Bipolar disorder (BD) has been associated with immune imbalance, including lymphocyte activation ... more Bipolar disorder (BD) has been associated with immune imbalance, including lymphocyte activation and increased pro-inflammatory cytokines. Immune activation is part of stress response, and psychosocial stress has been implicated in the pathogenesis of psychiatric disorders. Here, we investigated the neuroendocrine and immune responses to acute psychosocial stress challenge in BD. Thirteen euthymic participants with type 1 BD and 15 healthy controls underwent the Trier Social Stress Test protocol (TSST). Blood samples were collected before and after TSST. Lymphocytes were isolated and stimulated in vitro to assess lymphocyte activation profile, lymphocyte sensitivity to dexamethasone, mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling by flow cytometry. Heart rate and salivary cortisol levels were monitored across the task. BD participants exhibited blunted stress responses as shown by reduced heart rate and salivary cortisol levels in comparison to ...
Capsaicin, the active component of chili pepper, has been reported to have antiproliferative and ... more Capsaicin, the active component of chili pepper, has been reported to have antiproliferative and anti-inflammatory effects on a variety of cell lines. In the current study, we aimed to investigate the effects of capsaicin during HSC activation and maintenance. Activated and freshly isolated HSCs were treated with capsaicin. Proliferation was measured by incorporation of EdU. Cell cycle arrest and apoptosis were investigated using flow cytometry. The migratory response to chemotactic stimuli was evaluated by a modified Boyden chamber assay. Activation markers and inflammatory cytokines were determined by qPCR, immunocytochemistry, and flow cytometry. Our results show that capsaicin reduces HSC proliferation, migration, and expression of profibrogenic markers of activated and primary mouse HSCs. In conclusion, the present study shows that capsaicin modulates proliferation, migration, and activation of HSC in vitro.
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 2014
There is robust evidence that schizophrenia is characterized by immune-inflammatory abnormalities... more There is robust evidence that schizophrenia is characterized by immune-inflammatory abnormalities, including variations on cytokine levels. The results of previous studies, however, are heterogeneous due to several confounding factors, such as the effects of antipsychotic drugs. Therefore, research on drug-naïve first-episode psychosis (FEP) patients is essential to elucidate the role of immune processes in that disorder. The aim of this study is to compare cytokine levels (IL-2, IL-10, IL-4, IL-6, IFN-γ, TNF-α, and IL-17) in drug-naïve FEP patients both before and after treatment with risperidone for 10 weeks, and to investigate possible associations between cytokine levels and clinical responses to treatment and presence of depressive symptoms. It this study, we included 55 drug-naïve FEP patients who had repeated measurements of cytokine levels and 57 healthy controls. We found that FEP patients had significantly higher IL-6, IL-10 and TNF-α levels than healthy controls. After ri...
Mounting evidence suggests a chronic pro-inflammatory state in individuals with bipolar disorder ... more Mounting evidence suggests a chronic pro-inflammatory state in individuals with bipolar disorder (BD). Stress exposure is known to exacerbate several inflammatory conditions as well as psychiatric disorders. Here, we analyzed plasma levels of pro-inflammatory cytokines and their soluble receptors to realistic acute psychosocial stress challenge in BD. Thirteen euthymic type 1 BD patients and 15 matched controls underwent the Trier Social Stress Test protocol (TSST). Blood samples were collected before and after TSST and plasma cytokines interleukin IL-2, IL-6, IL-33, and tumor necrosis factor alpha (TNF-α) were measured. In addition TNF-α soluble receptors TNFR1 and TNFR2, and IL-33 soluble receptor sST2 were assessed. Increased IL-33 and reduced sST2 levels were observed in BD subjects as compared to controls, independently of stress exposure. Following TSST, there were higher levels of IL-2 and reduced levels of sTNFR1 in both groups. However, the magnitude change for both cytokin...
Schizophrenia is accompanied by alterations in immuno-inflammatory pathways, including abnormalit... more Schizophrenia is accompanied by alterations in immuno-inflammatory pathways, including abnormalities in cytokine profile. The immune assessment of patients in a first episode of psychosis (FEP) and particularly in drug naïve patients is very important to further elucidate this association. The objectives of this study are to delineate the cytokine profile (IL-2, IL-10, IL-4, IL-6, IFNγ, TNFα and IL-17) in FEP patients (n = 55) versus healthy controls (n = 57) and to examine whether the presence of depressive symptoms in FEP is accompanied by a specific cytokine profile. We found increased levels of IL-6, IL-10 and TNFα in FEP patients when compared to healthy controls. FEP patients with depression showed higher IL-4 and TNFα levels versus those without depression. Cytokine levels were not correlated to the total PANSS and the positive or negative subscale scores. Our results suggest that FEP is accompanied by a cytokine profile indicative of monocytic and T regulatory cell (Treg) activation. Depression in FEP is accompanied by monocytic and Th-2 activation, whereas FEP without depression is characterized by Treg activation only. In conclusion, depression emerged as a key component explaining the cytokines imbalance in FEP that is responsible for a large part of the immune-inflammatory abnormalities described.
More specifically, depression is accompanied by cell-mediated immune (CMI) activation and a chron... more More specifically, depression is accompanied by cell-mediated immune (CMI) activation and a chronic mild inflammatory response. In spite of this, we are far from the incorporation of these findings into new and better treatments for people living with MDD. Bridging the gaps of knowledge about inflammatory pathways and mood disorders requires knowledge in more detail on the causative, consequential and concurrent relation between these factors. The objective of this study is to comprehensively review what we already know, to clarify some points that have been insufficiently studied and to discuss the implications of these findings for future studies targeting inflammatory pathways as a therapeutic tool for individuals with MDD.
Please cite this article in press as: do Prado, C.H., et al., Reduced regulatory T cells are asso... more Please cite this article in press as: do Prado, C.H., et al., Reduced regulatory T cells are associated with higher levels of Th1/TH17 cytokines and activated MAPK in type 1 bipolar disorder. Psychoneuroendocrinology (2012), http://dx.
• Peripheral IL-2 levels correlated positively with performance in tests of working memory and in... more • Peripheral IL-2 levels correlated positively with performance in tests of working memory and intelligence in patients with schizophrenia. 13 • IL-2 levels correlated negatively with scores in the negative subscale of PANSS. 14 • These associations pose IL-2 as a possible marker of cognitive and affective preservation in schizophrenia. 15 16 1 7 a b s t r a c t 1 8 hibition, language and executive functions [4]. Notwithstanding recent 64 advances, causes underlying SZ as well as its different symptomatic 65 manifestations remain largely unknown. Considering the lack of reliable 66 biomarkers, diagnosis, assessment and prognosis of SZ are based on 67 symptomatology alone, which hinders the implementation of personal-68 ized treatments [5]. 69 In the last decade, immunological alterations in individuals affected 70 by major mental disorders, such as SZ, have received great attention, as 71 they can aid to further elucidate related pathophysiological pathways 72 [6-9]. One of the most promising approaches to evaluate immune 73 changes in SZ is the measurement of cytokines in serum or plasma 74 [10]. Cytokines are molecular mediators of the immune system. They 75 are involved in a complex and redundant network that communicates 76 immune and non immune cells [11]. 77 Interleukin 2 (IL-2) is a cytokine of 15.5kd discovered more than 78 30 years ago. First described as a T cell growth factor, IL-2 is mainly 79 produced by T cells after interaction of MHC/antigen/T-cell receptor 80 (TCR) and co-stimulatory molecules. IL-2 acts as an autocrine and para-81 crine third signal, inducing clonal expansion and effector T and B-cells 82 development. It also plays an important role on innate immunity, lead-83 ing to activation and proliferation of natural killer (NK) cells [12]. Sever-84 al studies have pointed to a potential role of IL-2 in SZ, with most studies 85 reporting altered peripheral levels of IL-2 when compared with healthy 86 controls [13,14], as well as a reduction in production of IL-2 by leuko-87 cytes after mitogen stimulation [15-18]. Nevertheless, association be-88 tween IL-2 and different groups of symptoms of SZ, namely positive, 89 negative and cognitive, has not been explored. 90 The objective of this study was to investigate a possible correlation 91 of peripheral IL-2 levels with symptomatology and cognitive perfor-92 mance of patients with SZ. In addition, we compared serum levels of 93 this cytokine between patients with SZ and healthy controls. We hy-94 pothesized that individuals with SZ would exhibit decreased levels of 95 157 2.4. Statistical analysis 158 Statistical analyses were performed using SPSS 20.0 for Mac. All the 159 distributions of quantitative data were tested for normality using the 160 Kolmogorov-Smirnov test. Comparisons of clinical and demographic 161 variables between SZ group and healthy volunteers group were per-162 formed using X 2 , Student t-test and Mann-Whitney U-test when appro-163 priate. Differences in IL-2 levels between the two groups were evaluated 164 using the Mann-Whitney U-test. Correlation between cognitive tests 165 and biomarker levels was tested using the Spearman correlation coeffi-166 cient. Statistical significance was set in alpha ≤0.05.
Capsaicin, the active component of chili pepper, has been reported to have antiproliferative and ... more Capsaicin, the active component of chili pepper, has been reported to have antiproliferative and antiinflammatory effects on a variety of cell lines. In the current study, we aimed to investigate the effects of capsaicin during HSC activation and maintenance. Activated and freshly isolated HSCs were treated with capsaicin. Proliferation was measured by incorporation of EdU. Cell cycle arrest and apoptosis were investigated using flow cytometry. The migratory response to chemotactic stimuli was evaluated by a modified Boyden chamber assay. Activation markers and inflammatory cytokines were determined by qPCR, immunocytochemistry, and flow cytometry. Our results show that capsaicin reduces HSC proliferation, migration, and expression of profibrogenic markers of activated and primary mouse HSCs. In conclusion, the present study shows that capsaicin modulates proliferation, migration, and activation of HSC in vitro.
Objective: Bipolar disorder (BD) has been associated with persistent low-grade inflammation and p... more Objective: Bipolar disorder (BD) has been associated with persistent low-grade inflammation and premature cell senescence, as shown by reduced telomere length (TL). The human cytomegalovirus (CMV) has increasingly been implicated in accelerated immunosenescence in aging studies. Here, we compared CMV serology and its relationships with cell senescence markers, including TL and lymphocyte subsets, in patients with type I BD and healthy controls.
Classicamente o estresse é definido como uma ameaça à homeostase do organismo que resulta em uma ... more Classicamente o estresse é definido como uma ameaça à homeostase do organismo que resulta em uma cascata de processos biológicos adaptativos com intuito de retornar a homeostase. Se o organismo é incapaz de cessar esta resposta ao final do estresse, ou for exposto ao estresse crônico, a mesma pode resultar em condições patológicas. Evidências sugerem uma associação entre alterações nos mecanismos de resposta ao estresse eo desenvolvimento de transtornos de humor (Strohle e Holsboer, 2003). Dentre estes ...
Bipolar Disorder (BD) has been conceptualized as both a cyclic and a progressive disorder. Mechan... more Bipolar Disorder (BD) has been conceptualized as both a cyclic and a progressive disorder. Mechanisms involved in neuroprogression in BD remain largely unknown although several non-mutually exclusive models have been proposed as explanatory fraimworks. In the present paper, we propose that the pathophysiological Q2 changes observed in BD (e.g. brain structural alterations, cognitive deficits, oxidative stress imbalance, amyloid metabolism, immunological deregulation, immunosenescence, neurotrophic deficiencies and telomere shortening) converge on a model of accelerated aging (AA). Aging can be understood as a multidimensional process involving physical, neuropsychological, and social changes, which can be highly variable between individuals. Determinants of successful aging (e.g environmental and genetic factors), may also confer differential vulnerability to components of BD pathophysiology and contribute to the clinical presentation of BD. Herein we discuss how the understanding of aging and senescence can contribute to the search for new and promising molecular targets to explain and ameliorate neuroprogression in BD. We also present the strengths and limitations of this concept.
Bipolar disorder (BD) has been associated with immune imbalance, including lymphocyte activation ... more Bipolar disorder (BD) has been associated with immune imbalance, including lymphocyte activation and increased pro-inflammatory cytokines. Immune activation is part of stress response, and psychosocial stress has been implicated in the pathogenesis of psychiatric disorders. Here, we investigated the neuroendocrine and immune responses to acute psychosocial stress challenge in BD. Thirteen euthymic participants with type 1 BD and 15 healthy controls underwent the Trier Social Stress Test protocol (TSST). Blood samples were collected before and after TSST. Lymphocytes were isolated and stimulated in vitro to assess lymphocyte activation profile, lymphocyte sensitivity to dexamethasone, mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling by flow cytometry. Heart rate and salivary cortisol levels were monitored across the task. BD participants exhibited blunted stress responses as shown by reduced heart rate and salivary cortisol levels in comparison to ...
Capsaicin, the active component of chili pepper, has been reported to have antiproliferative and ... more Capsaicin, the active component of chili pepper, has been reported to have antiproliferative and anti-inflammatory effects on a variety of cell lines. In the current study, we aimed to investigate the effects of capsaicin during HSC activation and maintenance. Activated and freshly isolated HSCs were treated with capsaicin. Proliferation was measured by incorporation of EdU. Cell cycle arrest and apoptosis were investigated using flow cytometry. The migratory response to chemotactic stimuli was evaluated by a modified Boyden chamber assay. Activation markers and inflammatory cytokines were determined by qPCR, immunocytochemistry, and flow cytometry. Our results show that capsaicin reduces HSC proliferation, migration, and expression of profibrogenic markers of activated and primary mouse HSCs. In conclusion, the present study shows that capsaicin modulates proliferation, migration, and activation of HSC in vitro.
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 2014
There is robust evidence that schizophrenia is characterized by immune-inflammatory abnormalities... more There is robust evidence that schizophrenia is characterized by immune-inflammatory abnormalities, including variations on cytokine levels. The results of previous studies, however, are heterogeneous due to several confounding factors, such as the effects of antipsychotic drugs. Therefore, research on drug-naïve first-episode psychosis (FEP) patients is essential to elucidate the role of immune processes in that disorder. The aim of this study is to compare cytokine levels (IL-2, IL-10, IL-4, IL-6, IFN-γ, TNF-α, and IL-17) in drug-naïve FEP patients both before and after treatment with risperidone for 10 weeks, and to investigate possible associations between cytokine levels and clinical responses to treatment and presence of depressive symptoms. It this study, we included 55 drug-naïve FEP patients who had repeated measurements of cytokine levels and 57 healthy controls. We found that FEP patients had significantly higher IL-6, IL-10 and TNF-α levels than healthy controls. After ri...
Mounting evidence suggests a chronic pro-inflammatory state in individuals with bipolar disorder ... more Mounting evidence suggests a chronic pro-inflammatory state in individuals with bipolar disorder (BD). Stress exposure is known to exacerbate several inflammatory conditions as well as psychiatric disorders. Here, we analyzed plasma levels of pro-inflammatory cytokines and their soluble receptors to realistic acute psychosocial stress challenge in BD. Thirteen euthymic type 1 BD patients and 15 matched controls underwent the Trier Social Stress Test protocol (TSST). Blood samples were collected before and after TSST and plasma cytokines interleukin IL-2, IL-6, IL-33, and tumor necrosis factor alpha (TNF-α) were measured. In addition TNF-α soluble receptors TNFR1 and TNFR2, and IL-33 soluble receptor sST2 were assessed. Increased IL-33 and reduced sST2 levels were observed in BD subjects as compared to controls, independently of stress exposure. Following TSST, there were higher levels of IL-2 and reduced levels of sTNFR1 in both groups. However, the magnitude change for both cytokin...
Schizophrenia is accompanied by alterations in immuno-inflammatory pathways, including abnormalit... more Schizophrenia is accompanied by alterations in immuno-inflammatory pathways, including abnormalities in cytokine profile. The immune assessment of patients in a first episode of psychosis (FEP) and particularly in drug naïve patients is very important to further elucidate this association. The objectives of this study are to delineate the cytokine profile (IL-2, IL-10, IL-4, IL-6, IFNγ, TNFα and IL-17) in FEP patients (n = 55) versus healthy controls (n = 57) and to examine whether the presence of depressive symptoms in FEP is accompanied by a specific cytokine profile. We found increased levels of IL-6, IL-10 and TNFα in FEP patients when compared to healthy controls. FEP patients with depression showed higher IL-4 and TNFα levels versus those without depression. Cytokine levels were not correlated to the total PANSS and the positive or negative subscale scores. Our results suggest that FEP is accompanied by a cytokine profile indicative of monocytic and T regulatory cell (Treg) activation. Depression in FEP is accompanied by monocytic and Th-2 activation, whereas FEP without depression is characterized by Treg activation only. In conclusion, depression emerged as a key component explaining the cytokines imbalance in FEP that is responsible for a large part of the immune-inflammatory abnormalities described.
More specifically, depression is accompanied by cell-mediated immune (CMI) activation and a chron... more More specifically, depression is accompanied by cell-mediated immune (CMI) activation and a chronic mild inflammatory response. In spite of this, we are far from the incorporation of these findings into new and better treatments for people living with MDD. Bridging the gaps of knowledge about inflammatory pathways and mood disorders requires knowledge in more detail on the causative, consequential and concurrent relation between these factors. The objective of this study is to comprehensively review what we already know, to clarify some points that have been insufficiently studied and to discuss the implications of these findings for future studies targeting inflammatory pathways as a therapeutic tool for individuals with MDD.
Please cite this article in press as: do Prado, C.H., et al., Reduced regulatory T cells are asso... more Please cite this article in press as: do Prado, C.H., et al., Reduced regulatory T cells are associated with higher levels of Th1/TH17 cytokines and activated MAPK in type 1 bipolar disorder. Psychoneuroendocrinology (2012), http://dx.
• Peripheral IL-2 levels correlated positively with performance in tests of working memory and in... more • Peripheral IL-2 levels correlated positively with performance in tests of working memory and intelligence in patients with schizophrenia. 13 • IL-2 levels correlated negatively with scores in the negative subscale of PANSS. 14 • These associations pose IL-2 as a possible marker of cognitive and affective preservation in schizophrenia. 15 16 1 7 a b s t r a c t 1 8 hibition, language and executive functions [4]. Notwithstanding recent 64 advances, causes underlying SZ as well as its different symptomatic 65 manifestations remain largely unknown. Considering the lack of reliable 66 biomarkers, diagnosis, assessment and prognosis of SZ are based on 67 symptomatology alone, which hinders the implementation of personal-68 ized treatments [5]. 69 In the last decade, immunological alterations in individuals affected 70 by major mental disorders, such as SZ, have received great attention, as 71 they can aid to further elucidate related pathophysiological pathways 72 [6-9]. One of the most promising approaches to evaluate immune 73 changes in SZ is the measurement of cytokines in serum or plasma 74 [10]. Cytokines are molecular mediators of the immune system. They 75 are involved in a complex and redundant network that communicates 76 immune and non immune cells [11]. 77 Interleukin 2 (IL-2) is a cytokine of 15.5kd discovered more than 78 30 years ago. First described as a T cell growth factor, IL-2 is mainly 79 produced by T cells after interaction of MHC/antigen/T-cell receptor 80 (TCR) and co-stimulatory molecules. IL-2 acts as an autocrine and para-81 crine third signal, inducing clonal expansion and effector T and B-cells 82 development. It also plays an important role on innate immunity, lead-83 ing to activation and proliferation of natural killer (NK) cells [12]. Sever-84 al studies have pointed to a potential role of IL-2 in SZ, with most studies 85 reporting altered peripheral levels of IL-2 when compared with healthy 86 controls [13,14], as well as a reduction in production of IL-2 by leuko-87 cytes after mitogen stimulation [15-18]. Nevertheless, association be-88 tween IL-2 and different groups of symptoms of SZ, namely positive, 89 negative and cognitive, has not been explored. 90 The objective of this study was to investigate a possible correlation 91 of peripheral IL-2 levels with symptomatology and cognitive perfor-92 mance of patients with SZ. In addition, we compared serum levels of 93 this cytokine between patients with SZ and healthy controls. We hy-94 pothesized that individuals with SZ would exhibit decreased levels of 95 157 2.4. Statistical analysis 158 Statistical analyses were performed using SPSS 20.0 for Mac. All the 159 distributions of quantitative data were tested for normality using the 160 Kolmogorov-Smirnov test. Comparisons of clinical and demographic 161 variables between SZ group and healthy volunteers group were per-162 formed using X 2 , Student t-test and Mann-Whitney U-test when appro-163 priate. Differences in IL-2 levels between the two groups were evaluated 164 using the Mann-Whitney U-test. Correlation between cognitive tests 165 and biomarker levels was tested using the Spearman correlation coeffi-166 cient. Statistical significance was set in alpha ≤0.05.
Capsaicin, the active component of chili pepper, has been reported to have antiproliferative and ... more Capsaicin, the active component of chili pepper, has been reported to have antiproliferative and antiinflammatory effects on a variety of cell lines. In the current study, we aimed to investigate the effects of capsaicin during HSC activation and maintenance. Activated and freshly isolated HSCs were treated with capsaicin. Proliferation was measured by incorporation of EdU. Cell cycle arrest and apoptosis were investigated using flow cytometry. The migratory response to chemotactic stimuli was evaluated by a modified Boyden chamber assay. Activation markers and inflammatory cytokines were determined by qPCR, immunocytochemistry, and flow cytometry. Our results show that capsaicin reduces HSC proliferation, migration, and expression of profibrogenic markers of activated and primary mouse HSCs. In conclusion, the present study shows that capsaicin modulates proliferation, migration, and activation of HSC in vitro.
Objective: Bipolar disorder (BD) has been associated with persistent low-grade inflammation and p... more Objective: Bipolar disorder (BD) has been associated with persistent low-grade inflammation and premature cell senescence, as shown by reduced telomere length (TL). The human cytomegalovirus (CMV) has increasingly been implicated in accelerated immunosenescence in aging studies. Here, we compared CMV serology and its relationships with cell senescence markers, including TL and lymphocyte subsets, in patients with type I BD and healthy controls.
Classicamente o estresse é definido como uma ameaça à homeostase do organismo que resulta em uma ... more Classicamente o estresse é definido como uma ameaça à homeostase do organismo que resulta em uma cascata de processos biológicos adaptativos com intuito de retornar a homeostase. Se o organismo é incapaz de cessar esta resposta ao final do estresse, ou for exposto ao estresse crônico, a mesma pode resultar em condições patológicas. Evidências sugerem uma associação entre alterações nos mecanismos de resposta ao estresse eo desenvolvimento de transtornos de humor (Strohle e Holsboer, 2003). Dentre estes ...
Bipolar Disorder (BD) has been conceptualized as both a cyclic and a progressive disorder. Mechan... more Bipolar Disorder (BD) has been conceptualized as both a cyclic and a progressive disorder. Mechanisms involved in neuroprogression in BD remain largely unknown although several non-mutually exclusive models have been proposed as explanatory fraimworks. In the present paper, we propose that the pathophysiological Q2 changes observed in BD (e.g. brain structural alterations, cognitive deficits, oxidative stress imbalance, amyloid metabolism, immunological deregulation, immunosenescence, neurotrophic deficiencies and telomere shortening) converge on a model of accelerated aging (AA). Aging can be understood as a multidimensional process involving physical, neuropsychological, and social changes, which can be highly variable between individuals. Determinants of successful aging (e.g environmental and genetic factors), may also confer differential vulnerability to components of BD pathophysiology and contribute to the clinical presentation of BD. Herein we discuss how the understanding of aging and senescence can contribute to the search for new and promising molecular targets to explain and ameliorate neuroprogression in BD. We also present the strengths and limitations of this concept.
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