93 results on '"Caso JR"'
Search Results
2. Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke.
- Author
-
Caso JR, Pradillo JM, Hurtado O, Lorenzo P, Moro MA, and Lizasoain I
- Published
- 2007
3. Paliperidone Prevents Brain Toll-Like Receptor 4 Pathway Activation and Neuroinflammation in Rat Models of Acute and Chronic Restraint Stress.
- Author
-
MacDowell, KS, Caso, JR, Martín-Hernández, D, Madrigal, JL, Leza, JC, and García-Bueno, B
- Subjects
DOPAMINE antagonists ,TOLL-like receptors ,ENCEPHALITIS ,LABORATORY rats ,IMMOBILIZATION stress ,PSYCHOTIC depression - Abstract
Background: Alterations in the innate immune/inflammatory system have been proposed to underlie the pathophysiology of psychotic disease, but the mechanisms implicated remain elusive. The main agents of the innate immunity are the family of toll-like receptors (TLRs), which detect circulating pathogen-associated molecular patterns and endogenous damage-associated molecular patterns (DAMPS). Current antipsychotics are able to modulate pro- and anti-inflammatory pathways, but their actions on TLRs remain unexplored. Methods: This study was conducted to elucidate the effects of paliperidone (1mg/Kg i.p.) on acute (6 hours) and chronic (6 hours/day during 21 consecutive days) restraint stress–induced TLR-4 pathway activation and neuroinflammation, and the possible mechanism(s) related (bacterial translocation and/or DAMPs activation). The expression of the elements of a TLR-4-dependent proinflammatory pathway was analyzed at the mRNA and protein levels in prefrontal cortex samples. Results: Paliperidone pre-treatment prevented TLR-4 activation and neuroinflammation in the prefrontal cortices of stressed rats. Regarding the possible mechanisms implicated, paliperidone regulated stress-induced increased intestinal inflammation and plasma lipopolysaccharide levels. In addition, paliperidone also prevented the activation of the endogenous activators of TLR-4 HSP70 and HGMB-1. Conclusions: Our results showed a regulatory role of paliperidone on brain TLR-4, which could explain the therapeutic benefits of its use for the treatment of psychotic diseases beyond its effects on dopamine and serotonin neurotransmission. The study of the mechanisms implicated suggests that gut-increased permeability, inflammation, and bacterial translocation of Gram-negative microflora and HSP70 and HGMB1 expression could be potential adjuvant therapeutic targets for the treatment of psychotic and other stress-related psychiatric pathologies. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
4. Racial and ethnic disparities in prostate cancer screening following the 2018 US Preventive Services Task Force recommendation statement.
- Author
-
VanderVeer-Harris N, Zippi ZD, Patel DP, Manoharan M, Caso JR, and Vaidean GD
- Abstract
Objective: In 2018, the United States Preventive Services Task Force promoted shared decision making between healthcare provider and patient for men aged 55 to 69. This study aimed to analyze rates of prostate-specific antigen (PSA) testing across racial and ethnic groups following this new recommendation., Methods: A secondary analysis was conducted of the 2020-2021 Behavioral Risk Factor Surveillance System database to assess men aged 55 or older without a history of prostate cancer. We defined four race-ethnicity groups: non-Hispanic Whites (NHWs), non-Hispanic Blacks (NHBs), Hispanics, and Other. The primary outcome was the most recent PSA test (MRT), defined as the respondent's most recent PSA test occurring pre-2018 or post-2018 guidelines. Logistic regression adjusted for covariates including age, socioeconomic status factors, marital status, smoking history, and healthcare access factors., Results: In the age 55 to 69 study sample, NHW men had the greatest proportion of MRT post-2018 guidelines (n = 15,864, 72.5%). NHB men had the lowest percentage of MRT post-2018 guidelines (n = 965, 66.6%). With NHW as referent, the crude odds of the MRT post-2018 guidelines was 0.68 (95% confidence interval (CI) = 0.53-0.90) for NHB. The maximally adjusted odds ratio was 0.78 (0.59-1.02)., Conclusions: We found that NHB aged 55 to 69 reported decreased rates of PSA testing after 2018 when compared to NHW. This was demonstrated on crude analysis but not after adjustment. Such findings suggest the influence of social determinants of health on preventative screening for at-risk populations., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
- Published
- 2024
- Full Text
- View/download PDF
5. Inflammatory profiles in women with eating disorder: Linking inflammatory biomarkers to clinical phenotypes.
- Author
-
Díaz-Marsá M, Ayad-Ahmed W, López-Villatoro JM, Fernández-Rodrigues V, Ruiz-Guerrero F, Gómez Del Barrio A, Beato-Fernández L, Polo-Montes F, León-Velasco M, Torre-Luque A, Carrasco JL, Caso JR, MacDowell KS, and Leza JC
- Subjects
- Humans, Female, Cyclooxygenase 2, Biomarkers, Phenotype, Bulimia diagnosis, Bulimia psychology, Feeding and Eating Disorders
- Abstract
Introduction: Eating disorders (ED) represent a group of very complex and serious diagnoses characterized by emotional dysregulation and impulsivity. New approaches are necessary to achieve effective diagnosis and treatments. Shifting biomarker research away from the constraints of diagnostic categories may effectively contribute to a dimensional differentiation across disorders according to neurobiology (e.g., inflammatory biomarkers). Thus, the aim of our study was to identify inflammatory profiles in patients with ED., Methods: A sample of 100 women with an ED (23.4 ± 8.55 years) and 59 healthy controls (HC) (20.22 ± 4.18 years) was used. K-means cluster analysis was followed to identify inflammatory clusters considering seven blood biomarkers (iNOS, TNFα, COX2, p38, ERK, TBARS and PPARγ). Moreover, a wide assessment of clinical features was conducted., Results: Two distinct clusters were identified. Cluster 1 patients were characterized by higher inflammatory levels of TNF-α, COX2, p38, and ERK, and had more restrictive anorexia diagnosis than cluster 2. Cluster 2 participants showed higher inflammatory levels of iNOS and were older than cluster 1 and controls and had lower BMI than HC. In addition, they had higher levels of bulimic symptoms than those from the cluster 1 and HC, and higher impulsivity than HC. All ED patients (regardless of cluster) showed higher ED symptoms and more trauma than HC., Conclusions: Our study revealed that inflammatory dysfunction may be linked with clinical endophenotypes in ED, one more restrictive (cluster 1) with an inflammation/oxidative endophenotype more cytokine and MAPK/ERK mediated, and the other more impulsive, with more bulimic symptoms (cluster 2) with NO free radical high output source iNOS. Trauma seems to be a vulnerability factor for both endophenotypes., Competing Interests: Declaration of Competing Interest This work was Supported by the Instituto de Salud Carlos III-FIS research grants [grant numbers PI16/01949 and PI13/00781); and cofounded by European Regional Development Funds (ERDF)., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
6. Differential regulation of innate immune system in frontal cortex and hippocampus in a "double-hit" neurodevelopmental model in rats.
- Author
-
Bris ÁG, MacDowell KS, Ulecia-Morón C, Martín-Hernández D, Moreno B, Madrigal JLM, García-Bueno B, Caso JR, and Leza JC
- Subjects
- Rats, Animals, Anti-Inflammatory Agents metabolism, Immune System metabolism, Hippocampus metabolism, Inflammasomes metabolism, Frontal Lobe metabolism
- Abstract
Neurodevelopmental disorders (NDs) are neuropsychiatric conditions affecting central nervous system development, characterized by cognitive and behavioural alterations. Inflammation has been recently linked to NDs. Animal models are essential for understanding their pathophysiology and identifying therapeutic targets. Double-hit models can reproduce neurodevelopmental and neuroinflammatory impairments. Sixty-seven newborn rats were assigned to four groups: Control, Maternal deprivation (MD, 24-h-deprivation), Isolation (Iso, 5 weeks), and Maternal deprivation + Isolation (MD + Iso, also known as double-hit). Cognitive dysfunction was assessed using behavioural tests. Inflammasome, MAPKs, and TLRs inflammatory elements expression in the frontal cortex (FC) and hippocampus (HP) was analysed through western blot and qRT-PCR. Oxidative/nitrosative (O/N) evaluation and corticosterone levels were measured in plasma samples. Double-hit group was affected in executive and working memory. Most inflammasomes and TLRs inflammatory responses were increased in FC compared to the control group, whilst MAPKs were downregulated. Conversely, hippocampal inflammasome and inflammatory components were reduced after the double-hit exposure, while MAPKs were elevated. Our findings reveal differential regulation of innate immune system components in FC and HP in the double-hit group. Further investigations on MAPKs are necessary to understand their role in regulating HP neuroinflammatory status, potentially linking our MAPKs results to cognitive impairments through their proliferative and anti-inflammatory activity., Competing Interests: Declaration of competing interest The authors declare no competing interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
7. Salivary secretory immunoglobulin A as a potential biomarker of psychosocial stress response during the first stages of life: A systematic review.
- Author
-
Castro-Quintas Á, Palma-Gudiel H, San Martín-González N, Caso JR, Leza JC, and Fañanás L
- Subjects
- Humans, Child, Stress, Psychological, Biomarkers, Circadian Rhythm, Immunoglobulin A, Secretory, Saliva
- Abstract
Mucosal secretory immunoglobulin A (s-IgA) has been recognized as a key component of human first line defense against infection. However, its reactivity to psychosocial stressors is poorly understood. This systematic review aimed to explore whether s-IgA levels changed after psychosocial stress in subjects under the age of 18. Fifteen articles were included. s-IgA basal levels are increased in children older than 9 years old exposed to stress. Furthermore, s-IgA seems to follow a circadian rhythm, which is altered under stress conditions. Finally, the collective evidence suggests that salivary s-IgA rapidly increases under acute stress after puberty. Overall, our review indicates that s-IgA could be considered a potential psychosocial stress biomarker of interest for pediatric and child-juvenile psychiatric population. Further studies are needed to validate the role of s-IgA circadian rhythm and basal levels as psychosocial stress biomarkers and disentangle the role of age and type of stressor., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
8. Immune System and Brain/Intestinal Barrier Functions in Psychiatric Diseases: Is Sphingosine-1-Phosphate at the Helm?
- Author
-
Martín-Hernández D, Muñoz-López M, Tendilla-Beltrán H, Caso JR, García-Bueno B, Menchén L, and Leza JC
- Subjects
- Humans, Sphingosine, Brain, Immune System, Mental Disorders drug therapy
- Abstract
Over the past few decades, extensive research has shed light on immune alterations and the significance of dysfunctional biological barriers in psychiatric disorders. The leaky gut phenomenon, intimately linked to the integrity of both brain and intestinal barriers, may play a crucial role in the origin of peripheral and central inflammation in these pathologies. Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates both the immune response and the permeability of biological barriers. Notably, S1P-based drugs, such as fingolimod and ozanimod, have received approval for treating multiple sclerosis, an autoimmune disease of the central nervous system (CNS), and ulcerative colitis, an inflammatory condition of the colon, respectively. Although the precise mechanisms of action are still under investigation, the effectiveness of S1P-based drugs in treating these pathologies sparks a debate on extending their use in psychiatry. This comprehensive review aims to delve into the molecular mechanisms through which S1P modulates the immune system and brain/intestinal barrier functions. Furthermore, it will specifically focus on psychiatric diseases, with the primary objective of uncovering the potential of innovative therapies based on S1P signaling.
- Published
- 2023
- Full Text
- View/download PDF
9. Editorial: Neuroinflammatory and oxidative/nitrosative pathways in neuropsychiatric and neurological diseases and their possible neuropharmacological regulation, Volume II.
- Author
-
Pereira MP, García-Bueno B, and Caso JR
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2023
- Full Text
- View/download PDF
10. The relationship between negative symptoms, social cognition, and social functioning in patients with first episode psychosis.
- Author
-
García-López M, Alonso-Sánchez M, Leal I, Martín-Hernández D, Caso JR, Díaz-Caneja CM, Andreu-Bernabeu Á, Arango C, Rodriguez-Jimenez R, Sánchez-Pastor L, Díaz-Marsá M, Mellor-Marsá B, Ibáñez Á, Malpica N, Bravo-Ortiz MF, Baca-Garcia E, Ayuso-Mateos JL, and Izquierdo A
- Subjects
- Humans, Social Adjustment, Social Cognition, Social Interaction, Psychotic Disorders psychology, Schizophrenia complications, Schizophrenia diagnosis
- Abstract
Introduction: Social functioning is severely affected in psychotic disorders. Negative symptoms and social cognition seem to play an important role in social functioning, although the preponderance and relationship between these three domains is not clear. In this study, we sought to assess the interrelation between social cognition, social functioning, and the expressiveness and experiential factors of negative symptoms in first-episode psychosis (FEP)., Sample and Methods: 216 patients, participants in a multicentre study (AGES-CM), comprised our study sample. The WHO Disability Assessment Schedule (WHODAS 2.0) was used to assess functioning, whereas the Positive and Negative Schizophrenia Syndrome Scale (PANSS) was used to measure the severity of negative symptoms, and the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) was applied to assess the emotional processing component of social cognition. Network analyses were conducted with the aim of analysing the patterns of relationships between social cognition, social functioning, and the expressiveness and experiential factors of negative symptoms., Results: Our findings suggest that there is a direct relationship between social cognition and social functioning (weight = -.077), but also an indirect connection between them, mediated by the experiential (but not the expressiveness) factor of negative symptoms (weight = 0.300)., Discussion: The importance of the affectation of subdomains of social cognition, as well as the role of negative symptoms, specifically the experiential factor, in the functioning of patients with FEP seems to be relevant. The inclusion of these factors in prevention and treatment programs would thus allow us to reduce their impact on the social functioning of these patients., Competing Interests: Declaration of competing interest Roberto Rodriguez-Jimenez has been a consultant for, spoken in activities of, or received grants from: Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (FIS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid Regional Government (S2010/BMD-2422 AGES; S2017/BMD-3740), JanssenCilag, Lundbeck, Otsuka, Pfizer, Ferrer, Juste, Takeda, Exeltis, Angelini, and Casen-Recordati. Angela Ibáñez has received research support from or served as speaker or advisor for Janssen-Cilag, Lundbeck, and Otsuka. Covadonga M. Díaz-Caneja has received grant support from Instituto de Salud Carlos III and the Spanish Ministry of Science and Innovation (PI17/00481, PI20/00721, JR19/00024), and has received honoraria or travel support from Exeltis, Angelini, Otsuka, and Janssen outside the submitted work. Celso Arango has been a consultant to or has received honoraria or grants from Acadia, Abbot, AMGEN, Angelini, AstraZeneca, Bristol-Myers Squibb, Caja Navarra, CIBERSAM, Fundación Alicia Koplowitz, Forum, Instituto de Salud Carlos III, Gedeon Richter, Janssen Cilag, Lundbeck, Merck, Medscape, Ministerio de Ciencia e Innovación, Ministerio de Sanidad, Ministerio de Economía y Competitividad, Mutua Madrileña, Otsuka, Pfizer, Roche, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovio, and Takeda. The other authors have not conflict of interest to declare., (Copyright © 2022. Published by Elsevier Ltd.)
- Published
- 2022
- Full Text
- View/download PDF
11. Editorial: Neuroinflammatory and oxidative/nitrosative pathways in neuropsychiatric and neurological diseases and their possible neuropharmacological regulation, volume I.
- Author
-
Pereira MP, García-Bueno B, and Caso JR
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2022
- Full Text
- View/download PDF
12. Noradrenaline in Alzheimer's Disease: A New Potential Therapeutic Target.
- Author
-
Gutiérrez IL, Dello Russo C, Novellino F, Caso JR, García-Bueno B, Leza JC, and Madrigal JLM
- Subjects
- Brain pathology, Humans, Locus Coeruleus pathology, Norepinephrine, Adrenergic Neurons pathology, Alzheimer Disease drug therapy, Alzheimer Disease pathology
- Abstract
A growing body of evidence demonstrates the important role of the noradrenergic system in the pathogenesis of many neurodegenerative processes, especially Alzheimer's disease, due to its ability to control glial activation and chemokine production resulting in anti-inflammatory and neuroprotective effects. Noradrenaline involvement in this disease was first proposed after finding deficits of noradrenergic neurons in the locus coeruleus from Alzheimer's disease patients. Based on this, it has been hypothesized that the early loss of noradrenergic projections and the subsequent reduction of noradrenaline brain levels contribute to cognitive dysfunctions and the progression of neurodegeneration. Several studies have focused on analyzing the role of noradrenaline in the development and progression of Alzheimer's disease. In this review we summarize some of the most relevant data describing the alterations of the noradrenergic system normally occurring in Alzheimer's disease as well as experimental studies in which noradrenaline concentration was modified in order to further analyze how these alterations affect the behavior and viability of different nervous cells. The combination of the different studies here presented suggests that the maintenance of adequate noradrenaline levels in the central nervous system constitutes a key factor of the endogenous defense systems that help prevent or delay the development of Alzheimer's disease. For this reason, the use of noradrenaline modulating drugs is proposed as an interesting alternative therapeutic option for Alzheimer's disease.
- Published
- 2022
- Full Text
- View/download PDF
13. Dysfunction of Inflammatory Pathways and Their Relationship With Psychological Factors in Adult Female Patients With Eating Disorders.
- Author
-
Caso JR, MacDowell KS, Soto M, Ruiz-Guerrero F, Carrasco-Díaz Á, Leza JC, Carrasco JL, and Díaz-Marsá M
- Abstract
The attempts to clarify the origin of eating disorders (ED) have not been completely successful and their etiopathogenesis remains unknown. Current research shows an activation of the immune response in neuropsychiatric diseases, including ED. We aimed to investigate immune response parameters in patients with ED and to identify psychological factors influencing the inflammatory response. The relationship between inflammation markers and impulsivity and affective symptomatology was explored as well. Thirty-four adult female patients with current diagnosis of ED, none of them under psychopharmacological treatment (excluding benzodiazepines), were included in this study. Patients were compared with a healthy control group of fifteen adult females. The levels of inflammatory markers and indicators of oxidative/nitrosative stress were evaluated in plasma and/or in peripheral blood mononuclear cells (PBMCs). Subjects were assessed by means of different ED evaluation tools. Additionally, the Barratt Impulsiveness Scale, the Montgomery-Asberg Depression Rating Scale and the Hamilton Anxiety Rating Scale were also employed. Patients with ED shown increased plasma levels of the pro-inflammatory nuclear factor kappa B (NFκB) and the cytokine tumor necrosis factor- alpha (TNF-α), among other factors and an increment in the oxidative/nitrosative stress as well as increased glucocorticoid receptor (GR) expression levels in their PBMCs. Moreover, the inflammatory prostaglandin E
2 (PGE2 ) correlated with impulsiveness and the anti-inflammatory prostaglandin J2 (15d-PGJ2 ) correlated with depressive symptomatology. Our results point towards a relationship between the immune response and impulsiveness and between the immune response and depressive symptomatology in female adult patients with ED., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Caso, MacDowell, Soto, Ruiz-Guerrero, Carrasco-Díaz, Leza, Carrasco and Díaz-Marsá.)- Published
- 2022
- Full Text
- View/download PDF
14. CCL2 Inhibition of Pro-Resolving Mediators Potentiates Neuroinflammation in Astrocytes.
- Author
-
Gutiérrez IL, Novellino F, Caso JR, García-Bueno B, Leza JC, and Madrigal JLM
- Subjects
- Animals, Chemokine CCL2 metabolism, Cytokines metabolism, Inflammation metabolism, Inflammation Mediators metabolism, Mice, Astrocytes metabolism, Neuroinflammatory Diseases
- Abstract
The chemokine CCL2 participates in multiple neuroinflammatory processes, mainly through the recruitment of glial cells. However, CCL2 has also been proven to exert different types of actions on these cells, including the modification of their response to inflammatory stimuli. In the present study we analyzed the effect of CCL2 on the resolution of inflammation in astrocytes. We observed that genetic removal of CCL2 increases the expression of the enzymes responsible for the synthesis of specialized pro-resolving mediators arachidonate 15-lipoxygenase and arachidonate 5-lipoxygenase in the brain cortex of 5xFAD mice. The expression of FPR2 receptor, known to mediate the activity of pro-resolving mediators was also increased in mice lacking CCL2.The downregulation of these proteins by CCL2 was also observed in cultured astrocytes. This suggests that CCL2 inhibition of the resolution of inflammation could facilitate the progression of neuroinflammatory processes. The production of the pro-inflammatory cytokine IL-1beta by astrocytes was analyzed, and allowed us to confirm that CCL2 potentiates the activation of astrocytes trough the inhibition of pro-resolving pathways mediated by Resolvin D1. In addition, the analysis of the expression of TNFalpha, MIP1alpha and NOS2 further confirmed CCL2 inhibition of inflammation resolution in astrocytes.
- Published
- 2022
- Full Text
- View/download PDF
15. Sphk2 deletion is involved in structural abnormalities and Th17 response but does not aggravate colon inflammation induced by sub-chronic stress.
- Author
-
Martín-Hernández D, Gutiérrez IL, González-Prieto M, MacDowell KS, Robledo-Montaña J, Tendilla-Beltrán H, Calleja-Rodríguez N, Bris ÁG, Ulecia-Morón C, Moreno B, Caso JR, García-Bueno B, Rodrigues-Mascarenhas S, Marín-Jiménez I, Leza JC, and Menchén L
- Subjects
- Animals, Cytokines immunology, Lysophospholipids metabolism, Mice, Mice, Knockout, Sphingosine metabolism, Colitis genetics, Colitis immunology, Colitis metabolism, Inflammatory Bowel Diseases genetics, Inflammatory Bowel Diseases immunology, Inflammatory Bowel Diseases metabolism, Phosphotransferases (Alcohol Group Acceptor) deficiency, Phosphotransferases (Alcohol Group Acceptor) immunology, Phosphotransferases (Alcohol Group Acceptor) metabolism, Stress, Psychological immunology, Stress, Psychological metabolism, Th17 Cells immunology, Th17 Cells metabolism
- Abstract
The chronic inflammatory process that characterizes inflammatory bowel diseases (IBD) is mainly driven by T-cell response to microbial and environmental antigens. Psychological stress is a potential trigger of clinical flares of IBD, and sphingosine-1-phosphate (S1P) is involved in T-cell recruitment. Hence, stress impact and the absence of sphingosine kinase 2 (Sphk2), an enzyme of S1P metabolism, were evaluated in the colon of mice after sub-chronic stress exposure. Here, we show that sub-chronic stress increased S1P in the mouse colon, possibly due to a decrease in its degradation enzymes and Sphk2. S1P accumulation could lead to inflammation and immune dysregulation reflected by upregulation of toll-like receptor 4 (TLR4) pathway, inhibition of anti-inflammatory mechanisms, cytokine-expression profile towards a T-helper lymphocyte 17 (Th17) polarization, plasmacytosis, decrease in IgA+ lymphoid lineage cells (CD45+)/B cells/plasmablasts, and increase in IgM+ B cells. Stress also enhanced intestinal permeability. Sphk2 knockout mice presented a cytokine-expression profile towards a boosted Th17 response, lower expression of claudin 3,4,7,8, and structural abnormalities in the colon. Intestinal pathophysiology should consider stress and S1P as modulators of the immune response. S1P-based drugs, including Sphk2 potentiation, represent a promising approach to treat IBD., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
16. Gut microbiota, innate immune pathways, and inflammatory control mechanisms in patients with major depressive disorder.
- Author
-
Caso JR, MacDowell KS, González-Pinto A, García S, de Diego-Adeliño J, Carceller-Sindreu M, Sarramea F, Caballero-Villarraso J, Gracia-García P, De la Cámara C, Agüera L, Gómez-Lus ML, Alba C, Rodríguez JM, and Leza JC
- Subjects
- Feces, Female, Humans, Immunity, Innate, Male, Depressive Disorder, Major, Gastrointestinal Microbiome, Microbiota
- Abstract
Although alterations in the gut microbiota have been linked to the pathophysiology of major depressive disorder (MDD), including through effects on the immune response, our understanding is deficient about the straight connection patterns among microbiota and MDD in patients. Male and female MDD patients were recruited: 46 patients with a current active MDD (a-MDD) and 22 in remission or with only mild symptoms (r-MDD). Forty-five healthy controls (HC) were also recruited. Psychopathological states were assessed, and fecal and blood samples were collected. Results indicated that the inducible nitric oxide synthase expression was higher in MDD patients compared with HC and the oxidative stress levels were greater in the a-MDD group. Furthermore, the lipopolysaccharide (an indirect marker of bacterial translocation) was higher in a-MDD patients compared with the other groups. Fecal samples did not cluster according to the presence or the absence of MDD. There were bacterial genera whose relative abundance was altered in MDD: Bilophila (2-fold) and Alistipes (1.5-fold) were higher, while Anaerostipes (1.5-fold) and Dialister (15-fold) were lower in MDD patients compared with HC. Patients with a-MDD presented higher relative abundance of Alistipes and Anaerostipes (1.5-fold) and a complete depletion of Dialister compared with HC. Patients with r-MDD presented higher abundance of Bilophila (2.5-fold) compared with HC. Thus, the abundance of bacterial genera and some immune pathways, both with potential implications in the pathophysiology of depression, appear to be altered in MDD, with the most noticeable changes occurring in patients with the worse clinical condition, the a-MDD group., (© 2021. The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
17. Inflammatory dysregulation in women with an eating disorder: Relationships with altered emotional reactivity.
- Author
-
Diaz-Marsa M, MacDowell K, de laTorre-Luque A, Caso JR, Faya M, Gutierrez S, Soto M, Pemau A, Diaz-Carracedo P, Carrasco-Diaz A, Leza JC, Graell M, and Carrasco JL
- Subjects
- Adolescent, Emotions, Female, Humans, Arousal, Feeding and Eating Disorders
- Abstract
Background: Some studies suggest that inflammatory signaling dysregulation may contribute to eating disorder (ED) pathophysiology. However, little is known about the influence of inflammatory response on altered processes seen among patients with ED, such as emotional processing and reactivity., Objectives: The objectives were: (a) to investigate the systemic inflammatory response in ED women; and (b) to analyze the role of inflammatory markers in emotional reactivity., Method: Concentrations of several intercellular and intracellular inflammatory mediators (cytokines, prostaglandin by-products and enzymes, TBARS, and MAPK proteins) were quantified in plasma and PBMCs from 68 women with an ED (m = 22.01 years, SD = 9.15) and 35 healthy controls (m = 18.54 years, SD = 4.21). Moreover, emotional reactivity to affective pictures (those without either food or thinness content) was studied using the adult (>18 years old) sample (n = 41)., Results: Between-group differences were revealed for most markers (TNF-α, PGE
2 , COX2, and ratio of activated MAPK proteins), pointing to increased inflammatory response in patients (p < .01). Women with ED showed heightened emotional reactivity, regardless of picture valence. Principal components derived from inflammatory markers showed an explanatory loading on patient's emotional reaction, in terms of valence and arousal., Conclusion: This study corroborates the altered systemic inflammatory response in patients with ED. The inflammatory dysregulation may contribute to ED phenotype, as seen by its relationship with heightened emotional reactivity, even though the inflammatory markers were not evaluated throughout the emotional reactivity protocol., (© 2021 Wiley Periodicals LLC.)- Published
- 2021
- Full Text
- View/download PDF
18. Analysis of Molecular Networks in the Cerebellum in Chronic Schizophrenia: Modulation by Early Postnatal Life Stressors in Murine Models.
- Author
-
Vera-Montecinos A, Rodríguez-Mias R, MacDowell KS, García-Bueno B, Bris ÁG, Caso JR, Villén J, and Ramos B
- Subjects
- 14-3-3 Proteins metabolism, Animals, Axons metabolism, Brain metabolism, Carrier Proteins metabolism, Computational Biology, Cytoskeleton metabolism, Disease Models, Animal, Gene Regulatory Networks, Humans, Male, Microtubule-Associated Proteins metabolism, NADH Dehydrogenase metabolism, Neutrophils metabolism, Proteomics methods, Rats, Rats, Wistar, Cerebellum metabolism, Neural Pathways, Schizophrenia metabolism, Schizophrenia physiopathology, Up-Regulation
- Abstract
Despite the growing importance of the cerebellum as a region highly vulnerable to accumulating molecular errors in schizophrenia, limited information is available regarding altered molecular networks with potential therapeutic targets. To identify altered networks, we conducted one-shot liquid chromatography-tandem mass spectrometry in postmortem cerebellar cortex in schizophrenia and healthy individuals followed by bioinformatic analysis (PXD024937 identifier in ProteomeXchange repository). A total of 108 up-regulated proteins were enriched in stress-related proteins, half of which were also enriched in axonal cytoskeletal organization and vesicle-mediated transport. A total of 142 down-regulated proteins showed an enrichment in proteins involved in mitochondrial disease, most of which were also enriched in energy-related biological functions. Network analysis identified a mixed module of mainly axonal-related pathways for up-regulated proteins with a high number of interactions for stress-related proteins. Energy metabolism and neutrophil degranulation modules were found for down-regulated proteins. Further, two double-hit postnatal stress murine models based on maternal deprivation combined with social isolation or chronic restraint stress were used to investigate the most robust candidates of generated networks. CLASP1 from the axonal module in the model of maternal deprivation was combined with social isolation, while YWHAZ was not altered in either model. METTL7A from the degranulation pathway was reduced in both models and was identified as altered also in previous gene expression studies, while NDUFB9 from the energy network was reduced only in the model of maternal deprivation combined with social isolation. This work provides altered stress- and mitochondrial disease-related proteins involved in energy, immune and axonal networks in the cerebellum in schizophrenia as possible novel targets for therapeutic interventions and suggests that METTL7A is a possible relevant altered stress-related protein in this context.
- Published
- 2021
- Full Text
- View/download PDF
19. Paliperidone attenuates chronic stress-induced changes in the expression of inflammasomes-related protein in the frontal cortex of male rats.
- Author
-
MacDowell KS, Martín-Hernández D, Ulecia-Morón C, Bris ÁG, Madrigal JLM, García-Bueno B, and Caso JR
- Subjects
- Animals, Caspase 1 metabolism, Chronic Disease, DNA-Binding Proteins metabolism, Disease Models, Animal, Frontal Lobe immunology, Frontal Lobe metabolism, Inflammation Mediators metabolism, Interleukin-1beta metabolism, Male, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Nerve Tissue Proteins metabolism, Rats, Wistar, Restraint, Physical, Stress, Psychological immunology, Stress, Psychological metabolism, Stress, Psychological psychology, Rats, Anti-Inflammatory Agents pharmacology, Antipsychotic Agents pharmacology, Frontal Lobe drug effects, Inflammasomes metabolism, Paliperidone Palmitate pharmacology, Stress, Psychological drug therapy
- Abstract
Several stress-related neuropsychiatric diseases are related to inflammatory phenomena. Thus, a better understanding of stress-induced immune responses could lead to enhanced treatment alternatives. Little is known about the possible involvement of inflammasomes in the stress-induced proinflammatory response. Antipsychotics have anti-inflammatory effects, but the possible antipsychotic treatment actions on inflammasomes remain unexplored. Our aim was to study whether inflammasomes are involved in the neuroinflammation induced by a paradigmatic model of chronic stress and whether the monoamine receptor antagonist paliperidone can modulate the possible stress-induced inflammasomes activation in the frontal cortex (FC). Thus, the effects of paliperidone (1 mg/Kg, oral gavage) administered during a chronic restraint stress protocol (6 h/day for 21 days) on the possible stress-related inflammasomes protein induction were evaluated through Western blot in the FC of male Wistar rats. Stress increased protein expression levels of the inflammasome complexes NALP1, NLRP3 and AIM2 and augmented caspase-1 and mature interleukin (IL)-1β protein levels. Paliperidone pre-treatment normalized the protein expression of the inflammasome pathway. In conclusion, our data indicate an induction of inflammasome complexes by chronic restraint stress in the FC of rats. The antipsychotic paliperidone has an inhibitory action on some of the stress-induced inflammasomes stimulation trying to normalize the neuroinflammatory scenario caused by stress. Considering the emerging role of inflammation in neuropsychiatric diseases, the development of new drugs targeting inflammasome pathways is a promising approach for future therapeutic interventions., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
20. Microglial CX3CR1 production increases in Alzheimer's disease and is regulated by noradrenaline.
- Author
-
González-Prieto M, Gutiérrez IL, García-Bueno B, Caso JR, Leza JC, Ortega-Hernández A, Gómez-Garre D, and Madrigal JLM
- Subjects
- Amyloid beta-Peptides, Animals, CX3C Chemokine Receptor 1 genetics, Mice, Norepinephrine, Rats, Reboxetine, Alzheimer Disease drug therapy, Microglia
- Abstract
The loss of noradrenergic neurons and subsequent reduction of brain noradrenaline (NA) levels are associated with the progression of Alzheimer's disease (AD). This seems to be due mainly to the ability of NA to reduce the activation of microglial cells. We previously observed that NA induces the production of the chemokine Fractalkine/CX3CL1 in neurons. The activation of microglial CX3CR1, sole receptor for CX3CL1, reduces the activation of microglia, which is known to largely contribute to the neuronal damage characteristic of AD. Therefore, alterations of CX3CR1 production in microglia could translate into the enhancement or inhibition of CX3CL1 anti-inflammatory effects. In order to determine if microglial CX3CR1 production is altered in AD and if NA can control it, CX3CR1 expression and synthesis were analyzed in 5xFAD mice and human AD brain samples. In addition, the effects of NA and its reuptake inhibitor reboxetine were analyzed in microglial cultures and mice respectively. Our results indicate that in AD CX3CR1 production is increased in the brain cortex and that reboxetine administration further increases it and enhances microglial reactivity toward amyloid beta plaques. However, direct administration of NA to primary rat microglia or human HMC3 cells inhibits CX3CR1 production, suggesting that microglia responses to NA may be altered in the absence of CX3CL1-producing neurons or other nonmicroglial external factors., (© 2020 Wiley Periodicals LLC.)
- Published
- 2021
- Full Text
- View/download PDF
21. Depletion of brain perivascular macrophages regulates acute restraint stress-induced neuroinflammation and oxidative/nitrosative stress in rat frontal cortex.
- Author
-
Sayd A, Vargas-Caraveo A, Perea-Romero I, Robledo-Montaña J, Caso JR, Madrigal JLM, Leza JC, Orio L, and Garcia-Bueno B
- Subjects
- Animals, Inflammation Mediators metabolism, Male, Phagocytosis physiology, Rats, Rats, Wistar, Restraint, Physical physiology, Restraint, Physical psychology, Stress, Psychological psychology, Frontal Lobe metabolism, Glymphatic System metabolism, Macrophages metabolism, Nitrosative Stress physiology, Oxidative Stress physiology, Stress, Psychological metabolism
- Abstract
The central nervous system can respond to peripheral immune stimuli through the activation of the neurovascular unit. One of the cellular types implicated are perivascular macrophages (PVMs), hematopoietic-derived brain-resident cells located in the perivascular space. PVMs have been implicated in the immune surveillance and in the regulation of the accumulation/trafficking of macromolecules in brain-blood interfaces. Recent studies suggested that the role of PVMs could vary depending on the nature and duration of the immune challenge applied. Here, we investigate the role of PVMs in stress-induced neuroinflammation and oxidative/nitrosative consequences. The basal phagocytic activity of PVMs was exploited to selectively deplete them by ICV injection of liposomes encapsulating the pro-apoptotic drug clodronate. Acute restraint stress-induced neuroinflammation and oxidative/nitrosative stress in rat brain frontal cortex samples were assessed by western blot and RT-PCR analyses. The depletion of PVMs: (1) decreased tumor necrosis-α levels (2) prevented the Janus kinase/signal transducers and activators of transcription pathway and increased interleukin-6 receptor protein-expression in stress conditions; (3) prevented the stress-induced Toll-like receptor 4/Myeloid differentiation primary response 88 protein signaling pathway; (4) down-regulated the pro-inflammatory nuclear factor κB/cyclooxygenase-2 pathway; (5) prevented stress-induced lipid peroxidation and the concomitant increase of the endogenous antioxidant mediators nuclear factor (erythroid-derived 2)-like 2, glutathione reductase 1 and Parkinsonism-associated deglycase mRNA expression. Our results point to PVMs as regulators of stress-induced neuroinflammation and oxidative/nitrosative stress. Much more scientific effort is still needed to evaluate whether their selective manipulation is promising as a therapeutic strategy for the treatment of stress-related neuropsychopathologies., (Copyright © 2020. Published by Elsevier B.V.)
- Published
- 2020
- Full Text
- View/download PDF
22. Dysfunction of inflammatory pathways in adolescent female patients with anorexia nervosa.
- Author
-
Caso JR, Graell M, Navalón A, MacDowell KS, Gutiérrez S, Soto M, Leza JC, Carrasco JL, and Marsá MD
- Subjects
- Adolescent, Anorexia Nervosa psychology, Biomarkers blood, Female, Humans, Leukocytes, Mononuclear metabolism, Anorexia Nervosa blood, Anorexia Nervosa diagnosis, Inflammation Mediators blood
- Abstract
Background: The pathogenesis of Eating Disorders is still unknown. However, a growing body of evidence shows that there are changes in cytokine levels and an alteration in the stress response in patients with anorexia nervosa (AN). For this reason, we decided to test whether there are differences in immune parameters involved in the regulation of the inflammatory response between female adolescents with AN and healthy adolescents., Methods: The sample 27 drug-naïve AN patients the study sample included 27 AN patients at a very early stage of the disease and 23 healthy controls. Plasma and peripheral blood mononuclear cells (PBMCs) were obtained for biochemical study., Results: Plasma levels of the pro-inflammatory cytokines TNF-α and IL-1β were significantly increased in patients with AN, while the levels of prostaglandins PGE
2 (proinflammatory) and 15d-PGJ2 , (anti-inflammatory) were lower compared with controls. Protein expression in PBMCs of cyclooxygenase-2 (COX-2) and the activated forms of the mitogen-activated protein kinases p38 and ERK were also increased in the AN group. Expression levels of the anti-inflammatory factor peroxisome proliferator-activated receptor gamma (PPARγ) were significantly decreased in patients. Plasma levels of lipid peroxidation markers -TBARS- were not increased in patients with AN. Components of the biochemical inflammatory response (COX-2, PGE2 , TBARS, 15d-PGJ2 , ERK, p65 NFκB) and glucocorticoid receptor -GR- expression and the scores on the impulsivity measures in the BARRATT, EDI and BITE questionnaires showed a significant correlation within the AN patients group., Conclusions: The results for female adolescent patients with AN indicate that there is a dysfunction of intra- and intercellular inflammatory pathways characterized by higher levels of pro-inflammatory parameters in plasma and a decrease in one of the controlling cytoplasmic-nuclear pathways implicated in their modulation (i.e. PPARγ) with, at this very early stage of the disease, no effect on oxidative stress markers plasma levels. Most notably, higher severity of illness (restrictive and purging behaviour) correlated with higher levels of inflammatory markers., (Copyright © 2019. Published by Elsevier Inc.)- Published
- 2020
- Full Text
- View/download PDF
23. Toll-like receptor 4 agonist and antagonist lipopolysaccharides modify innate immune response in rat brain circumventricular organs.
- Author
-
Vargas-Caraveo A, Sayd A, Robledo-Montaña J, Caso JR, Madrigal JLM, García-Bueno B, and Leza JC
- Subjects
- Animals, Brain drug effects, Circumventricular Organs drug effects, Immunity, Innate drug effects, Male, NF-kappa B immunology, Rats, Rats, Wistar, Toll-Like Receptor 4 agonists, Toll-Like Receptor 4 antagonists & inhibitors, Brain immunology, Circumventricular Organs immunology, Immunity, Innate immunology, Lipopolysaccharides pharmacology, Toll-Like Receptor 4 immunology
- Abstract
Background: The circumventricular organs (CVOs) are blood-brain-barrier missing structures whose activation through lipopolysaccharide (LPS) is a starting point for TLR-driven (Toll-like receptors) neuroinflammation. The aim of this study was to evaluate in the CVO area postrema (AP), subfornical organ (SFO), and median eminence (ME), the inflammatory response to two TLR4 agonists: LPS from Escherichia coli (EC-LPS), the strongest endotoxin molecule described, and LPS from Porphyromonas gingivalis (PG-LPS), a pathogenic bacteria present in the periodontium related to neuroinflammation in neurodegenerative/psychiatric diseases. The response to LPS from the cyanobacteria Rhodobacter sphaeroides (RS-LPS), a TLR4 antagonist with an interesting anti-inflammatory potential, was also assessed., Methods: LPSs were intraperitoneally administered to Wistar rats and, as indicatives of neuroinflammation in CVOs, the cellular localization of the nuclear factor NF-κB was studied by immunofluorescence, and microglia morphology was quantified by fractal and skeleton analysis., Results: Data showed that EC-LPS increased NF-κB nuclear translocation in the three CVOs studied and PG-LPS only induced NF-κB nuclear translocation in the ME. RS-LPS showed no difference in NF-κB nuclear translocation compared to control. Microglia in the three CVOs showed an ameboid-shape after EC-LPS exposure, whereas PG-LPS only elicited a mild tendency to induce an ameboid shape. On the other hand, RS-LPS produced a markedly elongated morphology described as "rod" microglia in the three CVOs., Conclusions: In conclusion, at the doses tested, EC-LPS induces a stronger neuroinflammatory response than PG-LPS in CVOs, which might be related to their different potency as TLR4 agonists. The non-reduction of basal NF-κB activation and induction of rod microglia by RS-LPS, a cell morphology only present in severe brain injury and infections, suggests that this molecule must be carefully studied before being proposed as an anti-inflammatory treatment for neuroinflammation related to neurodegenerative/psychiatric diseases.
- Published
- 2020
- Full Text
- View/download PDF
24. Reboxetine Treatment Reduces Neuroinflammation and Neurodegeneration in the 5xFAD Mouse Model of Alzheimer's Disease: Role of CCL2.
- Author
-
Gutiérrez IL, González-Prieto M, Caso JR, García-Bueno B, Leza JC, and Madrigal JLM
- Subjects
- Alzheimer Disease genetics, Alzheimer Disease pathology, Amyloid beta-Peptides metabolism, Animals, Apoptosis drug effects, Axons drug effects, Axons metabolism, Axons pathology, Biomarkers metabolism, Cyclooxygenase 2 metabolism, Disease Models, Animal, Gene Expression Regulation drug effects, Glial Fibrillary Acidic Protein metabolism, Inflammation complications, Inflammation genetics, Memory Disorders complications, Memory Disorders drug therapy, Mice, Inbred C57BL, Mice, Transgenic, Microglia drug effects, Microglia pathology, Nerve Degeneration complications, Nerve Degeneration genetics, Reboxetine pharmacology, Alzheimer Disease drug therapy, Chemokine CCL2 metabolism, Inflammation drug therapy, Nerve Degeneration drug therapy, Reboxetine therapeutic use
- Abstract
The reduction of brain noradrenaline levels is associated to the initiation of Alzheimer's disease and contributes to its progression. This seems to be due mainly to the anti-neuroinflammatory actions of noradrenaline. The analysis of noradrenaline effects on brain cells demonstrates that it also regulates the production of the chemokine CCL2. In the present study, we analyzed the effect of the selective noradrenaline reuptake inhibitor, reboxetine, on the inflammatory and neurodegenerative alterations present in 5xFAD mice, and how the genetic removal of CCL2 affects reboxetine actions. We observed that the removal of CCL2 reduced the memory impairments in 5xFAD mice as well as the neuroinflammatory response, the accumulation of amyloid beta plaques, and the degeneration of neurons in the brain cortex. The administration of reboxetine with osmotic pumps for 28 days also resulted in anti-inflammatory and neuroprotective changes in 5xFAD mice, even in the absence of CCL2. Yet, 6-month-old CCL2KO mice presented a significant degree of neuroinflammation and neuronal damage. These findings indicate that reboxetine treatment prevents the brain alterations caused by prolonged overproduction of amyloid beta, being these effects independent of CCL2, which is a mediator of the damage caused by amyloid beta in the brain cortex, but necessary for the prevention of the development of neurodegeneration in normal healthy conditions.
- Published
- 2019
- Full Text
- View/download PDF
25. Modulation of Monoaminergic Systems by Antidepressants in the Frontal Cortex of Rats After Chronic Mild Stress Exposure.
- Author
-
Martín-Hernández D, Pereira MP, Tendilla-Beltrán H, Madrigal JLM, García-Bueno B, Leza JC, and Caso JR
- Subjects
- Animals, Antidepressive Agents pharmacology, Chronic Disease, Frontal Lobe drug effects, Frontal Lobe metabolism, Male, Membrane Transport Proteins metabolism, Models, Biological, Norepinephrine metabolism, Rats, Wistar, Receptors, Adrenergic metabolism, Receptors, Serotonin metabolism, Serotonin metabolism, Antidepressive Agents therapeutic use, Biogenic Monoamines metabolism, Frontal Lobe pathology, Stress, Psychological drug therapy
- Abstract
The standard pharmacological treatment of the major depressive disorder (MDD) is still grounded in a monoaminergic approach. Consequently, antidepressant treatments pursue to heighten serotonergic and noradrenergic neurotransmissions. Thus, the aim of this study was to assess the impact of exposure to a well-characterized animal model, the chronic mild stress (CMS) on serotonin (5-HT) and noradrenaline (NE) levels, and reuptake transporters and receptors in the frontal cortex (FC) of CMS-exposed rats. Moreover, considering the diverse pharmacological profiles of existing antidepressants and the large number of patients not responding to treatments, we have investigated whether generally utilized antidepressants can modulate their expression. Male Wistar rats were exposed to CMS and some of them treated with desipramine, escitalopram, or duloxetine. Possible changes in the described monoaminergic neurotransmission elements were evaluated. CMS induced differences in the expression of reuptake transporters and receptors involved in the monoaminergic neurotransmission pointing towards the weakening of their signaling. CMS antidepressant-treated rats showed an improvement of the monoaminergic tone, being desipramine and duloxetine more influential than escitalopram over noradrenergic elements and having the three antidepressant-tested effects on serotonergic transmission. In summary, there are molecular alterations on the monoaminergic neurotransmission in FC induced by CMS exposure. Besides, antidepressant treatments modulate the elements of these neurotransmission systems differentially.
- Published
- 2019
- Full Text
- View/download PDF
26. Changes in brain kynurenine levels via gut microbiota and gut-barrier disruption induced by chronic ethanol exposure in mice.
- Author
-
Giménez-Gómez P, Pérez-Hernández M, O'Shea E, Caso JR, Martín-Hernandez D, Cervera LA, Centelles MLG, Gutiérrez-Lopez MD, and Colado MI
- Subjects
- Animals, Behavior, Animal drug effects, Ethanol administration & dosage, Male, Mice, Mice, Inbred C57BL, Brain metabolism, Ethanol toxicity, Gastrointestinal Microbiome drug effects, Kynurenine metabolism
- Abstract
Inflammatory processes have been shown to modify tryptophan (Trp) metabolism. Gut microbiota appears to play a significant role in the induction of peripheral and central inflammation. Ethanol (EtOH) exposure alters gut permeability, but its effects on Trp metabolism and the involvement of gut microbiota have not been studied. We analyzed several parameters of gut-barrier and of peripheral and central Trp metabolism following 2 different EtOH consumption patterns in mice, the binge model, drinking in the dark (DID), and the chronic intermittent (CI) consumption paradigm. Antibiotic treatment was used to evaluate gut microbiota involvement in the CI model. Mice exposed to CI EtOH intake, but not DID, show bacterial translocation and increased plasma LPS immediately after EtOH removal. Gut-barrier permeability to FITC-dextran is increased by CI, and, furthermore, intestinal epithelial tight-junction (TJ) disruption is observed (decreased expression of zonula occludens 1 and occludin) associated with increased matrix metalloproteinase (MMP)-9 activity and iNOS expression. CI EtOH, but not DID, increases kynurenine (Kyn) levels in plasma and limbic forebrain. Intestinal bacterial decontamination prevents the LPS increase but not the permeability to FITC-dextran, TJ disruption, or the increase in MMP-9 activity and iNOS expression. Although plasma Kyn levels are not affected by antibiotic treatment, the elevation of Kyn in brain is prevented, pointing to an involvement of microbiota in CI EtOH-induced changes in brain Trp metabolism. Additionally, CI EtOH produces depressive-like symptoms of anhedonia, which are prevented by the antibiotic treatment thus pointing to an association between anhedonia and the increase in brain Kyn and to the involvement of gut microbiota.-Giménez-Gómez, P., Pérez-Hernández, M., O'Shea, E., Caso, J. R., Martín-Hernández, D., Cervera, L. A., Centelles. M. L. G.-L., Gutiérrez-Lopez, M. D., Colado, M. I. Changes in brain kynurenine levels via gut microbiota and gut-barrier disruption induced by chronic ethanol exposure in mice.
- Published
- 2019
- Full Text
- View/download PDF
27. Early versus late stage schizophrenia. What markers make the difference?
- Author
-
García-Álvarez L, García-Portilla MP, Caso JR, de la Fuente-Tomás L, González-Blanco L, Sáiz Martínez P, Leza JC, and Bobes J
- Subjects
- Adult, Age Factors, Cohort Studies, Cross-Sectional Studies, Employment, Female, Health Status, Humans, Male, Middle Aged, Severity of Illness Index, Time Factors, Transcriptional Elongation Factors, Carrier Proteins blood, Disease Progression, Inflammation blood, Schizophrenia blood, Schizophrenia physiopathology
- Abstract
Objectives: To identify the psychopathological, cognitive, functional, physical health and inflammatory markers that differentiate between early-stage schizophrenia (ESSCH) and late-stage schizophrenia (LSSCH)., Methods: Cross-sectional, naturalistic study of 104 patients with SCH. The sample was divided in two groups: 35 ESSCH (≤7 years' duration of illness) and 69 LSSCH (>10 years' duration of illness)., Statistical Analysis: chi-square test and Student's t-test and ANCOVA (or Quade test) controlling for age, sex, BMI and number of cigarettes/day. Finally, a binomial logistic regression was made., Results: ESSCH show greater negative symptom severity (t = 2.465, p = 0.015), lower levels of IκBα (F = 7.644, p = 0.007), were more frequently classified as normal weight (40% vs 18.8%, p = 0.032) compared with LSSCH. The binomial logistic regression model included age (B = 0.127, p = 0.001) and IκBα (B = 0.025, p = 0.002) and accounted for 38.9% of the variance (model df =7, chi-square =41.841, p < 0.0001)., Conclusions: Age and IκBα are the unique markers that differentiate between ESSCH patients whose duration of illness is less than 7 years and LSSCH patients. These results support the hypothesis of toxicity of episodes and highlight the importance of preventing new episodes.
- Published
- 2019
- Full Text
- View/download PDF
28. Chronic Mild Stress Alters Kynurenine Pathways Changing the Glutamate Neurotransmission in Frontal Cortex of Rats.
- Author
-
Martín-Hernández D, Tendilla-Beltrán H, Madrigal JLM, García-Bueno B, Leza JC, and Caso JR
- Subjects
- Animals, Antidepressive Agents pharmacology, Antidepressive Agents therapeutic use, Chronic Disease, Cytokines metabolism, Frontal Lobe drug effects, Glutamate Plasma Membrane Transport Proteins genetics, Glutamate Plasma Membrane Transport Proteins metabolism, Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism, Inflammation Mediators metabolism, Kynurenic Acid metabolism, Male, Metabolic Networks and Pathways drug effects, Quinolinic Acid metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Rats, Wistar, Receptors, N-Methyl-D-Aspartate genetics, Receptors, N-Methyl-D-Aspartate metabolism, Stress, Psychological drug therapy, Tryptophan metabolism, Frontal Lobe pathology, Frontal Lobe physiopathology, Glutamic Acid metabolism, Kynurenine metabolism, Stress, Psychological metabolism, Stress, Psychological physiopathology, Synaptic Transmission drug effects
- Abstract
Immune stimulation might be involved in the pathophysiology of major depressive disorder (MDD). This stimulation induces indoleamine 2,3-dioxygenase (IDO), an enzyme that reduces the tryptophan bioavailability to synthesize serotonin. IDO products, kynurenine metabolites, exert neurotoxic/neuroprotective actions through glutamate receptors. Thus, we study elements of these pathways linked to kynurenine metabolite activity examining whether antidepressants (ADs) can modulate them. Male Wistar rats were exposed to chronic mild stress (CMS), and some of them were treated with ADs. The expression of elements of the IDO pathway, including kynurenine metabolites, and their possible modulation by ADs was studied in the frontal cortex (FC). CMS increased IDO expression in FC compared to control group, and ADs restored the IDO expression levels to control values. CMS-induced IDO expression led to increased levels of the excitotoxic quinolinic acid (QUINA) compared to control, and ADs prevented the rise in such levels. Neither CMS nor ADs changed significantly the antiexcitotoxic kynurenic acid (KYNA) levels. The QUINA/KYNA ratio, calculated as excitotoxicity risk indicator, increased after CMS and ADs prevented this increase. CMS lowered excitatory amino acid transporter (EAAT)-1 and EAAT-4 expression, and some ADs restored their expression levels. Furthermore, CMS decreased N-methyl-D-aspartate receptor (NMDAR)-2A and 2B protein expression, and ADs mitigated this decrease. Our research examines the link between CMS-induced pro-inflammatory cytokines and the kynurenine pathway; it shows that CMS alters the kynurenine pathway in rat FC. Importantly, it also reveals the ability of classic ADs to prevent potentially harmful situations related to the brain scenario caused by CMS.
- Published
- 2019
- Full Text
- View/download PDF
29. Alcohol binge disrupts the rat intestinal barrier: the partial protective role of oleoylethanolamide.
- Author
-
Antón M, Rodríguez-González A, Ballesta A, González N, Del Pozo A, de Fonseca FR, Gómez-Lus ML, Leza JC, García-Bueno B, Caso JR, and Orio L
- Subjects
- Alcoholism physiopathology, Animals, Inflammation drug therapy, Inflammation metabolism, Inflammation prevention & control, Intestinal Mucosa metabolism, Male, Rats, Rats, Wistar, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Endocannabinoids pharmacology, Ethanol administration & dosage, Ethanol adverse effects, Intestinal Mucosa drug effects, Oleic Acids pharmacology
- Abstract
Background and Purpose: Chronic alcohol consumption alters the gut-brain axis, but little is known about alcohol binge episodes on the functioning of the intestinal barrier. We investigated the influence of ethanol binges on bacterial translocation, gut inflammation and immunity, and tight junction (TJ) structure and the ability of the biolipid oleoylethanolamide (OEA) to prevent ethanol binge-induced intestinal barrier dysfunction., Experimental Approach: OEA was injected i.p. before repeated ethanol administration by oral gavage. Plasma, spleen, liver and mesenteric lymph nodes (MLN) were collected in sterile conditions for determination of bacterial load. Immune/inflammatory parameters, TJ proteins and apoptotic markers were determined in colonic tissue by RT-PCR and Western blotting. TJ ultrastructure was examined by transmission electron microscopy., Key Results: Ethanol binges induced bacterial translocation to the MLN (mainly) and spleen. Colonic tissues showed signs of inflammation, and activation of innate (Toll-like receptor-4) and adaptive (IgA) immune systems and TJ proteins (occludin and claudin-3) were decreased after ethanol binges. Pretreatment with OEA reduced intestinal inflammation and immune activation and partially preserved the TJ structure affected by alcohol binges but had no effect on alcohol-induced apoptosis. Ultrastructural analyses of colonic TJs revealed dilated TJs in all ethanol groups, with less electron-dense material in non-pretreated rats. The protective effects of i.p. OEA did not reduce bacterial translocation to the MLN. However, intragastric OEA administration significantly reduced plasma LPS levels and bacterial translocation to the MLN., Conclusion and Implications: OEA-based pharmacotherapies could potentially be useful to treat disorders characterized by intestinal barrier dysfunction, including alcohol abuse., (© 2018 The British Pharmacological Society.)
- Published
- 2018
- Full Text
- View/download PDF
30. CCL2 Induces the Production of β2 Adrenergic Receptors and Modifies Astrocytic Responses to Noradrenaline.
- Author
-
Gutiérrez IL, González-Prieto M, García-Bueno B, Caso JR, Feinstein DL, and Madrigal JLM
- Subjects
- Animals, Brain-Derived Neurotrophic Factor metabolism, CCAAT-Enhancer-Binding Proteins metabolism, Cell Death drug effects, Glycogen biosynthesis, Glycogenolysis drug effects, Lactic Acid metabolism, Models, Biological, Nitric Oxide Synthase Type II metabolism, Proteasome Endopeptidase Complex metabolism, Rats, Wistar, Receptors, Adrenergic, beta-2 genetics, Receptors, Adrenergic, beta-2 metabolism, Signal Transduction drug effects, Astrocytes metabolism, Chemokine CCL2 pharmacology, Norepinephrine pharmacology, Receptors, Adrenergic, beta-2 biosynthesis
- Abstract
The decline in brain noradrenaline levels is associated with the progression of certain neurodegenerative diseases. This seems to be due, at least in part, to the ability of noradrenaline to limit glial activation and to reduce the damage associated with it. Our previous studies of the mechanisms involved in this process indicate that noradrenaline induces the production of the chemokine CCL2 in astrocytes. While CCL2 can protect neurons against certain injuries, its overproduction has also proven to be harmful and to prevent noradrenaline neuroprotective effects. Therefore, in this study, we analyze if the modifications caused to astrocytes by an excessive production of CCL2 may alter their response to noradrenaline. Using primary cultures of rat cortical astrocytes, we observed that CCL2 enhances the production of beta 2 adrenergic receptors in these cells. While this potentiates noradrenaline signaling through cAMP, the activation of the transcription factor CREB is inhibited by CCL2. Furthermore, although CCL2 potentiates noradrenaline induction of glycogenolysis, this does not translate into an augmented release of lactate, one of the processes through which astrocytes help support neurons. Additionally, other neuroprotective actions of noradrenaline, such as the production of brain derived neurotrophic factor and the inhibition of the inducible nitric oxide synthase in astrocytes were modified by CCL2. These data suggest that some of the central nervous system alterations related to CCL2 could be due to its effects on adrenergic receptors and its interference with noradrenaline signaling.
- Published
- 2018
- Full Text
- View/download PDF
31. Intracellular inflammatory and antioxidant pathways in postmortem frontal cortex of subjects with major depression: effect of antidepressants.
- Author
-
Martín-Hernández D, Caso JR, Javier Meana J, Callado LF, Madrigal JLM, García-Bueno B, and Leza JC
- Subjects
- Analysis of Variance, Annexin A2 metabolism, Autopsy, Chaperonin 60 metabolism, DNA-Binding Proteins metabolism, Humans, Inflammation metabolism, NF-kappa B metabolism, S100 Proteins metabolism, Signal Transduction physiology, Toll-Like Receptor 4 metabolism, Transcription Factors metabolism, p38 Mitogen-Activated Protein Kinases metabolism, Antidepressive Agents therapeutic use, Antioxidants metabolism, Depressive Disorder, Major complications, Depressive Disorder, Major drug therapy, Depressive Disorder, Major pathology, Frontal Lobe drug effects, Frontal Lobe metabolism, Frontal Lobe pathology, Inflammation drug therapy, Signal Transduction drug effects
- Abstract
Background: Studies show that Toll-like receptors (TLRs), members of the innate immune system, might participate in the pathogenesis of the major depressive disorder (MDD). However, evidence of this participation in the brain of patients with MDD has been elusive., Methods: This work explores whether the protein expression by immunodetection assays (Western blot) of elements of TLR-4 pathways controlling inflammation and the oxidative/nitrosative stress are altered in postmortem dorsolateral prefrontal cortex of subjects with MDD. The potential modulation induced by the antidepressant treatment on these parameters was also assessed. Thirty MDD subjects (15 antidepressant-free and 15 under antidepressant treatment) were matched for gender and age to 30 controls in a paired design., Results: No significant changes in TLR-4 expression were detected. An increased expression of the TLR-4 endogenous ligand Hsp70 (+ 33%), but not of Hsp60, and the activated forms of mitogen-activated protein kinases (MAPKs) p38 (+ 47%) and JNK (+ 56%) was observed in MDD. Concomitantly, MDD subjects present a 45% decreased expression of DUSP2 (a regulator of MAPKs) and reduced (- 21%) expression of the antioxidant nuclear factor Nrf2. Antidepressant treatment did not modify the changes detected in the group with MDD and actually increased (+ 25%) the expression of p11, a protein linked with the transport of neurotransmitters and depression., Conclusion: Data indicate an altered TLR-4 immune response in the brain of subjects with MDD. Additional research focused on the mechanisms contributing to the antidepressant-induced TLR-4 pathway modulation is warranted and could help to develop new treatment strategies for MDD.
- Published
- 2018
- Full Text
- View/download PDF
32. The Hemodynamic Effects of Intracavernosal Phenylephrine for the Treatment of Ischemic Priapism.
- Author
-
Sidhu AS, Wayne GF, Kim BJ, Anderson AGS, Cordon BH, Caso JR, and Polackwich AS
- Subjects
- Adult, Blood Pressure, Dose-Response Relationship, Drug, Heart Rate drug effects, Humans, Injections, Ischemia drug therapy, Male, Middle Aged, Retrospective Studies, Vasoconstrictor Agents administration & dosage, Vasoconstrictor Agents adverse effects, Phenylephrine therapeutic use, Priapism drug therapy, Vasoconstrictor Agents therapeutic use
- Abstract
Aim: We sought to evaluate whether the administration of phenylephrine (PE) at concentrations higher than those described in guidelines resulted in any significant changes in vital signs or impacted outcomes., Methods: After receiving institutional review board approval, we retrospectively reviewed the charts of patients presenting to our emergency department between May 1, 2014, and August 15, 2016, using International Classification of Diseases, Ninth Edition and Internation Classification of Disease, Tenth Edition diagnosis codes for priapism. Treatment was reviewed, including corporal aspiration/irrigation, injection of PE, and shunt procedures. Vital signs were compared before and after treatment with PE. Baseline variables were explored with categorical data analysis (chi-squared tests, t-tests, and Mann-Whitney nonparametric tests). Where feasible, linear regression was used to evaluate outcomes., Main Outcome Measure: Detumescence and changes in blood pressure and heart rate., Results: We identified 74 different patient encounters of acute priapism. The median age was 36.5 years (interquartile range [IQR] = 27-47), and the median time to presentation was 5.4 hours (IQR = 4.0-9.6). 62 percent of cases were due to drug-induced priapism. In 58 (74%) encounters, patients received PE. The median dose of PE given was 1000 μg (IQR 500-2,000). Univariate regression found no association between PE dose and change in patient heart rate or blood pressure. A statistically significant decrease in heart rate (HR) (-4.2 BPM), systolic blood pressure (BP) (-1.8 mm Hg), and diastolic BP (-5.4 mm Hg) was noted. Fifty-three of 58 (91%) patients receiving PE experienced detumescence at the bedside, 2 required shunting in operating room, and 3 refused treatment and left against medical advice. No adverse events occurred., Conclusion: We frequently treat patients with high doses of PE and seldom notice adverse effects, typically resulting in resolution of priapism without any additional procedures. Careful administration of high doses of intracavernosal PE in patients presenting with priapism does not appear to significantly affect heart rate or blood pressure and may help prevent further ischemic damage and achieve detumescence effectively and efficiently. Sidhu AS, Wayne GF, Kim BJ, et al. The hemodynamic effects of intracavernosal phenylephrine for the treatment of ischemic priapism. J Sex Med 2018;15:990-996., (Copyright © 2018 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
33. Alternative Method to Detect Neuronal Degeneration and Amyloid β Accumulation in Free-Floating Brain Sections With Fluoro-Jade.
- Author
-
Gutiérrez IL, González-Prieto M, García-Bueno B, Caso JR, Leza JC, and Madrigal JLM
- Subjects
- Amyloid beta-Peptides toxicity, Amyloid beta-Protein Precursor genetics, Animals, Brain drug effects, Disease Models, Animal, Gene Expression Regulation drug effects, Gene Expression Regulation genetics, Humans, In Vitro Techniques, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation genetics, Nerve Degeneration genetics, Peptide Fragments toxicity, Presenilin-1 genetics, Amyloid beta-Peptides metabolism, Brain metabolism, Fluoresceins metabolism, Nerve Degeneration pathology
- Abstract
Fluoro-Jade is a fluorescein-derived fluorochrome which specifically binds to damaged neurons. Due to this characteristic, it is commonly used for the histochemical detection and quantification of neurodegeneration in mounted brain sections. Here, we describe an alternative and simpler histochemistry protocol based on the use of free-floating brain sections. For this purpose, we have used brain slices from wild-type and 5xFAD mice as well as from mice that received an intracerebral injection of oligomeric amyloid beta peptides. We observed that our histochemistry staining procedure allows for a well-defined labeling of degenerating neurons providing a better signal-to-noise ratio staining than the commonly used one. In addition, our modified protocol demonstrates the ability of Fluoro-Jade C to also fluorescently label amyloid beta plaques.
- Published
- 2018
- Full Text
- View/download PDF
34. Regulation of inflammatory pathways in schizophrenia: A comparative study with bipolar disorder and healthy controls.
- Author
-
García-Álvarez L, Caso JR, García-Portilla MP, de la Fuente-Tomás L, González-Blanco L, Sáiz Martínez P, Leza JC, and Bobes J
- Subjects
- Adult, Biomarkers analysis, Bipolar Disorder pathology, Bipolar Disorder psychology, Case-Control Studies, Cross-Sectional Studies, Female, Humans, Inflammation pathology, Inflammation psychology, Male, Middle Aged, PPAR gamma analysis, Prostaglandin D2 analogs & derivatives, Prostaglandin D2 analysis, Schizophrenia pathology, Schizophrenic Psychology, Young Adult, Bipolar Disorder immunology, Bipolar Disorder metabolism, Inflammation immunology, Inflammation metabolism, Schizophrenia immunology, Schizophrenia metabolism
- Abstract
Background: Immune-inflammatory processes have been implicated in schizophrenia (SCH), but their specificity is not clear., Main Aim: To identify potential differential intra-/intercellular biochemical pathways controlling immune-inflammatory response and their oxidative-nitrosative impact on SCH patients, compared with bipolar disorder (BD) patients and healthy controls (HC)., Methods: Cross-sectional, naturalistic study of a cohort of SCH patients (n=123) and their controls [BD (n=102) and HC (n=80)]., Statistical Analysis: ANCOVA (or Quade test) controlling for age and gender when comparing the three groups, and controlling for age, gender, length of illness, cigarettes per day, and body mass index (BMI) when comparing SCH and BD., Results: Pro-inflammatory biomarkers: Expression of COX-1 was statistically higher in SCH and BD than HC (P<0.0001; P<0.0001); NFκB and PGE2 were statistically higher in SCH compared with BD (P=0.001; P<0.0001) and HC (P=0.003; P<0.0001); NLRP3 was higher in BD than HC (P=0.005); and CPR showed a gradient among the three groups. Anti-inflammatory biomarkers: BD patients had lower PPARγ and higher 15d-PGJ2 levels than SCH (P=0.005; P=0.008) and HC (P=0.001; P=0.001). Differences between SCH and BD: previous markers of SCH (NFκB and PGE2) and BD (PPARγ and 15d-PGJ2) remained statistically significant and, interestingly, iNOS and COX-2 (pro-inflammatory biomarkers) levels were statistically higher in SCH than BD (P=0.019; P=0.040)., Conclusions: This study suggests a specific immune-inflammatory biomarker pattern for established SCH (NFκB, PGE2, iNOS, and COX-2) that differentiates it from BD and HC. In future, their pharmacological modulation may constitute a promising therapeutic target., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
35. Lipopolysaccharide enters the rat brain by a lipoprotein-mediated transport mechanism in physiological conditions.
- Author
-
Vargas-Caraveo A, Sayd A, Maus SR, Caso JR, Madrigal JLM, García-Bueno B, and Leza JC
- Subjects
- Animals, Apolipoprotein A-I metabolism, Fluorescent Antibody Technique, Lipopolysaccharide Receptors metabolism, Male, Rats, Rats, Wistar, Scavenger Receptors, Class B metabolism, Toll-Like Receptor 4 metabolism, Antibodies immunology, Brain metabolism, Lipopolysaccharides metabolism, Lipoproteins immunology, Lipoproteins metabolism
- Abstract
Physiologically, lipopolysaccharide (LPS) is present in the bloodstream and can be bound to several proteins for its transport (i.e.) LPS binding protein (LBP) and plasma lipoproteins). LPS receptors CD14 and TLR-4 are constitutively expressed in the Central Nervous System (CNS). To our knowledge, LPS infiltration in CNS has not been clearly demonstrated. A naturalistic experiment with healthy rats was performed to investigate whether LPS is present with its receptors in brain. Immunofluorescences showed that lipid A and core LPS were present in circumventricular organs, choroid plexus, meningeal cells, astrocytes, tanycytes and endothelial cells. Co-localization of LPS regions with CD14/TLR-4 was found. The role of lipoprotein receptors (SR-BI, ApoER2 and LDLr) in the brain as targets for a LPS transport mechanism by plasma apolipoproteins (i.e. ApoAI) was studied. Co-localization of LPS regions with these lipoproteins markers was observed. Our results suggest that LPS infiltrates in the brain in physiological conditions, possibly, through a lipoprotein transport mechanism, and it is bound to its receptors in blood-brain interfaces.
- Published
- 2017
- Full Text
- View/download PDF
36. Effects of the antipsychotic paliperidone on stress-induced changes in the endocannabinoid system in rat prefrontal cortex.
- Author
-
MacDowell KS, Sayd A, García-Bueno B, Caso JR, Madrigal JLM, and Leza JC
- Subjects
- Animals, Antipsychotic Agents administration & dosage, Down-Regulation, Male, Paliperidone Palmitate administration & dosage, Rats, Rats, Wistar, Amidohydrolases drug effects, Antipsychotic Agents pharmacology, Endocannabinoids metabolism, Lipoprotein Lipase drug effects, Paliperidone Palmitate pharmacology, Phosphatidylethanolamines metabolism, Prefrontal Cortex drug effects, Prefrontal Cortex metabolism, Receptor, Cannabinoid, CB1 drug effects, Stress, Psychological metabolism
- Abstract
Objectives There is a need to explore novel mechanisms of action of existing/new antipsychotics. One potential candidate is the endocannabinoid system (ECS). The present study tried to elucidate the effects of the antipsychotic paliperidone on stress-induced ECS alterations. Methods Wister rats were submitted to acute/chronic restraint stress. Paliperidone (1 mg/kg) was given prior each stress session. Cannabinoid receptors and endocannabinoids (eCBs) synthesis and degradation enzymes were measured in prefrontal cortex (PFC) samples by RT-PCR and Western Blot. Results In the PFC of rats exposed to acute stress, paliperidone increased CB1 receptor (CB1R) expression. Furthermore, paliperidone increased the expression of the eCB synthesis enzymes N-acylphosphatidylethanolamine- hydrolysing phospholipase D and DAGLα, and blocked the stress-induced increased expression of the degrading enzyme fatty acid amide hydrolase. In chronic conditions, paliperidone prevented the chronic stress-induced down-regulation of CB1R, normalised DAGLα expression and reverted stress-induced down-regulation of the 2-AG degrading enzyme monoacylglycerol lipase. ECS was analysed also in periphery. Acute stress decreased DAGLα expression, an effect prevented by paliperidone. Contrarily, chronic stress increased DAGLα and this effect was potentiated by paliperidone. Conclusions The results obtained described a preventive effect of paliperidone on stress-induced alterations in ECS. Considering the diverse alterations on ECS described in psychotic disease, targeting ECS emerges as a new therapeutic possibility.
- Published
- 2017
- Full Text
- View/download PDF
37. The Role of the Microbial Metabolites Including Tryptophan Catabolites and Short Chain Fatty Acids in the Pathophysiology of Immune-Inflammatory and Neuroimmune Disease.
- Author
-
Morris G, Berk M, Carvalho A, Caso JR, Sanz Y, Walder K, and Maes M
- Subjects
- Animals, Humans, Fatty Acids, Volatile metabolism, Inflammation metabolism, Inflammation microbiology, Metabolome, Microbiota, Neuroimmunomodulation, Tryptophan metabolism
- Abstract
There is a growing awareness that gut commensal metabolites play a major role in host physiology and indeed the pathophysiology of several illnesses. The composition of the microbiota largely determines the levels of tryptophan in the systemic circulation and hence, indirectly, the levels of serotonin in the brain. Some microbiota synthesize neurotransmitters directly, e.g., gamma-amino butyric acid, while modulating the synthesis of neurotransmitters, such as dopamine and norepinephrine, and brain-derived neurotropic factor (BDNF). The composition of the microbiota determines the levels and nature of tryptophan catabolites (TRYCATs) which in turn has profound effects on aryl hydrocarbon receptors, thereby influencing epithelial barrier integrity and the presence of an inflammatory or tolerogenic environment in the intestine and beyond. The composition of the microbiota also determines the levels and ratios of short chain fatty acids (SCFAs) such as butyrate and propionate. Butyrate is a key energy source for colonocytes. Dysbiosis leading to reduced levels of SCFAs, notably butyrate, therefore may have adverse effects on epithelial barrier integrity, energy homeostasis, and the T helper 17/regulatory/T cell balance. Moreover, dysbiosis leading to reduced butyrate levels may increase bacterial translocation into the systemic circulation. As examples, we describe the role of microbial metabolites in the pathophysiology of diabetes type 2 and autism.
- Published
- 2017
- Full Text
- View/download PDF
38. Paliperidone reverts Toll-like receptor 3 signaling pathway activation and cognitive deficits in a maternal immune activation mouse model of schizophrenia.
- Author
-
MacDowell KS, Munarriz-Cuezva E, Caso JR, Madrigal JL, Zabala A, Meana JJ, García-Bueno B, and Leza JC
- Subjects
- Animals, Antioxidants pharmacology, Cognition Disorders immunology, Disease Models, Animal, Female, Frontal Lobe drug effects, Frontal Lobe immunology, Male, Memory, Short-Term drug effects, Memory, Short-Term physiology, Mice, Inbred C57BL, Poly I-C, Pregnancy, Prenatal Exposure Delayed Effects, Random Allocation, Schizophrenia immunology, Schizophrenic Psychology, Signal Transduction drug effects, Spatial Memory drug effects, Spatial Memory physiology, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Antipsychotic Agents pharmacology, Cognition Disorders drug therapy, Paliperidone Palmitate pharmacology, Schizophrenia drug therapy, Toll-Like Receptor 3 metabolism
- Abstract
The pathophysiology of psychotic disorders is multifactorial, including alterations in the immune system caused by exogenous or endogenous factors. Epidemiological and experimental studies indicate that infections during the gestational period represent a risk factor to develop schizophrenia (SZ) along lifetime. Here, we tested the hypothesis that the antipsychotic paliperidone regulates immune-related brain effects in an experimental model of SZ. A well described prenatal immune activation model of SZ in mice by maternal injection of the viral mimetic poly(I:C) during pregnancy was used. Young-adult offspring animals (60PND) received paliperidone ip (0.05 mg/kg) for 21 consecutive days. One day after last injection, animals were submitted to a cognitive test and brain frontal cortex (FC) samples were obtained for biochemical determinations. The adults showed an activated innate immune receptor TLR-3 signaling pathway, oxidative/nitrosative stress and accumulation of pro-inflammatory mediators such as nuclear transcription factors (i.e., NFκB) and inducible enzymes (i.e., iNOS) in FC. Chronic paliperidone blocked this neuroinflammatory response possibly by the synergic activation and preservation of endogenous antioxidant/anti-inflammatory mechanisms such as NRF2 and PPARγ pathways, respectively. Paliperidone administration also stimulated the alternative polarization of microglia to the M2 anti-inflammatory profile. In addition, paliperidone treatment improved spatial working memory deficits of this SZ-like animal model. In conclusion, chronic administration of paliperidone to young-adult mice prenatally exposed to maternal immune (MIA) challenge elicits a general preventive anti-inflammatory/antioxidant effect at both intracellular and cellular polarization (M1/M2) level in FC, as well as ameliorates specific cognitive deficits., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
39. Noradrenaline induces CX3CL1 production and release by neurons.
- Author
-
Madrigal JL, Caso JR, García-Bueno B, Gutiérrez IL, and Leza JC
- Subjects
- ADAM10 Protein metabolism, ADAM17 Protein metabolism, Animals, Chemokine CX3CL1 metabolism, Microglia drug effects, Neurons drug effects, Norepinephrine administration & dosage, Primary Cell Culture, RNA, Messenger metabolism, Rats, Rats, Wistar, Receptors, Adrenergic, beta-2 metabolism, Chemokine CXCL1 metabolism, Microglia metabolism, Neurons metabolism, Norepinephrine physiology
- Abstract
CX3CL1 is a chemokine for which neurons constitute its primary source within the brain. Besides acting as a chemokine, CX3CL1 regulates multiple processes and is known to inhibit microglial activation. Because of this, CX3CL1 is considered as a messenger used by neurons to communicate with microglia. Similarly, the neurotransmitter noradrenaline reduces microglial activation and production of neurotoxic agents. Based on this, the regulation of neuronal CX3CXL1 by noradrenaline was analyzed. In primary cortical neurons, noradrenaline induced the accumulation of CX3CL1 protein and mRNA. Noradrenaline also increased CX3CL1 in its soluble form despite the inhibition of the activity and synthesis of ADAM10 and ADAM17, the main proteases known to cleave CX3CL1 from the neuronal membrane. Noradrenaline-treated neurons displayed a higher degree of dendritic arborization and a characteristic accumulation of CX3CL1 in the dendritic bifurcation zones. The soluble CX3CL1 produced by neurons after noradrenaline treatment, reduced the accumulation of nitrites in microglia. These findings indicate that NA anti-inflammatory actions are mediated by neuronal CX3CL1. In addition, CX3CL1 seems to be involved in the development of neuronal processes stimulated by noradrenaline., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
40. The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress.
- Author
-
MacDowell KS, Caso JR, Martín-Hernández D, Moreno BM, Madrigal JLM, Micó JA, Leza JC, and García-Bueno B
- Subjects
- Aldehydes metabolism, Analysis of Variance, Animals, Antipsychotic Agents pharmacology, Antipsychotic Agents therapeutic use, Catalase genetics, Catalase metabolism, Cytokines genetics, Disease Models, Animal, Male, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 metabolism, RNA, Messenger metabolism, Rats, Rats, Wistar, Restraint, Physical adverse effects, Stress, Psychological etiology, Superoxide Dismutase metabolism, Time Factors, Antioxidants metabolism, Cytokines metabolism, Paliperidone Palmitate pharmacology, Paliperidone Palmitate therapeutic use, Signal Transduction drug effects, Stress, Psychological drug therapy, Up-Regulation drug effects
- Abstract
Alterations in the innate inflammatory response may underlie the pathophysiology of psychiatric diseases. Current antipsychotics modulate pro-/anti-inflammatory pathways, but their specific actions on these pathways remain only partly explored. This study was conducted to elucidate the regulatory role of paliperidone (1 mg/kg i.p.) on acute (6 h) and chronic (6 h/day for 21 consecutive days) restraint stress-induced alterations in 2 emerging endogenous anti-inflammatory/antioxidant mechanisms: nuclear factor erythroid-related factor 2 (NRF2)/antioxidant enzymes pathway, and the cytokine milieu regulating M1/M2 polarization in microglia, analyzed at the mRNA and protein levels in prefrontal cortex samples. In acute stress conditions, paliperidone enhanced NRF2 levels, possibly related to phosphoinositide 3-kinase upregulation and reduced kelch-Like ECH-associated protein 1 expression. In chronic conditions, paliperidone tended to normalize NRF2 levels through a phosphoinositide 3-kinase related-mechanism, with no effects on kelch-Like ECH-associated protein 1. Antioxidant response element-dependent antioxidant enzymes were upregulated by paliperidone in acute stress, while in chronic stress, paliperidone tended to prevent stress-induced downregulation of the endogenous antioxidant machinery. However, paliperidone increased transforming growth factor-β and interleukin-10 in favor of an M2 microglia profile in acute stress conditions, which was also corroborated by paliperidone-induced increased levels of the M2 cellular markers arginase I and folate receptor 2. This latter effect was also produced in chronic conditions. Immunofluorescence studies suggested an increase in the number of microglial cells expressing arginase I and folate receptor 2 in the stressed animals pretreated with paliperidone. In conclusion, the enhancement of endogenous antioxidant/anti-inflammatory pathways by current and new antipsychotics could represent an interesting therapeutic strategy for the future., Competing Interests: Compliance with ethical standards Required Author Forms Disclosure forms provided by the authors are available with the online version of this article.
- Published
- 2016
- Full Text
- View/download PDF
41. Toward Omics-Based, Systems Biomedicine, and Path and Drug Discovery Methodologies for Depression-Inflammation Research.
- Author
-
Maes M, Nowak G, Caso JR, Leza JC, Song C, Kubera M, Klein H, Galecki P, Noto C, Glaab E, Balling R, and Berk M
- Subjects
- Animals, Drug Discovery, Humans, Biomedical Research, Depression pathology, Genomics, Inflammation pathology, Systems Biology
- Abstract
Meta-analyses confirm that depression is accompanied by signs of inflammation including increased levels of acute phase proteins, e.g., C-reactive protein, and pro-inflammatory cytokines, e.g., interleukin-6. Supporting the translational significance of this, a meta-analysis showed that anti-inflammatory drugs may have antidepressant effects. Here, we argue that inflammation and depression research needs to get onto a new track. Firstly, the choice of inflammatory biomarkers in depression research was often too selective and did not consider the broader pathways. Secondly, although mild inflammatory responses are present in depression, other immune-related pathways cannot be disregarded as new drug targets, e.g., activation of cell-mediated immunity, oxidative and nitrosative stress (O&NS) pathways, autoimmune responses, bacterial translocation, and activation of the toll-like receptor and neuroprogressive pathways. Thirdly, anti-inflammatory treatments are sometimes used without full understanding of their effects on the broader pathways underpinning depression. Since many of the activated immune-inflammatory pathways in depression actually confer protection against an overzealous inflammatory response, targeting these pathways may result in unpredictable and unwanted results. Furthermore, this paper discusses the required improvements in research strategy, i.e., path and drug discovery processes, omics-based techniques, and systems biomedicine methodologies. Firstly, novel methods should be employed to examine the intracellular networks that control and modulate the immune, O&NS and neuroprogressive pathways using omics-based assays, including genomics, transcriptomics, proteomics, metabolomics, epigenomics, immunoproteomics and metagenomics. Secondly, systems biomedicine analyses are essential to unravel the complex interactions between these cellular networks, pathways, and the multifactorial trigger factors and to delineate new drug targets in the cellular networks or pathways. Drug discovery processes should delineate new drugs targeting the intracellular networks and immune-related pathways.
- Published
- 2016
- Full Text
- View/download PDF
42. Innate immune receptor Toll-like receptor 4 signalling in neuropsychiatric diseases.
- Author
-
García Bueno B, Caso JR, Madrigal JL, and Leza JC
- Subjects
- Animals, Humans, Mental Disorders immunology, Toll-Like Receptor 4 metabolism
- Abstract
The innate immunity is a stereotyped first line of defense against pathogens and unspecified damage signals. One of main actors of innate immunity are the Toll-like receptors (TLRs), and one of the better characterized members of this family is TLR-4, that it is mainly activated by Gram-negative bacteria lipopolysaccharide. In brain, TLR-4 organizes innate immune responses against infections or cellular damage, but also possesses other physiological functions. In the last years, some evidences suggest a role of TLR-4 in stress and stress-related neuropsychiatric diseases. Peripheral and brain TLR-4 activation triggers sickness behavior, and its expression is a risk factor of depression. Some elements of the TLR-4 signaling pathway are up-regulated in peripheral samples and brain post-mortem tissue from depressed and suicidal patients. The "leaky gut" hypothesis of neuropsychiatric diseases is based on the existence of an increase of the intestinal permeability which results in bacterial translocation able to activate TLR-4. Enhanced peripheral TLR-4 expression/activity has been described in subjects diagnosed with schizophrenia, bipolar disorder and in autistic children. A role for TLR-4 in drugs abuse has been also proposed. The therapeutic potential of pharmacological/genetic modulation of TLRs signaling pathways in neuropsychiatry is promising, but a great preclinical/clinical scientific effort is still needed., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
43. Bacterial translocation affects intracellular neuroinflammatory pathways in a depression-like model in rats.
- Author
-
Martín-Hernández D, Caso JR, Bris ÁG, Maus SR, Madrigal JL, García-Bueno B, MacDowell KS, Alou L, Gómez-Lus ML, and Leza JC
- Subjects
- Animals, Anti-Bacterial Agents administration & dosage, Lipopolysaccharides blood, MAP Kinase Signaling System drug effects, Male, NF-E2-Related Factor 2 metabolism, Neuroglia metabolism, Neurons metabolism, Prefrontal Cortex metabolism, Rats, Rats, Wistar, Stress, Psychological, Tight Junction Proteins metabolism, Toll-Like Receptor 4 metabolism, Zonula Occludens-1 Protein metabolism, p38 Mitogen-Activated Protein Kinases metabolism, Bacterial Translocation drug effects, Depressive Disorder metabolism, Depressive Disorder microbiology, Encephalitis metabolism, Encephalitis microbiology, Microbiota, Signal Transduction drug effects
- Abstract
Recent studies have suggested that depression is accompanied by an increased intestinal permeability which would be related to the inflammatory pathophysiology of the disease. This study aimed to evaluate whether experimental depression presents with bacterial translocation that in turn can lead to the TLR-4 in the brain affecting the mitogen-activated protein kinases (MAPK) and antioxidant pathways. Male Wistar rats were exposed to chronic mild stress (CMS) and the intestinal integrity, presence of bacteria in tissues and plasma lipopolysaccharide levels were analyzed. We also studied the expression in the prefrontal cortex of activated forms of MAPK and some of their activation controllers and the effects of CMS on the antioxidant Nrf2 pathway. Our results indicate that after exposure to a CMS protocol there is increased intestinal permeability and bacterial translocation. CMS also increases the expression of the activated form of the MAPK p38 while decreasing the expression of the antioxidant transcription factor Nrf2. The actions of antibiotic administration to prevent bacterial translocation on elements of the MAPK and Nrf2 pathways indicate that the translocated bacteria are playing a role in these effects. In effect, our results propose a role of the translocated bacteria in the pathophysiology of depression through the p38 MAPK pathway which could aggravate the neuroinflammation and the oxidative/nitrosative damage present in this pathology. Moreover, our results reveal that the antioxidant factor Nrf2 and its activators may be involved in the consequences of the CMS on the brain., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
44. Modulation of the antioxidant nuclear factor (erythroid 2-derived)-like 2 pathway by antidepressants in rats.
- Author
-
Martín-Hernández D, Bris ÁG, MacDowell KS, García-Bueno B, Madrigal JL, Leza JC, and Caso JR
- Subjects
- Animals, Antioxidants metabolism, Corticosterone blood, Disease Models, Animal, Hippocampus drug effects, Lipid Peroxidation drug effects, Male, Nitrites blood, Oxidative Stress drug effects, PPAR gamma metabolism, Prefrontal Cortex drug effects, Rats, Rats, Wistar, Antidepressive Agents administration & dosage, Depressive Disorder metabolism, Hippocampus metabolism, NF-E2-Related Factor 2 metabolism, Prefrontal Cortex metabolism, Signal Transduction drug effects, Stress, Psychological metabolism
- Abstract
Patients with major depression who are otherwise medically healthy have activated inflammatory pathways in their organism. It has been described that depression is not only escorted by inflammation but also by induction of multiple oxidative/nitrosative stress pathways. Nevertheless, there are finely regulated mechanisms involved in preserving cells from damage, such as the antioxidant nuclear transcription factor Nrf2. We aim to explore in a depression-like model the Nrf2 pathway in the prefrontal cortex (PFC) and the hippocampus of rats and to analyze whether antidepressants affect the antioxidant activity of the Nrf2 pathway. Male Wistar rats were exposed to chronic mild stress (CMS) and some of them were treated with desipramine, escitalopram or duloxetine. We studied the expression of upstream and downstream elements of the Nrf2 pathway and the oxidative damage induced by the CMS. After CMS, there is an inhibition of upstream and downstream elements of the Nrf2 pathway in the PFC (e.g. PI3K/Akt, GPx…). Moreover, antidepressant treatments, particularly desipramine and duloxetine, are able to recover some of these elements and to reduce the oxidative damage induced by the CMS. However, in the hippocampus, Nrf2 pathways are not that affected and antidepressants do not have many actions. In conclusion, Nrf2 pathway is differentially regulated by antidepressants in the PFC and hippocampus. The Nrf2 pathway is involved in the oxidative/nitrosative damage detected in the PFC and antidepressants have a therapeutic action through this pathway. However, it seems that Nrf2 is not involved in the effects caused by CMS in the hippocampus., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
45. Therapeutic antidepressant potential of a conjugated siRNA silencing the serotonin transporter after intranasal administration.
- Author
-
Ferrés-Coy A, Galofré M, Pilar-Cuéllar F, Vidal R, Paz V, Ruiz-Bronchal E, Campa L, Pazos Á, Caso JR, Leza JC, Alvarado G, Montefeltro A, Valdizán EM, Artigas F, and Bortolozzi A
- Subjects
- Administration, Intranasal, Animals, Arabidopsis Proteins metabolism, Brain cytology, Brain drug effects, Brain metabolism, Corticosterone blood, DNA, Antisense pharmacology, Depression pathology, Disease Models, Animal, Endocytosis drug effects, Exploratory Behavior drug effects, Fluoxetine administration & dosage, Gene Expression Regulation drug effects, Intramolecular Transferases metabolism, Male, Mice, Mice, Inbred C57BL, Neurons drug effects, Neurons metabolism, Phosphopyruvate Hydratase metabolism, Serotonin metabolism, Serotonin Plasma Membrane Transport Proteins metabolism, Time Factors, Antidepressive Agents administration & dosage, Depression drug therapy, RNA, Small Interfering administration & dosage, Serotonin Plasma Membrane Transport Proteins genetics, Sertraline administration & dosage
- Abstract
Major depression brings about a heavy socio-economic burden worldwide due to its high prevalence and the low efficacy of antidepressant drugs, mostly inhibiting the serotonin transporter (SERT). As a result, ~80% of patients show recurrent or chronic depression, resulting in a poor quality of life and increased suicide risk. RNA interference (RNAi) strategies have been preliminarily used to evoke antidepressant-like responses in experimental animals. However, the main limitation for the medical use of RNAi is the extreme difficulty to deliver oligonucleotides to selected neurons/systems in the mammalian brain. Here we show that the intranasal administration of a sertraline-conjugated small interfering RNA (C-SERT-siRNA) silenced SERT expression/function and evoked fast antidepressant-like responses in mice. After crossing the permeable olfactory epithelium, the sertraline-conjugated-siRNA was internalized and transported to serotonin cell bodies by deep Rab-7-associated endomembrane vesicles. Seven-day C-SERT-siRNA evoked similar or more marked responses than 28-day fluoxetine treatment. Hence, C-SERT-siRNA (i) downregulated 5-HT1A-autoreceptors and facilitated forebrain serotonin neurotransmission, (ii) accelerated the proliferation of neuronal precursors and (iii) increased hippocampal complexity and plasticity. Further, short-term C-SERT-siRNA reversed depressive-like behaviors in corticosterone-treated mice. The present results show the feasibility of evoking antidepressant-like responses by selectively targeting neuronal populations with appropriate siRNA strategies, opening a way for further translational studies.
- Published
- 2016
- Full Text
- View/download PDF
46. The Microbiota and Gut-Brain Axis: Contributions to the Immunopathogenesis of Schizophrenia.
- Author
-
Caso JR, Balanzá-Martínez V, Palomo T, and García-Bueno B
- Subjects
- Animals, Bacterial Translocation immunology, Gastrointestinal Microbiome genetics, Humans, Inflammation immunology, Schizophrenia genetics, Schizophrenia physiopathology, Brain immunology, Gastrointestinal Microbiome immunology, Schizophrenia immunology
- Abstract
Background: The underlying pathophysiology of schizophrenia still remains elusive. Thus, there is a pressing need to identify novel targets for the development of new interventions and elucidate related biomarkers for the identification and monitoring of potentially responsive patients. In this sense, several hypotheses involving immune/inflammatory changes and the consequent oxidative/nitrosative stress, as well as a dysregulation in the immuno-inflammatory response have come into sight., Methods: Considering the great amount of genes encoded by the microbiome and the evidences pointing to the potential role of the gut microbiota on several neurologic and psychiatric diseases, the aim of this review is to evaluate the possible role of these organisms in the immunopathogenesis of schizophrenia. To that end, we will focus not only on gut microbiota dysbiosis but also on bacterial translocation as an inductor of neuroinflammation., Results: Studies have shown that the gut microbiota may play a key role in the immunopathogenesis of schizophrenia and that essential pathways implicated in the etiopathophysiology of schizophrenia are also regulated by the microbiota-gut-brain (MGB) axis. Moreover, studies also indicate a possible role of the innate immunity through the Toll-like receptors (TLRs) and their activation by bacterial translocation, as a consequence of intestinal dysfunction, in the pathophysiology of psychotic disorders., Conclusion: This is a promising area of investigation with huge potential to offer advances in the realm of personalized medicine and accordingly, future research should examine several microbiota-targeted therapies in order to improve symptoms and to decrease the immune dysregulation seen in patients with schizophrenia.
- Published
- 2016
- Full Text
- View/download PDF
47. The Role of Microbiota and Intestinal Permeability in the Pathophysiology of Autoimmune and Neuroimmune Processes with an Emphasis on Inflammatory Bowel Disease Type 1 Diabetes and Chronic Fatigue Syndrome.
- Author
-
Morris G, Berk M, Carvalho AF, Caso JR, Sanz Y, and Maes M
- Subjects
- Animals, Diabetes Mellitus, Type 1 physiopathology, Fatigue Syndrome, Chronic physiopathology, Humans, Inflammatory Bowel Diseases physiopathology, Intestinal Mucosa metabolism, Permeability, Diabetes Mellitus, Type 1 immunology, Fatigue Syndrome, Chronic immunology, Gastrointestinal Microbiome immunology, Inflammatory Bowel Diseases immunology, Intestines immunology
- Abstract
Background: In steady state conditions intestinal immune homeostasis is maintained by a sophisticated bidirectional dialogue between the microbiota and the intestinal immune system. This "cross talk" is enabled by the presence of highly adapted secretory cells, sampling cells and pattern recognition receptors in the gastric epithelium., Methods: Herein we discuss the mechanisms involved in the breakdown of intestinal homeostasis and the development of systemic immune activation and neuroinflammation with a view to discussing the importance of these processes, in tandem with genetic and environmental factors, in the pathophysiology of (auto)immune diseases.Data is presented explaining how immune tolerance is maintained and how it may breakdown., Conclusion: The breakdown of immune homeostasis following the development of gut inflammation, caused for example by gut dysbiosis, and the consequent increased intestinal permeability, is increasingly considered to be the ultimate source of the systemic immune activation and T helper 17/T regulatory cell imbalances, and maybe neurological disturbances, seen in autoimmune diseases such as Type 1 diabetes and inflammatory bowel disease. Increased intestinal permeability and translocation of commensal antigens into the systemic circulation is also a likely cause of the severe fatigue and an almost bewildering range of neurocognitive, neuroimaging and overall symptom presentations seen in patients with a diagnosis of Chronic Fatigue Syndrome.
- Published
- 2016
- Full Text
- View/download PDF
48. The Correlation of Media Ranking's "Best" Hospitals and Surgical Outcomes Following Radical Cystectomy for Urothelial Cancer.
- Author
-
Lascano D, Finkelstein JB, Barlow LJ, Kabat D, RoyChoudhury A, Caso JR, DeCastro GJ, Gold W, and McKiernan JM
- Subjects
- Aged, Aged, 80 and over, Cystectomy mortality, Female, Humans, Internet, Male, Middle Aged, New York epidemiology, Patient Readmission statistics & numerical data, Quality Indicators, Health Care, Carcinoma, Transitional Cell surgery, Cystectomy adverse effects, Hospitals, High-Volume standards, Mass Media, Quality Assurance, Health Care, Urinary Bladder Neoplasms surgery
- Abstract
Objective: To evaluate whether there is a correlation between publicized health ranking systems and surgical outcomes after radical cystectomy (RC) in New York State (NYS)., Materials and Methods: Using the Statewide Planning and Research Cooperative System, data were collected in an aggregated fashion per hospital for the 20 hospitals with the highest RC volume in NYS from 2009 to 2012. Hospital characteristics were obtained from the publicly available sources such as the Centers for Medicare and Medicaid Services. Publicized ranking systems evaluated included the US News & World Health Report for Urology ranking (USHR), Healthgrades (HG) score, and Consumer Reports (CR) safety ranking. Outcomes measured included mortality, readmissions, and causes of readmissions., Results: CR safety scores were inversely associated with overall death at 90 days after surgery (R = -0.527, P = .030), number of readmissions (R = -0.608, P = .030), and readmissions because of surgical complications (R = -0.523, P = .031) on a Pearson correlation test. On Kendall rank tau test, USHR and HG were not associated with any outcome of interest, although the scores correlated with increasing RC volume., Conclusion: In our analysis of 20 hospitals with the highest RC volume in NYS, USHR and HG scores were not strongly associated with any clinical outcome after RC. CR performed well in comparison with USHR and HG. Nevertheless, better metrics are needed to compare hospitals and to incorporate curative rates for morbid surgeries., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
49. Systemic administration of oleoylethanolamide protects from neuroinflammation and anhedonia induced by LPS in rats.
- Author
-
Sayd A, Antón M, Alén F, Caso JR, Pavón J, Leza JC, Rodríguez de Fonseca F, García-Bueno B, and Orio L
- Subjects
- Amides, Animals, Body Temperature Regulation drug effects, Brain metabolism, Brain physiopathology, Corticosterone blood, Cytokines genetics, Cytokines metabolism, Disease Models, Animal, Encephalitis chemically induced, Encephalitis genetics, Encephalitis metabolism, Encephalitis physiopathology, Encephalitis psychology, Ethanolamines administration & dosage, Food Preferences, Frontal Lobe drug effects, Frontal Lobe metabolism, Frontal Lobe physiopathology, Hypothalamo-Hypophyseal System drug effects, Hypothalamo-Hypophyseal System metabolism, Hypothalamo-Hypophyseal System physiopathology, Inflammation Mediators metabolism, Lipid Peroxidation drug effects, Male, Oxidative Stress drug effects, Palmitic Acids administration & dosage, Pituitary-Adrenal System drug effects, Pituitary-Adrenal System metabolism, Pituitary-Adrenal System physiopathology, Rats, Wistar, Taste Perception drug effects, Anhedonia drug effects, Anti-Inflammatory Agents administration & dosage, Behavior, Animal drug effects, Brain drug effects, Encephalitis prevention & control, Endocannabinoids administration & dosage, Endotoxins, Neuroprotective Agents administration & dosage, Oleic Acids administration & dosage
- Abstract
Background: The acylethanolamides oleoylethanolamide and palmitoylethanolamide are endogenous lipid mediators with proposed neuroprotectant properties in central nervous system (CNS) pathologies. The precise mechanisms remain partly unknown, but growing evidence suggests an antiinflammatory/antioxidant profile., Methods: We tested whether oleoylethanolamide/palmitoylethanolamide (10 mg/kg, i.p.) attenuate neuroinflammation and acute phase responses (hypothalamus-pituitary-adrenal (HPA) stress axis stress axis activation, thermoregulation, and anhedonia) induced by lipopolysaccharide (0.5 mg/kg, i.p.) in rats., Results: Lipopolysaccharide increased mRNA levels of the proinflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6, nuclear transcription factor-κB activity, and the expression of its inhibitory protein IκBα in cytoplasm, the inducible isoforms of nitric oxide synthase and cyclooxygenase-2, microsomal prostaglandin E2 synthase mRNA, and proinflammatory prostaglandin E2 content in frontal cortex 150 minutes after administration. As a result, the markers of nitrosative/oxidative stress nitrites (NO2(-)) and malondialdehyde were increased. Pretreatment with oleoylethanolamide/ palmitoylethanolamide reduced plasma tumor necrosis factor-α levels after lipopolysaccharide, but only oleoylethanolamide significantly reduced brain tumor necrosis factor-α mRNA. Oleoylethanolamide and palmitoylethanolamide prevented lipopolysaccharide-induced nuclear transcription factor-κB (NF-κB)/IκBα upregulation in nuclear and cytosolic extracts, respectively, the expression of inducible isoforms of nitric oxide synthase, cyclooxygenase-2, and microsomal prostaglandin E2 synthase and the levels of prostaglandin E2. Additionally, both acylethanolamides reduced lipopolysaccharide-induced oxidative/nitrosative stress. Neither oleoylethanolamide nor palmitoylethanolamide modified plasma corticosterone levels after lipopolysaccharide, but both acylethanolamides reduced the expression of hypothalamic markers of thermoregulation interleukin-1β, cyclooxygenase-2, and prostaglandin E2, and potentiated the hypothermic response after lipopolysaccharide. Interestingly, only oleoylethanolamide disrupted lipopolysaccharide-induced anhedonia in a saccharine preference test., Conclusions: Results indicate that oleoylethanolamide and palmitoylethanolamide have antiinflammatory/neuroprotective properties and suggest a role for these acylethanolamides as modulators of CNS pathologies with a neuroinflammatory component., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)
- Published
- 2014
- Full Text
- View/download PDF
50. Paliperidone prevents brain toll-like receptor 4 pathway activation and neuroinflammation in rat models of acute and chronic restraint stress.
- Author
-
MacDowell KS, Caso JR, Martín-Hernández D, Madrigal JL, Leza JC, and García-Bueno B
- Subjects
- Animals, Antipsychotic Agents pharmacology, Cyclooxygenase 2 metabolism, Dinoprostone metabolism, Disease Models, Animal, Dose-Response Relationship, Drug, Gene Expression Regulation drug effects, Gene Expression Regulation physiology, Isoxazoles pharmacology, Lipopolysaccharides blood, Lipopolysaccharides pharmacology, Male, Nitric Oxide Synthase Type II, Nitrites metabolism, Paliperidone Palmitate, Pyrimidines pharmacology, Rats, Rats, Wistar, Restraint, Physical adverse effects, Toll-Like Receptor 4 genetics, Antipsychotic Agents therapeutic use, Brain metabolism, Encephalitis etiology, Encephalitis pathology, Encephalitis prevention & control, Isoxazoles therapeutic use, Pyrimidines therapeutic use, Signal Transduction drug effects, Stress, Physiological physiology, Toll-Like Receptor 4 metabolism
- Abstract
Background: Alterations in the innate immune/inflammatory system have been proposed to underlie the pathophysiology of psychotic disease, but the mechanisms implicated remain elusive. The main agents of the innate immunity are the family of toll-like receptors (TLRs), which detect circulating pathogen-associated molecular patterns and endogenous damage-associated molecular patterns (DAMPS). Current antipsychotics are able to modulate pro- and anti-inflammatory pathways, but their actions on TLRs remain unexplored., Methods: This study was conducted to elucidate the effects of paliperidone (1mg/Kg i.p.) on acute (6 hours) and chronic (6 hours/day during 21 consecutive days) restraint stress-induced TLR-4 pathway activation and neuroinflammation, and the possible mechanism(s) related (bacterial translocation and/or DAMPs activation). The expression of the elements of a TLR-4-dependent proinflammatory pathway was analyzed at the mRNA and protein levels in prefrontal cortex samples., Results: Paliperidone pre-treatment prevented TLR-4 activation and neuroinflammation in the prefrontal cortices of stressed rats. Regarding the possible mechanisms implicated, paliperidone regulated stress-induced increased intestinal inflammation and plasma lipopolysaccharide levels. In addition, paliperidone also prevented the activation of the endogenous activators of TLR-4 HSP70 and HGMB-1., Conclusions: Our results showed a regulatory role of paliperidone on brain TLR-4, which could explain the therapeutic benefits of its use for the treatment of psychotic diseases beyond its effects on dopamine and serotonin neurotransmission. The study of the mechanisms implicated suggests that gut-increased permeability, inflammation, and bacterial translocation of Gram-negative microflora and HSP70 and HGMB1 expression could be potential adjuvant therapeutic targets for the treatment of psychotic and other stress-related psychiatric pathologies., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)
- Published
- 2014
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.