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Balaji S, Woodward TJ, Richter E, Chang A, Otiz R, Kulkarni PP, Balaji K, Bradshaw HB, Ferris CF. Palmitoylethanolamide causes dose-dependent changes in brain function and the lipidome. Front Neurosci 2024; 18:1506352. [PMID: 39664446 PMCID: PMC11631868 DOI: 10.3389/fnins.2024.1506352] [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: 10/07/2024] [Accepted: 11/11/2024] [Indexed: 12/13/2024] Open
Abstract
The present studies were undertaken to understand the effects of the commonly used nutraceutical PEA on brain function and lipid chemistry. These studies using MRI and broad-scale lipidomics are without precedent in animal or human research. During the MRI scanning session awake rats were given one of three doses of PEA (3, 10, or 30 mg/kg) or vehicle and imaged for changes in BOLD signal and functional connectivity. There was an inverse dose-response for negative BOLD suggesting a decrease in brain activity affecting the prefrontal ctx, sensorimotor cortices, basal ganglia and thalamus. However, there was a dose-dependent increase in functional connectivity in these same brain areas. Plasma and CNS levels of PEA and over 80 endogenous lipids (endolipids) were determined post treatment. While levels of PEA in the CNS were significantly higher after 30 mg/kg treatment, levels of the endocannabinoid, Anandamide, and at least 20 additional endolipids, were significantly lower across the CNS. Of the 78 endolipids that were detected in all CNS regions evaluated, 51 of them were modulated in at least one of the regions. Taken together, the functional connectivity and lipidomics changes provide evidence that PEA treatment drives substantial changes in CNS activity.
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Affiliation(s)
- Shreyas Balaji
- Center for Translational Neuroimaging, Northeastern University, Boston, MA, United States
| | - Taylor J. Woodward
- Department of Psychological and Brain Sciences, Program in Neuroscience, Indiana University, Bloomington, IN, United States
| | - Emily Richter
- Department of Psychological and Brain Sciences, Program in Neuroscience, Indiana University, Bloomington, IN, United States
| | - Arnold Chang
- Center for Translational Neuroimaging, Northeastern University, Boston, MA, United States
| | - Richard Otiz
- Department of Psychology, Northern Illinois University, DeKalb, IL, United States
| | - Praveen P. Kulkarni
- Center for Translational Neuroimaging, Northeastern University, Boston, MA, United States
| | - Kaashyap Balaji
- Center for Translational Neuroimaging, Northeastern University, Boston, MA, United States
| | - Heather B. Bradshaw
- Department of Psychological and Brain Sciences, Program in Neuroscience, Indiana University, Bloomington, IN, United States
| | - Craig F. Ferris
- Center for Translational Neuroimaging, Northeastern University, Boston, MA, United States
- Departments of Psychology and Pharmaceutical Sciences, Northeastern University Boston, Boston, MA, United States
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2
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Marusak HA, Ely SL, Zundel CG, Gowatch LC, Shampine M, Carpenter C, Tamimi R, Jaster AM, Shakir T, May L, deRoon-Cassini TA, Hillard CJ. Endocannabinoid dysregulation and PTSD in urban adolescents: Associations with anandamide concentrations and FAAH genotype. Psychopharmacology (Berl) 2024:10.1007/s00213-024-06717-3. [PMID: 39547971 DOI: 10.1007/s00213-024-06717-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 11/05/2024] [Indexed: 11/17/2024]
Abstract
BACKGROUND The endocannabinoid system, which regulates fear- and anxiety-related behaviors, is dysregulated in adults with posttraumatic stress disorder (PTSD), as indicated by higher circulating anandamide (AEA) concentrations. The C385A (rs324420) polymorphism in the fatty acid amide hydrolase (FAAH) gene, which catabolizes AEA, is linked to higher AEA concentrations and greater PTSD symptoms in adults. Given that adolescence is a critical period during which trauma and psychiatric disorders emerge, understanding this relationship in youth is essential. This study examines PTSD symptoms, AEA concentrations, and FAAH genotype in a diverse adolescent sample. METHODS This study included 102 Detroit-area adolescents (M ± SD = 13.33 ± 2.21 years, 54.9% female) and their parents/guardians. The sample consisted of 40.2% White Non-Hispanic, 34.3% Black Non-Hispanic, 6.9% White Hispanic, 4.9% Asian/Pacific Islander, and 12.7% Biracial adolescents. Trauma exposure and PTSD symptoms were assessed using the UCLA PTSD Reaction Index for DSM-5. Plasma concentrations of AEA were measured by liquid chromatography-tandem mass spectrometry, and FAAH genotype was determined from saliva samples and high-throughput screening. RESULTS The majority (90%) of adolescents reported trauma exposure, and 20% met PTSD criteria. Higher AEA concentrations were associated with more severe PTSD symptoms (p = 0.009), especially hyperarousal. The FAAH A-allele (present in 52.5% of participants) was associated with higher AEA concentrations (2.11 ± 0.69 pmol/ml, p = 0.013) and greater PTSD severity (22.65 ± 15.931, p = 0.027), particularly those with the reexperiencing cluster, compared to the CC genotype (1.79 ± 0.66 pmol/ml and 15.87 ±+ 13.043, respectively). CONCLUSION Elevated AEA concentrations and the FAAH A-allele were associated with greater PTSD symptom severity in urban adolescents. These findings suggest endocannabinoid dysregulation may play a role in adolescent PTSD, highlighting the need for further research and targeted interventions.
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Affiliation(s)
- Hilary A Marusak
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 3901 Chrysler Service Dr., Suite 2B, Detroit, MI, 48201, USA.
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA.
- Merrill Palmer Skillman Institute for Child and Family Development, Detroit, MI, USA.
| | - Samantha L Ely
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 3901 Chrysler Service Dr., Suite 2B, Detroit, MI, 48201, USA
- Merrill Palmer Skillman Institute for Child and Family Development, Detroit, MI, USA
| | - Clara G Zundel
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 3901 Chrysler Service Dr., Suite 2B, Detroit, MI, 48201, USA
| | - Leah C Gowatch
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 3901 Chrysler Service Dr., Suite 2B, Detroit, MI, 48201, USA
| | - MacKenna Shampine
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 3901 Chrysler Service Dr., Suite 2B, Detroit, MI, 48201, USA
| | - Carmen Carpenter
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 3901 Chrysler Service Dr., Suite 2B, Detroit, MI, 48201, USA
| | - Reem Tamimi
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 3901 Chrysler Service Dr., Suite 2B, Detroit, MI, 48201, USA
| | - Alaina M Jaster
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 3901 Chrysler Service Dr., Suite 2B, Detroit, MI, 48201, USA
| | - Tehmina Shakir
- Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 3901 Chrysler Service Dr., Suite 2B, Detroit, MI, 48201, USA
| | - Len May
- Endocanna Health, Burbank, CA, USA
| | | | - Cecilia J Hillard
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
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Seramur ME, Sink S, Cox AO, Furdui CM, Key CCC. ABHD4 regulates adipocyte differentiation in vitro but does not affect adipose tissue lipid metabolism in mice. J Lipid Res 2023; 64:100405. [PMID: 37352974 PMCID: PMC10400869 DOI: 10.1016/j.jlr.2023.100405] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 05/02/2023] [Accepted: 06/10/2023] [Indexed: 06/25/2023] Open
Abstract
Alpha/beta hydrolase domain-containing protein 4 (ABHD4) catalyzes the deacylation of N-acyl phosphatidyl-ethanolamine (NAPE) and lyso-NAPE to produce glycerophospho-N-acyl ethanolamine (GP-NAE). Through a variety of metabolic enzymes, NAPE, lyso-NAPE, and GP-NAE are ultimately converted into NAE, a group of bioactive lipids that control many physiological processes including inflammation, cognition, food intake, and lipolysis (i.e., oleoylethanolamide or OEA). In a diet-induced obese mouse model, adipose tissue Abhd4 gene expression positively correlated with adiposity. However, it is unknown whether Abhd4 is a causal or a reactive gene to obesity. To fill this knowledge gap, we generated an Abhd4 knockout (KO) 3T3-L1 pre-adipocyte. During adipogenic stimulation, Abhd4 KO pre-adipocytes had increased adipogenesis and lipid accumulation, suggesting Abhd4 is responding to (a reactive gene), not contributing to (not a causal gene), adiposity, and may serve as a mechanism for protecting against obesity. However, we did not observe any differences in adiposity and metabolic outcomes between whole-body Abhd4 KO or adipocyte-specific Abhd4 KO mice and their littermate control mice (both male and female) on chow or a high-fat diet. This might be because we found that deletion of Abhd4 did not affect NAE such as OEA production, even though Abhd4 was highly expressed in adipose tissue and correlated with fasting adipose OEA levels and lipolysis. These data suggest that ABHD4 regulates adipocyte differentiation in vitro but does not affect adipose tissue lipid metabolism in mice despite nutrient overload, possibly due to compensation from other NAPE and NAE metabolic enzymes.
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Affiliation(s)
- Mary E Seramur
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA
| | - Sandy Sink
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA
| | - Anderson O Cox
- Wake Forest Baptist Comprehensive Cancer Center Proteomics and Metabolomics Shared Resource, Wake Forest University School of Medicine, Winston Salem, NC, USA
| | - Cristina M Furdui
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA
| | - Chia-Chi Chuang Key
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA.
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Higuchi S, Wood C, Nasiri RH, Giddla LJ, Molina V, Diarra R, DiPatrizio NV, Kawamura A, Haeusler RA. The 16α-hydroxylated Bile Acid, Pythocholic Acid Decreases Food Intake and Increases Oleoylethanolamide in Male Mice. Endocrinology 2023; 164:bqad116. [PMID: 37490843 PMCID: PMC10407715 DOI: 10.1210/endocr/bqad116] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 07/20/2023] [Accepted: 07/21/2023] [Indexed: 07/27/2023]
Abstract
Modulation of bile acid (BA) structure is a potential strategy for obesity and metabolic disease treatment. BAs act not only as signaling molecules involved in energy expenditure and glucose homeostasis, but also as regulators of food intake. The structure of BAs, particularly the position of the hydroxyl groups of BAs, impacts food intake partly by intestinal effects: (1) modulating the activity of N-acyl phosphatidylethanolamine phospholipase D, which produces the anorexigenic bioactive lipid oleoylethanolamide (OEA) or (2) regulating lipid absorption and the gastric emptying-satiation pathway. We hypothesized that 16α-hydroxylated BAs uniquely regulate food intake because of the long intermeal intervals in snake species in which these BAs are abundant. However, the effects of 16α-hydroxylated BAs in mammals are completely unknown because they are not naturally found in mammals. To test the effect of 16α-hydroxylated BAs on food intake, we isolated the 16α-hydroxylated BA pythocholic acid from ball pythons (Python regius). Pythocholic acid or deoxycholic acid (DCA) was given by oral gavage in mice. DCA is known to increase N-acyl phosphatidylethanolamine phospholipase D activity better than other mammalian BAs. We evaluated food intake, OEA levels, and gastric emptying in mice. We successfully isolated pythocholic acid from ball pythons for experimental use. Pythocholic acid treatment significantly decreased food intake in comparison to DCA treatment, and this was associated with increased jejunal OEA, but resulted in no change in gastric emptying or lipid absorption. The exogenous BA pythocholic acid is a novel regulator of food intake and the satiety signal for OEA in the mouse intestine.
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Affiliation(s)
- Sei Higuchi
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
- Naomi Berrie Diabetes Center and Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA
| | - Courtney Wood
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521, USA
| | - Raidah H Nasiri
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Leela J Giddla
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Valentina Molina
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Rokia Diarra
- Department of Biological Sciences, St. John's University, Queens, NY 11439, USA
| | - Nicholas V DiPatrizio
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521, USA
| | - Akira Kawamura
- Department of Chemistry, Hunter College of CUNY, New York, NY 10065, USA
| | - Rebecca A Haeusler
- Naomi Berrie Diabetes Center and Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA
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Zhao JY, Yuan XK, Luo RZ, Wang LX, Gu W, Yamane D, Feng H. Phospholipase A and acyltransferase 4/retinoic acid receptor responder 3 at the intersection of tumor suppression and pathogen restriction. Front Immunol 2023; 14:1107239. [PMID: 37063830 PMCID: PMC10102619 DOI: 10.3389/fimmu.2023.1107239] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 03/22/2023] [Indexed: 04/03/2023] Open
Abstract
Phospholipase A and acyltransferase (PLAAT) 4 is a class II tumor suppressor with phospholipid metabolizing abilities. It was characterized in late 2000s, and has since been referred to as 'tazarotene-induced gene 3' (TIG3) or 'retinoic acid receptor responder 3' (RARRES3) as a key downstream effector of retinoic acid signaling. Two decades of research have revealed the complexity of its function and regulatory roles in suppressing tumorigenesis. However, more recent findings have also identified PLAAT4 as a key anti-microbial effector enzyme acting downstream of interferon regulatory factor 1 (IRF1) and interferons (IFNs), favoring protection from virus and parasite infections. Unveiling the molecular mechanisms underlying its action may thus open new therapeutic avenues for the treatment of both cancer and infectious diseases. Herein, we aim to summarize a brief history of PLAAT4 discovery, its transcriptional regulation, and the potential mechanisms in tumor prevention and anti-pathogen defense, and discuss potential future directions of PLAAT4 research toward the development of therapeutic approaches targeting this enzyme with pleiotropic functions.
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Affiliation(s)
- Jian-Yong Zhao
- Hospital of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Cangzhou, Hebei, China
| | - Xiang-Kun Yuan
- Hospital of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Cangzhou, Hebei, China
| | - Rui-Zhen Luo
- Hospital of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Cangzhou, Hebei, China
| | - Li-Xin Wang
- Hospital of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Cangzhou, Hebei, China
| | - Wei Gu
- School of Medicine, Chongqing University, Chongqing, China
| | - Daisuke Yamane
- Department of Diseases and Infection, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Hui Feng
- School of Medicine, Chongqing University, Chongqing, China
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6
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Lange T, Depmeier T, Strünker T, Lehr M. HPLC fluorescence assay for measuring the activity of NAPE-PLD and the action of inhibitors affecting this enzyme. J Pharm Biomed Anal 2023; 229:115354. [PMID: 37003086 DOI: 10.1016/j.jpba.2023.115354] [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: 01/23/2023] [Revised: 03/16/2023] [Accepted: 03/20/2023] [Indexed: 04/03/2023]
Abstract
N-Acyl phosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD) is the major enzyme for the biosynthesis of the endocannabinoid anandamide. The role of NAPE-PLD in various physiological and pathophysiological conditions is currently under investigation. For example, the enzyme might be involved in the control of neuronal activity, embryonic development and pregnancy, and prostate cancer. We synthesized a novel NAPE-PLD substrate with a fluorogenic pyrene substituent at the N-acyl residue as tool compound for studying this enzyme. As shown by HPLC with fluorescence detection, in rat brain microsomes the substrate was transformed into the expected pyrene-labeled N-acylethanolamine (NAE), but minor amounts of three by-products could also be detected. In the presence of pan-serine hydrolase and secretory phospholipase A2 inhibitors, the generation of these compounds, whose identity was verified using reference substances, was abolished. Based on these results, a method for determining the activity of NAPE-PLD was developed, validated, and applied to evaluate the action of known inhibitors of this enzyme. With human sperm, it was shown that the fluorescent substrate can also be used to study NAPE metabolism in intact cells.
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Affiliation(s)
- Thomas Lange
- Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstrasse 48, 48149 Münster, Germany
| | - Tim Depmeier
- Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstrasse 48, 48149 Münster, Germany
| | - Timo Strünker
- Centre of Reproductive Medicine and Andrology, University Hospital Münster, University of Münster, Domagkstrasse 11, 48149 Münster, Germany
| | - Matthias Lehr
- Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstrasse 48, 48149 Münster, Germany.
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7
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Martinez Ramirez CE, Ruiz-Pérez G, Stollenwerk TM, Behlke C, Doherty A, Hillard CJ. Endocannabinoid signaling in the central nervous system. Glia 2023; 71:5-35. [PMID: 36308424 PMCID: PMC10167744 DOI: 10.1002/glia.24280] [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: 02/01/2022] [Revised: 09/02/2022] [Accepted: 09/29/2022] [Indexed: 11/07/2022]
Abstract
It is hard to overestimate the influence of the endocannabinoid signaling (ECS) system on central nervous system (CNS) function. In the 40 years since cannabinoids were found to trigger specific cell signaling cascades, studies of the ECS system continue to cause amazement, surprise, and confusion! CB1 cannabinoid receptors are expressed widely in the CNS and regulate cell-cell communication via effects on the release of both neurotransmitters and gliotransmitters. CB2 cannabinoid receptors are difficult to detect in the CNS but seem to "punch above their weight" as compounds targeting these receptors have significant effects on inflammatory state and behavior. Positive and negative allosteric modulators for both receptors have been identified and examined in preclinical studies. Concentrations of the endocannabinoid ligands, N-arachidonoylethanolamine and 2-arachidonoylglycerol (2-AG), are regulated by a combination of enzymatic synthesis and degradation and inhibitors of these processes are available and making their way into clinical trials. Importantly, ECS regulates many essential brain functions, including regulation of reward, anxiety, inflammation, motor control, and cellular development. While the field is on the cusp of preclinical discoveries providing impactful clinical and therapeutic insights into many CNS disorders, there is still much to be learned about this remarkable and versatile modulatory system.
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Affiliation(s)
- César E Martinez Ramirez
- Neuroscience Research Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Gonzalo Ruiz-Pérez
- Neuroscience Research Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Todd M Stollenwerk
- Neuroscience Research Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Christina Behlke
- Neuroscience Research Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Ashley Doherty
- Neuroscience Research Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Cecilia J Hillard
- Neuroscience Research Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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Chen C, Qian J, Zhao X, Han X, Tang X, Gao J, Liu Y, Jiang J, Wen B. Metabolic profiling of emodin drug-induced liver injury and silybin treatment in rats using UPLC-Q-TOF-MS: A metabolomic and mechanistic approach. Biomed Chromatogr 2022; 36:e5469. [PMID: 35904380 DOI: 10.1002/bmc.5469] [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: 04/19/2022] [Revised: 07/22/2022] [Accepted: 07/25/2022] [Indexed: 11/08/2022]
Abstract
Silybin, an active component in the plant Silybum marianum (L.) Gaertn. is commonly used to protect against liver disease. We investigated silybin's protective potential in rat liver against emodin-induced liver injury 4wk. Aspartate aminotransferase and direct bilirubin serum biomarkers for liver toxicity were significantly increased and liver histopathology revealed cholestasis and necrosis in rats given emodin only, whereas AST and total bile acid in rats given emodin and silybin simultaneously were changed compared to rats given emodin. Liver gene and protein levels of Cyp7a1 and Bsep for cholesterol metabolism, bile acid synthesis and transport were significantly altered with emodin, where cotreatment with silybin attenuated emodin's adverse effect. Metabolomic analysis with UPLC-Q-TOF-MS determined eight potential metabolite biomarkers in serum, urine, and liver tissue. Network analysis was conducted to conceptualize interplay of genes, metabolites, and metabolic pathways for cholesterol metabolism and bile acid synthesis for liver injury. Overall, rats given only emodin was shown to be a sound model to investigate fat-associated DILI and that cotreatment with silybin prevents fatty liver injury. This metabolomic study reveal that emodin-induced fatty liver injury has disrupted bile acid synthesis, vitamin B6 and glycerophospholipid metabolism pathways, and that silybin ameliorates liver injury on these compromised pathways.
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Affiliation(s)
- Chang Chen
- Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, P. R. China
| | - Jiahui Qian
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Xinyu Zhao
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Xuyang Han
- Beijing Institute of Traditional Chinese Medicine, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, P. R. China
| | - Xu Tang
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Junfeng Gao
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, P. R. China
| | - Yan Liu
- Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, P. R. China
| | - Jinzhu Jiang
- Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, P. R. China
| | - Binyu Wen
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, P. R. China
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9
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Cifelli P, Ruffolo G, Ceccanti M, Cambieri C, Libonati L, Palma E, Inghilleri M. Classical and Unexpected Effects of Ultra-Micronized PEA in Neuromuscular Function. Biomolecules 2022; 12:biom12060758. [PMID: 35740883 PMCID: PMC9221058 DOI: 10.3390/biom12060758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 05/23/2022] [Accepted: 05/27/2022] [Indexed: 02/06/2023] Open
Abstract
Recently, the endocannabinoid system has attracted growing attention from the scientific community for its involvement in homeostatic and pathological processes as they pertains to human physiology. Among the constituents of the endocannabinoid system, the molecule palmitoyl ethanolamide has particularly been studied for its ability to reduce several inflammatory processes involving the central nervous system. Here, we reviewed published literature and summarized the main targets of the palmitoyl ethanolamide, along with its unique possible mechanisms for restoring correct functioning of the central nervous system. Moreover, we have highlighted a less-known characteristic of palmitoyl ethanolamide, namely its ability to modulate the function of the neuromuscular junction by binding to acetylcholine receptors in different experimental conditions. Indeed, there are several studies that have highlighted how ultra-micronized palmitoyl ethanolamide is an interesting nutraceutical support for the treatment of pathological neuromuscular conditions, specifically when the normal activity of the acetylcholine receptor is altered. Although further multicentric clinical trials are needed to confirm the efficacy of ultra-micronized palmitoyl ethanolamide in improving symptoms of neuromuscular diseases, all the literature reviewed here strongly supports the ability of this endocannabinoid-like molecule to modulate the acetylcholine receptors thus resulting as a valid support for the treatment of human neuromuscular diseases.
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Affiliation(s)
- Pierangelo Cifelli
- Department of Applied Clinical and Biotechnological Sciences, University of L’Aquila, 67100 L’Aquila, Italy
- Correspondence: (P.C.); (M.I.)
| | - Gabriele Ruffolo
- Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome Sapienza, 00185 Rome, Italy; (G.R.); (E.P.)
- IRCCS San Raffaele Roma, 00163 Rome, Italy
| | - Marco Ceccanti
- Department of Human Neuroscience, University of Rome Sapienza, 00185 Rome, Italy; (M.C.); (C.C.); (L.L.)
| | - Chiara Cambieri
- Department of Human Neuroscience, University of Rome Sapienza, 00185 Rome, Italy; (M.C.); (C.C.); (L.L.)
| | - Laura Libonati
- Department of Human Neuroscience, University of Rome Sapienza, 00185 Rome, Italy; (M.C.); (C.C.); (L.L.)
| | - Eleonora Palma
- Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome Sapienza, 00185 Rome, Italy; (G.R.); (E.P.)
| | - Maurizio Inghilleri
- Department of Human Neuroscience, University of Rome Sapienza, 00185 Rome, Italy; (M.C.); (C.C.); (L.L.)
- Correspondence: (P.C.); (M.I.)
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10
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Effects of Palmitoylethanolamide on Neurodegenerative Diseases: A Review from Rodents to Humans. Biomolecules 2022; 12:biom12050667. [PMID: 35625595 PMCID: PMC9138306 DOI: 10.3390/biom12050667] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 04/27/2022] [Accepted: 05/02/2022] [Indexed: 02/06/2023] Open
Abstract
Palmitoylethanolamide (PEA) stands out among endogenous lipid mediators for its neuroprotective, anti-inflammatory, and analgesic functions. PEA belonging to the N-acetylanolamine class of phospholipids was first isolated from soy lecithin, egg yolk, and peanut flour. It is currently used for the treatment of different types of neuropathic pain, such as fibromyalgia, osteoarthritis, carpal tunnel syndrome, and many other conditions. The properties of PEA, especially of its micronized or ultra-micronized forms maximizing bioavailability and efficacy, have sparked a series of innovative research to evaluate its possible application as therapeutic agent for neurodegenerative diseases. Neurodegenerative diseases are widespread throughout the world, and although they are numerous and different, they share common patterns of conditions that result from progressive damage to the brain areas involved in mobility, muscle coordination and strength, mood, and cognition. The present review is aimed at illustrating in vitro and in vivo research, as well as human studies, using PEA treatment, alone or in combination with other compounds, in the presence of neurodegeneration. Namely, attention has been paid to the effects of PEA in counteracting neuroinflammatory conditions and in slowing down the progression of diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Frontotemporal dementia, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis. Literature research demonstrated the efficacy of PEA in addressing the damage typical of major neurodegenerative diseases.
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11
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Inflammation and Nitro-oxidative Stress as Drivers of Endocannabinoid System Aberrations in Mood Disorders and Schizophrenia. Mol Neurobiol 2022; 59:3485-3503. [PMID: 35347586 DOI: 10.1007/s12035-022-02800-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 03/13/2022] [Indexed: 01/02/2023]
Abstract
The endocannabinoid system (ECS) is composed of the endocannabinoid ligands anandamide (AEA) and 2-arachidonoylgycerol (2-AG), their target cannabinoid receptors (CB1 and CB2) and the enzymes involved in their synthesis and metabolism (N-acyltransferase and fatty acid amide hydrolase (FAAH) in the case of AEA and diacylglycerol lipase (DAGL) and monoacylglycerol lipase (MAGL) in the case of 2-AG). The origins of ECS dysfunction in major neuropsychiatric disorders remain to be determined, and this paper explores the possibility that they may be associated with chronically increased nitro-oxidative stress and activated immune-inflammatory pathways, and it examines the mechanisms which might be involved. Inflammation and nitro-oxidative stress are associated with both increased CB1 expression, via increased activity of the NADPH oxidases NOX4 and NOX1, and increased CNR1 expression and DNA methylation; and CB2 upregulation via increased pro-inflammatory cytokine levels, binding of the transcription factor Nrf2 to an antioxidant response element in the CNR2 promoter region and the action of miR-139. CB1 and CB2 have antagonistic effects on redox signalling, which may result from a miRNA-enabled negative feedback loop. The effects of inflammation and oxidative stress are detailed in respect of AEA and 2-AG levels, via effects on calcium homeostasis and phospholipase A2 activity; on FAAH activity, via nitrosylation/nitration of functional cysteine and/or tyrosine residues; and on 2-AG activity via effects on MGLL expression and MAGL. Finally, based on these detailed molecular neurobiological mechanisms, it is suggested that cannabidiol and dimethyl fumarate may have therapeutic potential for major depressive disorder, bipolar disorder and schizophrenia.
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12
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Falasca V, Falasca M. Targeting the Endocannabinoidome in Pancreatic Cancer. Biomolecules 2022; 12:320. [PMID: 35204820 PMCID: PMC8869154 DOI: 10.3390/biom12020320] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/08/2022] [Accepted: 02/08/2022] [Indexed: 02/07/2023] Open
Abstract
Pancreatic Ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is an aggressive and lethal form of cancer with a very high mortality rate. High heterogeneity, asymptomatic initial stages and a lack of specific diagnostic markers result in an end-stage diagnosis when the tumour has locally advanced or metastasised. PDAC is resistant to most of the available chemotherapy and radiation therapy treatments, making surgery the most potent curative treatment. The desmoplastic tumour microenvironment contributes to determining PDAC pathophysiology, immune response and therapeutic efficacy. The existing therapeutic approaches such as FDA-approved chemotherapeutics, gemcitabine, abraxane and folfirinox, prolong survival marginally and are accompanied by adverse effects. Several studies suggest the role of cannabinoids as anti-cancer agents. Cannabinoid receptors are known to be expressed in pancreatic cells, with a higher expression reported in pancreatic cancer patients. Therefore, pharmacological targeting of the endocannabinoid system might offer therapeutic benefits in pancreatic cancer. In addition, emerging data suggest that cannabinoids in combination with chemotherapy can increase survival in transgenic pancreatic cancer murine models. This review provides an overview of the regulation of the expanded endocannabinoid system, or endocannabinoidome, in PDAC and will explore the potential of targeting this system for novel anticancer approaches.
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Affiliation(s)
- Valerio Falasca
- School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia;
| | - Marco Falasca
- Metabolic Signalling Group, Curtin Health Innovation Research Institute, Curtin Medical School, Curtin University, Perth, WA 6102, Australia
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13
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Repurposing Peroxisome Proliferator-Activated Receptor Agonists in Neurological and Psychiatric Disorders. Pharmaceuticals (Basel) 2021; 14:ph14101025. [PMID: 34681249 PMCID: PMC8538250 DOI: 10.3390/ph14101025] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/05/2021] [Accepted: 10/06/2021] [Indexed: 12/15/2022] Open
Abstract
Common pathophysiological mechanisms have emerged for different neurological and neuropsychiatric conditions. In particular, mechanisms of oxidative stress, immuno-inflammation, and altered metabolic pathways converge and cause neuronal and non-neuronal maladaptative phenomena, which underlie multifaceted brain disorders. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors modulating, among others, anti-inflammatory and neuroprotective genes in diverse tissues. Both endogenous and synthetic PPAR agonists are approved treatments for metabolic and systemic disorders, such as diabetes, fatty liver disease, and dyslipidemia(s), showing high tolerability and safety profiles. Considering that some PPAR-acting drugs permeate through the blood-brain barrier, the possibility to extend their scope from the periphery to central nervous system has gained interest in recent years. Here, we review preclinical and clinical evidence that PPARs possibly exert a neuroprotective role, thereby providing a rationale for repurposing PPAR-targeting drugs to counteract several diseases affecting the central nervous system.
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14
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Nkiliza A, Parks M, Cseresznye A, Oberlin S, Evans JE, Darcey T, Aenlle K, Niedospial D, Mullan M, Crawford F, Klimas N, Abdullah L. Sex-specific plasma lipid profiles of ME/CFS patients and their association with pain, fatigue, and cognitive symptoms. J Transl Med 2021; 19:370. [PMID: 34454515 PMCID: PMC8401202 DOI: 10.1186/s12967-021-03035-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 08/09/2021] [Indexed: 12/19/2022] Open
Abstract
Background Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex illness which disproportionally affects females. This illness is associated with immune and metabolic perturbations that may be influenced by lipid metabolism. We therefore hypothesized that plasma lipids from ME/CFS patients will provide a unique biomarker signature of disturbances in immune, inflammation and metabolic processes associated with ME/CFS. Methods Lipidomic analyses were performed on plasma from a cohort of 50 ME/CFS patients and 50 controls (50% males and similar age and ethnicity per group). Analyses were conducted with nano-flow liquid chromatography (nLC) and high-performance liquid chromatography (HPLC) systems coupled with a high mass accuracy ORBITRAP mass spectrometer, allowing detection of plasma lipid concentration ranges over three orders of magnitude. We examined plasma phospholipids (PL), neutral lipids (NL) and bioactive lipids in ME/CFS patients and controls and examined the influence of sex on the relationship between lipids and ME/CFS diagnosis. Results Among females, levels of total phosphatidylethanolamine (PE), omega-6 arachidonic acid-containing PE, and total hexosylceramides (HexCer) were significantly decreased in ME/CFS compared to controls. In males, levels of total HexCer, monounsaturated PE, phosphatidylinositol (PI), and saturated triglycerides (TG) were increased in ME/CFS patients compared to controls. Additionally, omega-6 linoleic acid-derived oxylipins were significantly increased in male ME/CFS patients versus male controls. Principal component analysis (PCA) identified three major components containing mostly PC and a few PE, PI and SM species—all of which were negatively associated with headache and fatigue severity, irrespective of sex. Correlations of oxylipins, ethanolamides and ME/CFS symptom severity showed that lower concentrations of these lipids corresponded with an increase in the severity of headaches, fatigue and cognitive difficulties and that this association was influenced by sex. Conclusion The observed sex-specific pattern of dysregulated PL, NL, HexCer and oxylipins in ME/CFS patients suggests a possible role of these lipids in promoting immune dysfunction and inflammation which may be among the underlying factors driving the clinical presentation of fatigue, chronic pain, and cognitive difficulties in ill patients. Further evaluation of lipid metabolism pathways is warranted to better understand ME/CFS pathogenesis. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-021-03035-6.
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Affiliation(s)
- Aurore Nkiliza
- Roskamp Institute, 2040 Whitfield Ave, Sarasota, FL, 34243, USA. .,James A. Haley Veterans' Hospital, 2040 Whitfield Ave, Tampa, FL, USA.
| | - Megan Parks
- Roskamp Institute, 2040 Whitfield Ave, Sarasota, FL, 34243, USA.,James A. Haley Veterans' Hospital, 2040 Whitfield Ave, Tampa, FL, USA
| | - Adam Cseresznye
- Roskamp Institute, 2040 Whitfield Ave, Sarasota, FL, 34243, USA.,James A. Haley Veterans' Hospital, 2040 Whitfield Ave, Tampa, FL, USA
| | - Sarah Oberlin
- Roskamp Institute, 2040 Whitfield Ave, Sarasota, FL, 34243, USA.,James A. Haley Veterans' Hospital, 2040 Whitfield Ave, Tampa, FL, USA
| | - James E Evans
- Roskamp Institute, 2040 Whitfield Ave, Sarasota, FL, 34243, USA.,James A. Haley Veterans' Hospital, 2040 Whitfield Ave, Tampa, FL, USA
| | - Teresa Darcey
- Roskamp Institute, 2040 Whitfield Ave, Sarasota, FL, 34243, USA.,James A. Haley Veterans' Hospital, 2040 Whitfield Ave, Tampa, FL, USA
| | - Kristina Aenlle
- Institute for NeuroImmune Medicine, VAMC, GRECC, Nova Southeastern University, Miami, USA
| | - Daniel Niedospial
- Roskamp Institute, 2040 Whitfield Ave, Sarasota, FL, 34243, USA.,James A. Haley Veterans' Hospital, 2040 Whitfield Ave, Tampa, FL, USA
| | - Michael Mullan
- Roskamp Institute, 2040 Whitfield Ave, Sarasota, FL, 34243, USA.,James A. Haley Veterans' Hospital, 2040 Whitfield Ave, Tampa, FL, USA
| | - Fiona Crawford
- Roskamp Institute, 2040 Whitfield Ave, Sarasota, FL, 34243, USA.,James A. Haley Veterans' Hospital, 2040 Whitfield Ave, Tampa, FL, USA
| | - Nancy Klimas
- Institute for NeuroImmune Medicine, VAMC, GRECC, Nova Southeastern University, Miami, USA
| | - Laila Abdullah
- Roskamp Institute, 2040 Whitfield Ave, Sarasota, FL, 34243, USA.,James A. Haley Veterans' Hospital, 2040 Whitfield Ave, Tampa, FL, USA
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15
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Morris G, Walder K, Kloiber S, Amminger P, Berk M, Bortolasci CC, Maes M, Puri BK, Carvalho AF. The endocannabinoidome in neuropsychiatry: Opportunities and potential risks. Pharmacol Res 2021; 170:105729. [PMID: 34119623 DOI: 10.1016/j.phrs.2021.105729] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 05/31/2021] [Accepted: 06/09/2021] [Indexed: 02/08/2023]
Abstract
The endocannabinoid system (ECS) comprises two cognate endocannabinoid receptors referred to as CB1R and CB2R. ECS dysregulation is apparent in neurodegenerative/neuro-psychiatric disorders including but not limited to schizophrenia, major depressive disorder and potentially bipolar disorder. The aim of this paper is to review mechanisms whereby both receptors may interact with neuro-immune and neuro-oxidative pathways, which play a pathophysiological role in these disorders. CB1R is located in the presynaptic terminals of GABAergic, glutamatergic, cholinergic, noradrenergic and serotonergic neurons where it regulates the retrograde suppression of neurotransmission. CB1R plays a key role in long-term depression, and, to a lesser extent, long-term potentiation, thereby modulating synaptic transmission and mediating learning and memory. Optimal CB1R activity plays an essential neuroprotective role by providing a defense against the development of glutamate-mediated excitotoxicity, which is achieved, at least in part, by impeding AMPA-mediated increase in intracellular calcium overload and oxidative stress. Moreover, CB1R activity enables optimal neuron-glial communication and the function of the neurovascular unit. CB2R receptors are detected in peripheral immune cells and also in central nervous system regions including the striatum, basal ganglia, frontal cortex, hippocampus, amygdala as well as the ventral tegmental area. CB2R upregulation inhibits the presynaptic release of glutamate in several brain regions. CB2R activation also decreases neuroinflammation partly by mediating the transition from a predominantly neurotoxic "M1" microglial phenotype to a more neuroprotective "M2" phenotype. CB1R and CB2R are thus novel drug targets for the treatment of neuro-immune and neuro-oxidative disorders including schizophrenia and affective disorders.
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Affiliation(s)
- Gerwyn Morris
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
| | - Ken Walder
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Deakin University, Centre for Molecular and Medical Research, School of Medicine, Geelong, Australia
| | - Stefan Kloiber
- Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 33 Ursula Franklin Street, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Paul Amminger
- Orygen, Parkville, Victoria, Australia; Centre for Youth Mental Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Michael Berk
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Orygen, The National Centre of Excellence in Youth Mental Health, Centre for Youth Mental Health, Florey Institute for Neuroscience and Mental Health and the Department of Psychiatry, The University of Melbourne, Melbourne, Australia
| | - Chiara C Bortolasci
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia
| | - Michael Maes
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia; Department of Psychiatry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand; Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria
| | | | - Andre F Carvalho
- Deakin University, IMPACT - the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, Australia.
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16
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Chatterjee S, Zhou J, Dasgupta R, Cramer-Blok A, Timmer M, van der Stelt M, Ubbink M. Protein Dynamics Influence the Enzymatic Activity of Phospholipase A/Acyltransferases 3 and 4. Biochemistry 2021; 60:1178-1190. [PMID: 33749246 PMCID: PMC8154263 DOI: 10.1021/acs.biochem.0c00974] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 03/04/2021] [Indexed: 11/29/2022]
Abstract
Phospholipase A/acyltransferase 3 (PLAAT3) and PLAAT4 are enzymes involved in the synthesis of bioactive lipids. Despite sequential and structural similarities, the two enzymes differ in activity and specificity. The relation between the activity and dynamics of the N-terminal domains of PLAAT3 and PLAAT4 was studied. PLAAT3 has a much higher melting temperature and exhibits less nanosecond and millisecond dynamics in the active site, in particular in loop L2(B6), as shown by NMR spectroscopy and molecular dynamics calculations. Swapping the L2(B6) loops between the two PLAAT enzymes results in strongly increased phospholipase activity in PLAAT3 but no reduction in PLAAT4 activity, indicating that this loop contributes to the low activity of PLAAT3. The results show that, despite structural similarity, protein dynamics differ substantially between the PLAAT variants, which can help to explain the activity and specificity differences.
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Affiliation(s)
- Soumya
Deep Chatterjee
- Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333
CC Leiden, The Netherlands
| | - Juan Zhou
- Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333
CC Leiden, The Netherlands
| | - Rubin Dasgupta
- Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333
CC Leiden, The Netherlands
| | - Anneloes Cramer-Blok
- Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333
CC Leiden, The Netherlands
| | - Monika Timmer
- Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333
CC Leiden, The Netherlands
| | - Mario van der Stelt
- Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333
CC Leiden, The Netherlands
| | - Marcellus Ubbink
- Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333
CC Leiden, The Netherlands
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17
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Sagheddu C, Torres LH, Marcourakis T, Pistis M. Endocannabinoid-Like Lipid Neuromodulators in the Regulation of Dopamine Signaling: Relevance for Drug Addiction. Front Synaptic Neurosci 2021; 12:588660. [PMID: 33424577 PMCID: PMC7786397 DOI: 10.3389/fnsyn.2020.588660] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 09/16/2020] [Indexed: 01/11/2023] Open
Abstract
The family of lipid neuromodulators has been rapidly growing, as the use of different -omics techniques led to the discovery of a large number of naturally occurring N-acylethanolamines (NAEs) and N-acyl amino acids belonging to the complex lipid signaling system termed endocannabinoidome. These molecules exert a variety of biological activities in the central nervous system, as they modulate physiological processes in neurons and glial cells and are involved in the pathophysiology of neurological and psychiatric disorders. Their effects on dopamine cells have attracted attention, as dysfunctions of dopamine systems characterize a range of psychiatric disorders, i.e., schizophrenia and substance use disorders (SUD). While canonical endocannabinoids are known to regulate excitatory and inhibitory synaptic inputs impinging on dopamine cells and modulate several dopamine-mediated behaviors, such as reward and addiction, the effects of other lipid neuromodulators are far less clear. Here, we review the emerging role of endocannabinoid-like neuromodulators in dopamine signaling, with a focus on non-cannabinoid N-acylethanolamines and their receptors. Mounting evidence suggests that these neuromodulators contribute to modulate synaptic transmission in dopamine regions and might represent a target for novel medications in alcohol and nicotine use disorder.
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Affiliation(s)
- Claudia Sagheddu
- Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy
| | - Larissa Helena Torres
- Department of Food and Drugs, School of Pharmaceutical Sciences, Federal University of Alfenas, Alfenas, Brazil
| | - Tania Marcourakis
- Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Marco Pistis
- Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy.,Neuroscience Institute, National Research Council of Italy (CNR), Section of Cagliari, Cagliari, Italy
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18
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Modulation of single cell circadian response to NMDA by diacylglycerol lipase inhibition reveals a role of endocannabinoids in light entrainment of the suprachiasmatic nucleus. Neuropharmacology 2021; 185:108455. [PMID: 33444638 DOI: 10.1016/j.neuropharm.2021.108455] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/23/2020] [Accepted: 01/05/2021] [Indexed: 12/11/2022]
Abstract
Suprachiasmatic nucleus (SCN) of the hypothalamus is the master clock that drives circadian rhythms in physiology and behavior and adjusts their timing to external cues. Neurotransmitter glutamate and glutamatergic receptors sensitive to N-methyl-d-aspartate (NMDA) play a dual role in the SCN by coupling astrocytic and neuronal single cell oscillators and by resetting their phase in response to light. Recent reports suggested that signaling by endogenous cannabinoids (ECs) participates in both of these functions. We have previously shown that ECs, such as 2-arachidonoylglycerol (2-AG), act via CB1 receptors to affect the SCN response to light-mimicking NMDA stimulus in a time-dependent manner. We hypothesized that this ability is linked to the circadian regulation of EC signaling. We demonstrate that circadian clock in the rat SCN regulates expression of 2-AG transport, synthesis and degradation enzymes as well as its receptors. Inhibition of the major 2-AG synthesis enzyme, diacylglycerol lipase, enhanced the phase delay and lowered the amplitude of explanted SCN rhythm in response to NMDAR activation. Using microscopic PER2 bioluminescence imaging, we visualized how individual single cell oscillators in different parts of the SCN respond to the DAGL inhibition/NMDAR activation and shape response of the whole pacemaker. Additionally, we present strong evidence that the zero amplitude behavior of the SCN in response to single NMDA stimulus in the middle of subjective night is the result of a loss of rhythm in individual SCN cells. The paper provides new insights into the modulatory role of endocannabinoid signaling during the light entrainment of the SCN.
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19
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Higuchi S, Ahmad TR, Argueta DA, Perez PA, Zhao C, Schwartz GJ, DiPatrizio NV, Haeusler RA. Bile acid composition regulates GPR119-dependent intestinal lipid sensing and food intake regulation in mice. Gut 2020; 69:1620-1628. [PMID: 32111630 PMCID: PMC7423635 DOI: 10.1136/gutjnl-2019-319693] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 01/21/2020] [Accepted: 02/06/2020] [Indexed: 12/23/2022]
Abstract
OBJECTIVES Lipid mediators in the GI tract regulate satiation and satiety. Bile acids (BAs) regulate the absorption and metabolism of dietary lipid in the intestine, but their effects on lipid-regulated satiation and satiety are completely unknown. Investigating this is challenging because introducing excessive BAs or eliminating BAs strongly impacts GI functions. We used a mouse model (Cyp8b1-/- mice) with normal total BA levels, but alterations in the composition of the BA pool that impact multiple aspects of intestinal lipid metabolism. We tested two hypotheses: BAs affect food intake by (1) regulating production of the bioactive lipid oleoylethanolamide (OEA), which enhances satiety; or (2) regulating the quantity and localisation of hydrolysed fat in small intestine, which controls gastric emptying and satiation. DESIGN We evaluated OEA levels, gastric emptying and food intake in wild-type and Cyp8b1-/- mice. We assessed the role of the fat receptor GPR119 in these effects using Gpr119-/- mice. RESULTS Cyp8b1-/- mice on a chow diet showed mild hypophagia. Jejunal OEA production was blunted in Cyp8b1-/- mice, thus these data do not support a role for this pathway in the hypophagia of Cyp8b1-/- mice. On the other hand, Cyp8b1 deficiency decreased gastric emptying, and this was dependent on dietary fat. GPR119 deficiency normalised the gastric emptying, gut hormone levels, food intake and body weight of Cyp8b1-/- mice. CONCLUSION BAs regulate gastric emptying and satiation by determining fat-dependent GPR119 activity in distal intestine.
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Affiliation(s)
- Sei Higuchi
- Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA
| | - Tiara R Ahmad
- Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA
| | - Donovan A Argueta
- Division of Biomedical Sciences, University of California Riverside, Riverside, California, USA
| | - Pedro A Perez
- Division of Biomedical Sciences, University of California Riverside, Riverside, California, USA
| | - Chen Zhao
- Institute of Human Nutrition, Columbia University, New York, New York, USA
| | - Gary J Schwartz
- Departments of Medicine and Neuroscience, Yeshiva University Albert Einstein College of Medicine, Bronx, New York, USA
| | - Nicholas V DiPatrizio
- Division of Biomedical Sciences, University of California Riverside, Riverside, California, USA
| | - Rebecca A Haeusler
- Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA
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20
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Abstract
PURPOSE OF REVIEW Studies have identified several effects of bile acids (BAs) in glucose homeostasis, energy expenditure, and body weight control, through receptor-dependent and independent mechanisms. BAs are produced from cholesterol and characterized by their structures, which result from enzymes in the liver and the gut microbiota. The aim of this review is to characterize the effects of BA structure and composition on diabetes. RECENT FINDINGS The hydroxyl groups of BAs interact with binding pockets of receptors and enzymes that affect glucose homeostasis. Human and animal studies show that BA composition is associated with insulin resistance and food intake regulation. The hydroxylation of BAs and BA composition contributes to glucose regulation. Modulation of BA composition has the potential to improve glucose metabolism.
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Affiliation(s)
- Sei Higuchi
- Naomi Berrie Diabetes Center and Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
- Russ Berrie Pavilion, Room 315, 1150 St. Nicholas Ave., New York, NY, 10032, USA.
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Transcriptome Analysis Reveals Long Intergenic Non-Coding RNAs Contributed to Intramuscular Fat Content Differences between Yorkshire and Wei Pigs. Int J Mol Sci 2020; 21:ijms21051732. [PMID: 32138348 PMCID: PMC7084294 DOI: 10.3390/ijms21051732] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 02/23/2020] [Accepted: 03/01/2020] [Indexed: 12/12/2022] Open
Abstract
Intramuscular fat (IMF) content is closely related to various meat traits, such as tenderness, juiciness, and flavor. The IMF content varies considerably among pig breeds with different genetic backgrounds. Long intergenic non-coding RNAs (lincRNAs) have been widely identified in many species and found to be an important class of regulators that can participate in multiple biological processes. However, the mechanism behind lincRNAs regulation of pig IMF content remains unknown and requires further study. In our study, we identified a total of 156 lincRNAs in the longissimus dorsi muscle of Wei (fat-type) and Yorkshire (lean-type) pigs using previously published data. These identified lincRNAs have shorter transcript length, longer exon length, lower exon number, and lower expression level as compared with protein-coding transcripts. We predicted potential target genes (PTGs) that are potentially regulated by lincRNAs in cis or trans regulation. Gene ontology and pathway analyses indicated that many potential lincRNAs target genes are involved in IMF-related processes or pathways, such as fatty acid catabolic process and adipocytokine signaling pathway. In addition, we analyzed quantitative trait locus (QTL) sites that differentially expressed lincRNAs (DE lincRNAs) between Wei and Yorkshire pigs co-localized. The QTL sites where DE lincRNAs co-localize are mostly related to IMF content. Furthermore, we constructed a co-expressed network between DE lincRNAs and their differentially expressed PTGs (DEPTGs). On the basis of their expression levels, we suggest that many DE lincRNAs can affect IMF development by positively or negatively regulating their PTGs. This study identified and analyzed some lincRNAs- and PTGs-related IMF development of the two pig breeds and provided new insight into research on the roles of lincRNAs in the two types of breeds.
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Edwards G, Arcuri J, Wang H, Ziebarth N, Zode G, Lee RK, Bhattacharya SK. Endogenous ocular lipids as potential modulators of intraocular pressure. J Cell Mol Med 2020; 24:3856-3900. [PMID: 32090468 PMCID: PMC7171415 DOI: 10.1111/jcmm.14975] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 12/04/2019] [Accepted: 12/21/2019] [Indexed: 12/13/2022] Open
Abstract
Elevated intraocular pressure (IOP) is a risk factor in glaucoma, a group of irreversible blinding diseases. Endogenous lipids may be involved in regulation of IOP homeostasis. We present comparative fold analysis of phospholipids and sphingolipids of aqueous humour and trabecular meshwork from human control vs primary open-angle glaucoma and mouse control (normotensive) vs ocular hypertensive state. The fold analysis in control vs disease state was based on ratiometric mass spectrometric data for above classes of lipids. We standardized in vitro assays for rapid characterization of lipids undergoing significant diminishment in disease state. Evaluation of lipids using in vitro assays helped select a finite number of lipids that may potentially expand cellular interstitial space embedded in an artificial matrix or increase fluid flow across a layer of cells. These assays reduced a number of lipids for initial evaluation using a mouse model, DBA/2J with spontaneous IOP elevation. These lipids were then used in other mouse models for confirmation of IOP lowering potential of a few lipids that were found promising in previous assessments. Our results provide selected lipid molecules that can be pursued for further evaluation and studies that may provide insight into their function.
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Affiliation(s)
- Genea Edwards
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA.,Department of Biochemistry and Molecular Biology, University of Miami, Miami, FL, USA
| | - Jennifer Arcuri
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA
| | - Haiyan Wang
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA.,Shanghai Key Laboratory of Ocular Fundus Diseases, Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Noel Ziebarth
- Department of Biomedical Engineering, University of Miami, Miami, FL, USA
| | - Gulab Zode
- North Texas Eye Research Institute, University of North Texas, Fort Worth, TX, USA
| | - Richard K Lee
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA
| | - Sanjoy K Bhattacharya
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA.,Department of Biochemistry and Molecular Biology, University of Miami, Miami, FL, USA
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23
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Sládek M, Houdek P, Sumová A. Circadian profiling reveals distinct regulation of endocannabinoid system in the rat plasma, liver and adrenal glands by light-dark and feeding cycles. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1864:158533. [DOI: 10.1016/j.bbalip.2019.158533] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 09/19/2019] [Accepted: 09/25/2019] [Indexed: 12/17/2022]
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24
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Abstract
Research in the cannabinoid field, namely on phytocannabinoids, the endogenous cannabinoids anandamide and 2-arachidonoyl glycerol and their metabolizing and synthetic enzymes, the cannabinoid receptors, and anandamide-like cannabinoid compounds, has expanded tremendously over the last few years. Numerous endocannabinoid-like compounds have been discovered. The Cannabis plant constituent cannabidiol (CBD) was found to exert beneficial effects in many preclinical disease models ranging from epilepsy, cardiovascular disease, inflammation, and autoimmunity to neurodegenerative and kidney diseases and cancer. CBD was recently approved in the United States for the treatment of rare forms of childhood epilepsy. This has triggered the development of many CBD-based products for human use, often with overstated claims regarding their therapeutic effects. In this article, the recently published research on the chemistry and biological effects of plant cannabinoids (specifically CBD), endocannabinoids, certain long-chain fatty acid amides, and the variety of relevant receptors is critically reviewed.
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Affiliation(s)
- Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20852, USA;
| | - Natalya M Kogan
- Institute for Drug Research, Faculty of Medicine, Hebrew University, Jerusalem 9112102, Israel;
| | - Raphael Mechoulam
- Institute for Drug Research, Faculty of Medicine, Hebrew University, Jerusalem 9112102, Israel;
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25
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Gómez-Boronat M, Isorna E, Armirotti A, Delgado MJ, Piomelli D, de Pedro N. Diurnal Profiles of N-Acylethanolamines in Goldfish Brain and Gastrointestinal Tract: Possible Role of Feeding. Front Neurosci 2019; 13:450. [PMID: 31133788 PMCID: PMC6514144 DOI: 10.3389/fnins.2019.00450] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 04/18/2019] [Indexed: 12/19/2022] Open
Abstract
N-acylethanolamines (NAEs) are a family of endogenous lipid signaling molecules that are involved in regulation of energy homeostasis in vertebrates with a putative role on circadian system. The aim of this work was to study the existence of daily fluctuations in components of NAEs system and their possible dependence on food intake. Specifically, we analyzed the content of oleoylethanolamide (OEA), palmitoylethanolamide (PEA), stearoylethanolamide (SEA), their precursors (NAPEs), as well as the expression of nape-pld (NAEs synthesis enzyme), faah (NAEs degradation enzyme), and pparα (NAEs receptor) in gastrointestinal and brain tissues of goldfish (Carassius auratus) throughout a 24-h cycle. Daily profiles of bmal1a and rev-erbα expression in gastrointestinal tissues were also quantified because these clock genes are also involved in lipid metabolism, are PPAR-targets in mammals, and could be a link between NAEs and circadian system in fish. Gastrointestinal levels of NAEs exhibited daily fluctuations, with a pronounced and rapid postprandial increase, the increment being likely caused by food intake as it is not present in fasted animals. Such periprandial differences were not found in brain, supporting that NAEs mobilization occurs in a tissue-specific manner and suggesting that these three NAEs could be acting as peripheral satiety signals. The abundance of pparα mRNA displayed a daily rhythm in the intestine and the liver, suggesting a possible rhythmicity in the NAEs functionality. The increment of pparα expression during the rest phase can be related with its role stimulating lipid catabolism to obtain energy during the fasting state of the animals. In addition, the clock genes bmal1a and rev-erbα also showed daily rhythms, with a bmal1a increment after feeding, supporting its role as a lipogenic factor. In summary, our data show the existence of all components of NAEs system in fish (OEA, PEA, SEA, precursors, synthesis and degradation enzymes, and the receptor PPARα), supporting the involvement of NAEs as peripheral satiety signals.
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Affiliation(s)
- Miguel Gómez-Boronat
- Departamento de Genética, Fisiología y Microbiología, Unidad Docente de Fisiología Animal, Facultad de Biología, Universidad Complutense de Madrid, Madrid, Spain
| | - Esther Isorna
- Departamento de Genética, Fisiología y Microbiología, Unidad Docente de Fisiología Animal, Facultad de Biología, Universidad Complutense de Madrid, Madrid, Spain
| | - Andrea Armirotti
- Analytical Chemistry Laboratory, Istituto Italiano di Tecnologia, Genoa, Italy
| | - María J Delgado
- Departamento de Genética, Fisiología y Microbiología, Unidad Docente de Fisiología Animal, Facultad de Biología, Universidad Complutense de Madrid, Madrid, Spain
| | - Daniele Piomelli
- Departments of Anatomy and Neurobiology, Pharmacology, and Biological Chemistry, University of California, Irvine, Irvine, CA, United States
| | - Nuria de Pedro
- Departamento de Genética, Fisiología y Microbiología, Unidad Docente de Fisiología Animal, Facultad de Biología, Universidad Complutense de Madrid, Madrid, Spain
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26
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Sabatucci A, Simonetti M, Tortolani D, Angelucci CB, Dainese E, Maccarrone M. Role of Steroids on the Membrane Binding Ability of Fatty Acid Amide Hydrolase. Cannabis Cannabinoid Res 2019; 4:42-50. [PMID: 30944869 PMCID: PMC6446164 DOI: 10.1089/can.2018.0051] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Background: Fatty acid amide hydrolase (FAAH) is a membrane-bound homodimeric enzyme that gets in contact with a lipophilic substrate in the lipid bilayer, and then cleaves it into water soluble products. FAAH plays a critical role in modulating in vivo content and biological activity of endocannabinoids (eCBs), and its function is affected by membrane lipids. Increasing evidence suggests that also steroids can modulate endocannabinoid signaling, both in the central nervous system and at the periphery. Methods: In this study, we interrogated the effect of six steroids with relevant biological activity (testosterone, hydrocortisone, estradiol, pregnenolone, progesterone, and cortisone) on the membrane binding ability of rat FAAH. The experimental data analysis obtained by Fluorescence Resonance Energy Transfer Spectroscopy was paralleled by computational docking analysis. Results: Our data revealed distinct effects of the different steroids on the interaction of rat FAAH with model membranes. Among them, pregnenolone was found to be the most effective in raising rat FAAH affinity for model membranes. A possible binding pocket for steroid molecules was identified by docking analysis in the membrane-embedded region of the enzyme; such a pocket could account for the observed increase of the membrane affinity in the presence of the tested molecules. Conclusions: Overall, the results point to steroids as new regulators of FAAH interaction with membranes, which may impact the biological activity of eCBs.
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Affiliation(s)
- Annalaura Sabatucci
- Faculty of Bioscience, and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Monica Simonetti
- Faculty of Bioscience, and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Daniel Tortolani
- Faculty of Bioscience, and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | | | - Enrico Dainese
- Faculty of Bioscience, and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy.,European Center for Brain Research (CERC)/Santa Lucia Foundation, Rome, Italy
| | - Mauro Maccarrone
- European Center for Brain Research (CERC)/Santa Lucia Foundation, Rome, Italy.,Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
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27
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Yu J, He JQ, Chen DY, Pan QL, Yang JF, Cao HC, Li LJ. Dynamic changes of key metabolites during liver fibrosis in rats. World J Gastroenterol 2019; 25:941-954. [PMID: 30833800 PMCID: PMC6397726 DOI: 10.3748/wjg.v25.i8.941] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 01/10/2019] [Accepted: 01/28/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Fibrosis is the single most important predictor of significant morbidity and mortality in patients with chronic liver disease. Established non-invasive tests for monitoring fibrosis are lacking, and new biomarkers of liver fibrosis and function are needed.
AIM To depict the process of liver fibrosis and look for novel biomarkers for diagnosis and monitoring fibrosis progression.
METHODS CCl4 was used to establish the rat liver fibrosis model. Liver fibrosis process was measured by liver chemical tests, liver histopathology, and Masson’s trichrome staining. The expression levels of two fibrotic markers including α-smooth muscle actin and transforming growth factor β1 were assessed using immunohistochemistry and real-time polymerase chain reaction. Dynamic changes in metabolic profiles and biomarker concentrations in rat serum during liver fibrosis progression were investigated using ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. The discriminatory capability of potential biomarkers was evaluated by receiver operating characteristic (ROC) curve analysis.
RESULTS To investigate the dynamic changes of metabolites during the process of liver fibrosis, sera from control and fibrosis model rats based on pathological results were analyzed at five different time points. We investigated the association of liver fibrosis with 21 metabolites including hydroxyethyl glycine, L-threonine, indoleacrylic acid, β-muricholic acid (β-MCA), cervonoyl ethanolamide (CEA), phosphatidylcholines, and lysophosphatidylcholines. Two metabolites, CEA and β-MCA, differed significantly in the fibrosis model rats compared to controls (P < 0.05) and showed prognostic value for fibrosis. ROC curve analyses performed to calculate the area under the curve (AUC) revealed that CEA and β-MCA differed significantly in the fibrosis group compared to controls with AUC values exceeding 0.8, and can clearly differentiate early stage from late stage fibrosis or cirrhosis.
CONCLUSION This study identified two novel biomarkers of fibrosis, CEA and β-MCA, which were effective for diagnosing fibrosis in an animal model.
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Affiliation(s)
- Jiong Yu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Jian-Qin He
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - De-Ying Chen
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Qiao-Ling Pan
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Jin-Feng Yang
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Hong-Cui Cao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
| | - Lan-Juan Li
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, Zhejiang Province, China
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28
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The role of fatty acids and their endocannabinoid-like derivatives in the molecular regulation of appetite. Mol Aspects Med 2018; 64:45-67. [DOI: 10.1016/j.mam.2018.01.002] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 01/05/2018] [Accepted: 01/07/2018] [Indexed: 02/07/2023]
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29
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Chiurchiù V, Leuti A, Smoum R, Mechoulam R, Maccarrone M. Bioactive lipids ALIAmides differentially modulate inflammatory responses of distinct subsets of primary human T lymphocytes. FASEB J 2018; 32:5716-5723. [PMID: 29879374 DOI: 10.1096/fj.201800107r] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Autacoid local injury antagonist amides (ALIAmides) are a family of endogenous bioactive acyl ethanolamides that include the renowned palmitoyl ethanolamide (PEA), oleoyl ethanolamide (OEA), and stearoyl ethanolamide (SEA), and that are involved in several biologic processes such as nociception, lipid metabolism, and inflammation. The role of ALIAmides in the control of inflammatory processes has recently gained much attention and prompted the use of these molecules or their analogs, and the pharmacologic manipulation of their endogenous levels, as plausible therapeutic strategies in the treatment of several chronic inflammatory conditions. Since chronic inflammation is mainly driven by cells of adaptive immunity, particularly T lymphocytes, we aimed at investigating whether such bioactive lipids could directly modulate T-cell responses. We found that OEA, PEA, and eicosatrienoyl ethanolamide (ETEA) could directly inhibit both T-cell responses by reducing their production of TNF-α and IFN-γ from CD8 T cells and TNF-α, IFN-γ and IL-17 from CD4 T cells. Furthermore, neither SEA nor docosatrienoyl ethanolamide (DTEA) could affect cytokine production from both T cell subsets. Interestingly, unlike OEA and ETEA, PEA was also able to enhance de novo generation of forkhead box P3 (FoxP3)-expressing regulatory T cells from CD4-naive T cells. Our findings show for the first time that specific ALIAmides can directly affect different T-cell subsets, and provide proof of their anti-inflammatory role in chronic inflammation, ultimately suggesting that these bioactive lipids could offer novel tools for the management of T-cell dependent chronic inflammatory diseases.-Chiurchiù, V., Leuti, A., Smoum, R., Mechoulam, R., Maccarrone, M. Bioactive lipids ALIAmides differentially modulate inflammatory responses of distinct subsets of primary human T lymphocytes.
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Affiliation(s)
- Valerio Chiurchiù
- Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy.,Neurochemistry of Lipids, European Center for Brain Research (CERC), Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia Foundation, Rome, Italy; and
| | - Alessandro Leuti
- Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy.,Neurochemistry of Lipids, European Center for Brain Research (CERC), Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia Foundation, Rome, Italy; and
| | - Reem Smoum
- Institute for Cannabinoid Research, Hebrew University Medical Faculty, Jerusalem, Israel
| | - Raphael Mechoulam
- Institute for Cannabinoid Research, Hebrew University Medical Faculty, Jerusalem, Israel
| | - Mauro Maccarrone
- Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy.,Neurochemistry of Lipids, European Center for Brain Research (CERC), Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia Foundation, Rome, Italy; and
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30
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Mammalian enzymes responsible for the biosynthesis of N-acylethanolamines. Biochim Biophys Acta Mol Cell Biol Lipids 2017; 1862:1546-1561. [PMID: 28843504 DOI: 10.1016/j.bbalip.2017.08.006] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 07/31/2017] [Accepted: 08/19/2017] [Indexed: 12/15/2022]
Abstract
Bioactive N-acylethanolamines (NAEs) are ethanolamides of long-chain fatty acids, including palmitoylethanolamide, oleoylethanolamide and anandamide. In animal tissues, NAEs are biosynthesized from membrane phospholipids. The classical "transacylation-phosphodiesterase" pathway proceeds via N-acyl-phosphatidylethanolamine (NAPE), which involves the actions of two enzymes, NAPE-generating Ca2+-dependent N-acyltransferase (Ca-NAT) and NAPE-hydrolyzing phospholipase D (NAPE-PLD). Recent identification of Ca-NAT as Ɛ isoform of cytosolic phospholipase A2 enabled the further molecular biological approaches toward this enzyme. In addition, Ca2+-independent NAPE formation was shown to occur by N-acyltransferase activity of a group of proteins named phospholipase A/acyltransferases (PLAAT)-1-5. The analysis of NAPE-PLD-deficient mice confirmed that NAEs can be produced through multi-step pathways bypassing NAPE-PLD. The NAPE-PLD-independent pathways involved three members of the glycerophosphodiesterase (GDE) family (GDE1, GDE4 and GDE7) as well as α/β-hydrolase domain-containing protein (ABHD)4. In this review article, we will focus on recent progress made and latest insights in the enzymes involved in NAE synthesis and their further characterization.
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31
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Oleic acid-derived oleoylethanolamide: A nutritional science perspective. Prog Lipid Res 2017; 67:1-15. [PMID: 28389247 DOI: 10.1016/j.plipres.2017.04.001] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Revised: 03/17/2017] [Accepted: 04/03/2017] [Indexed: 01/11/2023]
Abstract
The fatty acid ethanolamide oleoylethanolamide (OEA) is an endogenous lipid mediator derived from the monounsaturated fatty acid, oleic acid. OEA is synthesized from membrane glycerophospholipids and is a high-affinity agonist of the nuclear transcription factor peroxisome proliferator-activated receptor α (PPAR-α). Dietary intake of oleic acid elevates circulating levels of OEA in humans by increasing substrate availability for OEA biosynthesis. Numerous clinical studies demonstrate a beneficial relationship between high-oleic acid diets and body composition, with emerging evidence to suggest OEA may mediate this response through modulation of lipid metabolism and energy intake. OEA exposure has been shown to stimulate fatty acid uptake, lipolysis, and β-oxidation, and also promote food intake control. Future research on high-oleic acid diets and body composition is warranted to confirm these outcomes and elucidate the underlying mechanisms by which oleic acid exerts its biological effects. These findings have significant practical implications, as the oleic acid-derived OEA molecule may be a promising therapeutic agent for weight management and obesity treatment.
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32
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Baggelaar MP, van Esbroeck ACM, van Rooden EJ, Florea BI, Overkleeft HS, Marsicano G, Chaouloff F, van der Stelt M. Chemical Proteomics Maps Brain Region Specific Activity of Endocannabinoid Hydrolases. ACS Chem Biol 2017; 12:852-861. [PMID: 28106377 DOI: 10.1021/acschembio.6b01052] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
The biosynthetic and catabolic enzymes of the endocannabinoids tightly regulate endocannabinoid-mediated activation of the cannabinoid CB1 receptor. Monitoring the activities of these endocannabinoid hydrolases in different brain regions is, therefore, key to gaining insight into spatiotemporal control of CB1 receptor-mediated physiology. We have employed a comparative chemical proteomics approach to quantitatively map the activity profile of endocannabinoid hydrolases in various mouse brain regions at the same time. To this end, we used two different activity-based probes: fluorophosphonate-biotin (FP-biotin), which quantifies FAAH, ABHD6, and MAG-lipase activity, and MB108, which detects DAGL-α, ABHD4, ABHD6, and ABHD12. In total, 32 serine hydrolases were evaluated in the frontal cortex, hippocampus, striatum, and cerebellum. Comparison of endocannabinoid hydrolase activity in the four brain regions revealed that FAAH activity was highest in the hippocampus, and MAGL activity was most pronounced in the frontal cortex, whereas DAGL-α was most active in the cerebellum. Comparison of the activity profiles with a global proteomics data set revealed pronounced differences. This could indicate that post-translational modification of the endocannabinoid hydrolases is important to regulate their activity. Next, the effect of genetic deletion of the CB1 receptor was studied. No difference in the enzymatic activity was found in the cerebellum, striatum, frontal cortex, and hippocampus of CB1 receptor knockout animals compared to wild type mice. Our results are in line with previous reports and indicate that the CB1 receptor exerts no regulatory control over the basal production and degradation of endocannabinoids and that genetic deletion of the CB1 receptor does not induce compensatory mechanisms in endocannabinoid hydrolase activity.
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Affiliation(s)
- Marc P. Baggelaar
- Department
of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands
| | - Annelot C. M. van Esbroeck
- Department
of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands
| | - Eva J. van Rooden
- Department
of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands
| | - Bogdan I. Florea
- Department
of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands
| | - Herman S. Overkleeft
- Department
of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands
| | - Giovanni Marsicano
- Plateforme
de Chimie Analytique, NeuroCentre INSERM U862, Bordeaux, France
| | - Francis Chaouloff
- Plateforme
de Chimie Analytique, NeuroCentre INSERM U862, Bordeaux, France
| | - Mario van der Stelt
- Department
of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands
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33
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Aizpurua-Olaizola O, Elezgarai I, Rico-Barrio I, Zarandona I, Etxebarria N, Usobiaga A. Targeting the endocannabinoid system: future therapeutic strategies. Drug Discov Today 2017; 22:105-110. [DOI: 10.1016/j.drudis.2016.08.005] [Citation(s) in RCA: 95] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Revised: 07/07/2016] [Accepted: 08/11/2016] [Indexed: 02/03/2023]
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34
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Rahman IAS, Tsuboi K, Hussain Z, Yamashita R, Okamoto Y, Uyama T, Yamazaki N, Tanaka T, Tokumura A, Ueda N. Calcium-dependent generation of N-acylethanolamines and lysophosphatidic acids by glycerophosphodiesterase GDE7. Biochim Biophys Acta Mol Cell Biol Lipids 2016; 1861:1881-1892. [DOI: 10.1016/j.bbalip.2016.09.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Revised: 08/23/2016] [Accepted: 09/10/2016] [Indexed: 01/26/2023]
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35
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Deutsch DG. A Personal Retrospective: Elevating Anandamide (AEA) by Targeting Fatty Acid Amide Hydrolase (FAAH) and the Fatty Acid Binding Proteins (FABPs). Front Pharmacol 2016; 7:370. [PMID: 27790143 PMCID: PMC5062061 DOI: 10.3389/fphar.2016.00370] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 09/26/2016] [Indexed: 11/13/2022] Open
Abstract
This perspective was adapted from a Career Achievement Award talk given at the International Cannabinoid Research Society Symposium in Bukovina, Poland on June 27, 2016. As a biochemist working in the neurosciences, I was always fascinated with neurotransmitter inactivation. In 1993 we identified an enzyme activity that breaks down anandamide. We called the enzyme anandamide amidase, now called FAAH. We and other laboratories developed FAAH inhibitors that were useful reagents that also proved to have beneficial physiological effects and until recently, new generations of inhibitors were in clinical trials. Nearly all neurotransmitters are water soluble and as such, require a transmembrane protein transporter to pass through the lipid membrane for inactivation inside the cell. However, using model systems, we and others have shown that this is unnecessary for anandamide, an uncharged hydrophobic molecule that readily diffuses across the cellular membrane. Interestingly, its uptake is driven by the concentration gradient resulting from its breakdown mainly by FAAH localized in the endoplasmic reticulum. We identified the FABPs as intracellular carriers that "solubilize" anandamide, transporting anandamide to FAAH. Compounds that bind to FABPs block AEA breakdown, raising its level. The cannabinoids (THC and CBD) also were discovered to bind FABPs and this may be one of the mechanisms by which CBD works in childhood epilepsy, raising anandamide levels. Targeting FABPs may be advantageous since they have some tissue specificity and do not require reactive serine hydrolase inhibitors, as does FAAH, with potential for off-target reactions. At the International Cannabis Research Society Symposium in 1992, Raphe Mechoulam revealed that his laboratory isolated an endogenous lipid molecule that binds to the CB1 receptor (cannabinoid receptor type 1) and this became the milestone paper published in December of that year describing anandamide (AEA, Devane et al., 1992). As to be expected, this discovery raised the issues of AEA's synthesis and breakdown.
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Affiliation(s)
- Dale G Deutsch
- Department of Biochemistry and Cell Biology, Stony Brook University Stony Brook, NY, USA
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36
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Hussain Z, Uyama T, Kawai K, Rahman IAS, Tsuboi K, Araki N, Ueda N. Comparative analyses of isoforms of the calcium-independent phosphatidylethanolamine N-acyltransferase PLAAT-1 in humans and mice. J Lipid Res 2016; 57:2051-2060. [PMID: 27623847 DOI: 10.1194/jlr.m071290] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Indexed: 01/28/2023] Open
Abstract
N-Acylphosphatidylethanolamines (NAPEs) are a class of glycerophospholipids, which are known as precursors for different bioactive N-acylethanolamines. We previously reported that phospholipase A/acyltransferase-1 (PLAAT-1), which was originally found in mammals as a tumor suppressor, catalyzes N-acylation of phosphatidylethanolamines to form NAPEs. However, recent online database suggested the presence of an uncharacterized isoform of PLAAT-1 with an extra sequence at the N terminus. In the present study, we examined the occurrence, intracellular localization, and catalytic properties of this longer isoform, as well as the original shorter isoform from humans and mice. Our results showed that human tissues express the longer isoform but not the short isoform at all. In contrast, mice expressed both isoforms with different tissue distribution. Unlike the cytoplasmic localization of the shorter isoform, the long isoform was found in both cytoplasm and nucleus, inferring that the extra sequence harbors a nuclear localization signal. As assayed with purified proteins, neither isoform required calcium for full activity. Moreover, the overexpression of each isoform remarkably increased cellular NAPE levels. These results conclude that the new long isoform of PLAAT-1 is a calcium-independent N-acyltransferase existing in both cytoplasm and nucleus and suggest a possible formation of NAPEs in various membrane structures including nuclear membrane. J. Lipid Res 2016. 57: 2051-2060.
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Affiliation(s)
- Zahir Hussain
- Department of Biochemistry Kagawa University School of Medicine, Miki, Kagawa 761-0793, Japan
| | - Toru Uyama
- Department of Biochemistry Kagawa University School of Medicine, Miki, Kagawa 761-0793, Japan
| | - Katsuhisa Kawai
- Department of Histology and Cell Biology, Kagawa University School of Medicine, Miki, Kagawa 761-0793, Japan
| | - Iffat Ara Sonia Rahman
- Department of Biochemistry Kagawa University School of Medicine, Miki, Kagawa 761-0793, Japan
| | - Kazuhito Tsuboi
- Department of Biochemistry Kagawa University School of Medicine, Miki, Kagawa 761-0793, Japan
| | - Nobukazu Araki
- Department of Histology and Cell Biology, Kagawa University School of Medicine, Miki, Kagawa 761-0793, Japan
| | - Natsuo Ueda
- Department of Biochemistry Kagawa University School of Medicine, Miki, Kagawa 761-0793, Japan
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Ogura Y, Parsons WH, Kamat SS, Cravatt BF. A calcium-dependent acyltransferase that produces N-acyl phosphatidylethanolamines. Nat Chem Biol 2016; 12:669-71. [PMID: 27399000 PMCID: PMC4990470 DOI: 10.1038/nchembio.2127] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 05/18/2016] [Indexed: 12/11/2022]
Abstract
More than 30 years ago, a calcium-dependent enzyme activity was described that generates N-acyl phosphatidylethanolamines (NAPEs), which are precursors for N-acyl ethanolamine (NAE) lipid transmitters, including the endocannabinoid anandamide. The identity of this calcium-dependent N-acyltransferase (Ca-NAT) has remained mysterious. Here, we use activity-based protein profiling to identify the poorly characterized serine hydrolase PLA2G4E as a mouse brain Ca-NAT and show that this enzyme generates NAPEs and NAEs in mammalian cells.
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Affiliation(s)
- Yuji Ogura
- Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.,The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA
| | - William H Parsons
- Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.,The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA
| | - Siddhesh S Kamat
- Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.,The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA
| | - Benjamin F Cravatt
- Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.,The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA
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38
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Lutz B, Marsicano G, Maldonado R, Hillard CJ. The endocannabinoid system in guarding against fear, anxiety and stress. Nat Rev Neurosci 2016; 16:705-18. [PMID: 26585799 DOI: 10.1038/nrn4036] [Citation(s) in RCA: 337] [Impact Index Per Article: 37.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The endocannabinoid (eCB) system has emerged as a central integrator linking the perception of external and internal stimuli to distinct neurophysiological and behavioural outcomes (such as fear reaction, anxiety and stress-coping), thus allowing an organism to adapt to its changing environment. eCB signalling seems to determine the value of fear-evoking stimuli and to tune appropriate behavioural responses, which are essential for the organism's long-term viability, homeostasis and stress resilience; and dysregulation of eCB signalling can lead to psychiatric disorders. An understanding of the underlying neural cell populations and cellular processes enables the development of therapeutic strategies to mitigate behavioural maladaptation.
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Affiliation(s)
- Beat Lutz
- Institute of Physiological Chemistry, University Medical Center Mainz, Duesbergweg 6, 55128 Mainz, Germany
| | - Giovanni Marsicano
- Institut national de la santé et de la recherche médicale (INSERM), U862 NeuroCentre Magendie, Group Endocannabinoids and Neuroadaptation, Bordeaux 33077, France.,University of Bordeaux, 146 rue Léo Saignat, Bordeaux 33077, France
| | - Rafael Maldonado
- Laboratori de Neurofarmacologia, Facultat de Ciències de la Salut i de la Vida, Universitat Pompeu Fabra, Dr. Aiguader 88, 08003 Barcelona, Spain
| | - Cecilia J Hillard
- Department of Pharmacology and Toxicology, Neuroscience Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, USA
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Interactions between dietary oil treatments and genetic variants modulate fatty acid ethanolamides in plasma and body weight composition. Br J Nutr 2016; 115:1012-23. [DOI: 10.1017/s0007114515005425] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
AbstractFatty acid ethanolamides (FAE), a group of lipid mediators derived from long-chain fatty acids (FA), mediate biological activities including activation of cannabinoid receptors, stimulation of fat oxidation and regulation of satiety. However, how circulating FAE levels are influenced by FA intake in humans remains unclear. The objective of the present study was to investigate the response of six major circulating FAE to various dietary oil treatments in a five-period, cross-over, randomised, double-blind, clinical study in volunteers with abdominal obesity. The treatment oils (60 g/12 552 kJ per d (60 g/3000 kcal per d)) provided for 30 d were as follows: conventional canola oil, high oleic canola oil, high oleic canola oil enriched with DHA, flax/safflower oil blend and corn/safflower oil blend. Two SNP associated with FAE degradation and synthesis were studied. Post-treatment results showed overall that plasma FAE levels were modulated by dietary FA and were positively correlated with corresponding plasma FA levels; minor allele (A) carriers of SNP rs324420 in gene fatty acid amide hydrolase produced higher circulating oleoylethanolamide (OEA) (P=0·0209) and docosahexaenoylethanolamide (DHEA) levels (P=0·0002). In addition, elevated plasma DHEA levels in response to DHA intake tended to be associated with lower plasma OEA levels and an increased gynoid fat mass. In summary, data suggest that the metabolic and physiological responses to dietary FA may be influenced via circulating FAE. Genetic analysis of rs324420 might help identify a sub-population that appears to benefit from increased consumption of DHA and oleic acid.
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40
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Quintana PG, García Liñares G, Chanquia SN, Gorojod RM, Kotler ML, Baldessari A. Improved Enzymatic Procedure for the Synthesis of Anandamide andN-Fatty Acylalkanolamine Analogues: A Combination Strategy to Antitumor Activity. European J Org Chem 2015. [DOI: 10.1002/ejoc.201501263] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Palmitoylethanolamide, a Natural Retinoprotectant: Its Putative Relevance for the Treatment of Glaucoma and Diabetic Retinopathy. J Ophthalmol 2015; 2015:430596. [PMID: 26664738 PMCID: PMC4667059 DOI: 10.1155/2015/430596] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Revised: 10/11/2015] [Accepted: 11/01/2015] [Indexed: 12/11/2022] Open
Abstract
Retinopathy is a threat to the eyesight, and glaucoma and diabetes are the main causes for the damage of retinal cells. Recent insights pointed out a common pathogenetic pathway for both disorders, based on chronic inflammation. Palmitoylethanolamide (PEA) is an endogenous cell protective lipid. Since its discovery in 1957 as a biologically active component in foods and in many living organisms, around 500 scientific papers have been published on PEA's anti-inflammatory and neuron-protective properties. PEA has been evaluated for glaucoma, diabetic retinopathy, and uveitis, pathological states based on chronic inflammation, respiratory disorders, and various pain syndromes in a number of clinical trials since the 70s of 20th century. PEA is available as a food supplement (PeaPure) and as diet food for medical purposes in Italy (Normast, PeaVera, and Visimast). These products are notified in Italy for the nutritional support in glaucoma and neuroinflammation. PEA has been tested in at least 9 double blind placebo controlled studies, among which two studies were in glaucoma, and found to be safe and effective up to 1.8 g/day, with excellent tolerability. PEA therefore holds a promise in the treatment of a number of retinopathies. We discuss PEA as a putative anti-inflammatory and retinoprotectant compound in the treatment of retinopathies, especially related to glaucoma and diabetes.
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Pisanti S, Picardi P, Pallottini V, Martini C, Petrosino S, Proto MC, Vitale M, Laezza C, Gazzerro P, Di Marzo V, Bifulco M. Anandamide drives cell cycle progression through CB1 receptors in a rat model of synchronized liver regeneration. J Cell Physiol 2015; 230:2905-14. [PMID: 25684344 DOI: 10.1002/jcp.24959] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 02/09/2015] [Indexed: 01/15/2023]
Abstract
The endocannabinoid system, through cannabinoid receptor signaling by endocannabinoids, is involved in a wide range of functions and physiopathological conditions. To date, very little is known concerning the role of the endocannabinoids in the control and regulation of cell proliferation. An anti-proliferative action of CB1 signaling blockade in neurogenesis and angiogenesis argues in favor of proliferation-promoting functions of endocannabinoids through CB1 receptors when pro-growth signals are present. Furthermore, liver regeneration, a useful in vivo model of synchronized cell proliferation, is characterized by a peak of anandamide that elicits through CB1 receptor, the expression of critical mitosis genes. The aim of this study was to focus on the timing of endocannabinoid signaling changes during the different phases of the cell cycle, exploiting the rat liver regeneration model following partial hepatectomy, the most useful to study synchronized cell cycle in vivo. Hepatic regeneration led to increased levels of anandamide and endocannabinoid-like molecules oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) in the G1 phase of the cell cycle, with a concomitant increase in CB1 mRNA levels, whose protein expression peaked later during the S phase. Blocking of CB1 receptor with a low dose of the selective antagonist/inverse agonist SR141716 (0.7 mg/kg/dose) affected cell cycle progression reducing the expression of PCNA, and through the inhibition of pERK and pSTAT3 pathways. These results support the notion that the signaling mediated by anandamide through CB1 receptor may be important for the entry and progression of cells into the cell cycle and hence for their proliferation under mitogenic signals.
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Affiliation(s)
- Simona Pisanti
- Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno, Italy.,Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy
| | - Paola Picardi
- Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno, Italy.,Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy
| | - Valentina Pallottini
- Department of Science, Section Biomedical Science and Technologies, University Roma Tre, Rome, Italy
| | - Chiara Martini
- Department of Science, Section Biomedical Science and Technologies, University Roma Tre, Rome, Italy
| | | | - Maria Chiara Proto
- Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno, Italy.,Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy
| | - Mario Vitale
- Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno, Italy.,Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy
| | - Chiara Laezza
- Institute of Experimental Oncology and Endocrinology, IEOS, CNR, Naples, Italy
| | - Patrizia Gazzerro
- Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy
| | | | - Maurizio Bifulco
- Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno, Italy.,Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy
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43
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Hillard CJ. The Endocannabinoid Signaling System in the CNS: A Primer. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2015; 125:1-47. [PMID: 26638763 DOI: 10.1016/bs.irn.2015.10.001] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The purpose of this chapter is to provide an introduction to the mechanisms for the regulation of endocannabinoid signaling through CB1 cannabinoid receptors in the central nervous system. The processes involved in the synthesis and degradation of the two most well-studied endocannabinoids, 2-arachidonoylglycerol and N-arachidonylethanolamine are outlined along with information regarding the regulation of the proteins involved. Signaling mechanisms and pharmacology of the CB1 cannabinoid receptor are outlined, as is the paradigm of endocannabinoid/CB1 receptor regulation of neurotransmitter release. The reader is encouraged to appreciate the importance of the endocannabinoid/CB1 receptor signaling system in the regulation of synaptic activity in the brain.
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Affiliation(s)
- Cecilia J Hillard
- Neuroscience Research Center, and Department of Pharmacology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
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44
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Maccarrone M. Endocannabinoid signaling in female reproductive events: a potential therapeutic target? Expert Opin Ther Targets 2015; 19:1423-7. [PMID: 26126134 DOI: 10.1517/14728222.2015.1062878] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Nearly 30 years after the discovery in 1964 of the psychoactive ingredient of cannabis (Cannabis sativa), Δ(9)-tetrahydrocannabinol, its endogenous counterparts were discovered and collectively termed endocannabinoids (eCBs): N-arachidonoylethanolamine (anandamide) in 1992 and 2-arachidonoylglycerol in 1995. Since then, intense research has identified additional eCBs and an ensemble of proteins that bind, synthesize and degrade them, the so-called eCB system. Altogether, these new compounds have been recognized as key mediators of several aspects of human pathophysiology, and in particular of female fertility. Here, the main features of the eCB system are presented, in order to put in a better perspective the relevance of eCB signaling in virtually all steps of human reproduction and to highlight emerging hopes that elements of this system might indeed become novel targets to combat fertility problems.
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Affiliation(s)
- Mauro Maccarrone
- a 1 Campus Bio-Medico University of Rome, Center of Integrated Research , Via Álvaro del Portillo 21, 00128 Rome, Italy +39 06 2254 19169 ; +39 06 2254 1456 ; .,b 2 European Center for Brain Research, Santa Lucia Foundation , Rome, Italy
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45
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Maccarrone M, Bab I, Bíró T, Cabral GA, Dey SK, Di Marzo V, Konje JC, Kunos G, Mechoulam R, Pacher P, Sharkey KA, Zimmer A. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci 2015; 36:277-96. [PMID: 25796370 DOI: 10.1016/j.tips.2015.02.008] [Citation(s) in RCA: 463] [Impact Index Per Article: 46.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Revised: 02/10/2015] [Accepted: 02/19/2015] [Indexed: 12/19/2022]
Abstract
In 1964, the psychoactive ingredient of Cannabis sativa, Δ(9)-tetrahydrocannabinol (THC), was isolated. Nearly 30 years later the endogenous counterparts of THC, collectively termed endocannabinoids (eCBs), were discovered: N-arachidonoylethanolamine (anandamide) (AEA) in 1992 and 2-arachidonoylglycerol (2-AG) in 1995. Since then, considerable research has shed light on the impact of eCBs on human health and disease, identifying an ensemble of proteins that bind, synthesize, and degrade them and that together form the eCB system (ECS). eCBs control basic biological processes including cell choice between survival and death and progenitor/stem cell proliferation and differentiation. Unsurprisingly, in the past two decades eCBs have been recognized as key mediators of several aspects of human pathophysiology and thus have emerged to be among the most widespread and versatile signaling molecules ever discovered. Here some of the pioneers of this research field review the state of the art of critical eCB functions in peripheral organs. Our community effort is aimed at establishing consensus views on the relevance of the peripheral ECS for human health and disease pathogenesis, as well as highlighting emerging challenges and therapeutic hopes.
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Affiliation(s)
- Mauro Maccarrone
- Center of Integrated Research, Campus Bio-Medico University, Rome, Italy; Center for Brain Research, Santa Lucia Foundation IRCCS, Rome, Italy.
| | - Itai Bab
- Bone Laboratory, Hebrew University Medical Faculty, Jerusalem, Israel; Institute for Drug Research, Hebrew University Medical Faculty, Jerusalem, Israel
| | - Tamás Bíró
- DE-MTA 'Lendület' Cellular Physiology Research Group, Department of Physiology, Medical Faculty, University of Debrecen, Debrecen, Hungary
| | - Guy A Cabral
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA
| | - Sudhansu K Dey
- Division of Reproductive Sciences, Cincinnati Children's Research Foundation, Cincinnati, OH, USA
| | - Vincenzo Di Marzo
- Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Council of Research, Pozzuoli, Italy
| | - Justin C Konje
- Department of Obstetrics and Gynaecology, Sidra Medical and Research Center, Doha, Qatar
| | - George Kunos
- National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
| | - Raphael Mechoulam
- Institute for Drug Research, Hebrew University Medical Faculty, Jerusalem, Israel
| | - Pal Pacher
- National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
| | - Keith A Sharkey
- Hotchkiss Brain Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Alberta, Canada
| | - Andreas Zimmer
- Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany
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46
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Belluomo I, Matias I, Pernègre C, Marsicano G, Chaouloff F. Opposite control of frontocortical 2-arachidonoylglycerol turnover rate by cannabinoid type-1 receptors located on glutamatergic neurons and on astrocytes. J Neurochem 2015; 133:26-37. [DOI: 10.1111/jnc.13044] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Revised: 12/17/2014] [Accepted: 01/13/2015] [Indexed: 01/24/2023]
Affiliation(s)
- Ilaria Belluomo
- Plateforme de Chimie Analytique; NeuroCentre INSERM U862; Bordeaux France
| | - Isabelle Matias
- Plateforme de Chimie Analytique; NeuroCentre INSERM U862; Bordeaux France
| | - Camille Pernègre
- Equipe Endocannabinoïdes & NeuroAdaptation; NeuroCentre INSERM U862; Bordeaux France
| | - Giovanni Marsicano
- Equipe Endocannabinoïdes & NeuroAdaptation; NeuroCentre INSERM U862; Bordeaux France
| | - Francis Chaouloff
- Equipe Endocannabinoïdes & NeuroAdaptation; NeuroCentre INSERM U862; Bordeaux France
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Abstract
Cells in injured and inflamed tissues produce a number of proalgesic lipid-derived mediators, which excite nociceptive neurons by activating selective G-protein-coupled receptors or ligand-gated ion channels. Recent work has shown that these proalgesic factors are counteracted by a distinct group of lipid molecules that lower nociceptor excitability and attenuate nociception in peripheral tissues. Analgesic lipid mediators include endogenous agonists of cannabinoid receptors (endocannabinoids), lipid-amide agonists of peroxisome proliferator-activated receptor-α, and products of oxidative metabolism of polyunsaturated fatty acids via cytochrome P450 and other enzyme pathways. Evidence indicates that these lipid messengers are produced and act at different stages of inflammation and the response to tissue injury, and may be part of a peripheral gating mechanism that regulates the access of nociceptive information to the spinal cord and the brain. Growing knowledge about this peripheral control system may be used to discover safer medicines for pain.
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48
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Wood PL. Accumulation of N-Acylphosphatidylserines and N-Acylserines in the Frontal Cortex in Schizophrenia. ACTA ACUST UNITED AC 2015; 1. [PMID: 26120595 DOI: 10.14800/nt.263] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND While schizophrenia is generally considered a neurodevelopment disorder, our basic understanding of the biochemical processes involved in disease etiology and/or progression is limited. One class of biochemical mediators that has been suggested to play a role in the development of schizophrenia is N-acyl ethanolamine metabolites of N-acylphosphatidylethanolamines. However, no investigations of N-acylphosphatidylserines or their N-acylserine metabolites have been published. METHODS We undertook a targeted postmortem lipidomics analysis of N-acylphosphatidylserines (NAPS) and N-acylserines (NAS) in gray matter of the frontal cortex of schizophrenia subjects. RESULTS Our data are the first to demonstrate that NAPS and NAS are present in human brain. Furthermore, NAPS and their bioactive metabolites, N-acylserines (NAS), were found to be significantly elevated in the frontal cortex of schizophrenia subjects. CONCLUSIONS Elevated levels of NAPS lipid pools in schizophrenia may result in complex alterations in the structural function of neuronal membranes while increases in NAS may alter signal transduction pathways.
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Affiliation(s)
- Paul L Wood
- Metabolomics Unit, Dept. of Physiology and Pharmacology, DeBusk College of Osteopathic Medicine, Lincoln Memorial University, 6965 Cumberland Gap Pkwy, Harrogate, TN
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Golczak M, Sears AE, Kiser PD, Palczewski K. LRAT-specific domain facilitates vitamin A metabolism by domain swapping in HRASLS3. Nat Chem Biol 2015; 11:26-32. [PMID: 25383759 PMCID: PMC4270908 DOI: 10.1038/nchembio.1687] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Accepted: 09/05/2014] [Indexed: 12/21/2022]
Abstract
Cellular uptake of vitamin A, production of visual chromophore and triglyceride homeostasis in adipocytes depend on two representatives of the vertebrate N1pC/P60 protein family, lecithin:retinol acyltransferase (LRAT) and HRAS-like tumor suppressor 3 (HRASLS3). Both proteins function as lipid-metabolizing enzymes but differ in their substrate preferences and dominant catalytic activity. The mechanism of this catalytic diversity is not understood. Here, by using a gain-of-function approach, we identified a specific sequence responsible for the substrate specificity of N1pC/P60 proteins. A 2.2-Å crystal structure of the HRASLS3-LRAT chimeric enzyme in a thioester catalytic intermediate state revealed a major structural rearrangement accompanied by three-dimensional domain swapping dimerization not observed in native HRASLS proteins. Structural changes affecting the active site environment contributed to slower hydrolysis of the catalytic intermediate, supporting efficient acyl transfer. These findings reveal structural adaptation that facilitates selective catalysis and mechanism responsible for diverse substrate specificity within the LRAT-like enzyme family.
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Affiliation(s)
- Marcin Golczak
- Department of Pharmacology, Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106
| | - Avery E. Sears
- Department of Pharmacology, Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106
| | - Philip D. Kiser
- Department of Pharmacology, Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106
| | - Krzysztof Palczewski
- Department of Pharmacology, Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106
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50
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Harrison N, Lone MA, Kaul TK, Reis Rodrigues P, Ogungbe IV, Gill MS. Characterization of N-acyl phosphatidylethanolamine-specific phospholipase-D isoforms in the nematode Caenorhabditis elegans. PLoS One 2014; 9:e113007. [PMID: 25423491 PMCID: PMC4244089 DOI: 10.1371/journal.pone.0113007] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Accepted: 10/17/2014] [Indexed: 12/27/2022] Open
Abstract
N-acylethanolamines are an important class of lipid signaling molecules found in many species, including the nematode Caenorhabditis elegans (C. elegans) where they are involved in development and adult lifespan. In mammals, the relative activity of the biosynthetic enzyme N-acyl phosphatidylethanolamine-specific phospholipase-D and the hydrolytic enzyme fatty acid amide hydrolase determine N-acylethanolamine levels. C. elegans has two N-acyl phosphatidylethanolamine-specific phospholipase-D orthologs, nape-1 and nape-2, that are likely to have arisen from a gene duplication event. Here, we find that recombinant C. elegans NAPE-1 and NAPE-2 are capable of generating N-acylethanolamines in vitro, confirming their functional conservation. In vivo, they exhibit overlapping expression in the pharynx and the nervous system, but are also expressed discretely in these and other tissues, suggesting divergent roles. Indeed, nape-1 over-expression results in delayed growth and shortened lifespan only at 25°C, while nape-2 over-expression results in significant larval arrest and increased adult lifespan at 15°C. Interestingly, deletion of the N-acylethanolamine degradation enzyme faah-1 exacerbates nape-1 over-expression phenotypes, but suppresses the larval arrest phenotype of nape-2 over-expression, suggesting that faah-1 is coupled to nape-2, but not nape-1, in a negative feedback loop. We also find that over-expression of either nape-1 or nape-2 significantly enhances recovery from the dauer larval stage in the insulin signaling mutant daf-2(e1368), but only nape-1 over-expression reduces daf-2 adult lifespan, consistent with increased levels of the N-acylethanolamine eicosapentaenoyl ethanolamine. These results provide evidence that N-acylethanolamine biosynthetic enzymes in C. elegans have conserved function and suggest a temperature-dependent, functional divergence between the two isoforms.
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Affiliation(s)
- Neale Harrison
- Department of Metabolism & Aging, The Scripps Research Institute, Scripps Florida, Jupiter, Florida, United States of America
| | - Museer A. Lone
- Department of Metabolism & Aging, The Scripps Research Institute, Scripps Florida, Jupiter, Florida, United States of America
| | - Tiffany K. Kaul
- Department of Metabolism & Aging, The Scripps Research Institute, Scripps Florida, Jupiter, Florida, United States of America
| | - Pedro Reis Rodrigues
- Department of Metabolism & Aging, The Scripps Research Institute, Scripps Florida, Jupiter, Florida, United States of America
| | - Ifedayo Victor Ogungbe
- Department of Metabolism & Aging, The Scripps Research Institute, Scripps Florida, Jupiter, Florida, United States of America
| | - Matthew S. Gill
- Department of Metabolism & Aging, The Scripps Research Institute, Scripps Florida, Jupiter, Florida, United States of America
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