patients, including its effects on amyloid beta, oxidative stress, tau protein, gene expression, and cholinesterase enzymes. Based on the literature review, garlic has been revealed to have beneficiary effects on Alzheimer’s disease, especially in animal studies; however, more studies should be done on humans to find the exact mechanisms of garlic’s effects on AD patients.
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Affiliation(s)
- Mohammad Mahdi Ghazimoradi
- Faculty of pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Interdisciplinary Neuro-Brain Research and Education Network (INBREN), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Ehsan Ghoushi
- School of Medicine, Zhejiang University, Hangzhou, China
| | - Mozhgan Ghobadi Pour
- Department of Physiology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Mahmoud Rafieian-Kopaei
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
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20
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Jadhav VV, Han J, Fasina Y, Harrison SH. Connecting gut microbiomes and short chain fatty acids with the serotonergic system and behavior in Gallus gallus and other avian species. Front Physiol 2022; 13:1035538. [PMID: 36406988 PMCID: PMC9667555 DOI: 10.3389/fphys.2022.1035538] [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: 09/02/2022] [Accepted: 10/03/2022] [Indexed: 12/05/2022] Open
Abstract
The chicken gastrointestinal tract has a diverse microbial community. There is increasing evidence for how this gut microbiome affects specific molecular pathways and the overall physiology, nervous system and behavior of the chicken host organism due to a growing number of studies investigating conditions such as host diet, antibiotics, probiotics, and germ-free and germ-reduced models. Systems-level investigations have revealed a network of microbiome-related interactions between the gut and state of health and behavior in chickens and other animals. While some microbial symbionts are crucial for maintaining stability and normal host physiology, there can also be dysbiosis, disruptions to nutrient flow, and other outcomes of dysregulation and disease. Likewise, alteration of the gut microbiome is found for chickens exhibiting differences in feather pecking (FP) behavior and this alteration is suspected to be responsible for behavioral change. In chickens and other organisms, serotonin is a chief neuromodulator that links gut microbes to the host brain as microbes modulate the serotonin secreted by the host's own intestinal enterochromaffin cells which can stimulate the central nervous system via the vagus nerve. A substantial part of the serotonergic network is conserved across birds and mammals. Broader investigations of multiple species and subsequent cross-comparisons may help to explore general functionality of this ancient system and its increasingly apparent central role in the gut-brain axis of vertebrates. Dysfunctional behavioral phenotypes from the serotonergic system moreover occur in both birds and mammals with, for example, FP in chickens and depression in humans. Recent studies of the intestine as a major site of serotonin synthesis have been identifying routes by which gut microbial metabolites regulate the chicken serotonergic system. This review in particular highlights the influence of gut microbial metabolite short chain fatty acids (SCFAs) on the serotonergic system. The role of SCFAs in physiological and brain disorders may be considerable because of their ability to cross intestinal as well as the blood-brain barriers, leading to influences on the serotonergic system via binding to receptors and epigenetic modulations. Examinations of these mechanisms may translate into a more general understanding of serotonergic system development within chickens and other avians.
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Affiliation(s)
- Vidya V. Jadhav
- Department of Biology, North Carolina Agricultural and Technical State University, Greensboro, NC, United States
| | - Jian Han
- Department of Biology, North Carolina Agricultural and Technical State University, Greensboro, NC, United States
| | - Yewande Fasina
- Department of Animal Sciences, North Carolina Agricultural and Technical State University, Greensboro, NC, United States,*Correspondence: Yewande Fasina, ; Scott H. Harrison,
| | - Scott H. Harrison
- Department of Biology, North Carolina Agricultural and Technical State University, Greensboro, NC, United States,*Correspondence: Yewande Fasina, ; Scott H. Harrison,
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21
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Ameen AO, Freude K, Aldana BI. Fats, Friends or Foes: Investigating the Role of Short- and Medium-Chain Fatty Acids in Alzheimer's Disease. Biomedicines 2022; 10:2778. [PMID: 36359298 PMCID: PMC9687972 DOI: 10.3390/biomedicines10112778] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/18/2022] [Accepted: 10/26/2022] [Indexed: 08/26/2023] Open
Abstract
Characterising Alzheimer's disease (AD) as a metabolic disorder of the brain is gaining acceptance based on the pathophysiological commonalities between AD and major metabolic disorders. Therefore, metabolic interventions have been explored as a strategy for brain energetic rescue. Amongst these, medium-chain fatty acid (MCFA) supplementations have been reported to rescue the energetic failure in brain cells as well as the cognitive decline in patients. Short-chain fatty acids (SCFA) have also been implicated in AD pathology. Due to the increasing therapeutic interest in metabolic interventions and brain energetic rescue in neurodegenerative disorders, in this review, we first summarise the role of SCFAs and MCFAs in AD. We provide a comparison of the main findings regarding these lipid species in established AD animal models and recently developed human cell-based models of this devastating disorder.
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Affiliation(s)
- Aishat O. Ameen
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Kristine Freude
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark
| | - Blanca I. Aldana
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
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22
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Guo Y, Wang S, Chao X, Li D, Wang Y, Guo Q, Chen T. Multi-omics studies reveal ameliorating effects of physical exercise on neurodegenerative diseases. Front Aging Neurosci 2022; 14:1026688. [PMID: 36389059 PMCID: PMC9659972 DOI: 10.3389/fnagi.2022.1026688] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 09/28/2022] [Indexed: 08/27/2023] Open
Abstract
INTRODUCTION Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, are heavy burdens to global health and economic development worldwide. Mounting evidence suggests that exercise, a type of non-invasive intervention, has a positive impact on the life quality of elderly with neurodegenerative diseases. X-omics are powerful tools for mapping global biochemical changes in disease and treatment. METHOD Three major databases were searched related to current studies in exercise intervention on neurodegenerative diseases using omics tools, including metabolomics, metagenomics, genomics, transcriptomics, and proteomics. RESULT We summarized the omics features and potential mechanisms associated with exercise and neurodegenerative diseases in the current studies. Three main mechanisms by which exercise affects neurodegenerative diseases were summed up, including adult neurogenesis, brain-derived neurotrophic factor (BDNF) signaling, and short-chain fatty acids (SCFAs) metabolism. CONCLUSION Overall, there is compelling evidence that exercise intervention is a feasible way of preventing the onset and alleviating the severity of neurodegenerative diseases. These studies highlight the importance of exercise as a complementary approach to the treatment and intervention of neurodegenerative diseases in addition to traditional treatments. More mechanisms on exercise interventions for neurodegenerative diseases, the specification of exercise prescriptions, and differentiated exercise programs should be explored so that they can actually be applied to the clinic.
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Affiliation(s)
- Yuhuai Guo
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Shouli Wang
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Xiaowen Chao
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Ding Li
- Department of Gerontology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Ying Wang
- Department of Gerontology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Qihao Guo
- Department of Gerontology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Tianlu Chen
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
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23
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Intestinal Flora Affect Alzheimer's Disease by Regulating Endogenous Hormones. Neurochem Res 2022; 47:3565-3582. [DOI: 10.1007/s11064-022-03784-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/13/2022] [Accepted: 10/01/2022] [Indexed: 11/25/2022]
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24
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Gallagher CI, Ha DA, Harvey RJ, Vandenberg RJ. Positive Allosteric Modulators of Glycine Receptors and Their Potential Use in Pain Therapies. Pharmacol Rev 2022; 74:933-961. [PMID: 36779343 PMCID: PMC9553105 DOI: 10.1124/pharmrev.122.000583] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 04/26/2022] [Accepted: 05/13/2022] [Indexed: 11/22/2022] Open
Abstract
Glycine receptors are ligand-gated ion channels that mediate synaptic inhibition throughout the mammalian spinal cord, brainstem, and higher brain regions. They have recently emerged as promising targets for novel pain therapies due to their ability to produce antinociception by inhibiting nociceptive signals within the dorsal horn of the spinal cord. This has greatly enhanced the interest in developing positive allosteric modulators of glycine receptors. Several pharmaceutical companies and research facilities have attempted to identify new therapeutic leads by conducting large-scale screens of compound libraries, screening new derivatives from natural sources, or synthesizing novel compounds that mimic endogenous compounds with antinociceptive activity. Advances in structural techniques have also led to the publication of multiple high-resolution structures of the receptor, highlighting novel allosteric binding sites and providing additional information for previously identified binding sites. This has greatly enhanced our understanding of the functional properties of glycine receptors and expanded the structure activity relationships of novel pharmacophores. Despite this, glycine receptors are yet to be used as drug targets due to the difficulties in obtaining potent, selective modulators with favorable pharmacokinetic profiles that are devoid of side effects. This review presents a summary of the structural basis for how current compounds cause positive allosteric modulation of glycine receptors and discusses their therapeutic potential as analgesics. SIGNIFICANCE STATEMENT: Chronic pain is a major cause of disability, and in Western societies, this will only increase as the population ages. Despite the high level of prevalence and enormous socioeconomic burden incurred, treatment of chronic pain remains limited as it is often refractory to current analgesics, such as opioids. The National Institute for Drug Abuse has set finding effective, safe, nonaddictive strategies to manage chronic pain as their top priority. Positive allosteric modulators of glycine receptors may provide a therapeutic option.
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Affiliation(s)
- Casey I Gallagher
- Molecular Biomedicine, School of Medical Sciences, University of Sydney, Sydney, Australia (C.I.G., D.A.H., R.J.V.) and Biomedical Science, School of Health and Behavioural Sciences and Sunshine Coast Health Institute, University of the Sunshine Coast, Maroochydore, Australia (R.J.H.)
| | - Damien A Ha
- Molecular Biomedicine, School of Medical Sciences, University of Sydney, Sydney, Australia (C.I.G., D.A.H., R.J.V.) and Biomedical Science, School of Health and Behavioural Sciences and Sunshine Coast Health Institute, University of the Sunshine Coast, Maroochydore, Australia (R.J.H.)
| | - Robert J Harvey
- Molecular Biomedicine, School of Medical Sciences, University of Sydney, Sydney, Australia (C.I.G., D.A.H., R.J.V.) and Biomedical Science, School of Health and Behavioural Sciences and Sunshine Coast Health Institute, University of the Sunshine Coast, Maroochydore, Australia (R.J.H.)
| | - Robert J Vandenberg
- Molecular Biomedicine, School of Medical Sciences, University of Sydney, Sydney, Australia (C.I.G., D.A.H., R.J.V.) and Biomedical Science, School of Health and Behavioural Sciences and Sunshine Coast Health Institute, University of the Sunshine Coast, Maroochydore, Australia (R.J.H.)
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25
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Targeting the Sphingolipid Rheostat in Gliomas. Int J Mol Sci 2022; 23:ijms23169255. [PMID: 36012521 PMCID: PMC9408832 DOI: 10.3390/ijms23169255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 08/12/2022] [Accepted: 08/14/2022] [Indexed: 11/26/2022] Open
Abstract
Gliomas are highly aggressive cancer types that are in urgent need of novel drugs and targeted therapies. Treatment protocols have not improved in over a decade, and glioma patient survival remains among the worst of all cancer types. As a result, cancer metabolism research has served as an innovative approach to identifying novel glioma targets and improving our understanding of brain tumors. Recent research has uncovered a unique metabolic vulnerability in the sphingolipid pathways of gliomas that possess the IDH1 mutation. Sphingolipids are a family of lipid signaling molecules that play a variety of second messenger functions in cellular regulation. The two primary metabolites, sphingosine-1-phosphate (S1P) and ceramide, maintain a rheostat balance and play opposing roles in cell survival and proliferation. Altering the rheostat such that the pro-apoptotic signaling of the ceramides outweighs the pro-survival S1P signaling in glioma cells diminishes the hallmarks of cancer and enhances tumor cell death. Throughout this review, we discuss the sphingolipid pathway and identify the enzymes that can be most effectively targeted to alter the sphingolipid rheostat and enhance apoptosis in gliomas. We discuss each pathway’s steps based on their site of occurrence in the organelles and postulate novel targets that can effectively exploit this vulnerability.
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26
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Weighted Gene Co-Expression Network Analysis and Support Vector Machine Learning in the Proteomic Profiling of Cerebrospinal Fluid from Extraventricular Drainage in Child Medulloblastoma. Metabolites 2022; 12:metabo12080724. [PMID: 36005596 PMCID: PMC9412589 DOI: 10.3390/metabo12080724] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 07/25/2022] [Accepted: 08/02/2022] [Indexed: 11/17/2022] Open
Abstract
Medulloblastoma (MB) is the most common pediatric malignant central nervous system tumor. Overall survival in MB depends on treatment tuning. There is aneed for biomarkers of residual disease and recurrence. We analyzed the proteome of waste cerebrospinal fluid (CSF) from extraventricular drainage (EVD) from six children bearing various subtypes of MB and six controls needing EVD insertion for unrelated causes. Samples included total CSF, microvesicles, exosomes, and proteins captured by combinatorial peptide ligand library (CPLL). Liquid chromatography-coupled tandem mass spectrometry proteomics identified 3560 proteins in CSF from control and MB patients, 2412 (67.7%) of which were overlapping, and 346 (9.7%) and 805 (22.6%) were exclusive. Multidimensional scaling analysis discriminated samples. The weighted gene co-expression network analysis (WGCNA) identified those modules functionally associated with the samples. A ranked core of 192 proteins allowed distinguishing between control and MB samples. Machine learning highlighted long-chain fatty acid transport protein 4 (SLC27A4) and laminin B-type (LMNB1) as proteins that maximized the discrimination between control and MB samples. Machine learning WGCNA and support vector machine learning were able to distinguish between MB versus non-tumor/hemorrhagic controls. The two potential protein biomarkers for the discrimination between control and MB may guide therapy and predict recurrences, improving the MB patients' quality of life.
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27
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Ganesan R, Suk KT. Microbiome and metabolomics in alcoholic liver disease. Clin Mol Hepatol 2022; 28:580-582. [PMID: 35850497 PMCID: PMC9293603 DOI: 10.3350/cmh.2022.0171] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 07/01/2022] [Indexed: 12/24/2022] Open
Affiliation(s)
- Raja Ganesan
- Institute for Liver and Digestive Disease, Hallym University, Chuncheon, Korea
| | - Ki Tae Suk
- Institute for Liver and Digestive Disease, Hallym University, Chuncheon, Korea
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28
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Lu J, Hou W, Gao S, Zhang Y, Zong Y. The Role of Gut Microbiota—Gut—Brain Axis in Perioperative Neurocognitive Dysfunction. Front Pharmacol 2022; 13:879745. [PMID: 35774608 PMCID: PMC9237434 DOI: 10.3389/fphar.2022.879745] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 05/18/2022] [Indexed: 12/02/2022] Open
Abstract
With the aging of the world population and advances in medical and health technology, more and more elderly patients are undergoing anesthesia and surgery, and perioperative neurocognitive dysfunction (PND) is receiving increasing attention. The latest definition of PND, published simultaneously in November 2018 in 6 leading journals in the field of anesthesiology, clarifies that PND includes preoperatively cognitive impairment, postoperative delirium, delayed neurocognitive recovery, and postoperative cognitive dysfunction and meets the diagnostic criteria for neurocognitive impairment in the Diagnostic and Statistical Manual of Mental Disorders -fifth edition (DSM-5). The time frame for PND includes preoperatively and within 12 months postoperatively. Recent studies have shown that gut microbiota regulates central nervous function and behavior through the gut microbiota - gut - brain axis, but the role of the axis in the pathogenesis of PND remains unclear. Therefore, this article reviews the mechanism of the role of gut microbiota-gut-brain axis in PND, so as to help explore reasonable early treatment strategies.
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Affiliation(s)
- Jian Lu
- Department of Anesthesiology, The Second Hospital of Jiaxing, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Wenlong Hou
- Department of Anesthesiology, Bengbu Medical College, Bengbu, China
| | - Sunan Gao
- Department of Anesthesiology, The Second Hospital of Jiaxing, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Ye Zhang
- Department of Anesthesiology, The Second Hospital of Jiaxing, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Youming Zong
- Department of Anesthesiology, The Second Hospital of Jiaxing, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
- Department of Anesthesiology, Bengbu Medical College, Bengbu, China
- *Correspondence: Youming Zong,
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29
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Liu T, Xu Y, Yi CX, Tong Q, Cai D. The hypothalamus for whole-body physiology: from metabolism to aging. Protein Cell 2022; 13:394-421. [PMID: 33826123 PMCID: PMC9095790 DOI: 10.1007/s13238-021-00834-x] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 03/01/2021] [Indexed: 01/05/2023] Open
Abstract
Obesity and aging are two important epidemic factors for metabolic syndrome and many other health issues, which contribute to devastating diseases such as cardiovascular diseases, stroke and cancers. The brain plays a central role in controlling metabolic physiology in that it integrates information from other metabolic organs, sends regulatory projections and orchestrates the whole-body function. Emerging studies suggest that brain dysfunction in sensing various internal cues or processing external cues may have profound effects on metabolic and other physiological functions. This review highlights brain dysfunction linked to genetic mutations, sex, brain inflammation, microbiota, stress as causes for whole-body pathophysiology, arguing brain dysfunction as a root cause for the epidemic of aging and obesity-related disorders. We also speculate key issues that need to be addressed on how to reveal relevant brain dysfunction that underlines the development of these disorders and diseases in order to develop new treatment strategies against these health problems.
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Affiliation(s)
- Tiemin Liu
- grid.8547.e0000 0001 0125 2443State Key Laboratory of Genetic Engineering, Department of Endocrinology and Metabolism, Institute of Metabolism and Integrative Biology, Human Phenome Institute, and Collaborative Innovation Center for Genetics and Development, Zhongshan Hospital, School of Life Sciences, Fudan University, Shanghai, 200438 China
| | - Yong Xu
- grid.39382.330000 0001 2160 926XChildren’s Nutrition Research Center, Department of Pediatrics, Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA
| | - Chun-Xia Yi
- grid.7177.60000000084992262Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, Amsterdam Gastroenterology Endocrinology Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, Netherlands
| | - Qingchun Tong
- grid.453726.10000 0004 5906 7293Brown Foundation Institute of Molecular Medicine, Department of Neurobiology and Anatomy, University of Texas McGovern Medical School, Graduate Program in Neuroscience of MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030 USA
| | - Dongsheng Cai
- grid.251993.50000000121791997Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, NY 10461 USA
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30
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Abstract
Innate and adaptive immunity are essential for neurodevelopment and central nervous system (CNS) homeostasis; however, the fragile equilibrium between immune and brain cells can be disturbed by any immune dysregulation and cause detrimental effects. Accumulating evidence indicates that, despite the blood-brain barrier (BBB), overactivation of the immune system leads to brain vulnerability that increases the risk of neuropsychiatric disorders, particularly upon subsequent exposure later in life. Disruption of microglial function in later life can be triggered by various environmental and psychological factors, including obesity-driven chronic low-grade inflammation and gut dysbiosis. Increased visceral adiposity has been recognized as an important risk factor for multiple neuropsychiatric conditions. The review aims to present our current understanding of the topic.
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31
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Zhu W, Zhou Y, Tsao R, Dong H, Zhang H. Amelioratory Effect of Resistant Starch on Non-alcoholic Fatty Liver Disease via the Gut-Liver Axis. Front Nutr 2022; 9:861854. [PMID: 35662935 PMCID: PMC9159374 DOI: 10.3389/fnut.2022.861854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 04/19/2022] [Indexed: 11/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome with a global prevalence. Impaired gut barrier function caused by an unhealthy diet plays a key role in disrupting the immune-metabolic homeostasis of the gut-liver axis (GLA), leading to NAFLD. Therefore, dietary interventions have been studied as feasible alternative therapeutic approaches to ameliorate NAFLD. Resistant starches (RSs) are prebiotics that reduce systemic inflammation in patients with metabolic syndrome. The present review aimed to elucidate the mechanisms of the GLA in alleviating NAFLD and provide insights into how dietary RSs counteract diet-induced inflammation in the GLA. Emerging evidence suggests that RS intake alters gut microbiota structure, enhances mucosal immune tolerance, and promotes the production of microbial metabolites such as short-chain fatty acids (SCFAs) and secondary bile acids. These metabolites directly stimulate the growth of intestinal epithelial cells and elicit GPR41/GPR43, FXR, and TGR5 signaling cascades to sustain immune-metabolic homeostasis in the GLA. The literature also revealed the dietary-immune-metabolic interplay by which RSs exert their regulatory effect on the immune-metabolic crosstalk of the GLA and the related molecular basis, suggesting that dietary intervention with RSs may be a promising alternative therapeutic strategy against diet-induced dysfunction of the GLA and, ultimately, the risk of developing NAFLD.
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Affiliation(s)
- Weifeng Zhu
- Department of Food Nutrition and Safety, College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Ying Zhou
- Department of Food Nutrition and Safety, College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Rong Tsao
- Guelph Research and Development Centre, Agriculture and Agri-Food Canada, Guelph, ON, Canada
| | - Huanhuan Dong
- Department of Food Nutrition and Safety, College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
- *Correspondence: Huanhuan Dong,
| | - Hua Zhang
- Department of Food Nutrition and Safety, College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
- Hua Zhang, ;
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32
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Ganesan R, Jeong JJ, Kim DJ, Suk KT. Recent Trends of Microbiota-Based Microbial Metabolites Metabolism in Liver Disease. Front Med (Lausanne) 2022; 9:841281. [PMID: 35615096 PMCID: PMC9125096 DOI: 10.3389/fmed.2022.841281] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 04/19/2022] [Indexed: 12/12/2022] Open
Abstract
The gut microbiome and microbial metabolomic influences on liver diseases and their diagnosis, prognosis, and treatment are still controversial. Research studies have provocatively claimed that the gut microbiome, metabolomics understanding, and microbial metabolite screening are key approaches to understanding liver cancer and liver diseases. An advance of logical innovations in metabolomics profiling, the metabolome inclusion, challenges, and the reproducibility of the investigations at every stage are devoted to this domain to link the common molecules across multiple liver diseases, such as fatty liver, hepatitis, and cirrhosis. These molecules are not immediately recognizable because of the huge underlying and synthetic variety present inside the liver cellular metabolome. This review focuses on microenvironmental metabolic stimuli in the gut-liver axis. Microbial small-molecule profiling (i.e., semiquantitative monitoring, metabolic discrimination, target profiling, and untargeted profiling) in biological fluids has been incompletely addressed. Here, we have reviewed the differential expression of the metabolome of short-chain fatty acids (SCFAs), tryptophan, one-carbon metabolism and bile acid, and the gut microbiota effects are summarized and discussed. We further present proof-of-evidence for gut microbiota-based metabolomics that manipulates the host's gut or liver microbes, mechanosensitive metabolite reactions and potential metabolic pathways. We conclude with a forward-looking perspective on future attention to the “dark matter” of the gut microbiota and microbial metabolomics.
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33
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Tang CF, Wang CY, Wang JH, Wang QN, Li SJ, Wang HO, Zhou F, Li JM. Short-Chain Fatty Acids Ameliorate Depressive-Like Behaviors of High Fructose-Fed Mice by Rescuing Hippocampal Neurogenesis Decline and Blood–Brain Barrier Damage. Nutrients 2022; 14:nu14091882. [PMID: 35565849 PMCID: PMC9105414 DOI: 10.3390/nu14091882] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/26/2022] [Accepted: 04/28/2022] [Indexed: 12/04/2022] Open
Abstract
Excessive fructose intake is associated with the increased risk of mental illness, such as depression, but the underlying mechanisms are poorly understood. Our previous study found that high fructose diet (FruD)-fed mice exhibited neuroinflammation, hippocampal neurogenesis decline and blood–brain barrier (BBB) damage, accompanied by the reduction of gut microbiome-derived short-chain fatty acids (SCFAs). Here, we found that chronic stress aggravated these pathological changes and promoted the development of depressive-like behaviors in FruD mice. In detail, the decreased number of newborn neurons, mature neurons and neural stem cells (NSCs) in the hippocampus of FruD mice was worsened by chronic stress. Furthermore, chronic stress exacerbated the damage of BBB integrity with the decreased expression of zonula occludens-1 (ZO-1), claudin-5 and occludin in brain vasculature, overactivated microglia and increased neuroinflammation in FruD mice. These results suggest that high fructose intake combined with chronic stress leads to cumulative negative effects that promote the development of depressive-like behaviors in mice. Of note, SCFAs could rescue hippocampal neurogenesis decline, improve BBB damage and suppress microglia activation and neuroinflammation, thereby ameliorate depressive-like behaviors of FruD mice exposed to chronic stress. These results could be used to develop dietary interventions to prevent depression.
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Affiliation(s)
- Chuan-Feng Tang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China; (C.-F.T.); (C.-Y.W.); (J.-H.W.); (Q.-N.W.)
| | - Cong-Ying Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China; (C.-F.T.); (C.-Y.W.); (J.-H.W.); (Q.-N.W.)
| | - Jun-Han Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China; (C.-F.T.); (C.-Y.W.); (J.-H.W.); (Q.-N.W.)
| | - Qiao-Na Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China; (C.-F.T.); (C.-Y.W.); (J.-H.W.); (Q.-N.W.)
| | - Shen-Jie Li
- School of Food Science, Nanjing Xiaozhuang University, Nanjing 211171, China; (S.-J.L.); (H.-O.W.)
| | - Hai-Ou Wang
- School of Food Science, Nanjing Xiaozhuang University, Nanjing 211171, China; (S.-J.L.); (H.-O.W.)
| | - Feng Zhou
- School of Food Science, Nanjing Xiaozhuang University, Nanjing 211171, China; (S.-J.L.); (H.-O.W.)
- Correspondence: (F.Z.); (J.-M.L.)
| | - Jian-Mei Li
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China; (C.-F.T.); (C.-Y.W.); (J.-H.W.); (Q.-N.W.)
- Correspondence: (F.Z.); (J.-M.L.)
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Xiao W, Su J, Gao X, Yang H, Weng R, Ni W, Gu Y. The microbiota-gut-brain axis participates in chronic cerebral hypoperfusion by disrupting the metabolism of short-chain fatty acids. MICROBIOME 2022; 10:62. [PMID: 35430804 PMCID: PMC9013454 DOI: 10.1186/s40168-022-01255-6] [Citation(s) in RCA: 114] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 02/28/2022] [Indexed: 05/02/2023]
Abstract
BACKGROUND Chronic cerebral hypoperfusion (CCH) underlies secondary brain injury following certain metabolic disorders and central nervous system (CNS) diseases. Dysregulation of the microbiota-gut-brain axis can exacerbate various CNS disorders through aberrantly expressed metabolites such as short-chain fatty acids (SCFAs). Yet, its relationship with CCH remains to be demonstrated. And if so, it is of interest to explore whether restoring gut microbiota to maintain SCFA metabolism could protect against CCH. RESULTS Rats subjected to bilateral common carotid artery occlusion (BCCAO) as a model of CCH exhibited cognitive impairment, depressive-like behaviors, decreased gut motility, and compromised gut barrier functions. The 16S ribosomal RNA gene sequencing revealed an abnormal gut microbiota profile and decreased relative abundance of some representative SCFA producers, with the decreased hippocampal SCFAs as the further evidence. Using fecal microbiota transplantation (FMT), rats recolonized with a balanced gut microbiome acquired a higher level of hippocampal SCFAs, as well as decreased neuroinflammation when exposed to lipopolysaccharide. Healthy FMT promoted gut motility and gut barrier functions, and improved cognitive decline and depressive-like behaviors by inhibiting hippocampal neuronal apoptosis in BCCAO rats. Long-term SCFA supplementation further confirmed its neuroprotective effect in terms of relieving inflammatory response and hippocampal neuronal apoptosis following BCCAO. CONCLUSION Our results demonstrate that modulating the gut microbiome via FMT can ameliorate BCCAO-induced gut dysbiosis, cognitive decline, and depressive-like behaviors, possibly by enhancing the relative abundance of SCFA-producing floras and subsequently increasing SCFA levels. Video abstract.
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Affiliation(s)
- Weiping Xiao
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040 China
- Institute of Neurosurgery, Fudan University, Shanghai, 200052 China
| | - Jiabin Su
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040 China
- Institute of Neurosurgery, Fudan University, Shanghai, 200052 China
| | - Xinjie Gao
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040 China
- Institute of Neurosurgery, Fudan University, Shanghai, 200052 China
| | - Heng Yang
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040 China
- Institute of Neurosurgery, Fudan University, Shanghai, 200052 China
| | - Ruiyuan Weng
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040 China
- Institute of Neurosurgery, Fudan University, Shanghai, 200052 China
| | - Wei Ni
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040 China
- Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai, 200052 China
| | - Yuxiang Gu
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040 China
- Institute of Neurosurgery, Fudan University, Shanghai, 200052 China
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Sonali S, Ray B, Ahmed Tousif H, Rathipriya AG, Sunanda T, Mahalakshmi AM, Rungratanawanich W, Essa MM, Qoronfleh MW, Chidambaram SB, Song BJ. Mechanistic Insights into the Link between Gut Dysbiosis and Major Depression: An Extensive Review. Cells 2022; 11:cells11081362. [PMID: 35456041 PMCID: PMC9030021 DOI: 10.3390/cells11081362] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 12/11/2022] Open
Abstract
Depression is a highly common mental disorder, which is often multifactorial with sex, genetic, environmental, and/or psychological causes. Recent advancements in biomedical research have demonstrated a clear correlation between gut dysbiosis (GD) or gut microbial dysbiosis and the development of anxiety or depressive behaviors. The gut microbiome communicates with the brain through the neural, immune, and metabolic pathways, either directly (via vagal nerves) or indirectly (via gut- and microbial-derived metabolites as well as gut hormones and endocrine peptides, including peptide YY, pancreatic polypeptide, neuropeptide Y, cholecystokinin, corticotropin-releasing factor, glucagon-like peptide, oxytocin, and ghrelin). Maintaining healthy gut microbiota (GM) is now being recognized as important for brain health through the use of probiotics, prebiotics, synbiotics, fecal microbial transplantation (FMT), etc. A few approaches exert antidepressant effects via restoring GM and hypothalamus–pituitary–adrenal (HPA) axis functions. In this review, we have summarized the etiopathogenic link between gut dysbiosis and depression with preclinical and clinical evidence. In addition, we have collated information on the recent therapies and supplements, such as probiotics, prebiotics, short-chain fatty acids, and vitamin B12, omega-3 fatty acids, etc., which target the gut–brain axis (GBA) for the effective management of depressive behavior and anxiety.
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Affiliation(s)
- Sharma Sonali
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India; (S.S.); (B.R.); (H.A.T.); (T.S.); (A.M.M.)
- Centre for Experimental Pharmacology and Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
| | - Bipul Ray
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India; (S.S.); (B.R.); (H.A.T.); (T.S.); (A.M.M.)
- Centre for Experimental Pharmacology and Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
| | - Hediyal Ahmed Tousif
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India; (S.S.); (B.R.); (H.A.T.); (T.S.); (A.M.M.)
- Centre for Experimental Pharmacology and Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
| | | | - Tuladhar Sunanda
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India; (S.S.); (B.R.); (H.A.T.); (T.S.); (A.M.M.)
- Centre for Experimental Pharmacology and Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
| | - Arehally M. Mahalakshmi
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India; (S.S.); (B.R.); (H.A.T.); (T.S.); (A.M.M.)
- Centre for Experimental Pharmacology and Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
| | - Wiramon Rungratanawanich
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD 20892, USA;
| | - Musthafa Mohamed Essa
- Department of Food Science and Nutrition, CAMS, Sultan Qaboos University, Muscat 123, Oman;
- Aging and Dementia Research Group, Sultan Qaboos University, Muscat 123, Oman
| | - M. Walid Qoronfleh
- Q3CG Research Institute (QRI), Research and Policy Division, 7227 Rachel Drive, Ypsilant, MI 48917, USA;
| | - Saravana Babu Chidambaram
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India; (S.S.); (B.R.); (H.A.T.); (T.S.); (A.M.M.)
- Centre for Experimental Pharmacology and Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
- Correspondence: (S.B.C.); (B.-J.S.)
| | - Byoung-Joon Song
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD 20892, USA;
- Correspondence: (S.B.C.); (B.-J.S.)
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Curcumae Radix Decreases Neurodegenerative Markers through Glycolysis Decrease and TCA Cycle Activation. Nutrients 2022; 14:nu14081587. [PMID: 35458149 PMCID: PMC9024545 DOI: 10.3390/nu14081587] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/05/2022] [Accepted: 04/08/2022] [Indexed: 02/06/2023] Open
Abstract
Neurodegenerative diseases (ND) are being increasingly studied owing to the increasing proportion of the aging population. Several potential compounds are examined to prevent neurodegenerative diseases, including Curcumae radix, which is known to be beneficial for inflammatory conditions, metabolic syndrome, and various types of pain. However, it is not well studied, and its influence on energy metabolism in ND is unclear. We focused on the relationship between ND and energy metabolism using Curcumae radix extract (CRE) in cells and animal models. We monitored neurodegenerative markers and metabolic indicators using Western blotting and qRT-PCR and then assessed cellular glycolysis and metabolic flux assays. The levels of Alzheimer’s disease-related markers in mouse brains were reduced after treatment with the CRE. We confirmed that neurodegenerative markers decreased in the cerebrum and brain tumor cells following low endoplasmic reticulum (ER) stress markers. Furthermore, glycolysis related genes and the extracellular acidification rate decreased after treatment with the CRE. Interestingly, we found that the CRE exposed mouse brain and cells had increased mitochondrial Tricarboxylic acid (TCA) cycle and Oxidative phosphorylation (OXPHOS) related genes in the CRE group. Curcumae radix may act as a metabolic modulator of brain health and help treat and prevent ND involving mitochondrial dysfunction.
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Li F, Hu G, Long X, Cao Y, Li Q, Guo W, Wang J, Liu J, Fu S. Stearic Acid Activates the PI3K-mTOR-4EBP1/S6K and mTOR-SREBP-1 Signaling Axes through FATP4-CDK1 To Promote Milk Synthesis in Primary Bovine Mammary Epithelial Cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:4007-4018. [PMID: 35333520 DOI: 10.1021/acs.jafc.2c00208] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Stearic acid (SA), an 18-carbon long-chain saturated fatty acid, has great potential for promoting lactation. Therefore, this study investigates the effects and mechanism of SA on milk synthesis in primary bovine mammary epithelial cells (BMECs). In our study, we found that SA significantly increased β-casein and triglycerides, and the effect was most significant at 100 μM. Signaling pathway studies have found that SA affects milk synthesis by upregulating cyclin-dependent kinase 1 (CDK1) to activate PI3K-mTOR-4EBP1/S6K and mTOR-SREBP-1 pathways. Furthermore, we detected fatty acid transport proteins (FATPs) when BMECs were treated with SA; the mRNA levels of FATP3 (3.713 ± 0.583) and FATP4 (40.815 ± 8.959) were significantly upregulated at 100 μM. Subsequently, we constructed FATP4-siRNA and found that SA was transported by FATP4 into BMECs, promoting milk synthesis. Collectively, these results revealed that SA activated PI3K-mTOR-4EBP1/S6K and mTOR-SREBP-1 signaling axes through FATP4-CDK1 to promote milk synthesis in BMECs.
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Affiliation(s)
- Feng Li
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Guiqiu Hu
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Xiaoyu Long
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Yu Cao
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Qianqian Li
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Wenjin Guo
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Jiaxin Wang
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Juxiong Liu
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Shoupeng Fu
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
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Xu B, Chen L, Zhan Y, Marquez KNS, Zhuo L, Qi S, Zhu J, He Y, Chen X, Zhang H, Shen Y, Chen G, Gu J, Guo Y, Liu S, Xie T. The Biological Functions and Regulatory Mechanisms of Fatty Acid Binding Protein 5 in Various Diseases. Front Cell Dev Biol 2022; 10:857919. [PMID: 35445019 PMCID: PMC9013884 DOI: 10.3389/fcell.2022.857919] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 02/28/2022] [Indexed: 12/11/2022] Open
Abstract
In recent years, fatty acid binding protein 5 (FABP5), also known as fatty acid transporter, has been widely researched with the help of modern genetic technology. Emerging evidence suggests its critical role in regulating lipid transport, homeostasis, and metabolism. Its involvement in the pathogenesis of various diseases such as metabolic syndrome, skin diseases, cancer, and neurological diseases is the key to understanding the true nature of the protein. This makes FABP5 be a promising component for numerous clinical applications. This review has summarized the most recent advances in the research of FABP5 in modulating cellular processes, providing an in-depth analysis of the protein's biological properties, biological functions, and mechanisms involved in various diseases. In addition, we have discussed the possibility of using FABP5 as a new diagnostic biomarker and therapeutic target for human diseases, shedding light on challenges facing future research.
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Affiliation(s)
- Binyue Xu
- Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Lu Chen
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Yu Zhan
- Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Karl Nelson S. Marquez
- Clinical Medicine, Tongji Medical College, Huazhong University of Science and Technology, Hankou, China
| | - Lvjia Zhuo
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Shasha Qi
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Jinyu Zhu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Ying He
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Xudong Chen
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Hao Zhang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Yingying Shen
- Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Gongxing Chen
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Jianzhong Gu
- Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yong Guo
- Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Shuiping Liu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Tian Xie
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
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Ondaro J, Hernandez-Eguiazu H, Garciandia-Arcelus M, Loera-Valencia R, Rodriguez-Gómez L, Jiménez-Zúñiga A, Goikolea J, Rodriguez-Rodriguez P, Ruiz-Martinez J, Moreno F, Lopez de Munain A, Holt IJ, Gil-Bea FJ, Gereñu G. Defects of Nutrient Signaling and Autophagy in Neurodegeneration. Front Cell Dev Biol 2022; 10:836196. [PMID: 35419363 PMCID: PMC8996160 DOI: 10.3389/fcell.2022.836196] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/21/2022] [Indexed: 12/27/2022] Open
Abstract
Neurons are post-mitotic cells that allocate huge amounts of energy to the synthesis of new organelles and molecules, neurotransmission and to the maintenance of redox homeostasis. In neurons, autophagy is not only crucial to ensure organelle renewal but it is also essential to balance nutritional needs through the mobilization of internal energy stores. A delicate crosstalk between the pathways that sense nutritional status of the cell and the autophagic processes to recycle organelles and macronutrients is fundamental to guarantee the proper functioning of the neuron in times of energy scarcity. This review provides a detailed overview of the pathways and processes involved in the balance of cellular energy mediated by autophagy, which when defective, precipitate the neurodegenerative cascade of Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis or Alzheimer's disease.
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Affiliation(s)
- Jon Ondaro
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Haizea Hernandez-Eguiazu
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Maddi Garciandia-Arcelus
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Raúl Loera-Valencia
- Department of Neurology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet (KI), Stockholm, Sweden
| | - Laura Rodriguez-Gómez
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Andrés Jiménez-Zúñiga
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Julen Goikolea
- Department of Neurology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet (KI), Stockholm, Sweden
| | - Patricia Rodriguez-Rodriguez
- Department of Neurology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet (KI), Stockholm, Sweden
| | - Javier Ruiz-Martinez
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Donostia University Hospital, San Sebastian, Spain
| | - Fermín Moreno
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Donostia University Hospital, San Sebastian, Spain
| | - Adolfo Lopez de Munain
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Donostia University Hospital, San Sebastian, Spain
| | - Ian James Holt
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, United Kingdom
- IKERBASQUE Basque Foundation for Science, Bilbao, Spain
| | - Francisco Javier Gil-Bea
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Gorka Gereñu
- Department of Neuroscience, Biodonostia Health Research Institute (IIS Biodonostia), San Sebastian, Spain
- Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Department of Physiology, Faculty of Medicine and Nursing, University of Basque Country (UPV-EHU), Leioa, Spain
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Higashide M, Furuhashi M, Watanabe M, Itoh K, Suzuki S, Umetsu A, Tsugeno Y, Ida Y, Hikage F, Ohguro H. Fatty Acid-Binding Proteins 4 and 5 Are Involved in the Pathogenesis of Retinal Vascular Diseases in Different Manners. Life (Basel) 2022; 12:life12040467. [PMID: 35454958 PMCID: PMC9025502 DOI: 10.3390/life12040467] [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: 03/03/2022] [Revised: 03/21/2022] [Accepted: 03/21/2022] [Indexed: 11/16/2022] Open
Abstract
This study reports on the pathological significance of the vitreous fatty acid-binding protein (Vt-FABP) 4 and 5, and vascular endothelial growth factor A (Vt-VEGFA) in patients with retinal vascular diseases (RVDs) including proliferative diabetic retinopathy (PDR) and retinal vein occlusion (RVO). Subjects with PDR (n = 20), RVO (n = 10), and controls (epiretinal membrane, n = 18) who had undergone vitrectomies were enrolled in this study. The levels of Vt-FABP4, Vt-FABP5, and Vt-VEGFA were evaluated by enzyme-linked immunosorbent assays (ELISA). Retinal circulation levels were measured by a laser-speckle flow analyzer (LSFA) and other relevant data were collected. The Vt-FABP5 levels were significantly (p < 0.05) elevated in patients with RVDs compared to control patients. This elevation was more evident in patients with RVO than with PDR. Log Vt-FABP5 was significantly correlated negatively or positively with all the LSFA retinal circulation indexes or Log triglycerides (r = 0.31, p = 0.031), respectively. However, the elevations in the Vt-FABP4 and Vt-VEGFA levels were more evident in the PDR group (p < 0.05) and these factors were correlated positively with Log fasting glucose and negatively with some of the LSFA retinal circulation indexes. Multivariable regression analyses indicated that the LSFA blood flows of the optic disc at baseline was an independent effector with Log Vt-FABP5 other than several possible factors including age, gender, Log triglycerides, Log Vt-FABP4 and Log Vt-VEGFA. These current findings suggest that Vt-FABP5 is involved in the pathogenesis of RVD in a manner that is different from that for Vt-FABP4 and Vt-VEGFA, presumably by regulating retinal circulation.
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Affiliation(s)
- Megumi Higashide
- Departments of Ophthalmology, School of Medicine, Sapporo Medical University, Chuo-ku, Sapporo 060-8556, Japan; (M.H.); (M.W.); (K.I.); (S.S.); (A.U.); (Y.T.); (Y.I.); (F.H.)
| | - Masato Furuhashi
- Departments of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University, Sapporo 060-8556, Japan;
| | - Megumi Watanabe
- Departments of Ophthalmology, School of Medicine, Sapporo Medical University, Chuo-ku, Sapporo 060-8556, Japan; (M.H.); (M.W.); (K.I.); (S.S.); (A.U.); (Y.T.); (Y.I.); (F.H.)
| | - Kaku Itoh
- Departments of Ophthalmology, School of Medicine, Sapporo Medical University, Chuo-ku, Sapporo 060-8556, Japan; (M.H.); (M.W.); (K.I.); (S.S.); (A.U.); (Y.T.); (Y.I.); (F.H.)
| | - Soma Suzuki
- Departments of Ophthalmology, School of Medicine, Sapporo Medical University, Chuo-ku, Sapporo 060-8556, Japan; (M.H.); (M.W.); (K.I.); (S.S.); (A.U.); (Y.T.); (Y.I.); (F.H.)
| | - Araya Umetsu
- Departments of Ophthalmology, School of Medicine, Sapporo Medical University, Chuo-ku, Sapporo 060-8556, Japan; (M.H.); (M.W.); (K.I.); (S.S.); (A.U.); (Y.T.); (Y.I.); (F.H.)
| | - Yuri Tsugeno
- Departments of Ophthalmology, School of Medicine, Sapporo Medical University, Chuo-ku, Sapporo 060-8556, Japan; (M.H.); (M.W.); (K.I.); (S.S.); (A.U.); (Y.T.); (Y.I.); (F.H.)
| | - Yosuke Ida
- Departments of Ophthalmology, School of Medicine, Sapporo Medical University, Chuo-ku, Sapporo 060-8556, Japan; (M.H.); (M.W.); (K.I.); (S.S.); (A.U.); (Y.T.); (Y.I.); (F.H.)
| | - Fumihito Hikage
- Departments of Ophthalmology, School of Medicine, Sapporo Medical University, Chuo-ku, Sapporo 060-8556, Japan; (M.H.); (M.W.); (K.I.); (S.S.); (A.U.); (Y.T.); (Y.I.); (F.H.)
| | - Hiroshi Ohguro
- Departments of Ophthalmology, School of Medicine, Sapporo Medical University, Chuo-ku, Sapporo 060-8556, Japan; (M.H.); (M.W.); (K.I.); (S.S.); (A.U.); (Y.T.); (Y.I.); (F.H.)
- Correspondence: ; Tel.: +81-61-12-111
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Rupp SK, Stengel A. Bi-Directionality of the Microbiota-Gut-Brain Axis in Patients With Functional Dyspepsia: Relevance of Psychotherapy and Probiotics. Front Neurosci 2022; 16:844564. [PMID: 35295092 PMCID: PMC8919856 DOI: 10.3389/fnins.2022.844564] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 02/07/2022] [Indexed: 11/17/2022] Open
Abstract
Functional dyspepsia is one of the most commonly diagnosed disorders of the gut-brain interaction worldwide. The precise pathogenesis of functional dyspepsia is complex and remains incompletely understood. Therefore, advances in the understanding of functional dyspepsia could change clinical practice. The aim of this review is to highlight the relevance of psychotherapy and probiotics in the context of the microbiota-gut-brain axis in the pathophysiology and especially in the treatment of functional dyspepsia. Therefore, studies which have been conducted to investigate the role of psychotherapy and probiotics in FD and the microbiota-gut-brain axis in the pathophysiology of functional dyspepsia were examined, and the outcomes of this research summarized. There might be a link between changes in the microbiome and functional dyspepsia. Even though, specific alterations in the microbiome that may be pathognomonic in functional dyspepsia remain unclear, the use of probiotics became a viable treatment option for patients with functional dyspepsia. Since mental illness also plays an important role in the pathophysiology of functional dyspepsia, psychotherapy is a useful treatment method, with additional study results indicating that psychotherapy may also shift the microbiome in a favorable direction. Moreover, other findings suggest that probiotics can be used not only to alleviate gastrointestinal symptoms in functional dyspepsia, but also to treat or even prevent mental disorders in these patients. In summary, in this review we highlight the bi-directionality of the microbiota-gut-brain axis in the pathophysiology of functional dyspepsia. Although there are multiple treatment approaches, the burden of disease in patients with functional dyspepsia is still enormous and a definitive therapy to cure this disease does not (yet) exist. Lastly, there is a lack of studies on the impact of dysbiosis, mental health and probiotics on pathophysiology and symptomatology in functional dyspepsia which should be investigated in future studies.
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Affiliation(s)
- Sophia Kristina Rupp
- Department of Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen, Tübingen, Germany
| | - Andreas Stengel
- Department of Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen, Tübingen, Germany
- Charité Center for Internal Medicine and Dermatology, Department for Psychosomatic Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
- *Correspondence: Andreas Stengel,
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Chou MC, Lee HC, Liu YC, Yen PSY, Liu CK, Chen CH, Hsieh TH, Chen SL. Long-Term High-Fat Diet Consumption Depletes Glial Cells and Tyrosine Hydroxylase-Containing Neurons in the Brain of Middle-Aged Rats. Cells 2022; 11:295. [PMID: 35053411 PMCID: PMC8773849 DOI: 10.3390/cells11020295] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/05/2022] [Accepted: 01/11/2022] [Indexed: 12/30/2022] Open
Abstract
Epidemiologic studies have indicated that dyslipidemia may facilitate the progression of neuronal degeneration. However, the effects of chronic dyslipidemia on brain function, especially in older individuals, remain unclear. In this study, middle-aged 37-week-old male Wistar-Kyoto rats were fed a normal diet (ND) or a 45% high-fat diet (HFD) for 30 weeks (i.e., until 67 weeks of age). To study the effects of chronic dyslipidemia on the brain, we analyzed spontaneous locomotor activity, cognitive function, and brain tissues in both groups of rats after 30 weeks. Compared with age-matched rats fed a ND, Wistar-Kyoto rats fed a HFD had dyslipidemia and showed decreased movement but normal recognition of a novel object. In our brain analyses, we observed a significant decrease in astrocytes and tyrosine hydroxylase-containing neurons in the substantia nigra and locus coeruleus of rats fed a HFD compared with rats fed a ND. However, hippocampal pyramidal neurons were not affected. Our findings indicate that the long-term consumption of a HFD may cause lipid metabolism overload in the brain and damage to glial cells. The decrease in astrocytes may lead to reduced protection of the brain and affect the survival of tyrosine hydroxylase-containing neurons but not pyramidal neurons of the hippocampus.
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Affiliation(s)
- Mei-Chuan Chou
- Department of Neurology, Kaohsiung Medical University (KMU), Kaohsiung 807, Taiwan; (M.-C.C.); (C.-K.L.)
- Department of Neurology, Kaohsiung Municipal Ta-Tung Hospital, KMU, Kaohsiung 807, Taiwan
| | - Hsiang-Chun Lee
- Department of Internal Medicine, Division of Cardiology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Lipid Science and Aging Research Center, College of Medicine, KMU, Kaohsiung 807, Taiwan
| | - Yen-Chin Liu
- Department of Anesthesiology, KMU, Kaohsiung 807, Taiwan;
| | - Patrick Szu-Ying Yen
- Graduate Institute of Medicine, College of Medicine, KMU, Kaohsiung 807, Taiwan; (P.S.-Y.Y.); (T.-H.H.)
| | - Ching-Kuan Liu
- Department of Neurology, Kaohsiung Medical University (KMU), Kaohsiung 807, Taiwan; (M.-C.C.); (C.-K.L.)
- Graduate Institute of Medicine, College of Medicine, KMU, Kaohsiung 807, Taiwan; (P.S.-Y.Y.); (T.-H.H.)
| | - Chu-Huang Chen
- Vascular and Medicinal Research, Texas Heart Institute, Houston, TX 37660, USA;
| | - Tzu-Han Hsieh
- Graduate Institute of Medicine, College of Medicine, KMU, Kaohsiung 807, Taiwan; (P.S.-Y.Y.); (T.-H.H.)
| | - Shiou-Lan Chen
- Graduate Institute of Medicine, College of Medicine, KMU, Kaohsiung 807, Taiwan; (P.S.-Y.Y.); (T.-H.H.)
- Drug Development and Value Creation Research Center and MSc Program in Tropical Medicine, Department of Medicine Research, KMU Hospital, KMU, Kaohsiung 807, Taiwan
- College of Professional Studies, National Pingtung University, Pingtung 900, Taiwan
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Borek-Dorosz A, Pieczara A, Czamara K, Stojak M, Matuszyk E, Majzner K, Brzozowski K, Bresci A, Polli D, Baranska M. What is the ability of inflamed endothelium to uptake exogenous saturated fatty acids? A proof-of-concept study using spontaneous Raman, SRS and CARS microscopy. Cell Mol Life Sci 2022; 79:593. [PMID: 36380212 PMCID: PMC9666316 DOI: 10.1007/s00018-022-04616-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 10/16/2022] [Accepted: 10/27/2022] [Indexed: 11/17/2022]
Abstract
Endothelial cells (EC) in vivo buffer and regulate the transfer of plasma fatty acid (FA) to the underlying tissues. We hypothesize that inflammation could alter the functionality of the EC, i.e., their capacity and uptake of different FA. The aim of this work is to verify the functionality of inflamed cells by analyzing their ability to uptake and accumulate exogenous saturated FA. Control and inflammatory human microvascular endothelial cells stimulated in vitro with two deuterium-labeled saturated FA (D-FA), i.e., palmitic (D31-PA) and myristic (D27-MA) acids. Cells were measured both by spontaneous and stimulated Raman imaging to extract detailed information about uptaken FA, whereas coherent anti-Stokes Raman scattering and fluorescence imaging showed the global content of FA in cells. Additionally, we employed atomic force microscopy to obtain a morphological image of the cells. The results indicate that the uptake of D-FA in inflamed cells is dependent on their concentration and type. Cells accumulated D-FA when treated with a low concentration, and the effect was more pronounced for D27-MA, in normal cells, but even more so, in inflamed cells. In the case of D31-PA, a slightly increased uptake was observed for inflamed cells when administered at higher concentration. The results provide a better understanding of the EC inflammation and indicate the impact of the pathological state of the EC on their capacity to buffer fat. All the microscopic methods used showed complementarity in the analysis of FA uptake by EC, but each method recognized this process from a different perspective.
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Affiliation(s)
| | - Anna Pieczara
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland
| | - Krzysztof Czamara
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland
| | - Marta Stojak
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland
| | - Ewelina Matuszyk
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland
| | - Katarzyna Majzner
- Faculty of Chemistry, Jagiellonian University, 2 Gronostajowa Str., 30-387 Krakow, Poland ,Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland
| | - Krzysztof Brzozowski
- Faculty of Chemistry, Jagiellonian University, 2 Gronostajowa Str., 30-387 Krakow, Poland
| | - Arianna Bresci
- Physics Department, Politecnico di Milano, Piazza Leonardo da Vinci, 32, 20133 Milan, Italy
| | - Dario Polli
- Physics Department, Politecnico di Milano, Piazza Leonardo da Vinci, 32, 20133 Milan, Italy ,Institute for Photonics and Nanotechnology at CNR (CNR-IFN), Piazza Leonardo da Vinci, 32, 20133 Milan, Italy
| | - Malgorzata Baranska
- Faculty of Chemistry, Jagiellonian University, 2 Gronostajowa Str., 30-387 Krakow, Poland ,Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, 14 Bobrzynskiego Str., 30-348 Krakow, Poland
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Komanduri M, Savage K, Lea A, McPhee G, Nolidin K, Deleuil S, Stough C, Gondalia S. The Relationship between Gut Microbiome and Cognition in Older Australians. Nutrients 2021; 14:nu14010064. [PMID: 35010939 PMCID: PMC8746300 DOI: 10.3390/nu14010064] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/20/2021] [Accepted: 12/22/2021] [Indexed: 12/20/2022] Open
Abstract
Ageing is associated with changes in biological processes, including reductions in cognitive functions and gut microbiome diversity. However, not much is known about the relationship between cognition and the microbiome with increasing age. Therefore, we examined the relationship between the gut microbiome and cognition in 69 healthy participants aged 60–75 years. The gut microbiome was analysed with the 16S rRNA sequencing method. The cognitive assessment included the Cognitive Drug Research computerised assessment battery, which produced five cognitive factors corresponding to ‘Quality of Episodic Secondary Memory’, ‘Quality of Working Memory’, ‘Continuity of Attention, ‘Speed of Memory’ and ‘Power of Concentration’. Multiple linear regression showed that the bacterial family Carnobacteriaceae explained 9% of the variance in predicting Quality of Episodic Secondary Memory. Alcaligenaceae and Clostridiaceae explained 15% of the variance in predicting Quality of Working Memory; Bacteroidaceae, Barnesiellaceae, Rikenellaceae and Gemellaceae explained 11% of the variance in Power of Concentration. The present study provides specific evidence of a relationship between specific families of bacteria and different domains of cognition.
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Affiliation(s)
- Mrudhula Komanduri
- Centre for Human Psychopharmacology, Swinburne University of Technology, Hawthorn, VIC 3122, Australia; (K.S.); (A.L.); (G.M.); (K.N.); (S.D.); (C.S.); (S.G.)
- Correspondence:
| | - Karen Savage
- Centre for Human Psychopharmacology, Swinburne University of Technology, Hawthorn, VIC 3122, Australia; (K.S.); (A.L.); (G.M.); (K.N.); (S.D.); (C.S.); (S.G.)
| | - Ana Lea
- Centre for Human Psychopharmacology, Swinburne University of Technology, Hawthorn, VIC 3122, Australia; (K.S.); (A.L.); (G.M.); (K.N.); (S.D.); (C.S.); (S.G.)
| | - Grace McPhee
- Centre for Human Psychopharmacology, Swinburne University of Technology, Hawthorn, VIC 3122, Australia; (K.S.); (A.L.); (G.M.); (K.N.); (S.D.); (C.S.); (S.G.)
| | - Karen Nolidin
- Centre for Human Psychopharmacology, Swinburne University of Technology, Hawthorn, VIC 3122, Australia; (K.S.); (A.L.); (G.M.); (K.N.); (S.D.); (C.S.); (S.G.)
| | - Saurenne Deleuil
- Centre for Human Psychopharmacology, Swinburne University of Technology, Hawthorn, VIC 3122, Australia; (K.S.); (A.L.); (G.M.); (K.N.); (S.D.); (C.S.); (S.G.)
| | - Con Stough
- Centre for Human Psychopharmacology, Swinburne University of Technology, Hawthorn, VIC 3122, Australia; (K.S.); (A.L.); (G.M.); (K.N.); (S.D.); (C.S.); (S.G.)
| | - Shakuntla Gondalia
- Centre for Human Psychopharmacology, Swinburne University of Technology, Hawthorn, VIC 3122, Australia; (K.S.); (A.L.); (G.M.); (K.N.); (S.D.); (C.S.); (S.G.)
- Health and Biosecurity, Commonwealth Scientific and Industrial Research Organization, Adelaide, SA 5000, Australia
- Precision Health Future Science Platform, Commonwealth Scientific and Industrial Research Organisation, Adelaide, SA 5000, Australia
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Rekhi UR, Omar M, Alexiou M, Delyea C, Immaraj L, Elahi S, Febbraio M. Endothelial Cell CD36 Reduces Atherosclerosis and Controls Systemic Metabolism. Front Cardiovasc Med 2021; 8:768481. [PMID: 34888367 PMCID: PMC8650007 DOI: 10.3389/fcvm.2021.768481] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 10/20/2021] [Indexed: 01/08/2023] Open
Abstract
High-fat Western diets contribute to tissue dysregulation of fatty acid and glucose intake, resulting in obesity and insulin resistance and their sequelae, including atherosclerosis. New therapies are desperately needed to interrupt this epidemic. The significant idea driving this research is that the understudied regulation of fatty acid entry into tissues at the endothelial cell (EC) interface can provide novel therapeutic targets that will greatly modify health outcomes and advance health-related knowledge. Dysfunctional endothelium, defined as activated, pro-inflammatory, and pro-thrombotic, is critical in atherosclerosis initiation, in modulating thrombotic events that could result in myocardial infarction and stroke, and is a hallmark of insulin resistance. Dyslipidemia from high-fat diets overwhelmingly contributes to the development of dysfunctional endothelium. CD36 acts as a receptor for pathological ligands generated by high-fat diets and in fatty acid uptake, and therefore, it may additionally contribute to EC dysfunction. We created EC CD36 knockout (CD36°) mice using cre-lox technology and a cre-promoter that does not eliminate CD36 in hematopoietic cells (Tie2e cre). These mice were studied on different diets, and crossed to the low density lipoprotein receptor (LDLR) knockout for atherosclerosis assessment. Our data show that EC CD36° and EC CD36°/LDLR° mice have metabolic changes suggestive of an uncompensated role for EC CD36 in fatty acid uptake. The mice lacking expression of EC CD36 had increased glucose clearance compared with controls when fed with multiple diets. EC CD36° male mice showed increased carbohydrate utilization and decreased energy expenditure by indirect calorimetry. Female EC CD36°/LDLR° mice have reduced atherosclerosis. Taken together, these data support a significant role for EC CD36 in systemic metabolism and reveal sex-specific impact on atherosclerosis and energy substrate use.
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Affiliation(s)
- Umar R Rekhi
- Department of Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Mohamed Omar
- Department of Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Maria Alexiou
- Department of Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Cole Delyea
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada
| | - Linnet Immaraj
- Department of Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Shokrollah Elahi
- Department of Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Maria Febbraio
- Department of Dentistry, University of Alberta, Edmonton, AB, Canada
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Hu X, Ono M, Chimge NO, Chosa K, Nguyen C, Melendez E, Lou CH, Lim P, Termini J, Lai KKY, Fueger PT, Teo JL, Higuchi Y, Kahn M. Differential Kat3 Usage Orchestrates the Integration of Cellular Metabolism with Differentiation. Cancers (Basel) 2021; 13:cancers13235884. [PMID: 34884992 PMCID: PMC8656857 DOI: 10.3390/cancers13235884] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 11/12/2021] [Accepted: 11/19/2021] [Indexed: 11/29/2022] Open
Abstract
Simple Summary The coupling of metabolism with cellular status is critically important and highly evolutionarily conserved. However, how cells coordinate metabolism with transcription as they change their status is not clear. Utilizing multiomic and functional studies, we now demonstrate the dichotomous roles of the Kat3 coactivators CBP and p300 and, in particular, their extreme N-termini, in coordinating cellular metabolism with cell differentiation. Using multiple in vitro and in vivo systems, our study sheds new light on metabolic regulation in homeostasis and disease, including cancer. Abstract The integration of cellular status with metabolism is critically important and the coupling of energy production and cellular function is highly evolutionarily conserved. This has been demonstrated in stem cell biology, organismal, cellular and tissue differentiation and in immune cell biology. However, a molecular mechanism delineating how cells coordinate and couple metabolism with transcription as they navigate quiescence, growth, proliferation, differentiation and migration remains in its infancy. The extreme N-termini of the Kat3 coactivator family members, CBP and p300, by far the least homologous regions with only 66% identity, interact with members of the nuclear receptor family, interferon activated Stat1 and transcriptionally competent β-catenin, a critical component of the Wnt signaling pathway. We now wish to report based on multiomic and functional investigations, utilizing p300 knockdown, N-terminal p300 edited and p300 S89A edited cell lines and p300 S89A knockin mice, that the N-termini of the Kat3 coactivators provide a highly evolutionarily conserved hub to integrate multiple signaling cascades to coordinate cellular metabolism with the regulation of cellular status and function.
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Affiliation(s)
- Xiaohui Hu
- Department of Pathology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China;
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; (N.-O.C.); (K.C.); (C.N.); (E.M.); (P.L.); (J.T.); (K.K.Y.L.); (J.-L.T.); (Y.H.)
| | - Masaya Ono
- Department of Clinical Proteomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan;
| | - Nyam-Osor Chimge
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; (N.-O.C.); (K.C.); (C.N.); (E.M.); (P.L.); (J.T.); (K.K.Y.L.); (J.-L.T.); (Y.H.)
| | - Keisuke Chosa
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; (N.-O.C.); (K.C.); (C.N.); (E.M.); (P.L.); (J.T.); (K.K.Y.L.); (J.-L.T.); (Y.H.)
| | - Cu Nguyen
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; (N.-O.C.); (K.C.); (C.N.); (E.M.); (P.L.); (J.T.); (K.K.Y.L.); (J.-L.T.); (Y.H.)
| | - Elizabeth Melendez
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; (N.-O.C.); (K.C.); (C.N.); (E.M.); (P.L.); (J.T.); (K.K.Y.L.); (J.-L.T.); (Y.H.)
| | - Chih-Hong Lou
- Gene Editing and Viral Vector Core, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA;
- City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA;
| | - Punnajit Lim
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; (N.-O.C.); (K.C.); (C.N.); (E.M.); (P.L.); (J.T.); (K.K.Y.L.); (J.-L.T.); (Y.H.)
| | - John Termini
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; (N.-O.C.); (K.C.); (C.N.); (E.M.); (P.L.); (J.T.); (K.K.Y.L.); (J.-L.T.); (Y.H.)
- City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA;
| | - Keane K. Y. Lai
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; (N.-O.C.); (K.C.); (C.N.); (E.M.); (P.L.); (J.T.); (K.K.Y.L.); (J.-L.T.); (Y.H.)
- City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA;
| | - Patrick T. Fueger
- City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA;
- Department of Molecular and Cellular Endocrinology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
| | - Jia-Ling Teo
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; (N.-O.C.); (K.C.); (C.N.); (E.M.); (P.L.); (J.T.); (K.K.Y.L.); (J.-L.T.); (Y.H.)
| | - Yusuke Higuchi
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; (N.-O.C.); (K.C.); (C.N.); (E.M.); (P.L.); (J.T.); (K.K.Y.L.); (J.-L.T.); (Y.H.)
| | - Michael Kahn
- Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; (N.-O.C.); (K.C.); (C.N.); (E.M.); (P.L.); (J.T.); (K.K.Y.L.); (J.-L.T.); (Y.H.)
- City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA;
- Correspondence:
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Cheng J, Li W, Wang Y, Cao Q, Ni Y, Zhang W, Guo J, Chen B, Zang Y, Zhu Y. Electroacupuncture modulates the intestinal microecology to improve intestinal motility in spinal cord injury rats. Microb Biotechnol 2021; 15:862-873. [PMID: 34797954 PMCID: PMC8913878 DOI: 10.1111/1751-7915.13968] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 10/29/2021] [Accepted: 10/30/2021] [Indexed: 12/14/2022] Open
Abstract
Spinal cord injury (SCI) is a disease involving gastrointestinal disorders. The underlying mechanisms of the potential protective effects of electroacupuncture (EA) and 5-hydroxytryptamine (5-HT) system on SCI remain unknown. We investigated whether EA improves gut microbial dysbiosis in SCI and regulates the 5-HT system. 16S rDNA gene sequencing was applied to investigate alterations in the gut microbiome of the rats. Faecal metabolites and the expression of the 5-HT system were detected. EA and faecal microbiota transplantation (FMT) treatment facilitated intestinal transmission functional recovery and restored the colon morphology of SCI rats. The composition of the intestinal microbiota, including numbers of phylum Proteobacteria, class Clostridia, order Bacteroidales, and genus Dorea, were amplified in SCI rats, and EA and FMT significantly reshaped the intestinal microbiota. SCI resulted in disturbed metabolic conditions in rats, and the EA and FMT group showed increased amounts of catechin compared with SCI rats. SCI inhibited 5-HT system expression in the colon, which was significantly reversed by EA and FMT treatment. Therefore, EA may ameliorate SCI by modulating microbiota and metabolites and regulate the 5-HT system. Our study provides new insights into the pathogenesis and therapy of SCI from the perspective of microbiota and 5-HT regulation.
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Affiliation(s)
- Jie Cheng
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Weimin Li
- The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Ying Wang
- The Ninth People's Hospital of Wuxi affiliated to Soochow University, Wuxi, China.,Department of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Qing Cao
- Department of Kinesiology, Shanghai University of Sport, Shanghai, China.,Zigong Forth People's Hospital, Zigong, China
| | - Ying Ni
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenyi Zhang
- Zhongshan Rehabilitation Hospital Affiliated to Jiangsu Provincial People's Hospital, Nanjing, China
| | - Jiabao Guo
- The Second Clinical Medical School, Xuzhou Medical University, Xuzhou, China
| | - Binglin Chen
- The Second Clinical Medical School, Xuzhou Medical University, Xuzhou, China
| | - Yaning Zang
- Department of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Yi Zhu
- The Second Affiliated Hospital of Hainan Medical University, Haikou, China.,The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Jancovski N, Baldwin T, Orford M, Li M, Jones GD, Burbano LE, Rutherford T, Reid C, Heales S, Eaton S, Petrou S. Protective effects of medium chain triglyceride diet in a mouse model of Dravet syndrome. Epilepsia 2021; 62:3131-3142. [PMID: 34713469 DOI: 10.1111/epi.17101] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 09/27/2021] [Accepted: 10/05/2021] [Indexed: 01/10/2023]
Abstract
OBJECTIVE Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy with early childhood onset. Patients with DS do not respond well to antiepileptic drugs and have only a few treatment options available. Here, we evaluated the effect of medium chain triglyceride (MCT) diet therapy in a mouse model of DS. METHODS Scn1aR1407X/+ DS mice were given diets supplemented with MCTs with varying ratios of decanoic (C10) and octanoic (C8) acid or a control diet for 4 weeks. Video monitoring was performed to evaluate spontaneous convulsive seizure frequency. Susceptibility to hyperthermia-induced seizures was also examined. Medium chain fatty acids, and mitochondrial and antioxidant markers were assessed in brain homogenate. RESULTS Dietary intervention with MCTs significantly prolonged survival and reduced convulsive seizure frequency during the critical period of highest seizure occurrence in the Scn1aR1407X/+ DS mice. Moreover, MCT diet therapy showed protective effects against hyperthermia-induced seizures. We demonstrated that coadministration of C10/C8 was effective at reducing both seizures and mortality, whereas C10 alone only reduced mortality, suggesting that the ratio of C10 to C8 in the MCT is an important factor for efficacy. When C10 and C8 are supplemented at an 80:20 ratio in the diet, C10 accumulates in the brain in high enough concentrations to enhance brain energy metabolism by both stimulating mitochondrial enrichment and increasing its antioxidant status. SIGNIFICANCE The results from this study indicate that MCT diet therapy may provide therapeutic benefits in DS. Future clinical studies would elucidate whether these positive effects are mirrored in human patients.
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Affiliation(s)
- Nikola Jancovski
- Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
| | - Tomas Baldwin
- Developmental Biology and Cancer University College London Great Ormond Street Institute of Child Health, London, UK
| | - Michael Orford
- Developmental Biology and Cancer University College London Great Ormond Street Institute of Child Health, London, UK
| | - Melody Li
- Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
| | - Gabriel Davis Jones
- Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
| | - Lisseth Estefania Burbano
- Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
| | | | - Christopher Reid
- Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
| | - Simon Heales
- Inborn Errors of Metabolism, Chemical Pathology, University College London Metabolism, Great Ormond Street for Children Hospital, Chemical Pathology, Great Ormond Street Hospital, London, UK.,Neurometabolic Unit, National Hospital, London, UK
| | - Simon Eaton
- Developmental Biology and Cancer University College London Great Ormond Street Institute of Child Health, London, UK
| | - Steven Petrou
- Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
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Interactions between Endoplasmic Reticulum Stress and Autophagy: Implications for Apoptosis and Neuroplasticity-Related Proteins in Palmitic Acid-Treated Prefrontal Cells. Neural Plast 2021; 2021:8851327. [PMID: 34646319 PMCID: PMC8505096 DOI: 10.1155/2021/8851327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 09/03/2021] [Accepted: 09/05/2021] [Indexed: 12/02/2022] Open
Abstract
Lipotoxicity of palmitic acid (PA) or high-fat diets has been reported to increase endoplasmic reticulum (ER) stress and autophagy in peripheral tissue as well as apoptotic cell death. It also can lead to an AD-like pathological pattern. However, it has been unknown that PA-induced ER stress and autophagy are involved in the regulation of neuroplastic abnormalities. Here, we investigated the roles of ER stress and autophagy in apoptosis and neuroplasticity-related protein expression in PA-treated prefrontal cells. Prefrontal cells dissected from newborn Sprague-Dawley rats were treated with PA compound with ER stress inhibitor 4-phenylbutyric acid (4-PBA) and autophagy inhibitor 3-methyladenine (3-MA) or PA alone. PA promoted ER stress and autophagy and also cause apoptosis as well as a decline in the expression of neuroplasticity-related proteins. Inhibition of ER stress decreased the expressions of neuroplasticity-related proteins and reduced autophagy activation and apoptosis in PA-treated prefrontal cells. Inhibition of autophagy exacerbated apoptosis and enhanced ER stress in PA-treated prefrontal cells. The present study illustrated that both ER stress and autophagy could be involved in apoptosis and decreased neuroplasticity-related proteins, and the interaction between ER stress and autophagy may play a critical role in apoptosis in PA-treated prefrontal cells. Our results provide new insights into the molecular mechanisms in vitro of lipotoxicity in obesity-related cognitive dysfunction.
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50
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Sharma N, Tan MA, An SSA. Mechanistic Aspects of Apiaceae Family Spices in Ameliorating Alzheimer's Disease. Antioxidants (Basel) 2021; 10:1571. [PMID: 34679705 PMCID: PMC8533116 DOI: 10.3390/antiox10101571] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 09/30/2021] [Accepted: 10/01/2021] [Indexed: 02/02/2023] Open
Abstract
Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases worldwide. In an effort to search for new strategies for treating AD, natural products have become candidates of choice. Plants are a rich source of bioactive and effective compounds used in treating numerous diseases. Various plant extracts are known to display neuroprotective activities by targeting different pathophysiological pathways in association with the diseases, such as inhibiting enzymes responsible for degrading neurotransmitters, reducing oxidative stress, neuroprotection, inhibiting amyloid plaque formation, and replenishing mitochondrial function. This review presented a comprehensive evaluation of the available scientific literature (in vivo, in vitro, and in silico) on the neuroprotective mechanisms displayed by the extracts/bioactive compounds from spices belonging to the Apiaceae family in ameliorating AD.
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Affiliation(s)
- Niti Sharma
- Department of Bionano Technology, Gachon University, 1342 Seongnam-daero, Sujeong-Gu, Seongnam 461-701, Korea;
| | - Mario A. Tan
- College of Science and Research Center for the Natural and Applied Sciences, University of Santo Tomas, Manila 1015, Philippines;
| | - Seong Soo A. An
- Department of Bionano Technology, Gachon University, 1342 Seongnam-daero, Sujeong-Gu, Seongnam 461-701, Korea;
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