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Thapa D, Ghimire A, Warne LN, Carlessi R. Targeting the Endocannabinoidome: A Novel Approach to Managing Extraintestinal Complications in Inflammatory Bowel Disease. Pharmaceuticals (Basel) 2025; 18:478. [PMID: 40283915 PMCID: PMC12030576 DOI: 10.3390/ph18040478] [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: 02/27/2025] [Revised: 03/17/2025] [Accepted: 03/25/2025] [Indexed: 04/29/2025] Open
Abstract
Background: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder marked by persistent gastrointestinal inflammation and a spectrum of systemic effects, including extraintestinal manifestations (EIMs) that impact the joints, skin, liver, and eyes. Conventional therapies primarily target intestinal inflammation, yet they frequently fail to ameliorate these systemic complications. Recent investigations have highlighted the complex interplay among the immune system, gut, and nervous system in IBD pathogenesis, thereby underscoring the need for innovative therapeutic approaches. Methods: We conducted a comprehensive literature search using databases such as PubMed, Scopus, Web of Science, Science Direct, and Google Scholar. Keywords including "cannabinoids", "endocannabinoid system", "endocannabinoidome", "inflammatory bowel disease", and "extraintestinal manifestations" were used to identify peer-reviewed original research and review articles that explore the role of the endocannabinoidome (eCBome) in IBD. Results: Emerging evidence suggests that eCBome-a network comprising lipid mediators, receptors (e.g., CB1, CB2, GPR55, GPR35, PPARα, TRPV1), and metabolic enzymes-plays a critical role in modulating immune responses, maintaining gut barrier integrity, and regulating systemic inflammation. Targeting eCBome not only improves intestinal inflammation but also appears to mitigate metabolic, neurological, and extraintestinal complications such as arthritis, liver dysfunction, and dermatological disorders. Conclusions: Modulation of eCBome represents a promising strategy for comprehensive IBD management by addressing both local and systemic disease components. These findings advocate for further mechanistic studies to develop targeted interventions that leverage eCBome as a novel therapeutic avenue in IBD.
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Affiliation(s)
- Dinesh Thapa
- Curtin Medical Research Institute, Curtin Medical School, Curtin University, Perth, WA 6102, Australia; (A.G.); (L.N.W.)
| | - Anjali Ghimire
- Curtin Medical Research Institute, Curtin Medical School, Curtin University, Perth, WA 6102, Australia; (A.G.); (L.N.W.)
| | - Leon N. Warne
- Curtin Medical Research Institute, Curtin Medical School, Curtin University, Perth, WA 6102, Australia; (A.G.); (L.N.W.)
- The Vet Pharmacist, East Fremantle, WA 6158, Australia
| | - Rodrigo Carlessi
- Curtin Medical Research Institute, Curtin Medical School, Curtin University, Perth, WA 6102, Australia; (A.G.); (L.N.W.)
- Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6009, Australia
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2
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Thapa D, Patil M, Warne LN, Carlessi R, Falasca M. Enhancing Tetrahydrocannabinol's Therapeutic Efficacy in Inflammatory Bowel Disease: The Roles of Cannabidiol and the Cannabinoid 1 Receptor Allosteric Modulator ZCZ011. Pharmaceuticals (Basel) 2025; 18:148. [PMID: 40005963 PMCID: PMC11858241 DOI: 10.3390/ph18020148] [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: 01/09/2025] [Revised: 01/20/2025] [Accepted: 01/20/2025] [Indexed: 02/27/2025] Open
Abstract
Background/Objectives: Current inflammatory bowel disease (IBD) treatments focus on symptomatic relief, highlighting the need for innovative approaches. Dysregulation of the cannabinoid 1 (CB1) receptor, part of the endocannabinoid system, is linked to colitis. While tetrahydrocannabinol (THC) alleviates colitis via CB1 activation, its psychotropic effects limit clinical use. ZCZ011, a CB1R allosteric modulator, and cannabidiol (CBD), a non-psychoactive cannabinoid, offer alternatives. This study investigated combining sub-therapeutic THC doses with ZCZ011 or CBD in a murine model of dextran sodium sulphate (DSS)-induced colitis. Methods: Acute colitis was induced with 4% DSS for 7 days, followed by 3 days of water. Chronic colitis was modelled over 24 days with alternating DSS concentrations. The combination of 2.5 mg/kg THC with 20 mg/kg ZCZ011 or 10 mg/kg CBD was evaluated. Key markers were assessed to determine efficacy and safety, including disease activity index (DAI), inflammation, cytokine levels, GLP-1, and organ health. Results: DSS-induced colitis resulted in increased DAI scores, cytokines, organ inflammation and dysregulation of GLP-1 and ammonia. THC at 10 mg/kg significantly improved colitis markers but was ineffective at 2.5 and 5 mg/kg. ZCZ011 alone showed transient effects. However, combining 2.5 mg/kg THC with either 20 mg/kg ZCZ011 or 10 mg/kg CBD significantly alleviated colitis markers, restored colon integrity and reestablished GLP-1 homeostasis. This combination also maintained favourable haematological and biochemical profiles, including a notable reduction in colitis-induced elevated ammonia levels. Conclusions: This study demonstrates the synergistic potential of low-dose THC combined with CBD or ZCZ011 as a novel, effective and safer therapeutic strategy for ulcerative colitis.
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Affiliation(s)
- Dinesh Thapa
- Curtin Medical Research Institute, Curtin University, Perth, WA 6102, Australia; (M.P.); (L.N.W.); (R.C.)
| | - Mohan Patil
- Curtin Medical Research Institute, Curtin University, Perth, WA 6102, Australia; (M.P.); (L.N.W.); (R.C.)
| | - Leon N Warne
- Curtin Medical Research Institute, Curtin University, Perth, WA 6102, Australia; (M.P.); (L.N.W.); (R.C.)
- College of Science, Health, Engineering and Education, Murdoch University, Perth, WA 6150, Australia
| | - Rodrigo Carlessi
- Curtin Medical Research Institute, Curtin University, Perth, WA 6102, Australia; (M.P.); (L.N.W.); (R.C.)
- Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6009, Australia
| | - Marco Falasca
- College of Science, Health, Engineering and Education, Murdoch University, Perth, WA 6150, Australia
- Department of Medicine and Surgery, University of Parma, 43125 Parma, Italy
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Moriyasu K, Nakajima A, Morita M. Effects of Oral Ingestion of L-Ornithine on Mental Stress and Fatigue Based on the Trier Social Stress Test in Healthy Humans: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Trial. J Clin Med 2024; 13:7583. [PMID: 39768508 PMCID: PMC11676746 DOI: 10.3390/jcm13247583] [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: 11/05/2024] [Revised: 12/06/2024] [Accepted: 12/10/2024] [Indexed: 01/11/2025] Open
Abstract
Background: With changes in the social environment typified by COVID-19, an increasing number of people are suffering from mental stress in interpersonal relationships and the resulting fatigue in recent years. L-ornithine oral ingestion reportedly suppresses the secretion of cortisol, a stress marker, through the hypothalamic-pituitary-adrenal (HPA) axis. However, there is insufficient research to determine whether L-ornithine exerts an ameliorative effect on social stress. Therefore, in this study, we investigated how L-ornithine affects mental stress and fatigue after social stress in healthy participants. Methods: We randomly assigned 65 participants into two groups, ingesting orally either 1600 mg of L-ornithine or a placebo for 7 days. On the day of the Trier Social Stress Test (TSST), participants took test products one hour before the testing. We evaluated the effects on saliva cortisol and mood states, including fatigue. Results: While L-ornithine did not affect saliva cortisol levels, it significantly improved the fatigue-inertia and anger-hostility scales of the Profile of Mood States on the morning after the TSST in the L-ornithine group compared to the placebo group. Conclusions: In conclusion, L-ornithine could potentially improve interpersonal social-stress-associated fatigue without involving the HPA axis. Trial registration: UMIN Clinical Trials Registry: UMIN000048949.
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Affiliation(s)
- Kazuki Moriyasu
- Institute of Health Sciences, Kirin Holdings Company, Limited, Shonan Health Innovation Park 26-1-12-12 Muraoka-Higashi 2-chome, Fujisawa 251-8555, Japan;
| | - Atsushi Nakajima
- Ueno-Asagao Clinic, 6F Kairaku Building, 2-7-5, Higashiueno, Taito-ku, Tokyo 110-0015, Japan;
| | - Masahiko Morita
- Institute of Health Sciences, Kirin Holdings Company, Limited, Shonan Health Innovation Park 26-1-12-12 Muraoka-Higashi 2-chome, Fujisawa 251-8555, Japan;
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Thapa D, Patil M, Warne LN, Carlessi R, Falasca M. Comprehensive Assessment of Cannabidiol and HU308 in Acute and Chronic Colitis Models: Efficacy, Safety, and Mechanistic Innovations. Cells 2024; 13:2013. [PMID: 39682761 PMCID: PMC11640522 DOI: 10.3390/cells13232013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 11/26/2024] [Accepted: 12/02/2024] [Indexed: 12/18/2024] Open
Abstract
Cannabinoids are emerging as promising treatments for inflammatory diseases such as ulcerative colitis. Specifically, cannabinoid 2 (CB2) receptors, which are upregulated during inflammation, have been distinctively linked to anti-inflammatory and analgesic effects. HU308, a synthetic cannabinoid developed to activate CB2 receptors selectively, aims to minimize unwanted off-target side effects. This study evaluated the effectiveness of both cannabidiol (CBD) and HU308 in mouse models of dextran sodium sulphate (DSS)-induced colitis, which mimic the acute and chronic phases of ulcerative colitis. Mice were treated with DSS in drinking water (four percent for the acute model and one to two percent for the chronic model) to induce colitis, as indicated by increased disease activity index (DAI) scores and inflammatory markers. Treatment with 60 mg/kg of CBD, but not lower doses, significantly reduced colitis symptoms, such as inflammation, cytokine levels, and MPO activity, while also normalizing glucagon-like peptide-1 (GLP-1) levels. HU308 showed comparable efficacy to high-dose CBD (60 mg/kg) but at a much lower dose (2.5 mg/kg), without observable toxicity. HU308 effectively normalized DAI scores, colon inflammation, ammonia levels, and GLP-1 expression in both colitis models. These results suggest that both CBD and HU308 are promising treatments for ulcerative colitis. However, HU308 demonstrates enhanced therapeutic potential by achieving similar outcomes at a fraction of the dose required for CBD, reducing the risk of off-target side effects. The ability of HU308 to modulate GLP-1, a biomarker of gut endocrine function, further underscores its promise as a novel treatment option.
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Affiliation(s)
- Dinesh Thapa
- Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth, WA 6102, Australia; (M.P.); (L.N.W.); (R.C.)
| | - Mohan Patil
- Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth, WA 6102, Australia; (M.P.); (L.N.W.); (R.C.)
| | - Leon N Warne
- Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth, WA 6102, Australia; (M.P.); (L.N.W.); (R.C.)
- College of Science, Health, Engineering and Education, Murdoch University, Perth, WA 6150, Australia
| | - Rodrigo Carlessi
- Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth, WA 6102, Australia; (M.P.); (L.N.W.); (R.C.)
- Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6009, Australia
| | - Marco Falasca
- Department of Medicine and Surgery, University of Parma, 43125 Parma, Italy
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5
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Mambro A, Afshar A, Leone F, Dussault C, Stoové M, Savulescu J, Rich JD, Rowan DH, Sheehan J, Kronfli N. Reimbursing incarcerated individuals for participation in research: A scoping review. THE INTERNATIONAL JOURNAL OF DRUG POLICY 2024; 123:104283. [PMID: 38109837 DOI: 10.1016/j.drugpo.2023.104283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 11/18/2023] [Accepted: 11/29/2023] [Indexed: 12/20/2023]
Abstract
BACKGROUND Little is known about global practices regarding the provision of reimbursement for the participation of people who are incarcerated in research. To determine current practices related to the reimbursement of incarcerated populations for research, we aimed to describe international variations in practice across countries and carceral environments to help inform the development of more consistent and equitable practices. METHODS We conducted a scoping review by searching PubMed, Cochrane library, Medline, and Embase, and conducted a grey literature search for English- and French-language articles published until September 30, 2022. All studies evaluating any carceral-based research were included if recruitment of incarcerated participants occurred inside any non-juvenile carceral setting; we excluded studies if recruitment occurred exclusively following release. Where studies failed to indicate the presence or absence of reimbursement, we assumed none was provided. RESULTS A total of 4,328 unique articles were identified, 2,765 were eligible for full text review, and 426 were included. Of these, 295 (69%) did not offer reimbursement to incarcerated individuals. A minority (n = 13; 4%) included reasons explaining the absence of reimbursement, primarily government-level policies (n = 7). Among the 131 (31%) studies that provided reimbursement, the most common form was monetary compensation (n = 122; 93%); five studies (4%) offered possible reduced sentencing. Reimbursement ranged between $3-610 USD in total and 14 studies (11%) explained the reason behind the reimbursements, primarily researchers' discretion (n = 9). CONCLUSIONS The majority of research conducted to date in carceral settings globally has not reimbursed incarcerated participants. Increased transparency regarding reimbursement (or lack thereof) is needed as part of all carceral research and advocacy efforts are required to change policies prohibiting reimbursement of incarcerated individuals. Future work is needed to co-create international standards for the equitable reimbursement of incarcerated populations in research, incorporating the voices of people with lived and living experience of incarceration.
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Affiliation(s)
- Andrea Mambro
- Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Avideh Afshar
- Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Frederic Leone
- Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Camille Dussault
- Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Mark Stoové
- Burnet Institute, School of Public Health and Preventative Medicine, Monash University, Melbourne, Victoria, Australia
| | - Julian Savulescu
- Oxford Uehiro Centre for Practical Ethics, University of Oxford, Oxford, United Kingdom; Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Josiah D Rich
- Center for Health and Justice Transformation, The Miriam and Rhode Island Hospitals, Departments of Medicine and Epidemiology, Brown University, Providence, Rhode Island, USA
| | - Daniel H Rowan
- Division of Infectious Disease, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | | | - Nadine Kronfli
- Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada; Department of Medicine, Division of Infectious Disease and Chronic Viral Illness Service, McGill University, Montreal, Quebec, Canada.
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Wang P, Wu PF, Wang HJ, Liao F, Wang F, Chen JG. Gut microbiome-derived ammonia modulates stress vulnerability in the host. Nat Metab 2023; 5:1986-2001. [PMID: 37872351 DOI: 10.1038/s42255-023-00909-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 09/18/2023] [Indexed: 10/25/2023]
Abstract
Ammonia has been long recognized as a metabolic waste product with well-known neurotoxic effects. However, little is known about the beneficial function of endogenous ammonia. Here, we show that gut ammonia links microbe nitrogen metabolism to host stress vulnerability by maintaining brain glutamine availability in male mice. Chronic stress decreases blood ammonia levels by altering gut urease-positive microbiota. A representative urease-producing strain, Streptococcus thermophilus, can reverse depression-like behaviours induced by gut microbiota that was altered by stress, whereas pharmacological inhibition of gut ammonia production increases stress vulnerability. Notably, abnormally low blood ammonia levels limit the brain's availability of glutamine, a key metabolite produced by astrocytes that is required for presynaptic γ-aminobutyric acid (GABA) replenishment and confers stress vulnerability through cortical GABAergic dysfunction. Of therapeutic interest, ammonium chloride (NH4Cl), a commonly used expectorant in the clinic, can rescue behavioural abnormalities and GABAergic deficits in mouse models of depression. In sum, ammonia produced by the gut microbiome can help buffer stress in the host, providing a gut-brain signalling basis for emotional behaviour.
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Affiliation(s)
- Pei Wang
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peng-Fei Wu
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
- The Research Center for Depression, Tongji Medical College, Huazhong University of Science, Wuhan, China
- The Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, China
| | - Hua-Jie Wang
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fang Liao
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fang Wang
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China.
- The Research Center for Depression, Tongji Medical College, Huazhong University of Science, Wuhan, China.
- The Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, China.
| | - Jian-Guo Chen
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China.
- The Research Center for Depression, Tongji Medical College, Huazhong University of Science, Wuhan, China.
- The Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, China.
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7
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Custodio RJP, Hobloss Z, Myllys M, Hassan R, González D, Reinders J, Bornhorst J, Weishaupt AK, Seddek AL, Abbas T, Friebel A, Hoehme S, Getzmann S, Hengstler JG, van Thriel C, Ghallab A. Cognitive Functions, Neurotransmitter Alterations, and Hippocampal Microstructural Changes in Mice Caused by Feeding on Western Diet. Cells 2023; 12:2331. [PMID: 37759553 PMCID: PMC10529844 DOI: 10.3390/cells12182331] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 09/14/2023] [Accepted: 09/19/2023] [Indexed: 09/29/2023] Open
Abstract
Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) is the most common chronic liver disease in Western countries. It is becoming increasingly evident that peripheral organ-centered inflammatory diseases, including liver diseases, are linked with brain dysfunctions. Therefore, this study aims to unravel the effect of MASLD on brain histology, cognitive functions, and neurotransmitters. For this purpose, mice fed for 48 weeks on standard (SD) or Western diet (WD) were evaluated by behavioral tests, followed by sacrifice and analysis of the liver-brain axis including histopathology, immunohistochemistry, and biochemical analyses. Histological analysis of the liver showed features of Metabolic Dysfunction-Associated Steatohepatitis (MASH) in the WD-fed mice including lipid droplet accumulation, inflammation, and fibrosis. This was accompanied by an elevation of transaminase and alkaline phosphatase activities, increase in inflammatory cytokine and bile acid concentrations, as well as altered amino acid concentrations in the blood. Interestingly, compromised blood capillary morphology coupled with astrogliosis and microgliosis were observed in brain hippocampus of the WD mice, indicating neuroinflammation or a disrupted neurovascular unit. Moreover, attention was impaired in WD-fed mice along with the observations of impaired motor activity and balance, enhanced anxiety, and stereotyped head-twitch response (HTR) behaviors. Analysis of neurotransmitters and modulators including dopamine, serotonin, GABA, glutamate, and acetylcholine showed region-specific dysregulation in the brain of the WD-fed mice. In conclusion, the induction of MASH in mice is accompanied by the alteration of cellular morphology and neurotransmitter expression in the brain, associated with compromised cognitive functions.
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Affiliation(s)
- Raly James Perez Custodio
- Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), Ardeystrasse 67, 44139 Dortmund, Germany; (R.J.P.C.); (Z.H.); (M.M.); (R.H.); (D.G.); (J.R.); (S.G.)
| | - Zaynab Hobloss
- Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), Ardeystrasse 67, 44139 Dortmund, Germany; (R.J.P.C.); (Z.H.); (M.M.); (R.H.); (D.G.); (J.R.); (S.G.)
| | - Maiju Myllys
- Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), Ardeystrasse 67, 44139 Dortmund, Germany; (R.J.P.C.); (Z.H.); (M.M.); (R.H.); (D.G.); (J.R.); (S.G.)
| | - Reham Hassan
- Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), Ardeystrasse 67, 44139 Dortmund, Germany; (R.J.P.C.); (Z.H.); (M.M.); (R.H.); (D.G.); (J.R.); (S.G.)
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena 83523, Egypt;
| | - Daniela González
- Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), Ardeystrasse 67, 44139 Dortmund, Germany; (R.J.P.C.); (Z.H.); (M.M.); (R.H.); (D.G.); (J.R.); (S.G.)
| | - Jörg Reinders
- Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), Ardeystrasse 67, 44139 Dortmund, Germany; (R.J.P.C.); (Z.H.); (M.M.); (R.H.); (D.G.); (J.R.); (S.G.)
| | - Julia Bornhorst
- Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Gaußstraße 20, 42119 Wuppertal, Germany; (J.B.); (A.-K.W.)
| | - Ann-Kathrin Weishaupt
- Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Gaußstraße 20, 42119 Wuppertal, Germany; (J.B.); (A.-K.W.)
| | - Abdel-latif Seddek
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena 83523, Egypt;
| | - Tahany Abbas
- Histology Department, Faculty of Medicine, South Valley University, Qena 83523, Egypt;
| | - Adrian Friebel
- Institute of Computer Science & Saxonian Incubator for Clinical Research (SIKT), University of Leipzig, Haertelstraße 16-18, 04107 Leipzig, Germany; (A.F.); (S.H.)
| | - Stefan Hoehme
- Institute of Computer Science & Saxonian Incubator for Clinical Research (SIKT), University of Leipzig, Haertelstraße 16-18, 04107 Leipzig, Germany; (A.F.); (S.H.)
| | - Stephan Getzmann
- Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), Ardeystrasse 67, 44139 Dortmund, Germany; (R.J.P.C.); (Z.H.); (M.M.); (R.H.); (D.G.); (J.R.); (S.G.)
| | - Jan G. Hengstler
- Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), Ardeystrasse 67, 44139 Dortmund, Germany; (R.J.P.C.); (Z.H.); (M.M.); (R.H.); (D.G.); (J.R.); (S.G.)
| | - Christoph van Thriel
- Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), Ardeystrasse 67, 44139 Dortmund, Germany; (R.J.P.C.); (Z.H.); (M.M.); (R.H.); (D.G.); (J.R.); (S.G.)
| | - Ahmed Ghallab
- Leibniz Research Centre for Working Environment and Human Factors at TU Dortmund (IfADo), Ardeystrasse 67, 44139 Dortmund, Germany; (R.J.P.C.); (Z.H.); (M.M.); (R.H.); (D.G.); (J.R.); (S.G.)
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena 83523, Egypt;
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8
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Fakharbad MJ, Moshiri M, Ommati MM, Talebi M, Etemad L. A review of basic to clinical studies of the association between hyperammonemia, methamphetamine. Naunyn Schmiedebergs Arch Pharmacol 2022; 395:921-931. [PMID: 35604430 DOI: 10.1007/s00210-022-02248-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 04/28/2022] [Indexed: 10/18/2022]
Abstract
Methamphetamine (METH), an addictive psychostimulant drug, is the second most widely used type of drug all around the world. METH abusers are more likely to develop a psycho-neurological complication. Hyperammonemia (HAM) causes neuropsychiatric illnesses such as mental state changes and episodes of acute encephalopathy. Recently, there are some shreds of evidence about the relationship between METH complication and HAM. Both METH intoxication and HAM could induce psychosis, agitation, memory impairment, and psycho-neuronal disorders. They also have similar mechanisms of neuronal damages, such as excitotoxicity, oxidative stress, mitochondrial impairments, and inflammation responses, which can subsequently increase the glutamate level of the brain. Hence, the basic to clinical studies of the association between HAM and METH are reviewed by monitoring six case studies and a good body of animal studies literature. All instances of METH-associated HAM had changes in mental state and some level of confusion that were improved when the ammonia serum level returned to the normal level. Furthermore, most of them had typical vital signs. Several studies suggested some sources for METH-associated HAM, including METH-induced liver and renal damages, muscular hyperactivity, gut bacterial overgrowth, co-abuse of other substances, and using some forms of NH3 in METH cooking. In conclusion, it seems that mental status changes in METH abusers may be related to ammonia intoxication or HAM; therefore, it is important to assess the serum level of ammonia in METH intoxicated patients and resolve it.
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Affiliation(s)
- Marzieh Jafari Fakharbad
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Moshiri
- Medical Toxicology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Mehdi Ommati
- College of Life Sciences, Shanxi Agricultural University, Taigu, Shanxi, 030801, China
| | - Mehdi Talebi
- Department of Community and Family Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Leila Etemad
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran. .,Department of Drug Control, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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9
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Yan T, Liu B, Li F, Wu B, Xiao F, He B, Jia Y. Schizandrin ameliorates behavioral disorders in hepatic injury mice via regulation of oxidative stress and neuroinflammation. Immunopharmacol Immunotoxicol 2021; 43:212-222. [PMID: 33588680 DOI: 10.1080/08923973.2021.1879847] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Aim: The present study was aimed to evaluate the anxiolytic and antidepressant-like effects of schizandrin (from Schisandra chinensis (Turcz.) Baill. which is a functional food) against chronic liver injury in mice.Methods: Chronic liver injury was induced by the treatment of d-galactose (d-GaIN, 200 mg/kg, s.c.) for 8 weeks.Results: Administration of schizandrin (30 mg/kg, i.g.) significantly ameliorated d-GaIN-induced anxiety and depression-like behavior as evident from the results of open field test (OFT), sucrose preference test (SPT), tail suspension test (TST), forced swimming test (FST), novelty-suppressed feeding test (NSFT), and elevated plus maze (EPM) test. In addition, schizandrin remarkably reduced the oxidative stress due to its potential to enhance the levels of decreased CAT, GSH/GSSG, SOD, and increased MDA in peripheral and brain, the antioxidant activities might be related with the Nrf2/HO-1 pathway. Furthermore, schizandrin could dramatically inhibit the neuroinflammation in mice by reducing pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) through regulating NF-κB/NLRP3/Iba-1 signaling. Besides, the elevated levels of ammonia, AST, and ALT were significantly reduced by schizandrin.Conclusion: The present data revealed that hyperammonemia produced due to liver injury-induced oxidative stress and neuroinflammation in the hippocampus and prefrontal cortex resulting in anxiety and depression were improved by schizandrin.
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Affiliation(s)
- Tingxu Yan
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, China
| | - Bing Liu
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
| | - Fuyuan Li
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
| | - Bo Wu
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, China
| | - Feng Xiao
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, China
| | - Bosai He
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, China
| | - Ying Jia
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, China
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Xu C, Jia Q, Zhang L, Wang Z, Zhu S, Wang X, Liu Y, Li M, Zhang J, Wang X, Zhang J, Sun Q, Wang K, Zhu H, Duan L. Multiomics Study of Gut Bacteria and Host Metabolism in Irritable Bowel Syndrome and Depression Patients. Front Cell Infect Microbiol 2020; 10:580980. [PMID: 33194817 PMCID: PMC7658686 DOI: 10.3389/fcimb.2020.580980] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 10/07/2020] [Indexed: 12/20/2022] Open
Abstract
Background and Aims Irritable bowel syndrome (IBS) and depression have high tendencies of comorbidity. In particular, diarrhea-predominant IBS (IBS-D) and depression exhibit similar fecal microbiota signatures, yet little is known about their pathogenic mechanism. Here, we propose that the differences in structure and composition of IBS-D and depression gut microbiota give rise to different downstream functions, which lead to distinct clinical phenotypes via host metabolism and further influence the interaction of brain–gut axis. Methods We performed multiomics study, including fecal metagenome-wide sequencing and serum metabolomics profiling in 65 individuals with IBS-D (n=22), depression (n=15), comorbid patients (n=13), and healthy controls (n=15). We analyzed functional genes contributed by the primary genus and evaluated their correlations with clinical indices and host metabolites. Results Metagenomic analysis revealed 26 clusters of orthologous groups of protein (COG) categories consisting of a total of 4,631 functional genes. Trehalose and maltose hydrolase (COG1554) and fucose permease (COG0738) were the most relevant and enriched functional genes in the IBS-D patients; urease accessory proteins UreE (COG2371) was that in the depression patients. Context based genome annotation suggest that an alteration of Escherichia coli and Enterobacter cloacae in IBS-D and depression respectively may be responsible for the enrichment described above. Correlation with host metabolites, such as maltotriose and isomaltose in carbohydrate metabolism and anandamide in neuroactive metabolism, drew further connections between these findings. Conclusions These changes led us to propose a connection between genomic signatures and clinical differences observed in IBS-D and depression. Our findings provide further insights into the involvement of gut microbiota in diseases related to brain–gut disorder.
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Affiliation(s)
- Congmin Xu
- Department of Biomedical Engineering, College of Engineering, and Center for Quantitative Biology, Peking University, Beijing, China
| | - Qiong Jia
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Lu Zhang
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Zhe Wang
- Department of Biomedical Engineering, College of Engineering, and Center for Quantitative Biology, Peking University, Beijing, China
| | - Shiwei Zhu
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Xiaoqi Wang
- Department of Biomedical Engineering, College of Engineering, and Center for Quantitative Biology, Peking University, Beijing, China
| | - Yixuan Liu
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Mo Li
- Department of Biomedical Engineering, College of Engineering, and Center for Quantitative Biology, Peking University, Beijing, China
| | - Jingjing Zhang
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Xiangqun Wang
- Department of Psychiatry, Institute of Mental Health, Peking University, Beijing, China
| | - Jindong Zhang
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Qinghua Sun
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Kun Wang
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Huaiqiu Zhu
- Department of Biomedical Engineering, College of Engineering, and Center for Quantitative Biology, Peking University, Beijing, China
| | - Liping Duan
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
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Pang L, Yang C, Cao X, Tian Q, Li B. Experimental Investigation of Air Quality in a Subway Station with Fully Enclosed Platform Screen Doors. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:E5213. [PMID: 32707686 PMCID: PMC7400133 DOI: 10.3390/ijerph17145213] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/13/2020] [Accepted: 07/15/2020] [Indexed: 12/12/2022]
Abstract
In this study, the indoor air quality (IAQ) was investigated in a subway station with fully enclosed platform screen doors in Beijing, China. Eight indoor air pollutants, including PM2.5, PM10, SO2 (sulfur dioxide), NO2 (nitrogen dioxide), NH3 (ammonia), CO (carbon monoxide), CH2O (formaldehyde) and TVOC (total volatile organic compound), were measured for six consecutive days in October 2019. The results indicated that the IAQ in the subway station was basically stable at good levels for most times during the whole measurement period. All eight indoor air pollutants were far below their corresponding maximum allowable concentrations, except for the PM2.5 concentrations, which occasionally exceeded the concentration limits. The concentrations of indoor air pollutants in the subway station were basically within the corresponding standards. The correlation analyses showed that outdoor air pollutants have important influences on indoor air pollutants. The concentrations of PM10, PM2.5, SO2, NO2 and CO in the subway station were positively correlated with their corresponding outdoor concentrations. PM10 was statistically significantly correlated with the passenger flow and train frequency, but the other air pollutants were less impacted by the passenger flow and train frequency.
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Affiliation(s)
- Liping Pang
- School of Aeronautic Science and Engineering, Beihang University, Beijing 100191, China; (L.P.); (C.Y.)
- School of Aero-Engine, Shenyang Aerospace University, Shenyang 110136, China
| | - Chenyuan Yang
- School of Aeronautic Science and Engineering, Beihang University, Beijing 100191, China; (L.P.); (C.Y.)
| | - Xiaodong Cao
- School of Aeronautic Science and Engineering, Beihang University, Beijing 100191, China; (L.P.); (C.Y.)
| | - Qing Tian
- School of Information Science and Technology, North China University of Technology, Beijing 100144, China; (Q.T.); (B.L.)
| | - Bo Li
- School of Information Science and Technology, North China University of Technology, Beijing 100144, China; (Q.T.); (B.L.)
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Khan A, Shal B, Naveed M, Shah FA, Atiq A, Khan NU, Kim YS, Khan S. Matrine ameliorates anxiety and depression-like behaviour by targeting hyperammonemia-induced neuroinflammation and oxidative stress in CCl4 model of liver injury. Neurotoxicology 2019; 72:38-50. [DOI: 10.1016/j.neuro.2019.02.002] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 12/26/2018] [Accepted: 02/04/2019] [Indexed: 02/06/2023]
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Sasaki K, Furusawa H, Nagamine K, Tokito S. Charge-accumulative Potentiometric Measurements for Ammonia Detection Using an Enzymatic Cascade Reaction on a Prussian Blue Electrode. CHEM LETT 2018. [DOI: 10.1246/cl.180692] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Kai Sasaki
- Graduate School of Organic Materials Science, Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510, Japan
- Research Center for Organic Electronics (ROEL), Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510, Japan
| | - Hiroyuki Furusawa
- Research Center for Organic Electronics (ROEL), Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510, Japan
- Innovative Flex Course for Frontier Organic Material Systems (iFront), Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510, Japan
- Graduate School of Science and Engineering, Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510, Japan
| | - Kuniaki Nagamine
- Graduate School of Organic Materials Science, Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510, Japan
- Research Center for Organic Electronics (ROEL), Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510, Japan
| | - Shizuo Tokito
- Graduate School of Organic Materials Science, Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510, Japan
- Research Center for Organic Electronics (ROEL), Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510, Japan
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Liang S, Wu X, Jin F. Gut-Brain Psychology: Rethinking Psychology From the Microbiota-Gut-Brain Axis. Front Integr Neurosci 2018; 12:33. [PMID: 30271330 PMCID: PMC6142822 DOI: 10.3389/fnint.2018.00033] [Citation(s) in RCA: 159] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 07/19/2018] [Indexed: 12/12/2022] Open
Abstract
Mental disorders and neurological diseases are becoming a rapidly increasing medical burden. Although extensive studies have been conducted, the progress in developing effective therapies for these diseases has still been slow. The current dilemma reminds us that the human being is a superorganism. Only when we take the human self and its partner microbiota into consideration at the same time, can we better understand these diseases. Over the last few centuries, the partner microbiota has experienced tremendous change, much more than human genes, because of the modern transformations in diet, lifestyle, medical care, and so on, parallel to the modern epidemiological transition. Existing research indicates that gut microbiota plays an important role in this transition. According to gut-brain psychology, the gut microbiota is a crucial part of the gut-brain network, and it communicates with the brain via the microbiota-gut-brain axis. The gut microbiota almost develops synchronously with the gut-brain, brain, and mind. The gut microbiota influences various normal mental processes and mental phenomena, and is involved in the pathophysiology of numerous mental and neurological diseases. Targeting the microbiota in therapy for these diseases is a promising approach that is supported by three theories: the gut microbiota hypothesis, the "old friend" hypothesis, and the leaky gut theory. The effects of gut microbiota on the brain and behavior are fulfilled by the microbiota-gut-brain axis, which is mainly composed of the nervous pathway, endocrine pathway, and immune pathway. Undoubtedly, gut-brain psychology will bring great enhancement to psychology, neuroscience, and psychiatry. Various microbiota-improving methods including fecal microbiota transplantation, probiotics, prebiotics, a healthy diet, and healthy lifestyle have shown the capability to promote the function of the gut-brain, microbiota-gut-brain axis, and brain. It will be possible to harness the gut microbiota to improve brain and mental health and prevent and treat related diseases in the future.
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Affiliation(s)
- Shan Liang
- Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
| | - Xiaoli Wu
- Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Feng Jin
- Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
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