{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T05:40:00Z","timestamp":1783662000840,"version":"3.55.0"},"reference-count":82,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T00:00:00Z","timestamp":1758672000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Royal Golden Jubilee (RGJ) Advanced Program, Thailand Science Research and Innovation","award":["RAP61K0020"],"award-info":[{"award-number":["RAP61K0020"]}]},{"name":"Royal Golden Jubilee (RGJ) Advanced Program, Thailand Science Research and Innovation","award":["N42A670604"],"award-info":[{"award-number":["N42A670604"]}]},{"name":"Thammasat University grant for the international presentation of academic research, creative works, and innovative inventions","award":["RAP61K0020"],"award-info":[{"award-number":["RAP61K0020"]}]},{"name":"Thammasat University grant for the international presentation of academic research, creative works, and innovative inventions","award":["N42A670604"],"award-info":[{"award-number":["N42A670604"]}]},{"name":"National Research Council of Thailand (NRCT) and the National Science and Technology Development Agency","award":["RAP61K0020"],"award-info":[{"award-number":["RAP61K0020"]}]},{"name":"National Research Council of Thailand (NRCT) and the National Science and Technology Development Agency","award":["N42A670604"],"award-info":[{"award-number":["N42A670604"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic stress induces mood disturbances, disrupts gut barrier function, and promotes low-grade systemic inflammation. This study assessed the therapeutic effects of atomoxetine (ATX), escitalopram (ESC), cannabidiol (CBD), and CBD-loaded lipid nanoparticles (CBD\/LNP) in male rats exposed to repeated restraint stress. Stressed rats exhibited a 2.03-fold increase in interleukin-6 and a 1.89-fold increase in TNF-\u03b1, a 1.20-fold decrease in brain-derived neurotrophic factor, a 1.36-fold decrease in osteocalcin, accompanied by alterations in gut metabolites, particularly short-chain fatty acids (SCFAs; from 155.3 to 94.83 \u03bcmol\/L), polyamines (from 273.6 to 192.4 \u03bcmol\/L), and bile acids (BAs; from 21.19 to 14.53 \u03bcmol\/L), compared with the control group. Protein analysis revealed gut barrier disruption and microglial\/macrophage activation, accompanied by reduced synaptic plasticity. ATX improved gut permeability and reduced glial activation but did not restore osteocalcin. ESC provided neuroimmune benefits with limited and BA gut restoration and modulated the gut\u2013brain axis and improved anxiety-like behaviors, partly by altering gut microbiota and metabolites. CBD and CBD\/LNP treatment restored intestinal barrier function, as indicated by intestinal permeability in the range of 1.15\u20131.61-fold. These treatments also normalized bile acids (1.0\u20131.38-fold) and osteocalcin (1.0\u20131.28-fold) and significantly reduced glial activation (0.63\u20131.12-fold) as opposed to the non-treated stressed group. All treatments were found to be effective in correcting SCFA and polyamine levels. Histological analysis confirmed that CBD\/LNP, ATX, and ESC ameliorated tissue alterations. These findings highlight CBD\/LNP as a promising intervention for stress-induced gut\u2013brain\u2013bone axis disruption, supporting its potential as a therapeutic alternative through modulation of microbiota-driven gut\u2013brain communication in stress-associated disorders.<\/jats:p>","DOI":"10.3390\/ijms26199318","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T10:39:42Z","timestamp":1758710382000},"page":"9318","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cannabidiol Lipid Nanoparticles Stabilize Gut\u2013Brain\u2013Bone Axis Integrity and Enhance Neuroplasticity in Stressed Rats: A Comparison with Atomoxetine and Escitalopram"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8890-9109","authenticated-orcid":false,"given":"Sarawut","family":"Lapmanee","sequence":"first","affiliation":[{"name":"Chulabhorn International College of 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(2023). Understanding the Relationships between Physiological and Psychosocial Stress, Cortisol and Cognition. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1085950"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s40267-024-01079-4","article-title":"Glucocorticoid-Induced Osteoporosis\u2014From Molecular Mechanism to Clinical Practice","volume":"40","author":"Hsu","year":"2024","journal-title":"Drugs Ther. Perspect."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e17033","DOI":"10.7717\/peerj.17033","article-title":"Stress-Induced Changes in Cognitive Function and Intestinal Barrier Integrity Can Be Ameliorated by Venlafaxine and Synbiotic Supplementations","volume":"12","author":"Lapmanee","year":"2024","journal-title":"PeerJ"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4491","DOI":"10.1113\/JP281951","article-title":"The Impact of Acute and Chronic Stress on Gastrointestinal Physiology and Function: A Microbiota-Gut-Brain Axis Perspective the Stress Response: From Adaptation to Disease","volume":"601","author":"Leigh","year":"2023","journal-title":"J. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e2307971","DOI":"10.1002\/advs.202307971","article-title":"The Brain\u2013Gut\u2013Bone Axis in Neurodegenerative Diseases: Insights, Challenges, and Future Prospects","volume":"11","author":"Li","year":"2024","journal-title":"Adv. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Cho, D.E., Hong, J.P., Kim, Y., Sim, J.Y., Kim, H.S., Kim, S.R., Lee, B., Cho, H.S., Cho, I.H., and Shin, S. (2024). Role of Gut-Derived Bacterial Lipopolysaccharide and Peripheral TLR4 in Immobilization Stress-Induced Itch Aggravation in a Mouse Model of Atopic Dermatitis. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-56936-z"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s40813-022-00264-z","article-title":"Effects of Different Short-Chain Fatty Acids (SCFA) on Gene Expression of Proteins Involved in Barrier Function in IPEC-J2","volume":"8","author":"Saleri","year":"2022","journal-title":"Porc. Health Manag."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kasahara, N., Teratani, T., Yokota, S., Sakuma, Y., Sasanuma, H., Fujimoto, Y., Ijichi, T., Urahashi, T., Yoshitomi, H., and Kitayama, J. (2024). Dietary Polyamines Promote Intestinal Adaptation in an Experimental Model of Short Bowel Syndrome. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-55258-4"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Zeng, H., Umar, S., Rust, B., Lazarova, D., and Bordonaro, M. (2019). Secondary Bile Acids and Short Chain Fatty Acids in the Colon: A Focus on Colonic Microbiome, Cell Proliferation, Inflammation, and Cancer. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20051214"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s12974-018-1054-3","article-title":"Microglial Activation Mediates Chronic Mild Stress-Induced Depressive- and Anxiety-like Behavior in Adult Rats","volume":"15","author":"Wang","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/s44321-024-00189-w","article-title":"Macrophage-Induced Enteric Neurodegeneration Leads to Motility Impairment during Gut Inflammation","volume":"17","author":"Siemens","year":"2025","journal-title":"EMBO Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.neuroscience.2021.07.011","article-title":"Stress Diminishes BDNF-Stimulated TrkB Signaling, TrkB-NMDA Receptor Linkage and Neuronal Activity in the Rat Brain","volume":"473","author":"Robinson","year":"2021","journal-title":"Neuroscience"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/j.cmet.2019.08.012","article-title":"Mediation of the Acute Stress Response by the Skeleton","volume":"30","author":"Berger","year":"2019","journal-title":"Cell Metab."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"P\u00e9rez-Valenzuela, C., G\u00e1rate-P\u00e9rez, M.F., Sotomayor-Z\u00e1rate, R., Delano, P.H., and Dagnino-Subiabre, A. (2016). Reboxetine Improves Auditory Attention and Increases Norepinephrine Levels in the Auditory Cortex of Chronically Stressed Rats. Front. Neural Circuits, 10.","DOI":"10.3389\/fncir.2016.00108"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"110541","DOI":"10.1016\/j.neuropharm.2025.110541","article-title":"Increased C-Fos Immunoreactivity in Anxiety-Related Brain Regions Following Paroxetine Discontinuation","volume":"278","author":"Collins","year":"2025","journal-title":"Neuropharmacology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"118829","DOI":"10.1016\/j.neuroimage.2021.118829","article-title":"Escitalopram Modulates Learning Content-Specific Neuroplasticity of Functional Brain Networks","volume":"247","author":"Seiger","year":"2022","journal-title":"Neuroimage"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3792","DOI":"10.1007\/s10620-020-06702-8","article-title":"Sertraline and Citalopram Actions on Gut Barrier Function","volume":"66","author":"Bravo","year":"2021","journal-title":"Dig. Dis. Sci."},{"key":"ref_18","first-page":"22","article-title":"Liver Enzymes and Bilirubin Levels during Atomoxetine Treatment in Children and Adolescents","volume":"26","author":"Tanidir","year":"2013","journal-title":"Dusunen Adam J. Psychiatry Neurol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1089\/cap.2015.0137","article-title":"Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition","volume":"26","author":"Yu","year":"2016","journal-title":"J. Child Adolesc. Psychopharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"219","DOI":"10.2334\/josnusd.23-0077","article-title":"Atomoxetine and escitalopram migrate the derangement of the temporomandibular joint morphologic and histologic changes in rats exposed to stress-induced depression","volume":"65","author":"Songphaeng","year":"2023","journal-title":"J. Oral Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/s41413-022-00219-8","article-title":"Bone Remodeling: An Operational Process Ensuring Survival and Bone Mechanical Competence","volume":"10","author":"Bolamperti","year":"2022","journal-title":"Bone Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/s41398-022-02083-w","article-title":"Fluoxetine Improves Bone Microarchitecture and Mechanical Properties in Rodents Undergoing Chronic Mild Stress\u2014An Animal Model of Depression","volume":"12","author":"Lam","year":"2022","journal-title":"Transl. Psychiatry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"107761","DOI":"10.1016\/j.isci.2023.107761","article-title":"The Selective Norepinephrine Reuptake Inhibitor Reboxetine Promotes Late-Stage Fracture Healing in Mice","volume":"26","author":"Donat","year":"2023","journal-title":"iScience"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8825358","DOI":"10.1155\/2023\/8825358","article-title":"Emerging Therapeutic Potential of Cannabidiol (CBD) in Neurological Disorders: A Comprehensive Review","volume":"2023","author":"Singh","year":"2023","journal-title":"Behav. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Saad, N., Raviv, D., Mizrachi Zer-Aviv, T., and Akirav, I. (2023). Cannabidiol Modulates Emotional Function and Brain-Derived Neurotrophic Factor Expression in Middle-Aged Female Rats Exposed to Social Isolation. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242015492"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Stein, L., Vollstaedt, M.L., and Amasheh, S. (2024). Cannabidiol Strengthening of Gastric Tight Junction Complexes Analyzed in an Improved Xenopus Oocyte Assay. Membranes, 14.","DOI":"10.3390\/membranes14010018"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"119113","DOI":"10.1016\/j.jep.2024.119113","article-title":"Cannabidiol\/Cannabidiolic Acid-Rich Hemp (Cannabis sativa L.) Extract Attenuates Cognitive Impairments and Glial Activations in Rats Exposed to Chronic Stress","volume":"338","author":"Kamsrijai","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Gehring, R., Merino, G., and Conti, M.B. (2023). Pharmacokinetics of Cannabidiol Following Single Oral and Oral Transmucosal Administration in Dogs. Front. Vet. Sci., 9.","DOI":"10.3389\/fvets.2022.1104152"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Lapmanee, S., Bhubhanil, S., Wongchitrat, P., Charoenphon, N., Inchan, A., Ngernsutivorakul, T., Dechbumroong, P., Khongkow, M., and Namdee, K. (2024). Assessing the Safety and Therapeutic Efficacy of Cannabidiol Lipid Nanoparticles in Alleviating Metabolic and Memory Impairments and Hippocampal Histopathological Changes in Diabetic Parkinson\u2019s Rats. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16040514"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Lapmanee, S., Bhubhanil, S., Charoenphon, N., Inchan, A., Bunwatcharaphansakun, P., Khongkow, M., and Namdee, K. (2024). Cannabidiol-Loaded Lipid Nanoparticles Incorporated in Polyvinyl Alcohol and Sodium Alginate Hydrogel Scaffold for Enhancing Cell Migration and Accelerating Wound Healing. Gels, 10.","DOI":"10.3390\/gels10120843"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Aydin, S., Ozkul, C., Yucel, N.T., and Karaca, H. (2021). Gut Microbiome Alteration after Reboxetine Administration in Type-1 Diabetic Rats. Microorganisms, 9.","DOI":"10.3390\/microorganisms9091948"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e13261","DOI":"10.1111\/jne.13261","article-title":"Gestational Stress and Perinatal SSRIs Differentially Impact the Maternal and Neonatal Microbiome-Gut-Brain Axis","volume":"35","author":"Pawluski","year":"2023","journal-title":"J. Neuroendocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/s12276-025-01404-5","article-title":"Cannabidiol Reshapes the Gut Microbiome to Promote Endurance Exercise in Mice","volume":"57","author":"Chen","year":"2025","journal-title":"Exp. Mol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"171","DOI":"10.61186\/phypha.27.2.171","article-title":"Venlafaxine and Synbiotic Attenuated Learned Fear-like Behavior and Recognition Memory Impairment in Immobilized-Stressed Rats","volume":"27","author":"Lapmanee","year":"2023","journal-title":"Physiol. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"113523","DOI":"10.1016\/j.bbr.2021.113523","article-title":"Chronic Restraint Stress Induces Anxiety-like Behavior and Remodeling of Dendritic Spines in the Central Nucleus of the Amygdala","volume":"416","author":"Sandoval","year":"2022","journal-title":"Behav. Brain Res."},{"key":"ref_36","first-page":"181","article-title":"Stimulation of Systemic Low-Grade Inflammation by Psychosocial Stress","volume":"76","author":"Rohleder","year":"2014","journal-title":"Biopsychosoc. Sci. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.amjsurg.2019.07.006","article-title":"Chronic Stress Induces Persistent Low-Grade Inflammation","volume":"218","author":"Miller","year":"2019","journal-title":"Am. J. Surg."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Lapmanee, S., Charoenphandhu, J., Teerapornpuntakit, J., Krishnamra, N., and Charoenphandhu, N. (2017). Agomelatine, Venlafaxine, and Running Exercise Effectively Prevent Anxiety- and Depression-like Behaviors and Memory Impairment in Restraint Stressed Rats. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0187671"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"105404","DOI":"10.1016\/j.psyneuen.2021.105404","article-title":"Brain Derived Neurotrophic Factor Deficiency Exacerbates Inflammation-Induced Anhedonia in Mice","volume":"134","author":"Parrott","year":"2021","journal-title":"Psychoneuroendocrinology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"ENEURO.0406-23.2023","DOI":"10.1523\/ENEURO.0406-23.2023","article-title":"Reduction of BDNF Levels and Biphasic Changes in Glutamate Release in the Prefrontal Cortex Correlate with Susceptibility to Chronic Stress-Induced Anhedonia","volume":"10","author":"Hu","year":"2023","journal-title":"eNeuro"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1016\/j.cell.2015.12.023","article-title":"Neuro-Immune Interactions Drive Tissue Programming in Intestinal Macrophages","volume":"164","author":"Gabanyi","year":"2016","journal-title":"Cell"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Meena, A.S., Shukla, P.K., Rao, R., Canelas, C., Pierre, J.F., and Rao, R.K. (2023). TRPV6 Deficiency Attenuates Stress and Corticosterone-Mediated Exacerbation of Alcohol-Induced Gut Barrier Dysfunction and Systemic Inflammation. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1093584"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1111\/pcn.13368","article-title":"Abnormal Gut Microbiota and Bile Acids in Patients with First-Episode Major Depressive Disorder and Correlation Analysis","volume":"76","author":"Sun","year":"2022","journal-title":"Psychiatry Clin. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Skonieczna-\u017cydecka, K., Grochans, E., Maciejewska, D., Szkup, M., Schneider-Matyka, D., Jurczak, A., \u0141oniewski, I., Kaczmarczyk, M., Marlicz, W., and Czerwi\u0144ska-Rogowska, M. (2018). Faecal Short Chain Fatty Acids Profile Is Changed in Polish Depressive Women. Nutrients, 10.","DOI":"10.3390\/nu10121939"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Ney, L.M., Wipplinger, M., Grossmann, M., Engert, N., Wegner, V.D., and Mosig, A.S. (2023). Short Chain Fatty Acids: Key Regulators of the Local and Systemic Immune Response in Inflammatory Diseases and Infections. Open Biol., 13.","DOI":"10.1098\/rsob.230014"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s00281-024-01035-4","article-title":"Role of Polyamines in Intestinal Mucosal Barrier Function","volume":"47","author":"Nakamura","year":"2025","journal-title":"Semin. Immunopathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1038\/s43587-022-00322-9","article-title":"Mechanisms of Spermidine-Induced Autophagy and Geroprotection","volume":"2","author":"Hofer","year":"2022","journal-title":"Nat. Aging"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Dempsey, E., and Corr, S.C. (2022). Lactobacillus Spp. for Gastrointestinal Health: Current and Future Perspectives. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.840245"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1007\/s11914-023-00824-4","article-title":"Inflammatory Processes Affecting Bone Health and Repair","volume":"21","author":"Torres","year":"2023","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"50 Silva, B.C., and Bilezikian, J.P. (2015). Parathyroid Hormone: Anabolic and Catabolic Actions on the Skeleton. Curr. Opin. Pharmacol., 22, 41\u201350.","DOI":"10.1016\/j.coph.2015.03.005"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1080\/10253890.2022.2146998","article-title":"PLC, PTH and NF-\u039aB Increased during Orthodontic Bone Remodeling in Chronic Stress Rats","volume":"25","author":"Xiaotong","year":"2022","journal-title":"Stress"},{"key":"ref_52","first-page":"CD013044","article-title":"Noradrenaline Reuptake Inhibitors (NRIs) for Attention Deficit Hyperactivity Disorder (ADHD) in Adults","volume":"2018","author":"Ziganshina","year":"2018","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"387","DOI":"10.3390\/neurolint13030038","article-title":"Selective Serotonin Reuptake Inhibitors and Adverse Effects: A Narrative Review","volume":"13","author":"Edinoff","year":"2021","journal-title":"Neurol. Int."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Atalay, S., Jarocka-karpowicz, I., and Skrzydlewskas, E. (2020). Antioxidative and Anti-Inflammatory Properties of Cannabidiol. Antioxidants, 9.","DOI":"10.3390\/antiox9010021"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"G\u00e1ll, Z., Farkas, S., Albert, \u00c1., Ferencz, E., Vancea, S., Urkon, M., and Kolcs\u00e1r, M. (2020). Effects of Chronic Cannabidiol Treatment in the Rat Chronic Unpredictable Mild Stress Model of Depression. Biomolecules, 10.","DOI":"10.3390\/biom10050801"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Sabbag, T., Kritman, M., and Akirav, I. (2025). Cannabidiol Effects on Depressive-like Behavior and Neuroinflammation in Female Rats Exposed to High-Fat Diet and Unpredictable Chronic Mild Stress. Cells, 14.","DOI":"10.3390\/cells14120938"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1016\/j.ymthe.2024.03.004","article-title":"Targeting Lipid Nanoparticles to the Blood Brain Barrier to Ameliorate Acute Ischemic Stroke","volume":"32","author":"Nong","year":"2024","journal-title":"Mol. Ther."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Ibrahim, I., Syamala, S., Ayariga, J.A., Xu, J., Robertson, B.K., Meenakshisundaram, S., and Ajayi, O.S. (2022). Modulatory Effect of Gut Microbiota on the Gut-Brain, Gut-Bone Axes, and the Impact of Cannabinoids. Metabolites, 12.","DOI":"10.20944\/preprints202210.0465.v1"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Crowley, K., Kiraga, \u0141., Miszczuk, E., Skiba, S., Banach, J., Latek, U., Mendel, M., and Ch\u0142opecka, M. (2024). Effects of Cannabinoids on Intestinal Motility, Barrier Permeability, and Therapeutic Potential in Gastrointestinal Diseases. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25126682"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Sui, K., Tveter, K.M., Bawagan, F.G., Buckendahl, P., Martinez, S.A., Jaffri, Z.H., MacDonell, A.T., Wu, Y., Duran, R.M., and Shapses, S.A. (2022). Cannabidiol-Treated Ovariectomized Mice Show Improved Glucose, Energy, and Bone Metabolism With a Bloom in Lactobacillus. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.900667"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"203","DOI":"10.4062\/biomolther.2024.104","article-title":"Combination of Cannabidiol with Taurine Synergistically Treated Periodontitis in Rats","volume":"33","author":"Kim","year":"2025","journal-title":"Biomol. Ther."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Burdu\u0219el, A.C., and Andronescu, E. (2022). Lipid nanoparticles and liposomes for bone diseases treatment. Biomedicines, 10.","DOI":"10.3390\/biomedicines10123158"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Zamansky, M., Yariv, D., Feinshtein, V., Ben-Shabat, S., and Sintov, A.C. (2023). Cannabidiol-Loaded Lipid-Stabilized Nanoparticles Alleviate Psoriasis Severity in Mice: A New Approach for Improved Topical Drug Delivery. Molecules, 28.","DOI":"10.3390\/molecules28196907"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"210","DOI":"10.3390\/nutraceuticals3020016","article-title":"Nanostructured Lipid Carriers Loaded with Cannabidiol Enhance Its Bioaccessibility to The Small Intestine","volume":"3","author":"Grifoni","year":"2023","journal-title":"Nutraceuticals"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2722","DOI":"10.1007\/s13346-024-01766-9","article-title":"Enhancement of Cannabidiol Oral Bioavailability Through The Development of Nanostructured Lipid Carriers: In vitro and in vivo Evaluation Studies","volume":"15","author":"Taha","year":"2025","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.pnpbp.2018.06.002","article-title":"Antidepressant-Like Effect Induced by Cannabidiol is Dependent on Brain Serotonin Levels","volume":"86","author":"Sales","year":"2018","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"108679","DOI":"10.1016\/j.neuropharm.2021.108679","article-title":"Co-administration of Cannabidiol and Ketamine Induces Antidepressant-Like Effects Devoid of Hyperlocomotor Side-Effects","volume":"195","author":"Sartim","year":"2021","journal-title":"Neuropharmacology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.yhbeh.2016.10.011","article-title":"Anxiety-like Behaviors in Adulthood Are Altered in Male but Not Female Rats Exposed to Low Dosages of Polychlorinated Biphenyls in Utero","volume":"87","author":"Gillette","year":"2017","journal-title":"Horm. Behav."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Plongniras, P., Lapmanee, S., Thonapan, N., Thangsombat, P., Janthaphim, P., Lertkarnvijai, C., Chailertvanitkul, P., and Morkmued, S. (2025). Stress-Induced Depression and Its Effects on Tooth Wear in Rats: A 3D Dental Scan Imaging Perspective. Life, 15.","DOI":"10.20944\/preprints202503.1488.v1"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"615","DOI":"10.30802\/AALAS-JAALAS-22-000032","article-title":"Changes in the Behavior and Body Weight of Mature, Adult Male Wistar Han Rats after Reduced Social Grouping and Social Isolation","volume":"61","author":"Srbovan","year":"2022","journal-title":"J. Am. Assoc. Lab. Anim. Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.1523\/JNEUROSCI.4131-13.2014","article-title":"The Effects of Antidepressant Treatment in Prenatally Stressed Rats Support the Glutamatergic Hypothesis of Stress-Related Disorders","volume":"34","author":"Marrocco","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Serchov, T., van Calker, D., and Biber, K. (2016). Light\/Dark Transition Test to Assess Anxiety-like Behavior in Mice. Bio Protoc., 6.","DOI":"10.21769\/BioProtoc.1957"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1021\/acsmedchemlett.1c00275","article-title":"Synthesis of Benzoazepine Derivatives via Azide Rearrangement and Evaluation of Their Antianxiety Activities","volume":"12","author":"Reamtong","year":"2021","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Lapmanee, S., Bhubhanil, S., Sriwong, S., Yuajit, C., Wongchitrat, P., Teerapornpuntakit, J., Suntornsaratoon, P., Charoenphandhu, J., and Charoenphandhu, N. (2023). Oral Calcium and Vitamin D Supplements Differentially Alter Exploratory, Anxiety-like Behaviors and Memory in Male Rats. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0290106"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3278","DOI":"10.1016\/j.bbagen.2016.08.010","article-title":"Targeting Immunoproteasome and Glutamine Supplementation Prevent Intestinal Hyperpermeability","volume":"1861","author":"Ghouzali","year":"2017","journal-title":"Biochim. Biophys. Acta (BBA)-Gen. Subj."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Bahlouli, W., Breton, J., Lelouard, M., L\u2019Huillier, C., Tirelle, P., Salameh, E., Amamou, A., Atmani, K., Goichon, A., and B\u00f4le-Feysot, C. (2020). Stress-Induced Intestinal Barrier Dysfunction Is Exacerbated during Diet-Induced Obesity. J. Nutr. Biochem., 81.","DOI":"10.1016\/j.jnutbio.2020.108382"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1111\/cns.12485","article-title":"Brain Region-Specific Histopathological Effects of Varying Trajectories of Controlled Cortical Impact Injury Model of Traumatic Brain Injury","volume":"22","author":"Acosta","year":"2016","journal-title":"CNS Neurosci. Ther."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3692","DOI":"10.1039\/D3FO04904C","article-title":"Protective Effect of Pediococcus pentosaceus Li05 on Diarrhea-Predominant Irritable Bowel Syndrome in Rats","volume":"15","author":"Wu","year":"2024","journal-title":"Food Funct."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Ding, F., Wu, J., Liu, C., Bian, Q., Qiu, W., Ma, Q., Li, X., Long, M., Zou, X., and Chen, J. (2020). Effect of Xiaoyaosan on Colon Morphology and Intestinal Permeability in Rats with Chronic Unpredictable Mild Stress. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.01069"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e38297","DOI":"10.1016\/j.heliyon.2024.e38297","article-title":"Autologous ADSCs with Exogenous NPY Promotes Fracture Healing in Ovariectomized Rats","volume":"10","author":"Liu","year":"2024","journal-title":"Heliyon"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1186\/s13018-022-03471-0","article-title":"Histological Assessment of Cortical Bone Changes in Diabetic Rats","volume":"17","author":"Minami","year":"2022","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Fan, Y., Leape, C.P., Hugard, S., McCanne, M., Thomson, A., Wojtkiewicz, G.R., Weaver, M.J., Collins, J.E., Randolph, M., and Oral, E. (2023). A Longitudinal Rat Model for Assessing Postoperative Recovery and Bone Healing Following Tibial Osteotomy and Plate Fixation. BMC Musculoskelet. Disord., 24.","DOI":"10.1186\/s12891-023-06942-5"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/19\/9318\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:48:50Z","timestamp":1760035730000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/19\/9318"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,24]]},"references-count":82,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["ijms26199318"],"URL":"https:\/\/doi.org\/10.3390\/ijms26199318","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,24]]}}}