Postpartum depression (PPD) is a common psychological condition affecting 10-20% of postpartum women, characterized by emotional instability, anxiety, and, in severe cases, hallucinations or suicidal ideation. Growing evidence suggests a link between oxidative stress and depression, with nitrite-a key metabolite of nitric oxide (NO)-emerging as a potential biomarker. This study explores the association between salivary nitrite levels, perinatal anxiety, and PPD, aiming to identify predictive factors for early intervention.

A prospective clinical study was conducted involving 220 naturally delivered women. Saliva samples were collected at three time points: before labor analgesia, one hour post-analgesia, and on the discharge day. PPD was assessed using the Edinburgh Postnatal Depression Scale (EPDS) at 28 and 42 days postpartum. Logistic regression was applied to analyze the relationship between salivary nitrite levels and PPD risk (EPDS ≥ 9). Anxiety, information needs, and fear were evaluated as additional predictors.

Of 220 participants, 194 completed the study. The incidence of PPD was 10.82% at 28 days and 15.98% at 42 days postpartum. Higher pre-analgesia salivary nitrite levels were significantly associated with increased PPD risk at 28 days (OR = 1.017, p < 0.05) and 42 days (OR = 1.008, p < 0.05), with a stronger effect at 28 days. Preoperative anxiety was a strong predictor at 28 days (OR = 1.76, p = 0.019), while preoperative information needs were significant at 42 days (OR = 1.22, p = 0.043). Salivary nitrite levels significantly decreased after labor analgesia and remained low at discharge.

This study is the first to demonstrate a significant association between salivary nitrite levels and the occurrence of postpartum depression (PPD), with this association being particularly pronounced at 28 days postpartum. Perinatal anxiety and information needs were also identified as important predictors of PPD. This research provides a new perspective for the early screening and intervention of PPD and points the way for future studies to further explore its mechanisms and predictive factors.

Major depressive disorder (MDD) with comorbid anxiety is an intricate psychiatric condition, but limited research is available on the degree centrality (DC) between anxious MDD and nonanxious MDD patients.

To examine changes in DC values and their use as neuroimaging biomarkers in anxious and non-anxious MDD patients.

We examined 23 anxious MDD patients, 30 nonanxious MDD patients, and 28 healthy controls (HCs) using the DC for data analysis.

Compared with HCs, the anxious MDD group reported markedly reduced DC values in the right fusiform gyrus (FFG) and inferior occipital gyrus, whereas elevated DC values in the left middle frontal gyrus and left inferior parietal angular gyrus. The nonanxious MDD group exhibited surged DC values in the bilateral cerebellum IX, right precuneus, and opercular part of the inferior frontal gyrus. Unlike the nonanxious MDD group, the anxious MDD group exhibited declined DC values in the right FFG and bilateral calcarine (CAL). Besides, declined DC values in the right FFG and bilateral CAL negatively correlated with anxiety scores in the MDD group.

This study shows that abnormal DC patterns in MDD, especially in the left CAL, can distinguish MDD from its anxiety subtype, indicating a potential neuroimaging biomarker.

Background/Objectives: The health of military personnel in modern operational settings is critical for sustaining defense readiness. Extended exposure to extreme conditions can cause oxidative stress and systemic inflammation, potentially affecting performance. To address this problem, we developed an innovative diagnostic tool, the Post-Mission Integrated Risk Index (IIRPM), which integrates hematologic markers with key clinical variables. A novel aspect of the approach is the incorporation of ΔNLR, thus quantifying the change in the neutrophil-to-lymphocyte ratio measured before and after deployment, thereby providing a sensitive indicator of the inflammatory impact of operational stress. Methods: In this retrospective study, we analyzed comprehensive clinical and biological data from 443 military personnel over a ten-year period, with measurements taken before and after missions. We applied robust statistical techniques, including paired t-tests and Pearson correlation analyses, to assess variations in hematologic and metabolic parameters. Data segmentation was performed using Gaussian mixture models, and the predictive performance of the resulting model was validated with a multi-layer perceptron (MLP) neural network. Results: The analysis revealed significant post-mission increases in both the baseline NLR and ΔNLR, accompanied by notable shifts in metabolic markers. Data segmentation identified three distinct profiles: a reference profile characterized by stable immunologic parameters, an acute inflammatory response profile, and a proinflammatory metabolic profile marked by elevated cholesterol levels and higher mean age. Remarkably, the MLP model achieved 100% accuracy on the test set, with an average cross-validation accuracy of 97%. Conclusions: The IIRPM-which incorporates ΔNLR, age, mission duration, and cholesterol levels-offers a novel strategy to assess inflammatory risk among military personnel, thus facilitating personalized preventive interventions. Further validation in multicenter and longitudinal studies is anticipated to consolidate the clinical utility of this tool, ultimately fostering a more adaptive approach in military medicine to address the complex challenges of modern operational theaters.

Along with accelerated aging, the prevalence of late-life depression (LLD) exacerbates. Older people are more vulnerable to the adverse effects of antidepressants than the young. Therefore, creating antidepressants from medicinal herbs that are more effective and safer is inevitable. Ginkgo biloba L. leaf extract (EGb761) is broadly applied for treating various neuronal dysfunctions. The present study aimed to evaluate the ameliorative and antidepressant effects of EGb761 against reserpine (RES)-induced depression like symptoms and associated comorbidities in aged female rats. Besides, it compared its efficacy with the antidepressant duloxetine (DULX), offering a more comprehensive understanding of therapeutic potential of EGb 761. Rats grouped into control group, EGb 761-H group, RES group, RES plus either EGb 761-L, EGb 761-H, or DULX groups. The antidepressant effects of EGb 761 were evaluated through a series of behavioral tests, measurement of depression biochemical markers, performing neuronal histopathology and immunohistochemical analyses. EGb 761 significantly attenuated behavioral deficits in the open field test and reduced immobility time in the forced swimming test. Moreover, EGb 761 exerted antidepressant-like actions by ameliorating neurotransmitter imbalances, restoring redox homeostasis in cortical region. Also, EGb 761 increased level of ATP, diminished DNA fragmentation, decreased caspase-3 immunoreactivity and increased immunoreactivity of synaptophysin in the cerebral cortex, besides it enhanced the histological architecture of this region. Overall, EGb 761 has the potential effects to manage LLD focus on the role of both serotonergic and noradrenergic systems in mediating these effects, alongside the impact on oxidative/nitrosative stress.

This study aimed to investigate oxidative stress markers in the oral mucosal cells of individuals diagnosed with major depressive disorder (MDD).

A case-control design was used, including twenty patients diagnosed with MDD, based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria, and twenty healthy controls. Oral exfoliated cells were collected from all participants. Intracellular levels of reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), caspase-3 and -7 activity, and reduced glutathione (GSH) were measured in Arbitrary Fluorescence Units (AFU).

The MDD group demonstrated significantly elevated intracellular ROS levels (p = 0.0012) and caspase-3 and -7 activity (p = 0.0171) in comparison to the control group. Additionally, a decrease in ΔΨm expression was observed in the oral cells of MDD patients (p = 0.0265), whereas GSH expression levels did not differ significantly between the two groups (p = 0.8908).

The findings indicate heightened oxidative stress in the oral exfoliated cells of individuals with MDD. This study supports the potential use of oral cells as a non-invasive biomarker source for assessing oxidative stress in depressive disorders.

The aim of this study was to develop a novel antidepressant with high activity. Based on the findings of molecular docking, eight novel curcumin analogues were evaluated in vitro to check for antidepressant efficacy. Among them, CACN136 had the strongest antidepressant effect. Firstly, CACN136 had a stronger 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonate) radical ion scavenging ability (IC50: 17.500 ± 0.267 μg/mL) compared to ascorbic acid (IC50: 38.858 ± 0.263 μg/mL) and curcumin (27.189 ± 0.192 μg/mL). Secondly, only CACN136 demonstrated clear protective effects on cells damaged by glutamate and oxidative stress at all concentrations. Finally, only CACN136 showed ASP + inhibition and was more effective than fluoxetine hydrochloride (FLU) at low concentrations. To further confirm the antidepressant effect of CACN136 in vivo, the CUMS model was established. Following 28 days of oral administration of CUMS mice, CACN136 increased the central area residence time in the open-field test, significantly increased the sucrose preference rate in the sucrose preference test (P < 0.001) and significantly reduced the immobility period in the tail suspension test (P < 0.0001), all of which were more effective than those of FLU. Subsequent research indicated that the antidepressant properties of CACN136 were linked to a decrease in the metabolism of 5-HT and the modulation of oxidative stress levels in vivo. In particular, the activation of the Keap1-Nrf2/BDNF-TrkB signaling pathway by CACN136 resulted in elevated levels of antioxidant enzymes, enhancing the antioxidant capability in mice subjected to CUMS. In conclusion, CACN136 has the potential to treat depression and could be an effective antidepressant.

Bipolar disorder (BD) is one of the most encountered disorders in psychiatric clinics. Despite extensive research and advancements in BD treatment, little is known about the disease's primary etiopathogenesis and relationship with different pathophysiological traits. The present study is aimed to evaluate the pathophysiological role of oxidative and nitrosative stress in BD patients and identify their familial aggregation.

Blood samples from healthy individuals, drug-naive symptomatic BD patients, and their first-degree relatives were obtained, and intracellular reactive oxygen/nitrogen species (ROS/RNS), total nitrites, neuronal nitric oxide synthase (nNOS) mRNA expression, myeloperoxidase (MPO) activity in polymorphonuclear neutrophils (PMNs), and serum cortisol levels were assessed.

ROS, MPO activity, total-nitrite content, nNOS expression in PMNs, and serum cortisol concentration were considerably more in BD patients than in healthy volunteers. All these variables showed a substantial correlation with the YMRS score for disease severity and the presence of one or more manic episodes. Additionally, a positive correlation was noted between the MPO activity and serum cortisol levels of BD patients and their first-degree relatives.

The results of the present study advance our knowledge about the role of oxidative and nitrosative stress in BD pathophysiology and its familial aggregation. Additionally, the study demonstrates a direct correlation between the disease severity and levels of ROS/RNS, MPO, total nitrite, and nNOS transcripts in PMNs. However, future research with larger and more diverse participant populations is required to understand these pathways for use as potential biomarkers for a deeper understanding of BD pathophysiology and to improve therapeutic strategies.

Major depressive disorder (MDD) is a prevalent condition that affects approximately 350 million people worldwide. Several studies have identified changes in amino acids in the blood of MDD patients, suggesting their potential as biomarkers to better understand their role in depression. Gastrodia elata Blume (GEB) and its active compound gastrodin (GAS) are recognized for their antidepressant properties. However, their effects on amino acid profiles and their potential role in alleviating depression remain poorly understood. Understanding how GEB and GAS influence amino acid metabolism may offer novel insights into their mechanisms in alleviating depression, potentially leading to more targeted therapeutic strategies.

This study aimed to investigate the potential role of supplementing GEB and its active compound GAS to reverse altered amino acid profiles in depressed rats.

To achieve this, six-week-old SD rats were induced depressive-like behaviors by the UCMS rat model for 5 weeks. Groups receiving GEB or GAS were administered orally via gavage daily within the UCMS model. Serum samples were collected and analyzed using a targeted metabolomics approach employing LC-MS for amino acid profiling.

A total of 38 amino acid metabolites were identified, 17 of which were significantly altered following UCMS. UCMS rats exhibited perturbed arginine biosynthesis, arginine and proline metabolism pathways. Changes in key amino acids in these metabolic pathways were reversed following supplementation with GEB and GAS, which also alleviated depressive symptoms.

In conclusion, UCMS-induced depression in rats causes changes in some amino acid metabolites similar to those found in human depression, validating its relevance as a model for studying depression. Additionally, the research suggests that GEB and GAS may exert antidepressant effects by regulating amino acid metabolism.

Memory is a dynamic process of encoding, storing, and retrieving information. It includes sensory, short-term, and long-term memory, each with unique characteristics. Nitric oxide (NO) is a biological messenger synthesized on demand by neuronal nitric oxide synthase (nNOS) through a biochemical process initiated by glutamate binding to NMDA receptors, causing membrane depolarization and calcium influx. NO is known to regulate many signaling pathways including those related to memory consolidation. To throw light on the precise molecular mechanism of nitric oxide (NO) in memory consolidation and the possibility of targeting NO pathways as a therapeutic approach to scale down cognitive impairments. We conducted a search of the PubMed MEDLINE database, maintained by the US National Library of Medicine. The search strategy utilized Medical Subject Headings (MeSH) terms, including "nitric oxide and memory," "nitric oxide synthesis in the brain," "nitric oxide and Alzheimer's," "nitric oxide and Parkinson's," and "nitric oxide, neurodegenerative disorders, and psychiatric disorders." Additionally, relevant keywords such as "nitric oxide," "memory," and "cognitive disorders" were employed. We included the most recent preclinical and clinical studies pertinent to the review topic and limited the selection to articles published in English. NO exerts its role in memory consolidation by diffusing between neurons to promote synaptic plasticity, especially long-term potentiation (LTP). It acts as a retrograde messenger, neurotransmitter release modulator, and synaptic protein modifier. The dysregulation of NO balance in the brain can contribute to the pathogenesis of various neurodegenerative diseases, particularly Alzheimer's, Parkinson's, and psychiatric disorders. The disturbance in NO signaling is strongly correlated with synaptic signaling dysfunction and oxidative stress. NO plays a fundamental role in memory consolidation, and its dysregulation contributes to cognitive impairment-a hallmark of numerous neurodegenerative and psychiatric disorders. Future research should aim to deepen our understanding of the mechanisms underlying NO's involvement in memory consolidation and to explore therapeutic strategies targeting the NO pathway to mitigate cognitive decline in affected individuals.

The inheritance of the short SLC6A4 allele, encoding the serotonin transporter (SERT) in humans, increases susceptibility to neuropsychiatric and metabolic disorders, with aging and female sex further exacerbating these conditions. Both central and peripheral mechanisms of the compromised serotonin (5-HT) system play crucial roles in this context. Previous studies on SERT-deficient (Sert-/-) mice, which model human SERT deficiency, have demonstrated emotional and metabolic disturbances, exacerbated by exposure to a high-fat Western diet (WD). Growing evidence suggests the significance of hepatic regulatory mechanisms in the neurobiology of central nervous system disorders, supporting the 'liver-brain' concept. However, the relationship between aberrant behavior and hepatic alterations under conditions of SERT deficiency remains poorly investigated.

One-year-old female Sert-/- mice and their wild-type (WT) littermates were subjected to a control diet (CD) or the WD for a duration of three weeks. The WD had a higher caloric content and was characterized by an elevated saturated fat content (21%) compared to the CD (4.5%) and contained 0.2% cholesterol. Mice were evaluated for anxiety-like behavior, exploration and locomotor activity in the open field test, as well as glucose tolerance and histological indicators of hepatic steatosis. Hepatic pro-inflammatory and metabolism-related gene expression and markers of nitrosative stress, were analyzed utilizing real-time polymerase chain reaction (RT-PCR) and correlated with behavioral and histological outcomes.

In comparison to unchallenged mice, Sert-/-/WD mutants, but not the WT/WD group, had increased locomotion and anxiety-like behavior, increased hepatic steatosis, and elevated expression of insulin receptor B and pro-inflammatory cytokines interleukin-1β (Il-1β) and Tnf, as well as decreased expression of leptin receptor B. The two genotypes displayed distinct gene expression patterns of nitric oxide (NO)-related molecules inducible NO synthase (iNos) and arginase (Arg2), insulin receptor-related signaling factors: cluster of differentiation 36 (Cd36), ecto-nucleotide pyrophosphatase/phosphodiesterase (Enpp), protein tyrosine phosphatase N1 (Ptpn1), cytochrome P450 omega-hydroxylase 4A14 (Cyp4a14), acyl-CoA synthetase 1 (Acsl1) and phosphatase and tensin homolog (Pten). Furthermore, there were profound differences in correlations between molecular, histological, and behavioral measurements across the two genotypes.

Our findings suggest that the genetic deficiency of SERT results in abnormal hepatic pro-inflammatory and metabolic adaptations in response to WD. The significant correlations observed between behavioral measures and pro-inflammatory and metabolic alterations in WD-fed mice suggest the importance of liver-brain interactions and their role in the aberrant behaviors exhibited by Sert-/- mutants. This study presents the first evidence that altered liver functions are associated with pathological behaviors arising from genetic SERT deficiency.

This study aimed to explore the relationship between flavonoids intake and the prevalence and all-cause mortality of depressive symptoms in American adults.

Analyzing 2007-2008, 2009-2010, and 2017-2018 NHANES data, we examined the association between dietary flavonoid and depressive symptoms, including specific subclasses assessment and mortality outcomes tracking until December 31, 2019. Our methodology included weighted multivariate logistic regression, weighted cox proportional hazards regression and restricted cubic spline (RCS) models, supported by stratified and sensitivity analyses.

Among the 12,340 participants in total, 1129 exhibited depressive symptoms. The multiple logistic regression analysis showed a significant reduction in total flavonoid and subclass intake in individuals with current depressive symptoms. Adjusted odds ratios (ORs) for the highest quartiles were 0.69 for anthocyanidins and 0.63 for flavones. Interaction effects emerged in non-hypertensive, higher-income, and normal-weight groups for flavones intake. The RCS model indicated an L-shaped association between depressive symptoms and total flavonoid intake, with inflection points at 346 mg/day. During a median follow-up of 119 months, 148 deaths occurred among patients with depressive symptoms. Hazard ratios (HRs) for all-cause mortality showed a significant positive correlation between total flavonoid intake and survival in model 1 (HR = 0.56), with an optimal intake range of 45.2-948.3 mg/day according to the RCS model.

The study relied on U.S. population survey data, potentially limiting generalizability. Unmeasured confounding factors may exist, and genetic factors were not considered.

Adequate intake of flavonoids, especially anthocyanidins and flavones, is associated with reduced odds of depressive symptoms. Additionally, optimal intake ranges of flavonoid intake for mental health benefits were observed for all-cause mortality in population with depressive symptoms.

This paper provides a summary of the role of nitric oxide (NO) and hormones in the development of chronic stress, anxiety, depression, and post-traumatic stress disorder (PTSD). These mental health conditions are prevalent globally and involve complex molecular interactions. Although there is a significant amount of research and therapeutic options available, the underlying mechanisms of these disorders are still not fully understood. The primary pathophysiologic processes involved in chronic stress, anxiety, depression, and PTSD include dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, the intracellular influence of neuronal nitric oxide synthase (nNOS) on transcription factors, an inflammatory response with the formation of nitrergic oxidative species, and reduced serotonergic transmission in the dorsal raphe nucleus. Despite the extensive literature on this topic, there is a great need for further research to clarify the complexities inherent in these pathways, with the primary aim of improving psychiatric care.

Oxidative stress has been identified as a major factor in the development and progression of pain and psychiatric disorders, but the underlying biomarkers and molecular signaling pathways remain unclear. This study aims to identify oxidative stress-related biomarkers and signaling pathways in pain-depression comorbidity. Integrated bioinformatics analyses were applied to identify key genes by comparing pain-depression comorbidity-related genes and oxidative stress-related genes. A total of 580 differentially expressed genes and 35 differentially expressed oxidative stress-related genes (DEOSGs) were identified. By using a weighted gene co-expression network analysis and a protein-protein interaction network, 43 key genes and 5 hub genes were screened out, respectively. DEOSGs were enriched in biological processes and signaling pathways related to oxidative stress and inflammation. The five hub genes, RNF24, MGAM, FOS, and TKT, were deemed potential diagnostic and prognostic markers for patients with pain-depression comorbidity. These genes may serve as valuable targets for further research and may aid in the development of early diagnosis, prevention strategies, and pharmacotherapy tools for this particular patient population.

Depression represents a prevalent and enduring mental disorder of significant concern within the clinical domain. Extensive research indicates that depression is very complex, with many interconnected pathways involved. Most research related to depression focuses on monoamines, neurotrophic factors, the hypothalamic-pituitary-adrenal axis, tryptophan metabolism, energy metabolism, mitochondrial function, the gut-brain axis, glial cell-mediated inflammation, myelination, homeostasis, and brain neural networks. However, recently, Ketamine, an ionotropic N-methyl-D-aspartate (NMDA) receptor antagonist, has been discovered to have rapid antidepressant effects in patients, leading to novel and successful treatment approaches for mood disorders. This review aims to summarize the latest findings and insights into various signaling pathways and systems observed in depression patients and animal models, providing a more comprehensive view of the neurobiology of anxious-depressive-like behavior. Specifically, it highlights the key mechanisms of ketamine as a rapid-acting antidepressant, aiming to enhance the treatment of neuropsychiatric disorders. Moreover, we discuss the potential of ketamine as a prophylactic or therapeutic intervention for stress-related psychiatric disorders.

Multiple sclerosis (MS) is a chronic and immune-mediated disease of unknown etiology and leading to a physical and cognitive disability. Different studies suggest that nitrosative stress may play a pivotal role in the pathogenesis and disability in MS. Besides, reports evaluated NO and their metabolites, expressed by nitrite and nitrate (NOx) levels of MS patients compared with other pathologies, but did not evaluate disability and relapse/remission phases.

Thus, this study aimed to conduct a systematic review and meta-analysis of NOx levels in MS patients in relapse/remission phases and its involvement in patient disability.

The protocol was registered in PROSPERO (CRD42022327161). We used GRADE to estimate the articles' quality and evaluated the publication bias using Egger's and Begg's tests.

Here, through a search in the Pubmed, Scopus, and EMBASE databases, 5.276 studies were found, and after the selection process, 20 studies were included in this systematic review and meta-analysis. The studies included data from 1.474 MS patients and 1.717 healthy controls, 1.010 RRMS and 221 primary progressive MS (PPMS).

NOx levels are increased in relapsing-remitting MS (RRMS) patients in the relapse phase. Also, NOx levels were increased in MS patients with higher disability. However, further studies are still needed to control lifestyle habits, pain, and MS treatment effects in biased NOx levels.

A review of the association between microbes and mental illness is performed, including the history, relevant definitions, infectious agents associated with mental illnesses, complex interactive infections, total load theory, pathophysiology, psychoimmunology, psychoneuroimmunology, clinical presentations, early-life infections, clinical assessment, and treatment. Perspectives on the etiology of mental illness have evolved from demonic possession toward multisystem biologically based models that include gene expression, environmental triggers, immune mediators, and infectious diseases. Microbes are associated with a number of mental disorders, including autism, schizophrenia, bipolar disorder, depressive disorders, and anxiety disorders, as well as suicidality and aggressive or violent behaviors. Specific microbes that have been associated or potentially associated with at least one of these conditions include Aspergillus, Babesia, Bartonella, Borna disease virus, Borrelia burgdorferi (Lyme disease), Candida, Chlamydia, coronaviruses (e.g., SARS-CoV-2), Cryptococcus neoformans, cytomegalovirus, enteroviruses, Epstein-Barr virus, hepatitis C, herpes simplex virus, human endogenous retroviruses, human immunodeficiency virus, human herpesvirus-6 (HHV-6), human T-cell lymphotropic virus type 1, influenza viruses, measles virus, Mycoplasma, Plasmodium, rubella virus, Group A Streptococcus (PANDAS), Taenia solium, Toxoplasma gondii, Treponema pallidum (syphilis), Trypanosoma, and West Nile virus. Recognition of the microbe and mental illness association with the development of greater interdisciplinary research, education, and treatment options may prevent and reduce mental illness morbidity, disability, and mortality.

In a subset of patients, chronic exposure to stress is an etiological risk factor for neuroinflammation and depression. Neuroinflammation affects up to 27% of patients with MDD and is associated with a more severe, chronic, and treatment-resistant trajectory. Inflammation is not unique to depression and has transdiagnostic effects suggesting a shared etiological risk factor underlying psychopathologies and metabolic disorders. Research supports an association but not necessarily a causation with depression. Putative mechanisms link chronic stress to dysregulation of the HPA axis and immune cell glucocorticoid resistance resulting in hyperactivation of the peripheral immune system. The chronic extracellular release of DAMPs and immune cell DAMP-PRR signaling creates a feed forward loop that accelerates peripheral and central inflammation. Higher plasma levels of inflammatory cytokines, most consistently interleukin IL-1β, IL-6, and TNF-α, are correlated with greater depressive symptomatology. Cytokines sensitize the HPA axis, disrupt the negative feedback loop, and further propagate inflammatory reactions. Peripheral inflammation exacerbates central inflammation (neuroinflammation) through several mechanisms including disruption of the blood-brain barrier, immune cellular trafficking, and activation of glial cells. Activated glial cells release cytokines, chemokines, and reactive oxygen and nitrogen species into the extra-synaptic space dysregulating neurotransmitter systems, imbalancing the excitatory to inhibitory ratio, and disrupting neural circuitry plasticity and adaptation. In particular, microglial activation and toxicity plays a central role in the pathophysiology of neuroinflammation. Magnetic resonance imaging (MRI) studies most consistently show reduced hippocampal volumes. Neural circuitry dysfunction such as hypoactivation between the ventral striatum and the ventromedial prefrontal cortex underlies the melancholic phenotype of depression. Chronic administration of monoamine-based antidepressants counters the inflammatory response, but with a delayed therapeutic onset. Therapeutics targeting cell mediated immunity, generalized and specific inflammatory signaling pathways, and nitro-oxidative stress have enormous potential to advance the treatment landscape. Future clinical trials will need to include immune system perturbations as biomarker outcome measures to facilitate novel antidepressant development. In this overview, we explore the inflammatory correlates of depression and elucidate pathomechanisms to facilitate the development of novel biomarkers and therapeutics.

Alcohol (ethanol) is among the most popularly consumed beverages globally. Ethanol was earlier demonstrated to elicit cognitive impairment and depressive-like effects in both human and animal studies. Rutin (R) is known for its antioxidant, anti-inflammatory, immunomodulatory, and anti-depressive properties, among others. Herein, we investigate the impact of rutin on ethanol-induced cognitive impairment and depressive-like effects in rats and the involvement of the indoleaminergic pathway. Three groups of eight rats each were orally exposed to drinking water (group 1), ethanol (5 g/kg body weight)-group 2 (via oral gavage), and ethanol + R (5 g/kg body weight + 50 mg/kg body weight)-group 3 (via oral gavage) for 35 days. Results showed that exposure to ethanol significantly (p < 0.0001) reduced spontaneous alternation in the Y-maze and increased immobility time in the tail suspension test (TST), which indicates cognitive impairment and depressive-like behavior in rats. We observed increased IDO activity/expression, and inflammatory responses, with attendant disruption in antioxidant systems and concomitant elevation in malondialdehyde (MDA) levels in the cerebral cortex and hippocampus. Following rutin co-exposure, an ethanol-mediated increase in indoleamine 2,3-dioxygenase [IDO] activity/expression and decrease in antioxidant enzymes, in addition to an increase in markers of inflammatory response and MDA production, was significantly (p < 0.0001) prevented compared with controls. Additionally, altered behavioral indices were prevented by rutin co-exposure. Taken together, these findings reveal the involvement of the indoleaminergic pathway in rutin preventive influence against ethanol-induced cognitive impairment and depressive-like behavior in rats.

Depressive disorders can affect up to 350 million people worldwide, and in developed countries, the percentage of patients with depressive disorders may be as high as 10%. During depression, activation of pro-inflammatory pathways, mitochondrial dysfunction, increased markers of oxidative stress, and a reduction in the antioxidant effectiveness of the body are observed. It is estimated that approximately 30% of depressed patients do not respond to traditional pharmacological treatments. However, more and more attention is being paid to the influence of active ingredients in food on the course and risk of neurological disorders, including depression. The possibility of using foods containing polyphenols as an element of diet therapy in depression was analyzed in the review. The possibility of whether the consumption of products such as polyphenols could alleviate the course of depression or prevent the progression of it was also considered. Results from preclinical studies demonstrate the potential of phenolic compounds have the potential to reduce depressive behaviors by regulating factors related to oxidative stress, neuroinflammation, and modulation of the intestinal microbiota.

Major depressive disorder (MDD) is a psychiatric disease of still poorly understood molecular etiology. Extensive studies at different molecular levels point to a high complexity of numerous interrelated pathways as the underpinnings of depression. Major systems under consideration include monoamines, stress, neurotrophins and neurogenesis, excitatory and inhibitory neurotransmission, mitochondrial dysfunction, (epi)genetics, inflammation, the opioid system, myelination, and the gut-brain axis, among others. This review aims at illustrating how these multiple signaling pathways and systems may interact to provide a more comprehensive view of MDD's neurobiology. In particular, considering the pattern of synaptic activity as the closest physical representation of mood, emotion, and conscience we can conceptualize, each pathway or molecular system will be scrutinized for links to synaptic neurotransmission. Models of the neurobiology of MDD will be discussed as well as future actions to improve the understanding of the disease and treatment options.

Major depressive disorder (MDD) is widely accepted as having a heterogenous pathophysiology involving a complex mixture of systemic and CNS processes. A developmental etiology coupled to genetic and epigenetic risk factors as well as lifestyle and social process influences add further to the complexity. Consequently, antidepressant treatment is generally regarded as open to improvement, undoubtedly as a consequence of inappropriately targeted pathophysiological processes. This article reviews the diverse array of pathophysiological processes linked to MDD, and integrates these within a perspective that emphasizes alterations in mitochondrial function, both centrally and systemically. It is proposed that the long-standing association of MDD with suppressed serotonin availability is reflective of the role of serotonin as a precursor for the mitochondrial melatonergic pathway. Astrocytes, and the astrocyte mitochondrial melatonergic pathway, are highlighted as crucial hubs in the integration of the wide array of biological underpinnings of MDD, including gut dysbiosis and permeability, as well as developmental and social stressors, which can act to suppress the capacity of mitochondria to upregulate the melatonergic pathway, with consequences for oxidant-induced changes in patterned microRNAs and subsequent patterned gene responses. This is placed within a development context, including how social processes, such as discrimination, can physiologically regulate a susceptibility to MDD. Future research directions and treatment implications are derived from this.

Anthocyanins have been shown to be effective in chronic diseases because of their antioxidant and anti-inflammatory effects together with changes in the gut microbiota and modulation of neuropeptides such as insulin-like growth factor-1. This review will examine whether these mechanisms may be effective to moderate the symptoms of disorders of the central nervous system in humans, including schizophrenia, Parkinson's disease, Alzheimer's disease, autism spectrum disorder, depression, anxiety, attention-deficit hyperactivity disorder and epilepsy. Thus, anthocyanins from fruits and berries should be considered as complementary interventions to improve these chronic disorders.

Oxidative stress, impaired antioxidant defense and neuroinflammation are often associated with the onset and progression of neuropsychiatric diseases. Conversely, several piperazine compounds presents beneficial neuropharmacological effects as well as antioxidant activity, and some derivatives combine both activities. LQFM212 (2,6-di-tert-butyl-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenol) was synthesized to produce effects on CNS and to have an additional antioxidant effect. Previous preclinical tests have been shown anxiolytic- and antidepressant-like effects of LQFM212 in mice. Herein, the main objective was to verify the possible antioxidant potential and the effects of LQFM212 against behavioral changes, inflammatory and oxidative markers induced by lipopolysaccharide (LPS).

Initially, antioxidant potential of LQFM212 was evaluated by electrochemical assays. Afterwards, the effects of oral treatment with LQFM212 were evaluated in mice using LPS-induced models of systemic or local inflammation.

In LPS-induced neuroinflammation, LQFM212 treatment reverted changes caused by LPS, demonstrated by attenuated anxiogenic- and depressive-like behaviors, reduced pro-inflammatory cytokines (TNF-α and IL-1β) and increased anti-inflammatory cytokines (IL-4 and IL-10) on serum, and also improved oxidative stress-related changes (levels of nitrite, malondialdehyde, glutathione and carbonylated protein, and superoxide dismutase, catalase, myeloperoxidase and cholinesterase activities) on brain cortex and hippocampus. However, LQFM212 treatment did not attenuate the inflammatory changes in LPS-induced pleurisy model.

LQFM212 presents antioxidant activity and ameliorates behavioral, inflammatory and oxidative changes after LPS-induced neuroinflammation model. These effects do not seem to be secondary to a peripheral anti-inflammatory action of LQFM212, since this compound failed to attenuate the inflammatory changes in LPS-induced pleurisy model.

Major depressive disorder (MDD) and bipolar disorder (BD) with melancholia and psychotic features and suicidal behaviors are accompanied by activated immune-inflammatory and oxidative pathways, which may stimulate indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme of the tryptophan catabolite (TRYCAT) pathway resulting in increased tryptophan degradation and elevated tryptophan catabolites (TRYCTAs). The purpose of the current study is to systematically review and meta-analyze levels of TRP, its competing amino acids (CAAs) and TRYCATs in patients with severe affective disorders. Methods: PubMed, Google Scholar and SciFinder were searched in the present study and we recruited 35 studies to examine 4647 participants including 2332 unipolar (MDD) and bipolar (BD) depressed patients and 2315 healthy controls. Severe patients showed significant lower (p < 0.0001) TRP (standardized mean difference, SMD = -0.517, 95% confidence interval, CI: -0.735; -0.299) and TRP/CAAs (SMD = -0.617, CI: -0.957; -0.277) levels with moderate effect sizes, while no significant difference in CAAs were found. Kynurenine (KYN) levels were unaltered in severe MDD/BD phenotypes, while the KYN/TRP ratio showed a significant increase only in patients with psychotic features (SMD = 0.224, CI: 0.012; 0.436). Quinolinic acid (QA) was significantly increased (SMD = 0.358, CI: 0.015; 0.701) and kynurenic acid (KA) significantly decreased (SMD = -0.260, CI: -0.487; -0.034) in severe MDD/BD. Patients with affective disorders with melancholic and psychotic features and suicidal behaviors showed normal IDO enzyme activity but a lowered availability of plasma/serum TRP to the brain, which is probably due to other processes such as low albumin levels.

Depression is a serious psychiatric disorder that affects millions of individuals all over the world, thus demanding special attention from researchers in order to investigate its effective remedies. Curcumin, along with its synthetic derivatives, is recognized for its incredible pharmacological activities. In this study, methyl, methoxy and chloro-substituent synthetic curcumin analogues C1-C3 were respectively tested for free radical-scavenging activity. Behavioral studies were performed using chemical-induced and swimming endurance tests as stress models, and forced swim tests (FSTs) and tail suspension tests (TSTs) as depression mice models. Biochemical examinations were performed after a scopolamine-induced stress model by decapitating the mice, and brain tissues were isolated for biochemical assessment of catalase (CAT), superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA). The curcumin analogue C2 exhibited higher DPPH (2,2-diphenyl-1-picrylhydrazyl) and ABTS (2,2'-azinobis-3-ethylbenzothiazo-line-6-sulphonate) free radical-scavenging potential, having IC50 values of 45.18 µg/mL and 62.31 µg/mL, respectively, in comparison with reference curcumin and tocopherol. In the chemical-induced test, C2 (80.17%), C3 (72.79%) and C1 (51.85%) revealed higher antistress responses by significantly reducing the number of writhes, whereas the immobility time was significantly reduced by C2 and C3 in the swimming endurance test, indicating excellent antistress potential. Similarly, C2 and C3 significantly reduced the immobility times in FST and TST, demonstrating their antidepressant properties. The biomarkers study revealed that these compounds significantly enhanced hippocampus CAT, SOD and GSH, and reduced MDA levels in the scopolamine-induced stress mice model. These findings suggest the potential of curcumin analogues (C2 and C3) as antistress and antidepressant agents.

Background: Taking into account the role of oxidative stress in neurodegeneration, we sought to evaluate the expression of genes for select enzymes with antioxidant properties (paraoxonases PON1, PON2 and PON3 and myeloperoxidase MPO) at the mRNA and protein levels in patients with depressive disorders. We further sought to determine the impact of oxidative stress in the etiopathogenesis of this group of mood disorders. Methods: A total of 290 subjects (190 depressed patients, 100 healthy controls) took part in the study. Sociodemographic and clinical data were collected. The severity of depressive symptoms was assessed using the Hamilton Depression Rating Scale (HDRS). Venous blood was collected. RT-PCR was used to assess gene expression at the mRNA level, while enzyme-linked immunosorbent assay (ELISA) was used to assess gene expression at the protein level. Results: The expression of the PON2 and PON3 genes at the protein level was significantly higher in depressive patients than in healthy controls. mRNA expression of the PON1, PON2 and PON3 genes was slightly higher in patients with depressive disorders than in the control group, however, this relationship was not statistically significant. On the other hand, the expression of the MPO gene at both mRNA and protein levels was significantly lower in patients with depressive disorder than in the control group. Conclusions: Our results are not in agreement with many studies on enzymes involved in maintaining oxidative balance. Our findings may not support the utility of paraoxonases (PON) or myeloperoxidase (MPO) as promising biomarker candidates of depression pending larger and well controlled studies.

Evidence supports a strong bidirectional association between depression and Type 2 diabetes mellitus (T2DM). The harmful impact of oxidative stress and chronic inflammation on the development of both disorders is widely accepted. Nuclear factor erythroid 2-related factor 2 (NRF2) is a pertinent target in disease management owing to its reputation as the master regulator of antioxidant responses. NRF2 influences the expression of various cytoprotective phase 2 antioxidant genes, which is hampered in both depression and T2DM. Through interaction and crosstalk with several signaling pathways, NRF2 endeavors to contain the widespread oxidative damage and persistent inflammation involved in the pathophysiology of depression and T2DM. NRF2 promotes the neuroprotective and insulin-sensitizing properties of its upstream and downstream targets, thereby interrupting and preventing disease advancement. Standard antidepressant and antidiabetic drugs may be powerful against these disorders, but unfortunately, they come bearing distressing side effects. Therefore, exploiting the therapeutic potential of NRF2 activators presents an exciting opportunity to manage such bidirectional and comorbid conditions.