Oxidative And Nitrosative Stress

Post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) are debilitating psychiatric conditions that are frequently comorbid and linked to chronic immune dysregulation. Increasing evidence implicates cytokine-mediated inflammation in the pathophysiology of these disorders. Cytokines, key signaling molecules of the immune system, influence central nervous system (CNS) function by crossing the blood-brain barrier or signaling via neural routes, thereby affecting neuronal circuits involved in mood regulation and cognition. Elevated levels of pro-inflammatory cytokines-such as interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ)-have been observed in both peripheral and central compartments of individuals with PTSD and MDD. These molecules contribute to microglial activation, synaptic remodeling, hippocampal atrophy, and altered neurotransmission. Furthermore, chemokines such as CXCL12 and CCL2 are implicated in stress-induced neuroplasticity impairments. Moderating factors, including genetic polymorphisms (e.g, FKBP5, CRP), early-life adversity, sex differences, and exposure type, influence individual vulnerability to immune-related neuropsychiatric outcomes. This review synthesizes current molecular and clinical evidence, highlighting how cytokine dysregulation bridges peripheral inflammation and CNS pathology. It also explores emerging therapeutic strategies targeting inflammatory pathways and discusses the promise of biomarker-based approaches and machine learning for patient stratification and personalized treatment.

Clinical trials have identified autism spectrum disorder (ASD) as a complex neurodegenerative disease. Individuals with ASD have problems with social activities and abilities, mutual communication, stereotyped behaviors, and have a propensity to and have activities and interests. The immune system and neural development are linked from fetal development to maturity, and dysfunctions in this communication impair many immune system functions. One of the most widely held beliefs about ASD is that it is a condition caused by immune system dysfunction. When a pregnant woman is exposed to an infection, an inflammatory immune response is activated, and molecules such as maternal cytokines and chemokines that can cross the placenta are produced. It has been reported that the pro-inflammatory cytokine molecules IL-17 and IL-18, which pass from the placenta to the fetus, control the ASD pathway, induce neurotoxicity as a result of inflammation, and have an impact on ASD, which is a neurodegenerative disorder.

Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder among children and adults. Impulsivity, inattention, and hyperactivity are hallmark of ADHD. While ADHD is not on the autism spectrum, they are related in several ways as they have some overlapping symptoms. The pathogenesis of ADHD has so far remained enigmatic, however, there is some evidence suggesting critical association among ADHD and the level of oxidative stress which trigger cell membrane damage, changes in inner structure and function of proteins, as well as structural damage to DNA which eventually culminate into development of ADHD. Although stimulants as well as some classes of non-stimulants are used to ameliorate symptom of ADHD, various adverse effects have been associated with such compounds. To date, treatment of ADHD is done with a combination of medications, behavior modifications, psycho-education, family therapy and life-style changes. The American Academy of Pediatrics officially promote stimulant medications and/or behavior therapy as ‘first line of therapy’. In addition to the presently therapeutic armamentarium, evidences are emerging on relevancy of natural products. There has been an interest on the therapeutic role of antioxidants in the treatment of ADHD. The present review aims to highlight the beneficiary role played by different antioxidants in mitigating the symptoms of ADHD.

The correlation between the affective disorders and the almost ubiquitous pathological oxidative stress can be described in a multifactorial way, as an important mechanism of central nervous system impairment. Whether the obvious changes which occur in oxidative balance of the affective disorders are a part of the constitutive mechanism or a collateral effect yet remains as an interesting question. However it is now clear that oxidative stress is a component of these disorders, being characterized by different aspects in a disease-dependent manner. Still, there are a lot of controversies regarding the relevance of the oxidative stress status in most of the affective disorders and despite the fact that most of the studies are showing that the affective disorders development can be correlated to increased oxidative levels, there are various studies stating that oxidative stress is not linked with the mood changing tendencies. Thus, in this minireview we decided to describe the way in ...

Background and Objectives: The aim of this systematic review was to analyse which candidate genes were examined in genetic association studies and their association with major depressive disorder (MDD). Materials and Methods: We searched PUBMED for relevant studies published between 1 July 2012 and 31 March 2019, using combinations of keywords: “major depressive disorder” OR “major depression” AND “gene candidate”, “major depressive disorder” OR “major depression” AND “polymorphism”. Synthesis focused on assessing the likelihood of bias and investigating factors that may explain differences between the results of studies. For selected gene list after literature overview, functional enrichment analysis and gene ontology term enrichment analysis were conducted. Results: 141 studies were included in the qualitative review of gene association studies focusing on MDD. 86 studies declared significant results (p < 0.05) for 172 SNPs in 85 genes. The 13 SNPs associations were confirmed b...

BACKGROUND: In psychotic and mood disorders, immune alterations are hypothesized to underlie cognitive symptoms, as they have been associated with elevated blood levels of inflammatory cytokines, kynurenine metabolites, and markers of microglial activation. The current meta-analysis synthesizes all available clinical evidence on the associations between immunomarkers (IMs) and cognition in these psychiatric illnesses. METHODS: Pubmed, Web of Science, and Psycinfo were searched for peer-reviewed studies on schizophrenia spectrum disorder (SZ), bipolar disorder (BD), or major depressive disorder (MDD) including an association analysis between at least one baseline neuropsychological outcome measure (NP) and one IM (PROSPERO ID:CRD42021278371). Quality assessment was performed using BIOCROSS. Correlation meta-analyses, and random effect models, were conducted in Comprehensive Meta-Analysis version 3 investigating the association between eight cognitive domains and pro-inflammatory and anti-inflammatory indices (PII and AII) as well as individual IM. RESULTS: Seventy-five studies (n = 29,104) revealed global cognitive performance (GCP) to be very weakly associated to PII (r = −0.076; p = 0.003; I 2 = 77.4) or AII (r = 0.067; p = 0.334; I 2 = 38.0) in the combined patient sample. Very weak associations between blood-based immune markers and global or domain-specific GCP were found, either combined or stratified by diagnostic subgroup (GCP x PII: SZ: r = −0.036, p = 0.370, I 2 = 70.4; BD: r = −0.095, p = 0.013, I 2 = 44.0; MDD: r = −0.133, p = 0.040, I 2 = 83.5). We found evidence of publication bias. DISCUSSION: There is evidence of only a weak association between blood-based immune markers and cognition in mood and psychotic disorders. Significant publication and reporting biases were observed and most likely underlie the inflation of such associations in individual studies.

Background In psychotic and mood disorders, immune alterations are hypothesized to underlie cognitive symptoms, as they have been associated with elevated blood levels of inflammatory cytokines, kynurenine metabolites, and markers of microglial activation. The current meta-analysis synthesizes all available clinical evidence on the associations between immunomarkers (IMs) and cognition in these psychiatric illnesses. Methods Pubmed, Web of Science, and Psycinfo were searched for peer-reviewed studies on schizophrenia spectrum disorder (SZ), bipolar disorder (BD), or major depressive disorder (MDD) including an association analysis between at least one baseline neuropsychological outcome measure (NP) and one IM (PROSPERO ID:CRD42021278371). Quality assessment was performed using BIOCROSS. Correlation meta-analyses, and random effect models, were conducted in Comprehensive Meta-Analysis version 3 investigating the association between eight cognitive domains and pro-inflammatory and an...

Introduction 3. MDD among the leading causes for the global burden of diseases 3.1 Childhood depression 3.2 Depression: a common co-morbidity in auto-immune inflammatory arthritis 4. Current established treatments for MDD: mechanisms and inadequacies 4.1 Pharmacotherapy 4.2 Psychotherapy 4.3 Electroconvulsive therapy for TRD 5. Emerging treatments for MDD: mechanisms and inadequacies 5.1 Pharmacological approaches 5.2 Non-invasive neurological interventions 5.3 Invasive neurological approaches 6. Wider and complex perspective of MDD 6.1 MDD is a lifestyle disorder with heredity playing a minor role 6.2 Accelerated biological (cellular) aging at the core of depression and other lifestyle diseases 6.3 Cardinal hallmarks of cellular aging 6.4 Neural hallmarks of cellular aging 6.5 Mind-body communicative hallmarks of cellular aging 6.6 MDD is a social disorder (with details of social brain slowly emerging) that affects quality of life of the individual, family, workplace, and society as a whole 7. Novel directions for exploring treatments for MDD 8. Yoga-unravels the pharmacy within-a simple, but an ideal solution for MDD treatment 9. Mechanism of benefits of the yoga based lifestyle intervention in MDD 9.1 Classical mechanisms: anatomical concepts of yoga 9.2 Genetic, epigenetic and molecular mechanisms 9.3 Cellular mechanisms 9.4 Neural mechanisms 9.5 Mind-body communicative mechanisms 9.6 Lifestyle and social mechanisms 10. Summary and future directions 11. Author contributions 12. Ethics approval and consent to participate 13. Acknowledgment 14. Funding 15. Conflict of interest 16. References

BACKGROUND: Anxiety is characterized by prolonged preparation for real or perceived threat. This may manifest both as psychological and physiological activation, ultimately leading to greater risk for poor health. Chronic inflammation may play an integral role in this relationship given the influential role that it has in chronic illness. The aim of this metaanalysis is to examine levels of chronic inflammation, measured by inflammatory cytokines and CRP, in people with anxiety disorders, PTSD, or OCD compared to healthy controls. Several moderating variables, including specific diagnosis and depression comorbidity, were also assessed. METHODS: 76 full-text articles were screened for eligibility with 41 studies ultimately included in analysis. RESULTS: Results demonstrated a significant overall difference between HCs and people with anxiety disorders in pro-inflammatory cytokines (p = .013, Hedge's g =-0.39), which appears to be largely driven by IL-1β (p = .009, Hedge's g =-0.50), IL-6 (p < .001, Hedge's g =-0.93), and TNF-α (p = .030, Hedge's g =-0.56). Moderation analyses revealed a moderating effect of diagnosis (p = .050), as only individuals with PTSD demonstrated differences in inflammation between HCs (p = .004, hedge's g =-0.68). CONCLUSIONS: These data demonstrate the association between inflammatory dysregulation and diagnoses associated with chronic, impactful, and severe anxiety and provides insight into the way that anxiety, and in particular PTSD, is related to certain inflammatory markers. In doing so, these findings may provide an initial step in disentangling the relationship between anxiety and basic health processes.

Social anxiety disorder (SAD) is a common psychiatric condition associated with a high risk of psychiatric comorbidity and impaired social/occupational functioning when not promptly treated. The identification of biological markers may facilitate the diagnostic process, leading to an early and proper treatment. Our aim was to systematically review the available literature about potential biomarkers for SAD. A search in the main online repositories (PubMed, ISI Web of Knowledge, PsychInfo, etc.) was performed. Of the 662 records screened, 61 were included. Results concerning cortisol, neuropeptides and inflammatory/immunological/neurotrophic markers remain inconsistent. Preliminary evidence emerged about the role of chromosome 16 and the endomannosidase gene, as well as of epigenetic factors, in increasing vulnerability to SAD. Neuroimaging findings revealed an altered connectivity of different cerebral areas in SAD patients and amygdala activation under social threat. Some parameter...

This paper offers an in-depth exploration of the intricate relationship between environmental factors and autism spectrum disorder (ASD), with a special emphasis on seasonality. It reviews existing research, providing a comprehensive summary of findings and highlighting the multifaceted dimensions of several environmental factors influencing the etiology of ASD. The discussion encompasses various elements, including birth months, maternal health, dietary choices, and vitamin D deficiency, delving into the intricate interplay of seasonality with environmental influences such as viral infections and solar radiation. The present study raises essential questions regarding the timing of environmental influences and the factors contributing to the rising prevalence of ASD. Ultimately, it underscores the need for future epidemiological research to incorporate more extensive investigations of environmental risk factors and employ advanced statistical analyses. This comprehensive overview contributes to a deeper understanding of how environmental factors, particularly seasonality, may be linked to the occurrence of ASD and its increasing prevalence, recognizing the multifaceted and diverse nature of these interactions.

The tissue-specific expression and epigenetic dysregulation of many genes in cells derived from the postmortem brains of patients have been reported to provide a fundamental biological framework for major mental diseases such as autism, schizophrenia, bipolar disorder, and major depression. However, until recently, the impact of non-neuronal brain cells, which arises due to cell-type-specific alterations, has not been adequately scrutinized; this is because of the absence of techniques that directly evaluate their functionality. With the emergence of single-cell technologies, such as RNA sequencing (RNA-seq) and other novel techniques, various studies have now started to uncover the cell-type-specific expression and DNA methylation regulation of many genes (e.g., TREM2, MECP2, SLC1A2, TGFB2, NTRK2, S100B, KCNJ10, and HMGB1, and several complement genes such as C1q, C3, C3R, and C4) in the non-neuronal brain cells involved in the pathogenesis of mental diseases. Additionally, several...

Background: Child maltreatment is a common negative experience and has potential long-lasting adverse consequences for mental and physical health, including increased risk for major depressive disorder (MDD) and metabolic syndrome. In addition, child maltreatment may increase the risk for comorbid physical health conditions to psychiatric conditions, with inflammation as an important mediator linking child maltreatment to poor adult health. However, it remains unresolved whether experiencing child maltreatment increases the risk for the development of comorbid metabolic syndrome to MDD. Therefore, we investigated whether child maltreatment increased the risk for comorbid metabolic syndrome to depressed mood. Subsequently, we examined whether C-reactive protein (CRP), as an inflammatory marker, mediated this association. In addition, we investigated whether effects differed between men and women. Methods: Associations were examined within cross-sectional data from the multiethnic HELIUS study (N = 21,617). Adult residents of Amsterdam, Netherlands, self-reported on child maltreatment (distinct and total number of types experienced before the age of 16 years) as well as current depressed mood (PHQ-9 score ≥ 10), and underwent physical examination to assess metabolic syndrome. The CRP levels were assessed in N = 5,998 participants. Logistic and linear regressions were applied for binary and continuous outcomes, respectively. All analyses were adjusted for relevant demographic, socioeconomic, and lifestyle characteristics, including ethnicity.

Glutathionylation, that is, the formation of mixed disulfides between protein cysteines and glutathione (GSH) cysteines, is a reversible post-translational modification catalyzed by different cellular oxidoreductases, by which the redox state of the cell modulates protein function. So far, most studies on the identification of glutathionylated proteins have focused on cellular proteins, including proteins involved in host response to infection, but there is a growing number of reports showing that microbial proteins also undergo glutathionylation, with modification of their characteristics and functions. In the present review, we highlight the signaling role of GSH through glutathionylation, particularly focusing on microbial (viral and bacterial) glutathionylated proteins (GSSPs) and host GSSPs involved in the immune/inflammatory response to infection; moreover, we discuss the biological role of the process in microbial infections and related host responses.

Major depression is a devastating disease affecting an increasing number of people from a young age worldwide, a situation that is expected to be worsened by the COVID-19 pandemic. New approaches for the treatment of this disease are urgently needed since available treatments are not effective for all patients, take a long time to produce an effect, and are not well-tolerated in many cases; moreover, they are not safe for all patients. There is solid evidence showing that the antioxidant capacity is lower and the oxidative damage is higher in the brains of depressed patients as compared with healthy controls. Mitochondrial disfunction is associated with depression and other neuropsychiatric disorders, and this dysfunction can be an important source of oxidative damage. Additionally, neuroinflammation that is commonly present in the brain of depressive patients highly contributes to the generation of reactive oxygen species (ROS). There is evidence showing that pro-inflammatory diets...

Background: The incidence and prevalence of psychiatric comorbidity are increased in inflammatory bowel disease (IBD) compared to the general population. In the longitudinal Manitoba IBD Cohort study (n = 388), the prevalence of mood disorders was elevated before diagnosis as compared to the general population. An increased prevalence several years before IBD diagnosis might suggest that the increased burden of psychiatric comorbidity reflects biologic effects. Objective: To determine the prevalence of psychiatric comorbidity five years before the diagnosis of IBD as compared to the general population. Methods: Using population-based administrative health data from Manitoba, Canada, we identified all persons with incident IBD between 1989 and 2012 using a validated algorithm (n=6119), and a cohort from the general population matched 5:1 on year of birth, sex and region (n= 30573). We then identified members of these groups with ≥5 years of residency before and after the first health contact for IBD (diagnosis date). We applied validated algorithms for psychiatric disorders in general (i.e. depression, anxiety, bipolar disorder, schizophrenia), and specific algorithms for depression, anxiety, and personality disorder, to determine their point prevalence 5 years before and after diagnosis date. We compared the prevalence between populations using a prevalence ratio. Results: The prevalence estimates for psychiatric comorbidity are shown in the Table. As compared to controls, the prevalence of any psychiatric disorder 5 years before IBD diagnosis was elevated (prevalence ratio 1.50; 95%CI: 1.36-1.66), and the prevalence ratio was slightly higher for depression than anxiety. Findings were similar for persons with Crohn's disease and ulcerative colitis. The prevalence of psychiatric comorbidity remained elevated in IBD as compared to the matched population 5 years after diagnosis. Conclusion: The prevalence of psychiatric comorbidity is elevated in the IBD population as compared to the general population as early as five years before diagnosis. This raises questions as to whether psychiatric disorders and IBD share common biologic mechanisms or if psychiatric disorders are a risk factor for developing IBD.

Background Major depressive disorder (MDD) is a complex mental health condition that results in several obstacles including disabilities, loss of productivity, and economic burdens on both patients and society. Etiopathogenesis of MDD involves several factors such as sociodemographic, genetic, and biological determinants. However, any suitable biomarkers for risk assessment of depression have not been established yet. Alterations of cytokine are assumed to be involved in the pathophysiology and severity of the depressive disorder. Therefore, we aimed to evaluate serum adiponectin and interleukin-8 (IL-8) among MDD patients in Bangladesh. Methods We recruited a total of 63 MDD patients and 94 age-sex matched healthy controls (HCs) in the present study. MDD patients were enrolled from a tertiary care teaching hospital, Dhaka, Bangladesh, and HCs from surrounding parts of Dhaka city. A psychiatrist assessed all the study participants following the criteria mentioned in the DSM-5. We ap...

Background The etiological and pathophysiological factors of learning disorder (LD) and attention deficit hyperactivity disorder (ADHD) are currently not well understood. These disorders disrupt some cognitive abilities. Identifying biomarkers for these disorders is a cornerstone to their proper management. Kynurenine (KYN) and oxidative stress markers have been reported to influence some cognitive abilities. Therefore, the aim was to measure the level of KYN and some oxidative stress indicators in children with LD with and without ADHD and to investigate their correlations with the abilities of children with LD. Methods The study included 154 participants who were divided into 3 groups: one for children who have LD (N = 69); another for children with LD and ADHD (N = 31); and a group for neurotypical (NT) children (N = 54). IQ testing, reading, writing, and other ability performance evaluation was performed for children with LD. Measuring plasma levels of KYN, malondialdehyde, glut...

Background Both the Crohn’s disease exclusion diet combined with partial enteral nutrition (CDED+PEN) and exclusive enteral nutrition (EEN) can induce remission in mild-to-moderate pediatric Crohn’s disease and are associated with a marked decrease in fecal kynurenine levels. This suggests a link between clinical outcome of dietary therapy and changes in tryptophan metabolism pathways. Here, we characterize the changes in several fecal tryptophan metabolites induced by CDED+PEN or EEN and their association with remission. Methods A total of 21 tryptophan metabolites were quantified in fecal samples from a 12-week prospective randomized trial with CDED+PEN or EEN for induction of remission in mild to moderate pediatric Crohn’s disease. Tryptophan metabolites at week 0 (W0), W6, and W12 of 73 samples were quantitatively measured by liquid chromatography coupled with triple quadrupole mass spectrometry, and data were analyzed according to clinical groups of baselines (W0), induced remi...

The heterogeneous phenomenology of autism together with diverse patterns of comorbidities led in the past to formulation of manifold theories and hypotheses on different explanatory levels. We scrutinize most recent findings from genetics, neurobiology and physiology and derive testable hypotheses about possible physiological links between domains. With focus on altered sensory perception and neuronal processing in ASD, we assume two intertwined regulatory feedback circuits under the umbrella of genetics and environmental factors. Both regulatory circuits are highly variable between individuals in line with the heterogeneous spectrum of ASD. The circuits set off from altered pathways and connectivity in ASD, fueling HPA-axis activity and distress. In the first circuit altered tryptophan metabolism leads to higher neurotoxic substances and reinforces the excitation:inhibition imbalance in the brain. The second circuit focuses on the impact and interaction with the environment and its rhythms in ASD. With lower melatonin levels, as the pacemaker molecule of the circadian system, we assume misalignment to outer and inner states corroborated from the known comorbidities in ASD. Alterations of the microbiome composition in ASD are supposed to act as a regulatory linking factor for both circuits. Overall, we assume that altered internal balance on cellular and neurophysiological levels is one of the main reasons leading to a lower ability in ASD to adapt to the environment and own internal changing states, leading to the conceptualization of autism as a condition of generalized imbalance in adaptation. This comprehensive framework opens up new perspectives on possible intervention and prevention strategies.

One of the most universally accepted facts about autism is that it is heterogenous. Individuals diagnosed with autism spectrum disorder have a wide range of behavioral presentations and a variety of co-occurring medical and mental health conditions. The identification of more homogenous subgroups is likely to lead to a better understanding of etiologies as well as more targeted interventions and treatments. In 2006, we initiated the UC Davis MIND Institute Autism Phenome Project (APP) with the overarching goal of identifying clinically meaningful subtypes of autism. This ongoing longitudinal multidisciplinary study now includes over 400 children and involves comprehensive medical, behavioral, and neuroimaging assessments from early childhood through adolescence (2–19 years of age). We have employed several strategies to identify sub-populations within autistic individuals: subgrouping by neural, biological, behavioral or clinical characteristics as well as by developmental trajector...

To evaluate effects of different concentrations of nanosilver colloid on the cell culture of Sertoli cells, the proportion of lipid peroxidation, antioxidant capacity, nitric oxide (NO) production and genes expression of superoxide dismutases (SOD1 and SOD2) and nitric oxide synthases (eNOS and iNOS) were measured. Sertoli cells were incubated at concentrations of 25, 75 and 125 ppm nanosilver for 48 h. There was progressive lipid peroxidation in treatments according to increasing of nanosilver. Lipid peroxidation, as indicated by malondialdehyde levels, was significantly elevated by the highest concentration of silver colloid (125 ppm), although antioxidant capacity, as measured by ferric ion reduction, was unaffected. Nitrite, as an index of NO production was reduced only in 125 ppm of nanosilver. Expression of SOD1 gene was reduced in nanosilver-treated cells at all concentrations, whereas expression of SOD2 gene was reduced only in cells treated with 125 ppm nanosilver. Expressi...

The bidirectional connection between the brain and the gut within psychiatric entities has gained increasing scientific attention over the last years. As a regulator of intestinal permeability, zonulin acts as a key player on the interface of this interplay. Like several psychiatric disorders, intestinal permeability was associated with inflammation in previous findings. Methods: In this study we explored differences in zonulin serum levels in currently depressed (n = 55) versus currently euthymic (n = 37) individuals with an affective disorder. Further, we explored sex differences and possible influences on zonulin and affective symptoms like medication, age, body mass index, and smoking status. Results: Serum zonulin was significantly higher in females than in men independent from affective status (z =-2.412, p = .016). More specifically, females in the euthymic subgroup had higher zonulin levels than euthymic men (z =-2.114, p = .035). There was no difference in zonulin serum levels in individuals taking or not taking a specific psychopharmacotherapy. We found no correlation between zonulin serum levels and depression severity. Discussion: Increased serum zonulin levels as a proxy for increased intestinal permeability in women may indicate a state of elevated susceptibility for depression-inducing stimuli.

Background: The therapeutic effects of exercise from structured activity programmes have recently been questioned; as a result, this study examines the impact of an Individualised Activity Program (IAP) on the relationship with cardiovascular, mitochondrial and fatigue parameters. Methods: Chronic fatigue syndrome (CFS) patients were assessed using Chalder Fatigue Questionnaire (CFQ), Fatigue Severity Score (FSS) and the Fatigue Impact Scale (FIS). VO2peak, VO2submax and heart rate (HR) were assessed using cardiopulmonary exercise testing. Mfn1 and Mfn2 levels in plasma were assessed. A Task Force Monitor was used to assess ANS functioning in supine rest and in response to the Head-Up Tilt Test (HUTT). Results: Thirty-four patients completed 16 weeks of the IAP. The CFQ, FSS and FIS scores decreased significantly along with a significant increase in Mfn1 and Mfn2 levels (p = 0.002 and p = 0.00005, respectively). The relationships between VO2 peak and Mfn1 increase in response to IAP...

Background The etiological and pathophysiological factors of learning disorder (LD) and attention deficit hyperactivity disorder (ADHD) are currently not well understood. These disorders disrupt some cognitive abilities. Identifying biomarkers for these disorders is a cornerstone to their proper management. Kynurenine (KYN) and oxidative stress markers have been reported to influence some cognitive abilities. Therefore, the aim was to measure the level of KYN and some oxidative stress indicators in children with LD with and without ADHD and to investigate their correlations with the abilities of children with LD. Methods The study included 154 participants who were divided into 3 groups: one for children who have LD (N = 69); another for children with LD and ADHD (N = 31); and a group for neurotypical (NT) children (N = 54). IQ testing, reading, writing, and other ability performance evaluation was performed for children with LD. Measuring plasma levels of KYN, malondialdehyde, glut...

Posttraumatic stress disorder (PTSD) represents a pressing and generally invalidating syndrome that is triggered by a terrifying or stressful experience, relying on recurrently reliving the traumatic event feelings associated to it, which is subsequently linked to ongoing activations of stress-related neurobiological pathways and is often associated with neurodegeneration. In this paper, we examine what lies beneath this disorder, reviewing evidence that connects PTSD with a wide array of mechanisms and its intertwined pathways that can lead to the decompensation of different pathologies, such as cardiovascular disease, gastrointestinal ailments, autoimmune disorders, and endocrine diseases. Also, the significance of the oxidative stress in this frame of reference is debated. Thus, knowing and identifying the main features of the distressing experience, the circumstances around it, as well as the neuropsychological and emotional characteristics of people prone to develop PTSD after ...

Background Autism spectrum disorder (ASD) evolves from an interplay between genetic and environmental factors during prenatal development. Since identifying maternal biomarkers associated with ASD risk in offspring during early pregnancy might result in new strategies for intervention, we investigated maternal metabolic biomarkers in relation to occurrence of ASD in offspring using both univariate logistic regression and multivariate network analysis. Methods Serum samples from 100 women with an offspring diagnosed with ASD and 100 matched control women with typically developing offspring were collected at week 14 of pregnancy. Concentrations of 62 metabolic biomarkers were determined, including amino acids, vitamins (A, B, D, E, and K), and biomarkers related to folate (vitamin B9) metabolism, lifestyle factors, as well as C-reactive protein (CRP), the kynurenine-tryptophan ratio (KTR), and neopterin as markers of inflammation and immune activation. Results We found weak evidence f...

Growing evidence suggests that early-life interactions among genetic, immune, and environment factors may modulate neurodevelopment and cause psycho-cognitive deficits. Maternal immune activation (MIA) induces autism-like behaviors in offspring, but how it interplays with perinatal brain injury (especially birth asphyxia or hypoxia ischemia [HI]) is unclear. Herein we compared the effects of MIA (injection of poly[I:C] to dam at gestational day 12.5), HI at postnatal day 10, and the combined MIA/HI insult in murine offspring of both sexes. We found that MIA induced autistic-like behaviors without microglial activation but amplified post-HI NFjB signaling, pro-inflammatory responses, and brain injury in offspring. Conversely, HI neither provoked autistic-like behaviors nor concealed them in the MIA offspring. Instead, the dual MIA/HI insult added autistic-like behaviors with diminished synaptic density and reduction of autism-related PSD-95 and Homer-1 in the hippocampus, which were missing in the singular MIA or HI insult. Further, the dual MIA/HI insult enhanced the brain influx of Otx2-positive monocytes that are associated with an increase of perineuronal net-enwrapped parvalbumin neurons. Using CCR2-CreER mice to distinguish monocytes from the resident microglia, we found that the monocytic infiltrates gradually adopted a ramified morphology and expressed the microglial signature genes (Tmem119, P2RY12, and Sall1) in post-MIA/HI brains, with some continuing to express the proinflammatory cytokine TNFa. Finally, genetic or pharmacological obstruction of monocytic influx significantly reduced perineuronal net-enwrapped parvalbumin neurons and autistic-like behaviors in MIA/HI offspring. Together, these results suggest a pathologic role of monocytes in the two-hit (immune plus neonatal HI) model of neurodevelopmental defects.

As one of the most widespread illnesses today, depression has a big social and economical significance. Therefore, enormous efforts are made in getting deeper insights into its etiology and pathogenesis, which are still unknown to us. Owing to the fast technological development, neurosciences have started to develop intensively. Neuroimaging technologies and new sensitive laboratory tests enable the discovery of active molecules that take part in pathophysiological processes so that they can be considered as potential biomarkers. Although the biomarker which would be specific for depression has not been isolated yet, there are a lot of studies that confirm the existence of changes of the level of active substances in depressive patients with the regard to control ones. In this paper, we will take a look into potential biomarkers that ere in the centre of the research: the factors of growth, that is, brain-derived neurophic factor (BDNF), inflammatory and neuroendocrine biomarkers, as well as potential indicators of the oxidative and nitrosative stress. This kind of the possibility of the insight into biological bases of the depressive processes would enable new ranges in diagnostics, therapies and prognosis of this disorder and would contribute to the better quality of life of patients and their families.

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One of the most universally accepted facts about autism is that it is heterogenous. Individuals diagnosed with autism spectrum disorder have a wide range of behavioral presentations and a variety of co-occurring medical and mental health conditions. The identification of more homogenous subgroups is likely to lead to a better understanding of etiologies as well as more targeted interventions and treatments. In 2006, we initiated the UC Davis MIND Institute Autism Phenome Project (APP) with the overarching goal of identifying clinically meaningful subtypes of autism. This ongoing longitudinal multidisciplinary study now includes over 400 children and involves comprehensive medical, behavioral, and neuroimaging assessments from early childhood through adolescence (2–19 years of age). We have employed several strategies to identify sub-populations within autistic individuals: subgrouping by neural, biological, behavioral or clinical characteristics as well as by developmental trajector...

The problem of depression in adolescents is discussed increasingly more often. A lot of researchers devote their careers to investigating this subject. The issue becomes vital, since the number of young people with depressive symptoms is constantly on the rise. The diagnosis can be difficult, as many a time the changes so typical for the puberty period appear. They include mood swings, explosiveness, propulsion disorders, puissance, insomnia, concentration problems etc. These might be the first symptoms of depression as well. It is impossible to point to one cause of depression because it is a disease conditioned by many different factors, ranging from independent factors like genetic, biological, hormonal, through the influence of the family or the environment influence and socio-cultural components.Early depression symptoms, long time exposure to stress, challenges or adversities - things every young person has to deal with - are a breeding ground for risky behaviors among adolesc...

Available online xxxx Objective: C-reactive protein (CRP), a marker of systemic inflammation, has been associated with psychiatric disorders including major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). Some research suggests that exposure to trauma can trigger increased activity in the inflammatory system. Dissociation is associated with chronic trauma exposure and may be an important factor in understanding the risk for psychiatric outcomes associated with inflammation. The main objective of the current study was to understand how CRP was related to trauma, dissociation, PTSD and MDD in a sample of 55 traumatized African American women with type 2 diabetes mellitus recruited from an urban hospital. Method: High sensitivity CRP (hsCRP) was assayed through blood samples; psychiatric disorders were assessed with structured clinical interviews, dissociation was assessed with the Multiscale Dissociation Inventory, and exposure to trauma in childhood and adulthood was assessed with the Childhood Trauma Questionnaire and the Traumatic Events Inventory, respectively. Results: Correlational results showed a significant association between higher concentrations of hsCRP and child abuse (p b 0.05), overall dissociation severity (p b 0.001), and PTSD symptoms (p b 0.01). ANOVA results showed significantly higher levels of hsCRP in those with current MDD, current PTSD, and remitted PTSD. A hierarchical linear regression model demonstrated a significant association between dissociation symptoms and greater hsCRP levels independent of childhood abuse, PTSD, and MDD (R 2 Δ = 0.11, p = 0.001) and independent of emotion dysregulation (p b 0.05). Conclusion: These findings suggest that dissociation symptoms among those with a history of trauma may be particularly associated with higher levels of inflammation.

Introduction: The purpose of our study was to investigate heme oxygenase-1 (HO-1), nuclear factor erythroid-2-related factor 2 (NRF2), and kelch-like ECH-associated protein 1 (KEAP1) levels in children with autism spectrum disorder (ASD) and to reveal their association with the severity of autism. Methods: This study measured serum HO-1, KEAP1, and NRF2 levels in 43 patients with ASD (aged 3-12 years) and in 41 age-and gendermatched healthy controls. ASD severity was rated using the Childhood Autism Rating Scale (CARS). HO-1, KEAP1, and NRF2 levels were determined in the biochemistry laboratory using the ELISA technique. Results: HO-1 levels were significantly lower in patients aged 3-12 years compared to controls aged 3-12, while KEAP1 and NRF2 levels were significantly higher (p=0.020, p<0.001, and p=0.017, respectively). No correlation was determined between ASD severity on the basis of total CARS scores and HO-1, KEAP1 or NRF2 (p>0.05). Conclusion: This study suggests that oxidative stress is higher in children with ASD and that HO-1 levels are insufficient to achieve oxidative balance.

To the Editor, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multisystem and often debilitating disorder of unknown etiology. (1) It is a complicated disease characterized by at least six months (in pediatrics 3 months) of extreme fatigue that is not alleviated by rest and a group of other symptoms that are constant for a period of time. (1)

Background: There is a strong comorbidity between mood disorders and metabolic syndrome (MetS). Increased levels of reactive oxygen and nitrogen species (RONS) and nitro-oxidative stress toxicity (NOSTOX) partially underpin this comorbidity. Aims: To examine the associations of RONS/NOSTOX biomarkers with MetS after adjusting for the significant effects of mood disorders (major depression, and bipolar type 1 and 2), generalized anxiety disorder (GAD), tobacco use disorder (TUD), and male sex. Methods: The study included subjects with (n=65) and without (n=107) MetS and measured levels of superoxide dismutase 1 (SOD1), lipid hydroperoxides (LOOH), nitric oxide metabolites (NOx), malondialdehyde (MDA), and advanced oxidation protein products (AOPP) and computed z unit-weighted composite scores which reflect RONS/NOSTOX. The study included 105 patients with mood disorders, 46 with GAD, and 95 with TUD. Results: MetS was associated with increased levels of MDA and AOPP, independently from mood disorders, TUD, sex and GAD. Atherogenicity and insulin resistance (IR) were significantly associated with a NOSTOX composite score. Mood disorders, TUD, GAD, male sex and MetS independently contribute to increased RONS/NOSTOX. The RONS/NOSTOX profile of MetS was different from that of GAD, which showed increased SOD1 and NOx levels. TUD was accompanied by increased SOD1, LOOH and MDA, and male sex by increased LOOH and AOPP. Conclusions: MetS is characterized by increased lipid peroxidation with aldehyde formation and chlorinative stress, and atherogenicity and IR are strongly mediated by RONS/NOSTOX. Partially shared RONS/NOSTOX pathways underpin the comorbidity of MetS with mood disorders, GAD, and TUD.

Family history and traumatic experiences are factors linked to bipolar disorder. It is known that the lifetime risk of bipolar disorder in relatives of a bipolar proband are 5-10% for first degree relatives and 40-70% for monozygotic co-twins. It is also known that patients with early childhood trauma present earlier onset of bipolar disorder, increased number of manic episodes, and more suicide attempts. We have recently reported that childhood trauma partly mediates the effect of family history on bipolar disorder diagnosis. In light of these findings from the scientific literature, we reviewed the work of British writer Virginia Woolf, who allegedly suffered from bipolar disorder. Her disorder was strongly related to her family background. Moreover, Virginia Woolf was sexually molested by her half siblings for nine years. Her bipolar disorder symptoms presented a pernicious course, associated with hospitalizations, suicidal behavioral, and functional impairment. The concept of ne...

Background Many studies have predicted major depressive disorder (MDD) as the leading cause of global health by 2030 due to its high prevalence, disability, and illness. However, the actual pathophysiological mechanism behind depression is unknown. Scientists consider alterations in cytokines might be tools for understanding the pathogenesis and treatment of MDD. Several past studies on several inflammatory cytokine expressions in MDD reveal that an inflammatory process is activated, although the precise causes of that changes in cytokine levels are unclear. Therefore, we aimed to investigate resistin and G-CSF in MDD patients and controls to explore their role in the pathogenesis and development of depression. Methods We included 220 participants in this study. Among them, 108 MDD patients and 112 age-sex matched healthy control (HCs). We used DSM-5 to evaluate study participants. Also, we applied the Ham-D rating scale to assess the severity of patients. Serum resistin and G-CSF l...

Immune-mediated inflammatory processes and oxidative stress are involved in the aetiopathogenesis of bipolar disorder (BD) and weight-associated comorbidities. Tryptophan breakdown via indoleamine 2,3-dioxygenase-1 (IDO-1) along the kynurenine axis concomitant with a pro-inflammatory state was found to be more active in BD, and associated with overweight/obesity. This study aimed to investigate tryptophan metabolism in BD compared to controls (C), stratified by weight classes, in a longitudinal setting, dependent on the incidence of BD episodes. Peripheral tryptophan, kynurenine, and neopterin were assessed in the serum of 226 BD individuals and 142 C. Three samples in a longitudinal assessment were used for 75 BD individuals. Results showed a higher kynurenine/tryptophan in both BD compared to C and overweight compared to normal weight persons. Levels remained stable over time. In the longitudinal course, no differences were found between individuals who were constantly euthymic or...

Background: The therapeutic effects of exercise from structured activity programmes have recently been questioned; as a result, this study examines the impact of an Individualised Activity Program (IAP) on the relationship with cardiovascular, mitochondrial and fatigue parameters. Methods: Chronic fatigue syndrome (CFS) patients were assessed using Chalder Fatigue Questionnaire (CFQ), Fatigue Severity Score (FSS) and the Fatigue Impact Scale (FIS). VO2peak, VO2submax and heart rate (HR) were assessed using cardiopulmonary exercise testing. Mfn1 and Mfn2 levels in plasma were assessed. A Task Force Monitor was used to assess ANS functioning in supine rest and in response to the Head-Up Tilt Test (HUTT). Results: Thirty-four patients completed 16 weeks of the IAP. The CFQ, FSS and FIS scores decreased significantly along with a significant increase in Mfn1 and Mfn2 levels (p = 0.002 and p = 0.00005, respectively). The relationships between VO2 peak and Mfn1 increase in response to IAP...

MiR-155p5 is a pro-inflammatory microRNA reported to be involved in several neurol-inflammatory diseases. Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social interactions and communication, as well as stereotypic movements. Inflammation of the brain due to activation of microglia has been reported in ASD. We investigated miR-155p5 gene expression in postmortem human brain tissues [amygdala and dorsolateral prefrontal cortex regions (DLPFC)]. There was significant increase of miR-155p5 in amygdala (P ≤ 0.0001), but not in DLFC, in ASD children (n = 8) compared to non-ASD (n = 7) controls. The increased gene expression of miR-155p5 in amygdala of children of ASD support the presence of localized inflammation in the brain and indicates miR-155p5 may be targeted for therapy of ASD.

Evidence indicates that major depression is accompanied by increased translocation of gut commensal Gramnegative bacteria (leaky gut) and consequent activation of oxidative and nitrosative (O&NS) pathways. This present study examined the associations among chronic apical periodontitis (CAP), root canal endotoxin levels (lipopolysaccharides, LPS), O&NS pathways, depressive symptoms, and quality of life. Measurements included advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), lipid peroxides (LOOH), −sulfhydryl (SH) groups, total radical trapping antioxidant parameter (TRAP), and paraoxonase (PON)1 activity in participants with CAP, with and without depression, as well as healthy controls (no depression, no CAP). Root canal LPS levels were positively associated with CAP, clinical depression, severity of depression (as measured with the Hamilton Depression Rating Scale (HDRS) and the Beck Depression Inventory) and O&NS biomarkers, especially NOx and TRAP. CAP-related depression was accompanied by increased levels of NOx, LOOH, AOPP, and TRAP. In CAP participants, there was a strong correlation (r = 0.734, p < 0.001) between root canal LPS and the HDRS score. There were significant and positive associations between CAP or root canal endotoxin with the vegetative and physiosomatic symptoms of the HDRS as well as a significant inverse association between root canal endotoxin and quality of life with strong effects on psychological, environmental, and social domains. It is concluded that increased root canal LPS accompanying CAP may cause depression and a lowered quality of life, which may be partly explained by activated O&NS pathways, especially NOx thereby enhancing

Early life trauma (ELT) may increase the risk towards bipolar disorder (BD) and major depression (MDD), disorders associated with activated neuro-oxidative and neuro-nitrosative stress (O&NS) pathways. It has remained elusive whether ELTs are associated with O&NS and which ELTs are associated with distinct affective disorder phenotypes. This case-control study examined patients with BD (n = 68) and MDD (n = 37) and healthy controls (n = 66). The Child Trauma Questionnaire (CTQ) was used to assess specific ELT. We measured malondialdehyde (MDA), lipid hydroperoxides (LOOH), superoxide dismutase (SOD), catalase, advanced oxidation protein products (AOPP); NO metabolites (NOx), paraoxonase 1 activity, zinc, albumin, high density lipoprotein cholesterol and -SH groups and computed z-unit weighted composite scores. Physical neglect significantly predicts higher z-unit weighted composite scores of LOOH+SOD, LOOH+SOD+NOx, LOOH+SOD+NOx + MDA and LOOH+SOD+NOx + AOPP. Sexual abuse was associa...