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Huang J, Walters TD. Growth Impairment in Pediatric Inflammatory Bowel Disease. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2023:151-172. [DOI: 10.1007/978-3-031-14744-9_12] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Hariyanto TI, Kurniawan A. Appetite problem in cancer patients: Pathophysiology, diagnosis, and treatment. Cancer Treat Res Commun 2021; 27:100336. [PMID: 33607591 DOI: 10.1016/j.ctarc.2021.100336] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 02/01/2021] [Accepted: 02/06/2021] [Indexed: 01/02/2023]
Abstract
AIM This study aims to review the current evidence regarding appetite problem in cancer patients, mainly focusing on pathophysiology, diagnosis, and treatment. INTRODUCTION Anorexia is the common symptom of malnutrition in cancer patients. Recently, the understanding of the pathophysiological mechanism of the appetite problem in cancer patients has been increasing that give impact to rigorous research to find the therapies for improving appetite in cancer patients. DISCUSSION The development of anorexia in cancer patients is a complex process that involves many cytokines, receptors, chemical mediators/substances, hormones, and peptides. Growth and differentiation factor-15 (GDF-15) and toll-like receptor (TLR-4) have recently been found to be implicated in the pathogenesis of anorexia. To help diagnose the appetite problem in cancer patients, several questionnaires can be used, starting from well-known questionnaires such as Functional Assessment of Anorexia Cachexia Therapy (FAACT), Visual Analog Scale (VAS), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ30). Several drugs with different mechanisms of action have been studied to help in improving appetite in cancer patients. New repurposed agents such as anamorelin, mirtazapine, thalidomide, and eicosapentaenoic acid (EPA) have shown a beneficial effect in improving appetite and quality of life in cancer patients, however more phase 3 clinical trial studies is still needed. CONCLUSION The pathophysiology of appetite problems in cancer patients is a complex process that involves many factors. Several drugs that target those factors have been studied, however more phase 3 clinical trial studies are needed to confirm the findings from previous studies.
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Affiliation(s)
- Timotius Ivan Hariyanto
- Faculty of Medicine, Pelita Harapan University, Boulevard Jendral Sudirman street, Karawaci, Tangerang, Banten 15811, Indonesia
| | - Andree Kurniawan
- Department of Internal Medicine, Faculty of Medicine, Pelita Harapan University, Boulevard Jendral Sudirman street, Karawaci, Tangerang, Banten 15811, , Indonesia.
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Amaro F, Chiarelli F. Growth and Puberty in Children with Inflammatory Bowel Diseases. Biomedicines 2020; 8:biomedicines8110458. [PMID: 33138015 PMCID: PMC7692295 DOI: 10.3390/biomedicines8110458] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/27/2020] [Accepted: 10/28/2020] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are gastrointestinal tract pathologies of unknown etiology; they have an alternating trend, with active and silent phases. IBD are classified in two main forms: ulcerative colitis (UC) and Crohn’s disease (CD). Both have chronic and recurrent course, gastrointestinal symptoms, and extraintestinal manifestations. The altered immune response role seems to be important both in UC and CD. In the majority of cases, CD begins with abdominal pain, diarrhea, decrease in appetite, and weight loss; there can be also perianal fistulas, rhagades, and perianal recurrent abscesses. In addition, retarded growth and delayed puberty can precede the development of the disease or can even be predominant at onset. Growth retardation is found in 40% of IBD patients, but the underlying mechanism of this and other extra-intestinal manifestations are partially known: the main hypotheses are represented by malnutrition and inflammatory response during the active phase of the disease. The increased level of pro-inflammatory cytokines can influence growth, but also the onset of puberty and its progression. In addition, it could be essential to clarify the role and the possible effects of all the currently used treatments concerning growth failure and delayed puberty.
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Lopes F, Vicentini FA, Cluny NL, Mathews AJ, Lee BH, Almishri WA, Griffin L, Gonçalves W, Pinho V, McKay DM, Hirota SA, Swain MG, Pittman QJ, Sharkey KA. Brain TNF drives post-inflammation depression-like behavior and persistent pain in experimental arthritis. Brain Behav Immun 2020; 89:224-232. [PMID: 32592863 DOI: 10.1016/j.bbi.2020.06.023] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 06/02/2020] [Accepted: 06/18/2020] [Indexed: 12/21/2022] Open
Abstract
Patients with rheumatoid arthritis experience chronic pain, depression and fatigue, even when inflammation of the joints is well controlled. To study the relationship between arthritis, depression, and sustained pain when articular inflammation is no longer observed, we tested the hypothesis that brain TNF drives post-inflammation depression-like behavior and persistent pain in experimental arthritis. The murine model of antigen-induced arthritis (AIA) was used to evaluate the effects of knee inflammation on sustained pain and depression-like behavior. We measured joint pain using an automated dynamic plantar algesiometer and depression-like behavior with the tail suspension test. Cytokines were measured by Luminex assay and ELISA. TNF in the brain was blocked by intracerebroventricular injection of anti-TNF antibodies. Histological damage and elevated levels of cytokines were observed in the knee 24 h after antigen treatment, but not at 13 days. Reduced pain thresholds were seen 24 h and 13 days after treatment. Depression-like behavior was observed on day 13. Treatment with the antidepressant imipramine reduced both depression-like behavior and persistent pain. However, blocking joint pain with the analgesic dipyrone did not alter depression-like behavior. Elevated levels of TNF, CCL2, and CXCL-1 were observed in the hippocampus 24 h after treatment, with TNF remaining elevated at day 13. Intracerebroventricular infusion of an anti-TNF antibody blocked depression-like behavior and reduced persistent pain. We have demonstrated that depression-like behavior and pain is sustained in AIA mice after the resolution of inflammation. These changes are associated with elevated levels of TNF in the hippocampus and are dependent upon brain TNF. The findings reveal an important mechanistic link between the expression of chronic pain and depression in experimental arthritis. Furthermore, they suggest treating depression in rheumatoid arthritis may positively impact other debilitating features of this condition.
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Affiliation(s)
- Fernando Lopes
- Institute of Parasitology, McGill University, Ste-Anne-de-Bellevue, QC, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.
| | - Fernando A Vicentini
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada; Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Nina L Cluny
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada; Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Alexander J Mathews
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada; Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Benjamin H Lee
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada; Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Wagdi A Almishri
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, AB, Canada
| | - Lateece Griffin
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada; Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - William Gonçalves
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Vanessa Pinho
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Derek M McKay
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada; Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Simon A Hirota
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada; Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Mark G Swain
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, AB, Canada
| | - Quentin J Pittman
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada; Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Keith A Sharkey
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada; Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
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Collins SM. Interrogating the Gut-Brain Axis in the Context of Inflammatory Bowel Disease: A Translational Approach. Inflamm Bowel Dis 2020; 26:493-501. [PMID: 31970390 PMCID: PMC7054772 DOI: 10.1093/ibd/izaa004] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Indexed: 12/14/2022]
Abstract
This review examines preclinical and clinical studies relevant to our understanding of how the bidirectional gut-brain axis influences the natural history of inflammatory bowel disease. Preclinical studies provide proof of concept that preexisting behavioral illness, such as depression, results in increased susceptibility to inflammatory stimuli and that commonly used classes of antidepressants protect against this vulnerability. However, clinical studies suggesting behavioral illness as a risk factor for IBD and a protective role for antidepressants have relied primarily on symptom-reporting rather than objective measurements of inflammation. In terms of gut-to-brain signaling, there is emerging evidence from preclinical and clinical observation that intestinal inflammation alters brain functions, including the induction of mood disorders, alteration of circadian rhythm both centrally and peripherally, and changes in appetitive behaviors. Furthermore, preclinical studies suggest that effective treatment of intestinal inflammation improves associated behavioral impairment. Taken together, the findings of this review encourage a holistic approach to the management of patients with IBD, accommodating lifestyle issues that include the avoidance of sleep deprivation, optimized nutrition, and the monitoring and appropriate management of behavioral disorders. The review also acknowledges the need for better-designed clinical studies evaluating the impact of behavioral disorders and their treatments on the natural history of IBD, utilizing hard end points to assess changes in the inflammatory process as opposed to reliance on symptom-based assessments. The findings of the review also encourage a better understanding of changes in brain function and circadian rhythm induced by intestinal inflammation.
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Affiliation(s)
- Stephen M Collins
- Farncombe Family Digestive Health Research Institute, Department of Medicine, Division of Gastroenterology, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada,Address correspondence to: Stephen M. Collins, MBBS, FRCPC, FRSC, Farncombe Family Digestive Health Research Institute, Faculty of Health Sciences, Room 3N8B, McMaster University Medical Centre, Hamilton, Ontario, CANADA L8N 3Z5. E-mail:
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Exogenous leptin reinforces intestinal barrier function and protects from colitis. Pharmacol Res 2019; 147:104356. [DOI: 10.1016/j.phrs.2019.104356] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 06/19/2019] [Accepted: 07/15/2019] [Indexed: 02/07/2023]
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Ishige T. Growth failure in pediatric onset inflammatory bowel disease: mechanisms, epidemiology, and management. Transl Pediatr 2019; 8:16-22. [PMID: 30881894 PMCID: PMC6382509 DOI: 10.21037/tp.2018.12.04] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 12/26/2018] [Indexed: 12/16/2022] Open
Abstract
Impairment of growth is recognized as one of the most significant complications of inflammatory bowel disease (IBD) in pediatric patients. The reported incidence of growth failure at diagnosis is 15-40% in pediatric onset Crohn's disease (CD) and 3-10% in ulcerative colitis (UC). Growth failure is associated with decreased appetite, abdominal symptoms, malabsorption due to mucosal inflammation, growth hormone (GH) resistance due to inflammation, and even genetic factors. Several population-based studies and cohort studies suggest that patients with pre-pubertal onset CD have a higher risk of growth failure at disease onset. Final adult height is still lower than that of healthy controls; however, its prevalence is generally lower than that at the disease onset. Several IBD treatments were reported to improve patients' growth. In addition to enteral nutrition therapy, treatment with anti-tumor necrosis factor (TNF) agents was reported to have favorable effects on growth of patients with pre-pubertal onset CD. Avoiding corticosteroids (CS) and achieving deep remission seems to be important to maintain optimal growth in patients with pediatric onset IBD.
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Affiliation(s)
- Takashi Ishige
- Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
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Takahashi A, Flanigan ME, McEwen BS, Russo SJ. Aggression, Social Stress, and the Immune System in Humans and Animal Models. Front Behav Neurosci 2018; 12:56. [PMID: 29623033 PMCID: PMC5874490 DOI: 10.3389/fnbeh.2018.00056] [Citation(s) in RCA: 136] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 03/06/2018] [Indexed: 01/25/2023] Open
Abstract
Social stress can lead to the development of psychological problems ranging from exaggerated anxiety and depression to antisocial and violence-related behaviors. Increasing evidence suggests that the immune system is involved in responses to social stress in adulthood. For example, human studies show that individuals with high aggression traits display heightened inflammatory cytokine levels and dysregulated immune responses such as slower wound healing. Similar findings have been observed in patients with depression, and comorbidity of depression and aggression was correlated with stronger immune dysregulation. Therefore, dysregulation of the immune system may be one of the mediators of social stress that produces aggression and/or depression. Similar to humans, aggressive animals also show increased levels of several proinflammatory cytokines, however, unlike humans these animals are more protected from infectious organisms and have faster wound healing than animals with low aggression. On the other hand, subordinate animals that receive repeated social defeat stress have been shown to develop escalated and dysregulated immune responses such as glucocorticoid insensitivity in monocytes. In this review we synthesize the current evidence in humans, non-human primates, and rodents to show a role for the immune system in responses to social stress leading to psychiatric problems such as aggression or depression. We argue that while depression and aggression represent two fundamentally different behavioral and physiological responses to social stress, it is possible that some overlapped, as well as distinct, pattern of immune signaling may underlie both of them. We also argue the necessity of studying animal models of maladaptive aggression induced by social stress (i.e., social isolation) for understanding neuro-immune mechanism of aggression, which may be relevant to human aggression.
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Affiliation(s)
- Aki Takahashi
- Laboratory of Behavioral Neuroendocrinology, University of Tsukuba, Tsukuba, Japan.,Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, United States
| | - Meghan E Flanigan
- Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Bruce S McEwen
- Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, United States
| | - Scott J Russo
- Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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Abstract
Crohn's disease in childhood causes linear growth retardation, which has a substantial effect on management of this disease. By contrast, growth is rarely a problem in children presenting with ulcerative colitis. Depending on how growth failure is defined, approximately one-third of children with Crohn's disease have growth retardation at diagnosis. Although corticosteroids can suppress growth, decreased height at diagnosis demonstrates that this finding is a consequence of the disease and not merely an adverse effect of treatment. Both inflammation and undernutrition contribute to decreased height velocity. Increased cytokine production acts both on the hepatic expression of insulin-like growth factor 1 (IGF-1) and at chondrocytes of the growth plates of long bones. Growth hormone insensitivity caused by deranged immune function is a major mechanism in growth retardation. Resolution of inflammation is the cornerstone of treatment, but current studies on growth hormone and IGF-1 might yield therapies for those children whose inflammation is refractory to treatment.
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Affiliation(s)
- Ian R Sanderson
- Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London. 4 Newark Street, London E1 2AT, UK
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Zhang XJ, Leung FP, Hsiao WWL, Tan S, Li S, Xu HX, Sung JJY, Bian ZX. Proteome profiling of spinal cord and dorsal root ganglia in rats with trinitrobenzene sulfonic acid-induced colitis. World J Gastroenterol 2012; 18:2914-28. [PMID: 22736915 PMCID: PMC3380319 DOI: 10.3748/wjg.v18.i23.2914] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2011] [Revised: 09/24/2011] [Accepted: 04/12/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate proteomic changes in spinal cord and dorsal root ganglia (DRG) of rats with trinitrobenzene sulfonic acid (TNBS)-induced colitis.
METHODS: The colonic myeloperoxidase (MPO) activity and tumor necrosis factor-α (TNF-α) level were determined. A two-dimensional electrophoresis (2-DE)-based proteomic technique was used to profile the global protein expression changes in the DRG and spinal cord of the rats with acute colitis induced by intra-colonic injection of TNBS.
RESULTS: TNBS group showed significantly elevated colonic MPO activity and increased TNF-α level. The proteins derived from lumbosacral enlargement of the spinal cord and DRG were resolved by 2-DE; and 26 and 19 proteins that displayed significantly different expression levels in the DRG and spinal cord were identified respectively. Altered proteins were found to be involved in a number of biological functions, such as inflammation/immunity, cell signaling, redox regulation, sulfate transport and cellular metabolism. The overexpression of the protein similar to potassium channel tetramerisation domain containing protein 12 (Kctd 12) and low expression of proteasome subunit α type-1 (psma) were validated by Western blotting analysis.
CONCLUSION: TNBS-induced colitis has a profound impact on protein profiling in the nervous system. This result helps understand the neurological pathogenesis of inflammatory bowel disease.
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Effect of feeding status on adjuvant arthritis severity, cachexia, and insulin sensitivity in male Lewis rats. Mediators Inflamm 2010; 2010. [PMID: 20953376 PMCID: PMC2952917 DOI: 10.1155/2010/398026] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2010] [Accepted: 09/09/2010] [Indexed: 12/23/2022] Open
Abstract
We studied the effect of food restriction, overfeeding, and normofeeding on cachexia, inflammatory and metabolic parameters, and insulin sensitivity in chronic adjuvant arthritis (AA) in rats. Food restriction during AA increased circulating ghrelin, corticosterone, decreased leptin, and ameliorated arthrogram score and systemic inflammation compared to normofeeding. Overfeeding worsened arthrogram score and systemic inflammation, and led to lipid accumulation in the liver, but not to alterations of adipokine and ghrelin plasma levels relative to normofeeding. Independently of feeding status, AA induced cachexia, in which modulation of mRNA expressions for appetite-regulating neuropeptides (NPY, AgRP, POMC, CART) in the arcuate nucleus (ARC) does not play a primary role. The overexpression of IL-1β mRNA in the ARC suggests its role in the mechanisms of impaired energy balance during AA under all feeding conditions. Normal HOMA index in all arthritic groups does not indicate the development of insulin resistance by feeding interventions in these rats.
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Abstract
Nutrition plays a role in inflammatory bowel disease (IBD) primarily in prevention and treatment of malnutrition and growth failure. Furthermore, in Crohn disease (CD), nutrition can induce remission, maintain remission, and prevent relapse. Malnutrition is common in IBD and the mechanisms involved include decreased food intake, malabsorption, increased nutrient loss, increased energy requirements, and drug-nutrient interactions. At the time of diagnosis, up to 85% of pediatric patients with CD and 65% of those with ulcerative colitis (UC) have weight loss. Growth failure occurs in 15% to 40% of children with IBD and is less common in UC compared with CD, both at diagnosis and during follow-up. In CD, nutritional therapy with enteral formulas induces remission at a rate comparable with that achieved with steroids. In adults with CD, limited information suggests that enteral nutrition (EN) may play a role in maintenance of remission. In children with CD colitis, one study suggested that children without colitis respond better to EN than children with colitis, and another study found no such difference but reported a trend toward earlier relapse in those with isolated colonic involvement. Finally, nutrition may play a role in IBD via the possible protective effect of breastfeeding against UC and CD. In summary, although only CD may benefit from nutrition as primary therapy for remission induction and possibly maintenance of remission, nutrition plays an important role in the prevention and treatment of malnutrition in IBD, and may have a protective role, via the effect of breast-feeding on disease occurrence.
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Pecchi E, Dallaporta M, Jean A, Thirion S, Troadec JD. Prostaglandins and sickness behavior: old story, new insights. Physiol Behav 2009; 97:279-92. [PMID: 19275907 DOI: 10.1016/j.physbeh.2009.02.040] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2008] [Revised: 02/23/2009] [Accepted: 02/26/2009] [Indexed: 12/31/2022]
Abstract
Previous evidence has shown that prostaglandins play a key role in the development of sickness behavior observed during inflammatory states. In particular, prostaglandin E2 (PGE2) is produced in the brain by a variety of inflammatory signals such as endotoxins or cytokines. Its injection has been also shown to induce symptoms of sickness behavior. The role of cyclooxygenase enzymes (COX), the rate-limiting enzymes converting arachidonic acid into prostaglandins, in sickness behavior has been extensively studied, and it has been demonstrated that strategies aiming at inhibiting these enzymes limit anorexia, body weight loss and fever in animals with inflammatory diseases. However, inhibiting COX activity may lead to negative gastric or cardiovascular effects, since COX enzymes play a role in the synthesis of others prostanoids with various and sometimes contrasting properties. Recently, prostaglandin E synthases (PGES), which specifically catalyze the final step of PGE2 biosynthesis, were characterized. Among these enzymes, the microsomal prostaglandin E synthase-1 (mPGES-1) was of a particular interest since it was shown to be up-regulated by inflammatory signals in a variety of cell types. Moreover, mPGES-1 was shown to be crucial for correct immune-to-brain communication and induction of fever and anorexia by pro-inflammatory agents. This review takes stock of previous knowledge and recent advances in understanding the role of prostaglandins and of their specific synthesizing enzymes in the molecular mechanisms underlying sickness behavior. The review concludes with a short summary of key questions that remain to be addressed and points out therapeutic developments in this research field.
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Affiliation(s)
- Emilie Pecchi
- Centre de Recherche en Neurobiologie-Neurophysiologie de Marseille, UMR 6231 CNRS, USC INRA 2027, Université Paul Cézanne et Université de la Méditerranée, Marseille, France
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Bhatt S, Bhatt R, Zalcman SS, Siegel A. Role of IL-1 beta and 5-HT2 receptors in midbrain periaqueductal gray (PAG) in potentiating defensive rage behavior in cat. Brain Behav Immun 2008; 22:224-33. [PMID: 17890051 PMCID: PMC2276628 DOI: 10.1016/j.bbi.2007.07.011] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2007] [Revised: 07/17/2007] [Accepted: 07/28/2007] [Indexed: 11/26/2022] Open
Abstract
Feline defensive rage, a form of aggressive behavior that occurs in response to a threat can be elicited by electrical stimulation of the medial hypothalamus or midbrain periaqueductal gray (PAG). Our laboratory has recently begun a systematic examination of the role of cytokines in the regulation of rage and aggressive behavior. It was shown that the cytokine, interleukin-2 (IL-2), differentially modulates defensive rage when microinjected into the medial hypothalamus and PAG by acting through separate neurotransmitter systems. The present study sought to determine whether a similar relationship exists with respect to interleukin 1-beta (IL-1 beta), whose receptor activation in the medial hypothalamus potentiates defensive rage. Thus, the present study identified the effects of administration of IL-1 beta into the PAG upon defensive rage elicited from the medial hypothalamus. Microinjections of IL-1 beta into the dorsal PAG significantly facilitated defensive rage behavior elicited from the medial hypothalamus in a dose and time dependent manner. In addition, the facilitative effects of IL-1 beta were blocked by pre-treatment with anti-IL-1 beta receptor antibody, while IL-1 beta administration into the PAG had no effect upon predatory attack elicited from the lateral hypothalamus. The findings further demonstrated that IL-1 beta's effects were mediated through 5-HT(2) receptors since pretreatment with a 5-HT(2C) receptors antagonist blocked the facilitating effects of IL-1 beta. An extensive pattern of labeling of IL-1 beta and 5-HT(2C) receptors in the dorsal PAG supported these findings. The present study demonstrates that IL-beta in the dorsal PAG, similar to the medial hypothalamus, potentiates defensive rage behavior and is mediated through a 5-HT(2C) receptor mechanism.
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Affiliation(s)
- Suresh Bhatt
- Department of Neurology & Neurosciences, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA
| | - Rekha Bhatt
- Department of Neurology & Neurosciences, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA
| | - Steven S Zalcman
- Department of Psychiatry, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA
| | - Allan Siegel
- Department of Neurology & Neurosciences, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA
- Department of Psychiatry, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA
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Free tryptophan/large neutral amino acids ratios in blood plasma do not predict cerebral spinal fluid tryptophan concentrations in interleukin-1-induced anorexia. Pharmacol Biochem Behav 2007; 89:31-5. [PMID: 18045669 DOI: 10.1016/j.pbb.2007.10.019] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2007] [Revised: 10/28/2007] [Accepted: 10/30/2007] [Indexed: 12/21/2022]
Abstract
Peripheral administration of interleukin-1 (IL-1) reduces food intake and affects brain serotonergic activity, suggesting a causal relationship. Furthermore, IL-1 increases the brain concentrations of the serotonin precursor, tryptophan (TRP), by unclear mechanism(s). We aimed at confirming the link between IL-1 administration, raised brain TRP concentrations and the development of anorexia, and at investigating the mechanisms of TRP entry into the brain. Thirty adult, overnight fasted Sprague-Dawley rats were randomly assigned to i.p. injections of 1 mug/kg BW of IL-1 alpha (n=10) or vehicle (n=10), or to pair-feeding with IL-1 animals (n=10). After 2 h, food intake, blood plasma concentrations of total TRP, free TRP, large neutral amino acids (LNAA; competing with TRP for brain entry) were measured. Cerebral spinal fluid (CSF) TRP concentrations were also measured. TRP brain availability was assessed by calculating the plasma ratio free TRP/LNAA. Following IL-1 injection, food intake significantly declined in IL-1 rats, which was paralleled by decreased plasma free TRP and increased plasma LNAA. Despite a decrease in the free TRP/LNAA ratios in plasma, IL-1 significantly increased concentrations of TRP in CSF. These data show that the acute peripheral administration of IL-1 induces anorexia and raises CSF TRP levels. Considering the possible role of the raised CSF TRP in influencing brain serotonin activity, it is postulated that increased serotonergic neurotransmission could be involved in IL-1 induced anorexia.
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Daddaoua A, Martínez-Plata E, López-Posadas R, Vieites JM, González M, Requena P, Zarzuelo A, Suárez MD, de Medina FS, Martínez-Augustin O. Active hexose correlated compound acts as a prebiotic and is antiinflammatory in rats with hapten-induced colitis. J Nutr 2007; 137:1222-8. [PMID: 17449585 DOI: 10.1093/jn/137.5.1222] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Active hexose correlated compound (AHCC) is a product prepared from the mycelium of edible Basidiomycete fungi that contains oligosaccharides. Here we have studied the antiinflammatory effect of AHCC in the trinitrobenzenesulfonic acid (TNBS) model of colitis in rats. Rats received AHCC (100 or 500 mg/kg) daily starting 2 d before (pretreatment) colitis induction and were killed 6 d after the TNBS challenge. The status of the rats was assessed by morphological and biochemical methods. The effect of AHCC on the colonic microflora was also assessed by studying the bacteria profile in feces by standard culture techniques. AHCC administration attenuated colonic inflammation, improving rat weight, food intake, damage score, extension of necrosis, colonic weight, colonic weight-to-length ratio, myeloperoxidase and alkaline phosphatase activities, glutathione concentration, and the expression of proinflammatory cytokines and chemokines (IL-1beta, IL-1 receptor antagonist, TNF, and monocyte chemoattractant protein-1) and of mucins 2-4 and trefoil factor 3. The magnitude of the antiinflammatory effect of AHCC was similar to that of sulfasalazine (200 mg/kg). The study of colonic microflora indicated that rats treated with AHCC had higher aerobic and lactic acid bacteria counts as well as higher bifidobacteria counts, whereas clostridia were reduced when compared with the TNBS group. Therefore, our results indicate that AHCC is antiinflammatory and could be useful as a prebiotic to design functional foods for inflammatory bowel disease patients.
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Affiliation(s)
- Abdelali Daddaoua
- Department of Biochemistry and Molecular Biology, University of Granada, Granada 18071, Spain
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18
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Magro F, Fraga S, Azevedo I, Soares-da-Silva P. Intestinal 5-hydroxytryptamine and mast cell infiltration in rat experimental colitis. Dig Dis Sci 2006; 51:495-501. [PMID: 16614958 DOI: 10.1007/s10620-006-3161-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2005] [Accepted: 04/06/2005] [Indexed: 12/09/2022]
Abstract
The present study evaluated the extent of dysfunction of the 5-hydroxytryptaminergic system in inflamed (distal colon) and noninflamed segments (jejunum and ileum) after intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) in the rat. Dexamethasone was administered to control rats and TNBS-treated animals before and for 7 days after TNBS treatment. Tissue levels of 5-hydroxytryptamine (5-HT) in the inflamed colon were higher than in controls. The density of mast cells was also markedly increased. Treatment with dexamethasone attenuated the inflammatory response but did not prevent the increase in colonic 5-HT. In the noninflamed jejunum and terminal ileum, 5-HT tissue levels were markedly increased, but treatment with dexamethasone prevented this increase. It is concluded that the increase in 5-HT levels in the inflamed colon in TNBS-induced colitis may result from mast cell infiltration. In the noninflamed intestine, 5-HT tissue levels were also increased, favoring the view of a generalized mast cell infiltration.
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Affiliation(s)
- F Magro
- Institute of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, 4200-319, Porto, Portugal
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19
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Gay J, Kokkotou E, O'Brien M, Pothoulakis C, Karalis KP. Interleukin-6 genetic ablation protects from trinitrobenzene sulfonic acid-induced colitis in mice. Putative effect of antiinflammatory cytokines. Neuroimmunomodulation 2006; 13:114-21. [PMID: 17077645 DOI: 10.1159/000096656] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2006] [Accepted: 06/14/2006] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Interleukin (IL)-6 is a proinflammatory cytokine implicated in the pathogenesis of inflammatory bowel disease. IL-6 is locally upregulated in inflammatory bowel disease patients and in murine models of experimental colitis. Treatment with anti-IL-6 receptor antibody ameliorates intestinal inflammation. OBJECTIVE It was the aim of this study to investigate the role of genetic IL-6 deficiency in trinitrobenzene sulfonic acid (TNBS)-mediated colitis, an experimental model inflammation that shares several features with Crohn's disease in humans. METHODS Acute colitis was induced in wild-type and IL-6-deficient (Il-6(-/-)) mice by intracolonic administration of TNBS. Forty-eight hours after treatment, the local and systemic features of inflammation, i.e. food intake, weight loss, histological markers of colitis, cytokine expression by real-time PCR, food intake and body weight changes, were assessed. RESULTS In wild-type mice, TNBS administration increased both IL-6 serum levels and local expression of IL-6 by 36 and 9 fold, respectively, compared with control, vehicle-injected mice. Compared with the wild-type mice, the Il-6(-/-) mice had significantly reduced intestinal inflammation as evidenced by epithelial damage, neutrophil infiltration, colon thickness and proinflammatory cytokine expression, following treatment with TNBS. Moreover, baseline levels of the antiinflammatory cytokines IL-10 and tumor growth factor-beta were significantly elevated in Il-6(-/-)compared with the wild-type mice. CONCLUSIONS Our results demonstrate that Il-6(-/-)are partially protected from the development of TNBS-induced acute experimental colitis, most likely via their significantly elevated baseline levels of antiinflammatory cytokines.
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Affiliation(s)
- Jérôme Gay
- Division of Endocrinology, Children's Hospital, Boston, MA, USA
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20
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Guijarro A, Laviano A, Meguid MM. Hypothalamic integration of immune function and metabolism. PROGRESS IN BRAIN RESEARCH 2006; 153:367-405. [PMID: 16876587 PMCID: PMC7119041 DOI: 10.1016/s0079-6123(06)53022-5] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The immune and neuroendocrine systems are closely involved in the regulation of metabolism at peripheral and central hypothalamic levels. In both physiological (meals) and pathological (infections, traumas and tumors) conditions immune cells are activated responding with the release of cytokines and other immune mediators (afferent signals). In the hypothalamus (central integration), cytokines influence metabolism by acting on nucleus involved in feeding and homeostasis regulation leading to the acute phase response (efferent signals) aimed to maintain the body integrity. Peripheral administration of cytokines, inoculation of tumor and induction of infection alter, by means of cytokine action, the normal pattern of food intake affecting meal size and meal number suggesting that cytokines acted differentially on specific hypothalamic neurons. The effect of cytokines-related cancer anorexia is also exerted peripherally. Increase plasma concentrations of insulin and free tryptophan and decrease gastric emptying and d-xylose absorption. In addition, in obesity an increase in interleukin (IL)-1 and IL-6 occurs in mesenteric fat tissue, which together with an increase in corticosterone, is associated with hyperglycemia, dyslipidemias and insulin resistance of obesity-related metabolic syndrome. These changes in circulating nutrients and hormones are sensed by hypothalamic neurons that influence food intake and metabolism. In anorectic tumor-bearing rats, we detected upregulation of IL-1beta and IL-1 receptor mRNA levels in the hypothalamus, a negative correlation between IL-1 concentration in cerebro-spinal fluid and food intake and high levels of hypothalamic serotonin, and these differences disappeared after tumor removal. Moreover, there is an interaction between serotonin and IL-1 in the development of cancer anorexia as well as an increase in hypothalamic dopamine and serotonin production. Immunohistochemical studies have shown a decrease in neuropeptide Y (NPY) and dopamine (DA) and an increase in serotonin concentration in tumor-bearing rats, in first- and second-order hypothalamic nuclei, while tumor resection reverted these changes and normalized food intake, suggesting negative regulation of NPY and DA systems by cytokines during anorexia, probably mediated by serotonin that appears to play a pivotal role in the regulation of food intake in cancer. Among the different forms of therapy, nutritional manipulation of diet in tumor-bearing state has been investigated. Supplementation of tumor bearing rats with omega-3 fatty acid vs. control diet delayed the appearance of tumor, reduced tumor-growth rate and volume, negated onset of anorexia, increased body weight, decreased cytokines production and increased expression of NPY and decreased alpha-melanocyte-stimulating hormone (alpha-MSH) in hypothalamic nuclei. These data suggest that omega-3 fatty acid suppressed pro-inflammatory cytokines production and improved food intake by normalizing hypothalamic food intake-related peptides and point to the possibility of a therapeutic use of these fatty acids. The sum of these data support the concept that immune cell-derived cytokines are closely related with the regulation of metabolism and have both central and peripheral actions, inducing anorexia via hypothalamic anorectic factors, including serotonin and dopamine, and inhibiting NPY leading to a reduction in food intake and body weight, emphasizing the interconnection of the immune and neuroendocrine systems in regulating metabolism during infectious process, cachexia and obesity.
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Affiliation(s)
- Ana Guijarro
- Surgical Metabolism and Nutrition Laboratory, Neuroscience Program, University Hospital, SUNY Upstate Medical University, 750 Adams St., Syracuse, NY 13210, USA
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21
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Iuras A, Telles MM, Bertoncini CRA, Ko GM, de Andrade IS, Silveira VLF, Ribeiro EB. Central administration of a nitric oxide precursor abolishes both the hypothalamic serotonin release and the hypophagia induced by interleukin-1beta in obese Zucker rats. ACTA ACUST UNITED AC 2005; 124:145-50. [PMID: 15544852 DOI: 10.1016/j.regpep.2004.07.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2004] [Accepted: 07/02/2004] [Indexed: 01/23/2023]
Abstract
Serotonin-induced anorexia has long been recognized as an important part of the CNS mechanisms controlling energy balance. More recently, interleukin-1beta and nitric oxide have been suggested to influence this control, possibly through modulation of hypothalamic serotonin. The present work aimed at investigating the interaction of these systems. We addressed whether 5-HT is affected during IL-1beta-induced anorexia in obese Zucker rats and the influence of the central NO system on this IL-1beta/5-HT interaction. Using microdialysis, we observed that an intracerebroventricular injection of 10 ng IL-1beta significantly stimulated 5-HT extracellular levels in the VMH, with a peak variation of 102+/-41% above baseline. IL-1beta also significantly reduced the 4-h feeding by 33% and the 24-h feeding by 42%. Contrarily, these effects were absent when IL-1beta was injected 2 h after the i.c.v. administration of 20 microg of the NO precursor L-arginine. The results suggest that, in obese Zucker rats, activation of the serotonergic system in the medial hypothalamus participates in IL-1beta-induced anorexia. Since L-arginine, probably through NO stimulation, abolished both the anorexia and the serotonergic activation, it can be proposed that the NO system, either directly or indirectly, counteracts IL-1beta anorexia. The hypothalamic serotonergic system is likely to mediate this NO effect.
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Affiliation(s)
- Anderson Iuras
- Department of Physiology, Federal University of São Paulo, Rua Botucatu, 862-2 Andar, Vila Clementino, São Paulo, SP 04023-060, Brazil
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22
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Daddaoua A, Puerta V, Zarzuelo A, Suárez MD, Sánchez de Medina F, Martínez-Augustin O. Bovine glycomacropeptide is anti-inflammatory in rats with hapten-induced colitis. J Nutr 2005; 135:1164-70. [PMID: 15867298 DOI: 10.1093/jn/135.5.1164] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Milk kappa-casein-derived glycomacropeptide has immunomodulatory and bacterial toxin binding effects. The intestinal anti-inflammatory activity of glycomacropeptide was assessed in trinitrobenzenesulfonic acid-induced colitis in rats. Rats were administered glycomacropeptide daily starting either 2 d before (pretreatment) or 3 h after (post-treatment) colitis induction. Pretreatment with glycomacropeptide had a dose-dependent anti-inflammatory effect, characterized by lower body weight loss, decreased anorexia (57%), colonic damage (65%), and weight to length ratio (32%), as well as a reduction in colonic alkaline phosphatase activity (42%) and interleukin 1, trefoil factor 3, and inducible nitric oxide synthase mRNA levels (P < 0.05). The mechanism of action of glycomacropeptide is unknown but is consistent with an inhibition of the activation of immune cells. The magnitude of the anti-inflammatory effect was generally comparable to that of sulfasalazine, an established drug used in the treatment of inflammatory bowel disease. Bovine glycomacropeptide may play a role in the management of patients with inflammatory bowel disease.
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Affiliation(s)
- Abdelali Daddaoua
- Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Granada, Spain
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23
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Simmons DA, Broderick PA. Cytokines, stressors, and clinical depression: augmented adaptation responses underlie depression pathogenesis. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29:793-807. [PMID: 15923072 DOI: 10.1016/j.pnpbp.2005.03.009] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/01/2005] [Indexed: 12/01/2022]
Abstract
By influencing the central nervous system, cytokines, which regulate immune function innately and adaptively, may play a key role in mediating depression-like neuro-behavioral changes. However, the similarity between cytokine and stressor-effects in animal models raises a question about the degree to which behavioral and neurochemical outcomes of cytokine challenge represent depressive disorder per se. The present review attempts to illustrate the degree of overlap between cytokines and stressors with respect to their effects on neurochemistry and behavior in animal models. The review also shows how short-term effects of cytokine exposure in typical animals may be discerned from characteristics that might otherwise be described as depression-like. By comparing outcomes of immune challenge in typical rodent strains (e.g., Sprague-Dawley [SD], Wistar) and an accepted animal model of depression (e.g., Fawn Hooded [FH] rodent strain), differences between short-term effects of cytokines and depression-like characteristics in rodents are demonstrated. Additionally, because it is known that preexisting vulnerability to depression may affect outcomes of immune challenge, we further compare immunological, biochemical and behavioral effects of cytokines between SD and FH rodent strains. Interestingly, the acute neurochemical and behavioral effects of the cytokine interleukin 1alpha (IL-1alpha) reveal stressor-like responses during behavioral habituation in both strains, though this appears to a stronger degree in FH animals. Further, the subacute response to IL-1alpha vastly differed between strains, indicating differences in adaptive mechanisms. Thus, stressor-like effects of immune challenge, particularly in FH animals, provide validation for recent "cross-sensitization" models of depression pathogenesis that incorporate immune factors.
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Affiliation(s)
- Donn A Simmons
- Department of Psychology, Emory University, Atlanta, GA, USA
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24
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25
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Bazar KA, Yun AJ, Lee PY. “Starve a fever and feed a cold”: feeding and anorexia may be adaptive behavioral modulators of autonomic and T helper balance. Med Hypotheses 2005; 64:1080-4. [PMID: 15823688 DOI: 10.1016/j.mehy.2004.05.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2004] [Accepted: 05/04/2004] [Indexed: 11/21/2022]
Abstract
Anorexia is a common symptom accompanying infections, but the teleology of the phenomenon remains unexplained. We hypothesize that anorexia may represent a prehistoric behavioral adaptation to fight infection by maintaining T helper (Th)2 bias, which is particularly vital in fighting bacterial pathogens. Specifically, we propose that anorexia may avert the reduction of Th2/Th1 ratio by preventing feeding-induced neurohormonal and vagal output from the gut. Emerging evidence suggests that the vagal and neurohormonal output of the gut during feeding promotes Th1 function, which is desirable in fighting viral infections. Since fever may be an adaptation to fight bacteria and "colds" are generally viral in origin, the adage "starve a fever and feed a cold" may reflect a sensible behavioral strategy to tilt autonomic and Th balance in directions that are optimal for fighting the particular type of infection. The ability to modulate T helper balance through the neurohormonal and autonomic axis by adjusting food intake may be the mechanism behind other unexplained clinical observations such as the improved outcomes of ICU patients after enteric versus parenteric feedings. Compared to the prehistoric period when bacterial infection was commonplace, the anorexic response may be less adaptive today when viruses and cancers have become common triggers of anorexia. By promoting host anorexia, cachexia, and insomnia, cancers and viruses can deter behaviors such as digestion and sleep that would raise vagal and Th1 activity against tumors and viruses. Hydration and sleep, unexplained but widely accepted recommendations for flu patients, may also work by promoting vagal and Th1 functions. Modulating feeding, hydration, and sleep may prove beneficial in treating other conditions associated with abnormal autonomic and Th balance.
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Affiliation(s)
- Kimberly A Bazar
- Department of Dermatology, San Mateo Medical Center, 222 West, 39th Avenue, San Mateo, CA 94403, USA.
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26
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Jurjus AR, Khoury NN, Reimund JM. Animal models of inflammatory bowel disease. J Pharmacol Toxicol Methods 2004; 50:81-92. [PMID: 15385082 DOI: 10.1016/j.vascn.2003.12.002] [Citation(s) in RCA: 201] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2003] [Accepted: 12/24/2003] [Indexed: 12/16/2022]
Abstract
In inflammatory bowel disease (IBD), experimental models have proven to be important tools for detecting potential therapeutic agents and for investigating the mechanisms of pathogenesis. This review is intended to cover recent advances in basic IBD model applications. The use of more than 20 animal models has allowed the detection of numerous protective pharmacological agents, including a number of immunomodulatory agents that have entered the therapeutic armamentarium. The models have been classified into five main categories based on the methods of induction: gene knockout (KO), transgenic, chemical, adoptive transfer, and spontaneous (each with subcategories).
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Affiliation(s)
- Abdo R Jurjus
- Department of Human Morphology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
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27
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Hassanain M, Zalcman S, Bhatt S, Siegel A. Interleukin-1 beta in the hypothalamus potentiates feline defensive rage: role of serotonin-2 receptors. Neuroscience 2003; 120:227-33. [PMID: 12849755 DOI: 10.1016/s0306-4522(03)00264-1] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
The neurochemistry of aggression and rage has largely focused on the roles played by neurotransmitters and their receptor mechanisms. In contrast, little attention has been given to the possible functions of other substances. Interleukin-1beta is an immune and brain-derived cytokine that is present in the hypothalamus. Functionally, interleukin-1 has been shown to induce the release of serotonin (5-HT), a neurotransmitter known to potently affect aggression and rage behavior. Thus, the goal of the present study was to test the hypothesis that interleukin-1beta in the medial hypothalamus could modulate defensive rage behavior in the cat. In the first experiment, electrical stimulation of sites in the medial hypothalamus from which defensive rage could be elicited and where microinjections of specific compounds were later placed, facilitated defensive rage elicited from the periaqueductal gray (PAG), thus demonstrating the functional relationship between these two regions. In the second experiment, microinjections of relatively low doses of interleukin-1beta into the medial hypothalamus potentiated defensive rage behavior elicited from the midbrain periaqueductal gray in a dose-related manner. In the third experiment, pretreatment with a selective 5-HT2 receptor antagonist, LY-53857, blocked the facilitating effects of interleukin-1beta upon defensive rage. These findings reveal for the first time that brain cytokines can dramatically alter aggressive behavior. In particular, interleukin-1beta in the medial hypothalamus potentiates defensive rage behavior elicited from the periaqueductal gray in the cat, and the potentiating effects of interleukin-1beta on this form of emotional behavior are mediated via a 5-HT2 receptor mechanism.
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Affiliation(s)
- M Hassanain
- Department of Neurosciences, New Jersey Medical School, Medical Science Building, Room H-512, 185 South Orange Avenue, Newark, NJ 07103, USA
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28
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29
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Maier SF. Bi-directional immune-brain communication: Implications for understanding stress, pain, and cognition. Brain Behav Immun 2003; 17:69-85. [PMID: 12676570 DOI: 10.1016/s0889-1591(03)00032-1] [Citation(s) in RCA: 215] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Abstract
The immune system and the central nervous system form a bi-directional communication network. The critical roles of pro-inflammatory cytokines in both the periphery and the nervous system are discussed. In the periphery, these cytokines initiate the processes that signal the brain that immune activation has occurred, and communicate this information over both neural and blood-borne routes. The arrival of these signals in the central nervous system induces a neural cascade that includes the de novo induction of pro-inflammatory cytokines. The functions of these cytokines in the nervous system are discussed, and it is argued that they play a key role in regulating the neural control of immune processes in the periphery. In addition, it is argued that these cytokines play a variety of other roles, and some implications of the cytokine network for understanding stress, behavior, sensory processing, mood, and cognition are described. The overall argument is that because brain-mediated host defense involves behavioral, sensory, mood, and cognitive alterations, immune activation, and immune products such as the cytokines can have a pervasive effect on these functions. Finally, these phenomena are placed in an evolutionary perspective.
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Affiliation(s)
- Steven F Maier
- Department of Psychology and Center for Neuroscience, University of Colorado, Campus box 345 80309-0345, Boulder, CO, USA.
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