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Oxidative stress, inflammation and treatment response in major depression

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Abstract

Objective: Increased inflammation and oxidative stress have been shown in Major Depressive Disorder (MDD), although there is significant heterogeneity across studies. Whether markers of inflammation and oxidative stress are associated with antidepressant treatment response in MDD is currently unclear. The goals of the present study are to investigate markers of inflammation and oxidative stress in unmedicated MDD subjects and controls and test the relationship between these markers and antidepressant response in MDD subjects. Methods: Interleukin (IL)-6, tumor necrosis factor (TNF)-α, C-reactive protein, F2-isoprostanes, 8-OH 2-deoxyguanosine (8-OHdG), glutathione peroxidase, glutathione, and vitamin C were quantified in blood samples from 50 unmedicated MDD subjects and 55 healthy controls. Depression symptom severity was rated with the 17-item Hamilton Depression Rating Scale (HDRS). All subjects were somatically healthy and free from medications that could interfere with inflammation and oxidative stress markers. A subgroup of 22 MDD subjects underwent open-label selective serotonin reuptake inhibitor (SSRI) antidepressant treatment for eight weeks, after which blood sampling and the HDRS were repeated. Antidepressant treatment "response" was defined as ≥50% decrease in HDRS ratings over 8 weeks of treatment. Results: After controlling for the effects of age, sex, body mass index and smoking, MDD subjects had significantly higher levels of IL-6 (p<0.001), TNF-α (p<0.001), 8-OHdG (p=0.018), and F2-isoprostanes (p=0.012). Compared to Responders, Non-responders to SSRI antidepressant treatment had higher levels of F2-isoprostanes at baseline (p=0.006), and after eight weeks of treatment (p=0.031). Non-responders showed a significant increase in 8-OHdG over the course of treatment (p=0.021), whereas Responders showed a significant decrease in IL-6 over the course of treatment (p=0.019). Conclusion: Our results are in line with previous reports of increased levels of markers of inflammation and oxidative stress in MDD. Moreover, poorer antidepressant treatment response was related to higher baseline levels of the major oxidative stress marker, F2-isoprostanes, in vivo. Further, antidepressant response was associated with changes in oxidative (8-OHdG) and inflammatory (IL-6) markers.

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... A study conducted by Lindqvist stated that the concentration of IL-6 biomarker increased in the depression group with an average value of 0.35 pg/mL and an increase in the concentration of the biomarker TNF-with an average value of 2.75 pg/mL. 26,[29][30][31] Both of these studies showed the same concentration of IL-,6, TNF-α, and IL-10 values in depressed patients with traumatic brain injury. The increase in the concentration of these biomarkers is related to the HPA-axis which is activated by the inflammatory response system, thus will then affect corticotroropin and adrenocorticotropic hormones, thereby increasing the turnover of catecholamines and serotonin. ...
... This is what causes an increase in concentration of depressive inflammatory biomarkers in traumatic brain injury. 30,32,33 Differences in inflammatory biomarker concentrations could be due to the different onset of TBI in 2 studies and sampling techniques. Tamar's study took serum that processed within 90 min of blood collecting process, frozen at -80°C, and stored until analyzed using an immunosorbent assay. ...
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Depression is one of the long-term complications of traumatic brain injury (TBI) associated with the inflammatory process. This study aims to analyze the role of proinflammatory biomarkers on depression due to TBI and determine the types of proinflammatory biomarkers of depression in TBI. This systematic review and meta-analysis used the preferred reporting items for systematic reviews and meta-analyses (PRISMA) protocol with the population, intervention, comparison, outcome method. The selected research articles consisted of 4 cohort studies and 2 cross-sectional studies. Participants were all participants who experienced TBI without any previous infectious disease and neurobehavior disorders. Article searches are limited to the last 10 years using digital libraries including Pubmed, Science Direct, Wiley, Google Scholar. Assessment of the risk of bias using the ROBINS-1 tool, research quality using the GradePro application, and meta-analysis using review manager software 5.4.1. The results of a meta-analysis of proinflammatory biomarkers of depression using 2 cross-sectional studies showed a risk of bias and a moderate level of certainty. The most common types of proinflammatory biomarkers are IL-6, TNF-α, and IL-10. These proinflammatory biomarkers are markers of depression in TBI and have an effect on depression in TBI, especially in recurrent TBI and high post-traumatic stress disorder with depression accompanied by an increase in the concentration value of these biomarkers. Increased proinflammatory biomarkers IL-6, TNF-α, and IL-10 were found in depression with TBI. This proinflammatory biomarker has a significant relationship so that it can be used as a marker of depression in TBI.
... [59][60][61][62][63] In the blood samples of MDD subjects, similar changes were also noted, along with increased levels of oxidative stress markers, such as lipid peroxidation products (F2-isoprostanes and malondialdehyde), thiobarbituric acid reactive substances, deoxyguanosine, and uric acid. 60,[64][65][66] Mechanistically, oxidative stress can cause mitochondrial damage, and the ensuing inflammatory reactions against damaged mitochondrial components exacerbate mitochondrial dysfunction, leading to increased production of ROS, which could also trigger inflammasome activation and inflammation-induced cell death, heightening oxidative stress. 67,68 These hypotheses were supported by both experimental evidence and clinical correlates. ...
... 211 Notably, the clinical efficacy of SSRI also appeared to be inversely correlated with the baseline level of lipid peroxidation products (F2-isoprostanes) and was monitorable by a reduction in IL-6 expression. 66,212 Altogether, these findings emphasize the therapeutic utility of targeting oxidative stress-inflammation signaling in depressive disorders. Given the close connection between oxidative stress and neuroexcitotoxicity, inhibition of this pathway might also provide fruitful outcomes for SB prevention. ...
Article
KEY POINTS • Inflammation is a prominent feature in depression and suicidal behavior (SB) etiopathogenesis. • It has different origins. • Neuroendocrine abnormalities can be involved in depression- and SB-associated inflammation. • Immune dysregulation can also result in inflammation in these psychiatric conditions. • Dysbiosis and infection, furthermore, can contribute. CLINICAL CARE POINTS • Distinct inflammatory pathology might be present in different subtypes of depression, or in suicidal ideation vs. different subtypes of suicidal behavior (SB). • Inflammatory pathology could be monitored for diagnosis, prevention, and treatment responsiveness in these psychiatric conditions. • Pathway-focused blockade of inflammation treatment might be useful for to improve outcomes.
... Oxidative stress is defined as an imbalance between the generation of reactive oxygen species (ROS) and the antioxidant defences [5]. Abundant evidence suggests that oxidative stress plays a critical role in the pathophysiology of depression [6][7][8]. ROS/reactive nitrogen species (RNS) refer to free radicals (superoxide, hydroxyl radical) or nonradical molecules (hydrogen peroxide) and their derivatives [9]. Physiological levels of ROS/RNS are involved in many metabolic processes in the organism [6,7,10]. ...
... The brain is a major consumer of oxygen and is rich in oxidative lipids, making it more vulnerable to damage from oxidative stress. Oxidative stress markers, such as 8-OH 2-deoxyguanosine (8-OHdG) and F2-isoprostanes are found to be significantly increased in major depressive disorder (MDD) [8]. ...
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The balance between oxidation and antioxidant is crucial for maintaining homeostasis. Once disrupted, it can lead to various pathological outcomes and diseases, such as depression. Oxidative stress can result in or aggravate a battery of pathological processes including mitochondrial dysfunction, neuroinflammation, autophagical disorder and ferroptosis, which have been found to be involved in the development of depression. Inhibition of oxidative stress and related pathological processes can help improve depression. In this regard, the nuclear factor erythroid 2-related factor 2 (Nrf2) in the antioxidant defense system may play a pivotal role. Nrf2 activation can not only regulate the expression of a series of antioxidant genes that reduce oxidative stress and its damages, but also directly regulate the genes related to the above pathological processes to combat the corresponding alterations. Therefore, targeting Nrf2 has great potential for the treatment of depression. Activation of Nrf2 has antidepressant effect, but the specific mechanism remains to be elucidated. This article reviews the key role of Nrf2 in depression, focusing on the possible mechanisms of Nrf2 regulating oxidative stress and related pathological processes in depression treatment. Meanwhile, we summarized some natural and synthetic compounds targeting Nrf2 in depression therapy. All the above may provide new insights into targeting Nrf2 for the treatment of depression and provide a broad basis for clinical transformation.
... [3] Emerging evidence implicates inflammatory and oxidative stress in depression pathophysiology. [4,5] COVID-19 subjects show dysregulated cytokine responses with inflammation. [6,7] The severity of depressive symptoms in COVID-19 subjects correlated well with inflammatory indicator C-reactive protein (CRP). ...
... Macrophage-induced inflammation has been identified as a prominent biological risk factor in the pathogenesis of depression (Porter & O'Connor, 2022;Smith, 1991) and many clinical and animal studies highlight strong associations between inflammation and behavioral symptoms of depression (Kitaoka, 2022;Kohler et al., 2016;Lindqvist et al., 2017;Miller et al., 2009;Zhang et al., 2019). For example, high concentration of proinflammatory cytokines TNF-alpha and IL-6 were found in patients with major depression (Beurel et al., 2020;Dowlati et al., 2010) and clinical trials have indicated beneficial effects of anti-inflammatory medications on major depression symptoms (Akhondzadeh et al., 2009;Muller et al., 2006). ...
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Introduction Several studies have linked inflammation and oxidative stress with the pathogenesis of depression. Artesunate is a commonly used medication to treat malaria and has been shown to produce antioxidant, anti‐inflammatory, and immunomodulatory effects. However, its prophylactic effects on depression and depression‐related brain pathology are unknown. Methods In Experiment 1, using a PC12 cell line, we investigated whether artesunate can prevent hydrogen peroxide (H2O2)‐induced oxidative injury that mimics oxidative stress commonly observed in the depressed brain. Next, using lipopolysaccharide (LPS)‐induced mouse model of depression, we investigated whether artesunate can prevent behavioral deficits observed in the open field test, novelty‐suppressed feeding test, sucrose preference test, forced swimming test, and tail suspension procedure. Results We found that artesunate significantly prevented a H2O2‐induced reduction in PC12 cell activity, suggesting its antioxidant potential. We also found that mice pretreated with artesunate (5, 15 mg/kg) intraperitoneally (i.p.) prior to the LPS (.8 mg/kg, i.p.) treatment showed fewer and less severe depression‐ and anxiety‐like behaviors than the LPS‐treated control mice. Conclusion Our findings indicate that artesunate produces antioxidant effect, as well as antidepressant and anxiolytic effects. Importantly, our findings first demonstrate that artesunate can prevent LPS‐induced depression‐ and anxiety‐like symptoms, strongly suggesting its prophylactic potential in the treatment of depression and, perhaps, other psychiatric disorders associated with inflammation and oxidative stress.
... The prior study reported increased levels of markers of inflammation and oxidative stress in MDD. Moreover, likewise poorer antidepressant treatment response was related to higher baseline levels of the major oxidative stress marker, F2-isoprostanes, in vivo [32]. However, when treating patients with depression in clinical settings, physicians should deliberately select an antidepressant based on the specific presenting and individual symptom profiles of the patient. ...
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Background Depression is a common and debilitating disease, and even residual symptoms of depression can cause significant functional impairment. To achieve normal functioning, residual symptoms should also be identified and targeted by a competent treatment strategy. Thus, this study aimed to examine residual symptoms of depression and their associated factors among patients with depression. Methods A cross-sectional study surveyed Thai patients with depression at two psychiatric outpatient clinics, Songklanagarind Hospital, and Songkhla hospital; from June to October 2021. The questionnaires inquired about: (1) demographic information, (2) the PHQ-9 Thai version, (3) a questionnaire focusing on depressive symptoms that impacted daily life, and were originally expected to be improved due to antidepressants. All data were analyzed using descriptive statistics, and associated factors concerning depressive symptoms were analyzed by a Chi-square and a logistic regression. Results Of all 566 respondents, the majority of them were female (75.4%). The overall mean age was 43.8 ± 18.1 years. The depressive symptoms that had high frequency, high impact on daily life, and that the participants expected that they are resolved or get better via antidepressants were: sleeping problems (81.6%), feeling depressed (79.9%), and lack of pleasure (75.4%). Most of the participants (65.7%) received one type of antidepressant, and the most prescribed antidepressants were selective serotonin reuptake inhibitors (51.1%). In regard to objectives, 45.4% of participants reported having residual depressive symptoms which included sleeping problems (71.2%), feeling down (62.6%), lack of pleasure (62.3%), and poor appetite (61.9%). The associated factors relating to residual depressive symptoms were younger age, high education level, and having physical illness. Conclusion Almost half of patients with depression had residual symptoms, and they showed symptoms with high individual variability. Further to receiving effective treatment, a focused and individualized approach aiming for symptomatic remission, functional recovery, and quality of life improvements is key to recovery. Therefore, shared decision-making, and taking into account drug efficacy based on symptom profiles are both highly recommended.
... Studies with humans highlight that the higher expression of IL-6, MPO, and other in ammatory molecules directly in uences the lower response to treatment with antidepressants (Miller and Raison, 2016;Lindqvist et al. 2017). In this way, anti-in ammatory strategies can reduce depressive conditions (Kopschina Feltes et al. 2017). ...
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Major depressive disorder (MDD) etiology is still not completely understood, and many individuals resist the traditional treatments. Chronic exposure to stressful events can contribute to development and progression and be involved in biological changes underlying MDD. Among the biological mechanisms involved, inflammatory changes and oxidative balance are associated with MDD pathophysiology. Quetiapine, a second-generation antipsychotic, induces a better therapeutic response in individuals refractory to traditional treatments. The main objectives of this research were: To evaluate the effect of chronic mild stress (CMS) on depressive-like behaviors, oxidative stress, and inflammation in adult rats; to evaluate the possible antidepressant, antioxidant and anti-inflammatory effects of quetiapine. The animals were submitted to CMS protocols. At the end of the CMS, the animals were submitted to a chronic treatment for 14 days with the following drugs: quetiapine, imipramine, and escitalopram. At the end of the treatments, the animals were evaluated in the open field tests, anhedonia (splash test), and forced swimming. The animals were euthanized after the behavioral tests, and serum samples were collected. Myeloperoxidase (MPO) activity and interleukin-6 levels were analyzed. CMS induced an increase in depressive-like behaviors, and quetiapine significantly reduced these behaviors. MPO activity and IL-6 levels increased in the serum of animals submitted to CMS. Quetiapine significantly reduced MPO activity and IL-6 levels. These results corroborate other evidence, indicating that chronic stress is a relevant phenomenon in the etiology of depression and suggesting that quetiapine induces an antidepressant effect because it reduces oxidative and inflammatory mechanisms.
... Studies focusing on older adults also showed significantly higher lipid peroxidation markers (Pomara et al., 2012) and an imbalance between oxidative stress vs. anti-oxidative stress markers in MDD (Diniz et al., 2018b) compared to non-depressed controls. Moreover, increased oxidative stress has been associated with poor response to antidepressant treatment (Lindqvist et al., 2017). ...
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Major depressive disorder (MDD) is characterized by psychological and physiological manifestations contributing to the disease severity and outcome. In recent years, several lines of evidence have suggested that individuals with MDD have an elevated risk of age-related adverse outcomes across the lifespan. This review provided evidence of a significant overlap between the biological abnormalities in MDD and biological changes commonly observed during the aging process (i.e., hallmarks of biological aging). Based on such evidence, we formulate a mechanistic model showing how abnormalities in the hallmarks of biological aging can be a common denominator and mediate the elevated risk of age-related health outcomes commonly observed in MDD. Finally, we proposed a roadmap for novel studies to investigate the intersection between the biology of aging and MDD, including the use of geroscience-guided interventions, such as senolytics, to delay or improve major depression by targeting biological aging.
... Increasingly, further possible mechanisms of MDD are emerging, such as neurotransmission alternation, neurotrophic changes, neuroendocrine changes including the HPA axis, inflammation, nutrition, and the brain-gut axis [2]. Recent studies have suggested that oxidative stress and inflammation may be the main causes of MDD [3,4]. Oxidative stress is caused by a homeostatic impairment-induced imbalance between antioxidants and reactive oxygen species (ROS), which can lead to DNA, proteins, or lipid damage. ...
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Major Depression disorder (MDD) is a potentially life-threatening mental illness, however, many patients have a poor response to current treatments. Recent studies have suggested that stress- or trauma-induced oxidative stress and inflammation could be important factors involved in the development of MDD, but the mechanisms remain unclear. We showed that the glymphatic system is a recently discovered structure in the brain that may be involved in the clearance of large molecular and cell debris in extracellular space. In addition, the glymphatic system can help with the removal of reactive oxygen species (ROS) and cytokines such as IL-1β and HIF-1α. Glymphatic impairment can lead to ROS accumulation in the microenvironment, inducing cellular injury signaling and activating NLRP3 in microglia to induce inflammation and, thus, many brain diseases, including psychiatric disorders. Therefore, trauma-induced glymphatic impairment could induce oxidative stress and inflammation, and thus MDD. This paper will review recent advances with regard to stress-induced glymphatic system impairment and ROS-mediated inflammation in MDD.
... The pathogenesis of both CKD and depression involves a combination of oxidative stress and inflammatory responses. [25][26][27] β-sitosterol may regulate the GSH redox cycle by blocking intracellular reactive oxygen species (ROS) accumulation. 28 Furthermore, it had a stronger affinity for estrogen receptors, acting as an antioxidant with the help of estrogen or stimulating antioxidant enzymes, thereby enhancing the protective effect of intracellular antioxidant defense. ...
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Background: Depression in Chronic Kidney Disease (CKD) seriously affects the prognosis of patients and Modified Danggui-Shaoyao-San (MDSS) is based on the traditional Chinese formula Danggui-Shaoyao-San (DSS) for the treatment of depression, which is further optimized. The aim of this study was to evaluate the clinical efficacy and safety of MDSS for the treatment of depression in CKD, and to explain the molecular mechanism of MDSS for the treatment of depression in CKD through pharmacology and molecular docking. Methods: 62 patients were randomly divided into treatment group (treated with MDSS) and control group (treated with placebo) and assessed by Hamilton Depression Scale, and the primary outcome was to evaluate the efficacy of MDSS in improving depressive symptoms and the effect on liver and kidney function, electrolytes. In addition, we identified the core compounds and potential targets of MDSS through the TCMSP database. The GeneCards, OMIM and Disgenet databases were then used to identify molecular targets for CKD and depression. The target protein-protein interaction network was built using STRING database. Core targets were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Molecular docking was used to verify the relationship between core active compounds and proteins. Results: Clinical results showed that CKD patients in the MDSS group had significantly improved depressive status with no significant adverse effects. By network pharmacology analysis, we found that the compound-target network mainly contained 47 compounds and 69 corresponding targets. 844 terms were analyzed by GO enrichment, and 254 signaling pathways in KEGG. Molecular docking showed that the top active compounds had high affinity with four targets. Conclusion: We preliminarily investigated the efficacy of MDSS in the treatment of depression in CKD and revealed the characteristics of multiple compounds and multiple targets in MDSS.
... Oxidative stress in adolescence contributes to the development of inflammation in the CNS, disturbed the development of the neural network, and myelination (Chelini et al., 2018). The role of oxidative stress in the development of both schizophrenia and affective diseases has been described (Lindqvist et al., 2017), which is another argument confirming that MMP-9 is important in the pathogenesis of these diseases and GEMIN genes through MMP9 and inflammation that is possibly associated with depression. Inflammation is a known etiological factor in depression. ...
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Background The role of miRNA in depression is widely described by many researchers. miRNA is a final product of many genes involved in its formation (maturation). One of the final steps in the formation of miRNAs is the formation of the RISC complex, called the RNA-induced silencing complex, which includes, among others, GEMIN proteins. Single-nucleotide polymorphisms (SNPs) may lead to disturbance of miRNA biogenesis and function. The objective of our research was to assess the relationship between the appearance of depression and single nucleotide polymorphisms in the GEMIN3 ( rs197388 ) and GEMIN4 ( rs7813 ; rs3744741 ) genes. Our research provides new knowledge on the genetic factors that influence the risk of depression. They can be used as an element of diagnostics helpful in identifying people at increased risk, as well as indicating people not at risk of depression. Methods A total of 218 participants were examined, including individuals with depressive disorders ( n = 102; study group) and healthy people ( n = 116, control group). All the patients in the study group and the people in the control group were non-related native Caucasian Poles from central Poland. Blood was collected from study and control groups in order to assess the SNPs of GEMIN genes. Results An analysis of the results obtained showed that in patient population, the risk of depression is almost doubled by polymorphic variants of the genes: rs197388 /GEMIN3 genotype A/A in the recessive model and rs3744741 /GEMIN4 genotype T/T, codominant and recessive model. The dual role of rs7813 /GEMIN4 is noteworthy, where the G/A genotype in the codominant and over dominant model protects against depression.
... Although there is no consensus on the etiology of depression, it involves a variety of factors such as oxidative stress, and environmental, genetic, sociocultural, social, and psychological factors [43]. Oxidative damage caused by free radicals plays a significant role in the pathogenesis of depression and related mental diseases [16,44]. Therefore, in recent years, to reduce the risk of depressive symptoms, a large number of studies on antioxidants and depressive symptoms have been conducted. ...
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Given the important role of oxidative stress in the pathogenesis of depression, the potential role of dietary antioxidant supplementation in the prevention of depression has attracted considerable attention. Most studies suggest that dietary carotenoids may play a role in maintaining depressive symptoms due to their antioxidant activity, but some studies concluded the contrary. This study conducted a meta-analysis of observational studies to test the relationship between carotenoid supplements and depressive symptoms. After a comprehensive search of the Cochrane Library, PubMed, Embase Scopus, and Web of Science databases from their inception to 28 July 2022, 12 publications met the inclusion and exclusion criteria, of which 8 were cross-sectional studies, 3 were case–control studies, and 1 was a cohort study, involving a total of 33,466 participants. Pooled meta-analysis found that intake of total carotenoids (OR = 0.61, 95% CI [0.53, 0.71], p < 0.01), beta-carotene (OR = 0.61, 95% CI [0.52, 0.70], p < 0.01), alpha-carotene (OR = 0.71, 95% CI [0.60, 0.83], p < 0.01), lycopene (OR = 0.71, 95% CI [0.55, 0.90], p < 0.01), lutein, and/or corn xanthin (OR = 0.53, 95% CI [0.43, 0.66], p < 0.01) was significantly inversely associated with depressive symptoms, while beta-cryptoxanthin (OR = 1.07, 95% CI [0.52, 2.21], p = 0.86) had no significance. At the same time, this meta-analysis was free of publication bias and heterogeneity. Although further studies are needed to elucidate the causal relationship between carotenoids and depressive symptoms, and to further reveal the mechanism of their association, the results of our meta-analysis suggest that carotenoids are protective factors for depressive symptoms, and dietary intake may help in reducing the risk of depressive symptoms.
... Several biochemical and psychosocial factors are likely responsible for our finding. For instance, it is well known that individuals with depression have decreased levels of markers of neurogenesis and hippocampal volumes [36] and increased levels of inflammatory and oxidant markers [37] and that physical activity could attenuate these problems [34,38]. For example, physical activity may increase hippocampal volume [39] and neurogenesis levels [40] and adjust the imbalance between anti-and proinflammatory and oxidant markers [41]. ...
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Background The 24-h movement guidelines for youth and adults recommend the specific duration of physical activity, sedentary time, and sleep duration to ensure optimal health, but little is known about its relationship to mental health indicators. The aim of the study was to explore the association between 24-h movement guidelines in adolescence and its trajectories from middle adolescence (12–17 years old) to adulthood (33–39 years old) with depression and suicidal ideation in adulthood. Methods This prospective cohort study included individuals who participated in Waves I (1994–1995) and V (2016–2018) of the National Longitudinal Study of Adolescent Health (Add Health) in the United States. Physical activity, screen time and sleep duration were measured using questionnaires. Adults were categorized as having depression if they had a self-reported history of depression and/or prescription medication-use for depression in the previous four weeks. Suicidal ideation was assessed by a self-reported single question in both waves. Poisson regression analyses were used to estimate the incidence rate ratio (IRR) of depression and suicidal ideation at adulthood, according to meeting specific and combinations of 24-h movement guidelines at Wave I and its trajectories from adolescence to adulthood. Results The study included 7,069 individuals (56.8% women). Adolescents who met physical activity guidelines and all three guidelines at middle adolescence had lower risk of depression (IRR = 0.84, 95%CI 0.72 to 0.98) and suicidal ideation (IRR = 0.74, 95%CI 0.55 to 0.99) at adulthood than those who did not meet any of these guidelines, respectively. Individuals who met the guidelines for screen time and all three guidelines in both adolescence and adulthood had lower risk of depression (screen time, IRR = 0.87, 95% CI 0.72 to 0.98; all three, IRR = 0.3 7 , 95% CI 0.15 to 0.92) and suicidal ideation (screen time, IRR = 0.74, 95% CI 0.51 to 0.97; all three, IRR = 0.12, 95% CI 0.06 to 0.33) than those who never met the guidelines. Additionally, individuals who did not meet all three guidelines in adolescence but met the guidelines in adulthood had lower risk of suicidal ideation than those who never met the guidelines (IRR = 0.81, 95%CI 0.45 to 0.89). Conclusion Our findings highlight the importance of promoting and maintaining adherence to the 24-h movement guidelines from middle adolescence to adulthood to prevent mental health problems. However, our findings must be interpreted carefully due to declared limitations, e.g., the self-reported assessments which are subject to sources of error and bias or that the dataset used to gauge meeting a guidelines (1994–1996) was made later (2016).
... Studies with humans highlight that the higher expression of IL-6, MPO, and other in ammatory molecules directly in uences the lower response to treatment with antidepressants (Miller and Raison, 2016;Lindqvist et al. 2017). In this way, anti-in ammatory strategies can reduce depressive conditions (Kopschina Feltes et al. 2017). ...
Preprint
Full-text available
Major depressive disorder (MDD) etiology is still not completely understood, and many individuals resist the traditional treatments. Chronic exposure to stressful events can contribute to development and progression and be involved in biological changes underlying MDD. Among the biological mechanisms involved, inflammatory changes and oxidative balance are associated with MDD pathophysiology. Quetiapine, a second-generation antipsychotic, induces a better therapeutic response in individuals refractory to traditional treatments. The main objectives of this research were: To evaluate the effect of chronic mild stress (CMS) on depressive-like behaviors, oxidative stress, and inflammation in adult rats; to evaluate the possible antidepressant, antioxidant and anti-inflammatory effects of quetiapine. The animals were submitted to CMS protocols. At the end of the CMS, the animals were submitted to a chronic treatment for 14 days with the following drugs: quetiapine, imipramine, and escitalopram. At the end of the treatments, the animals were evaluated in the open field tests, anhedonia (splash test), and forced swimming. The animals were euthanized after the behavioral tests, and serum samples were collected. Myeloperoxidase (MPO) activity and interleukin-6 levels were analyzed. CMS induced an increase in depressive-like behaviors, and quetiapine significantly reduced these behaviors. MPO activity and IL-6 levels increased in the serum of animals submitted to CMS. Quetiapine significantly reduced MPO activity and IL-6 levels. These results corroborate other evidence, indicating that chronic stress is a relevant phenomenon in the etiology of depression and suggesting that quetiapine induces an antidepressant effect because it reduces oxidative and inflammatory mechanisms.
... Unfortunately, the brain is one of the most vulnerable organs to ROS damage, which may account for ROS involvement in depression. Inflammation could initiate oxidative stress [16]. Vice versa, oxidative stress also plays a critical role in the development of inflammation [17]. ...
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Objective: Traditional Chinese medicine formula Kai-Xin-San (KXS) is used to treat psychiatric disorders, especially in anxiety and depression. However, the precise molecular mechanism of action remains unclear. In this study, we investigated the antidepressant effect of KXS on inhibiting inflammation and oxidative stress in corticosterone (CORT)-induced depression. Methods: The therapeutic efficacy of KXS was evaluated in a mouse model of depression induced by CORT. Behavioral tests were conducted to evaluate the effectiveness of KXS in treating depressive-like behavior. Nissl staining and β-galactosidase staining were used to assess the effects of KXS on neuronal injury in depressed mice. To screen key potential therapeutic targets of KXS, transcriptome sequences and data analysis were performed. Then, Iba1 immunofluorescence staining and their relative inflammatory factors mRNA expression were conducted to assess the effect of KXS in inhibiting microglial inflammation activation response. Concurrently, the measurement of 4-Hydroxynonenal (4-HNE) immunohistochemistry staining, malondialdehyde (MDA), superoxide dismutase (SOD), and reactive oxygen species (ROS) were performed to evaluate the effect of KXS on anti-oxidative stress of depression in vivo. Besides, nitric oxide (NO), relative inflammatory factors mRNA expression, JC-1 staining, and ROS were used to evaluate the effect of KXS by lipopolysaccharide (LPS)/interferon-gamma (IFNγ)-induced BV2 cells. Results: KXS significantly relieved the depressive-like symptoms induced by CORT, as well as ameliorating the neuronal damage, which decreased microglia inflammatory activation response of IL-1β, IL-6, and tumor necrosis factor α (TNFα) in vivo or in vitro too. Transcriptome Sequencing and Data Analysis showed that KXS mainly by regulating immune system and transduction pathways decreased CORT-induced depression in mice. And showed that there were 19 Principal components and 10 genes in the main regulatory position with the strongest correlation in depression mice. Meanwhile, KXS effectively decreased senescence, the expression of 4-HNE, MDA content, and the production of ROS, while increasing the SOD activity in CORT-induced mice. Besides, KXS significantly reversed the mitochondrial membrane potential loss and excessive ROS production in LPS/IFNγ-induced BV2 cells. Conclusion: Our research suggested that KXS might protect depressed mice against CORT-induced neuronal injury by inhibiting microglia activation and oxidative stress.
... Multiple studies have demonstrated that the complex mechanism of depression is mainly related to monoamine neurotransmitters, inflammation and oxidative stress response, HPA axis dysfunction, synaptic plasticity, neurotrophic factor secretion disorder, circadian rhythm disorder and so on (Lindqvist et al. 2017;Erjavec et al. 2021). Studies have shown that the abnormalities of various serotonergic activity in serum, such as deranged 5-HT synthesis, release, reuptake and metabolism may initiate or trigger depression (Dell'osso et al. 2016). ...
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Context Lily bulb and Rehmannia decoction (LBRD), consisting of Lilium henryi Baker (Liliaceae) and Rehmannia glutinosa (Gaertn) DC (Plantaginaceae), is a specialized traditional Chinese medicine formula for treating depression. However, the underlying mechanisms, especially the relationship between LBRD efficacy and metabolomics, remains unclear. Objective This study was aimed to investigate the metabolic mechanism of LBRD in treating depression. Materials and methods Network pharmacology was conducted using SwissTargetPrediction, DisGeNET, DrugBank, Metascape, etc., to construct component-target-pathway networks. The depression-like model was induced by intraperitoneal injection with lipopolysaccharide (LPS) (0.3 mg/kg) for 14 consecutive days. After the administration of LBRD (90 g/kg) and fluoxetine (2 mg/kg) for 14 days, we assessed behaviour and the levels of neurotransmitter, inflammatory cytokine and circulating stress hormone. Prefrontal metabolites of rats were detected by using liquid chromatography–mass spectrometry metabolomics method. Results The results of network pharmacology showed that LBRD mainly acted on neurotransmitter and second messenger pathways. Compared to the model group, LBRD significantly ameliorated depressive phenotypes and increased the level of 5-HT (13.4%) and GABA (24.8%), as well as decreased IL-1β (30.7%), IL-6 (32.8%) and TNF-α (26.6%). Followed by LBRD treatment, the main metabolites in prefrontal tissue were contributed to retrograde endocannabinoid signalling, glycerophospholipid metabolism, glycosylphosphatidylinositol-anchor biosynthesis, autophagy signal pathway, etc. Discussion and conclusions LBRD were effective at increasing neurotransmitter, attenuating proinflammatory cytokine and regulating glycerophospholipid metabolism and glutamatergic synapse, thereby ameliorating depressive phenotypes. This research will offer reference for elucidating the metabolomic mechanism underlying novel antidepressant agents contained LBRD formula.
... Clinical studies indicated that oxidative stress markers and inflammatory factors were elevated in depressed patients, a phenomenon that had also been validated in rat models of depression Lindqvist et al. 2017). Diabetes mellitus and depression were closely related in terms of pathophysiological mechanisms, and glucose-lowering treatment increased monoamine neurotransmitter levels and improves depression-like behaviors in depressed rats Shivavedi et al. 2017). ...
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Cherry leaves (Prunus pseudocerasus Lindl. [Rosaceae]), a traditional Chinese herbal medicine, can regulate the factors closely related to depression including inflammatory cytokines, oxidative stress and blood glucose level. However, the antidepressant effects of cherry leaves and underlying neuromodulatory mechanisms remain relatively have not been elucidated explicitly. The present study investigated the antidepressant effects of cherry leaf decoction (CLD). The underlying neuromodulatory mechanism was explored by examining the glutamate (Glu)/γ-aminobutyric acid (GABA)-glutamine (Gln) metabolic loop. The chronic unpredictable mild stress (CUMS) rodent model was used in this study. The main flavonoids components of CLD were identified using high-performance liquid chromatography (HPLC). The antidepressant effects of CLD were assessed throughout behavioural tests including the bodyweight, sucrose preference test (SPT), forced swimming test (FPT) and tail suspension test (TST). Moreover, The baseline levels of serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were quantified. The expression of proteins integrally involved in the Glu/GABA-Gln metabolic loop were observed and quantified by Western blotting, reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. This study found that CLD ameliorated depressive-like behaviours induced by CUMS. The increase of serum ACTH and CORT baseline levels induced by CUMS was also reversed after CLD intervention. Furthermore, CUMS reduced the expression of GAD65, GAD67, GLT-1, GS and GABAA and increased NMDAR1 levels in the rat hippocampus, which was normalized by CLD treatment. The findings demonstrated that CLD could ameliorate the depression-like behaviours induced by CUMS, potentially through the inhibition of hypothalamic–pituitary–adrenal (HPA) axis hyperactivity and the regulation of Glu/GABA-Gln metabolic loop. Graphical abstract
... Oxidative stress is created by an imbalance between oxidation and antioxidation in the body, which consequently leads to oxidize tissue damage. A growing number of evidence suggest that increased oxidative stress plays a significant role in the etiology of MDD [33]. Based on our findings, the muscone group saw a significantly lower level of MDA and GSH-Px as well as a significantly higher level of SOD following muscone treatment. ...
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Major depressive disorder (MDD) is a common mental disorder with high morbidity. Stress negatively affects for MDD development, whereby transport of stress-induced inflammatory mediators to the central nervous system (CNS) is associated with the etiology of mood disorders. Muscone is a pharmacologically active ingredient isolated from musk, with anti-inflammatory and neuroprotective effects. We hypothesized that muscone may ameliorate depression-like behavior by regulating inflammatory responses. To test this hypothesis, we used the chronic restraint stress (CRS) depression model, and CRS mice were treated with muscone (10 mg/kg, i.g., respectively) for 14 days. The effects of the drug on depressive-like behaviors were evaluated via the open field test (OFT), novelty-suppressed feeding test (NSFT), tail suspension test (TST), and forced swimming test (FST). Quantitative reverse transcription-PCR (qRT-PCR) was utilized to assess levels of proinflammatory cytokines (IL-6, TNF-α, COX2, and IL-1) and the anti-inflammatory cytokines (IL-4 and IL-10). We also determined levels of oxidative stress factors (malondialdehyde, superoxide dismutase, and glutathione peroxidase), as well as doublecortin (DCX) expression by immunofluorescence. The results showed that depression-like behavior and inflammatory levels were improved after muscone treatment. Muscone also significantly improved neurogenesis in the CRS mouse hippocampus and decreased oxidative stress in both the central and peripheral nervous systems. In conclusion, this work is the first to demonstrate that muscone has an antidepressant effect using a CRS model. Oxidative stress, neurogenesis, and inflammatory pathways are key factors affected by the drug and may represent new therapeutic targets to treat MDD, in this impact. These results may represent a new therapeutic target for MDD.
... However, albiflorin is easily metabolized to benzoic acid by microorganisms in the gastrointestinal tract. After oral administration, the absolute intracerebral drug concentration is low and the absolute bioavailability is low [184,185]. Wang et al. prepared albiflorin-loaded alginate nanogels for nasal administration to avoid gastrointestinal degradation. Fluorescent labeling showed that albiflorin could quickly reach the brain for distribution after intranasal administration (≤30 min). ...
Article
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As a mental disease in modern society, depression shows an increasing occurrence, with low cure rate and high recurrence rate. It has become the most disabling disease in the world. At present, the treatment of depression is mainly based on drug therapy combined with psychological therapy, physical therapy, and other adjuvant therapy methods. Antidepressants are primarily administered peripherally (oral and intravenous) and have a slow onset of action. Antidepressant active ingredients, such as neuropeptides, natural active ingredients, and some chemical agents, are limited by factors such as the blood–brain barrier (BBB), first-pass metabolism, and extensive adverse effects caused by systemic administration. The potential anatomical link between the non-invasive nose–brain pathway and the lesion site of depression may provide a more attractive option for the delivery of antidepressant active ingredients. The purpose of this article is to describe the specific link between intranasal administration and depression, the challenges of intranasal administration, as well as studies of intranasal administration of antidepressant active ingredients.
... Further, meta-analysis data show that anti-inflammatory treatment can help alleviate depression, and antidepressants improve COVID-19 symptoms [244,245]. In addition, there are data that show elevated inflammation in individuals who respond poorly to SSRIs [246]. In relation to mast cell function, MAOIs can suppress mouse mast cell degranulation, and SSRIs can decrease IL-1β and TNF mRNA expression [247,248]. ...
Article
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The incidence of allergic disease has grown tremendously in the past three generations. While current treatments are effective for some, there is considerable unmet need. Mast cells are critical effectors of allergic inflammation. Their secreted mediators and the receptors for these mediators have long been the target of allergy therapy. Recent drugs have moved a step earlier in mast cell activation, blocking IgE, IL-4, and IL-13 interactions with their receptors. In this review, we summarize the latest therapies targeting mast cells as well as new drugs in clinical trials. In addition, we offer support for repurposing FDA-approved drugs to target mast cells in new ways. With a multitude of highly selective drugs available for cancer, autoimmunity, and metabolic disorders, drug repurposing offers optimism for the future of allergy therapy.
... Studies have confirmed increased oxidative stress and reduced antioxidant capacity in patients with depression (42). Under pathological conditions, oxidative stress may induce neurodegeneration via various pathways such as the induction of apoptosis, excitotoxicity, and axonal damage (43). The levels of reactive oxygen species (ROS), antioxidants, and antioxidant enzymes can reflect the body's redox homeostasis, and these markers have been extensively studied in psychiatric disorders. ...
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Background Depression is a common mental disorder and the diagnosis is still based on the descriptions of symptoms. Biomarkers can reveal disease characteristics for diagnosis, prognosis, and treatment. In recent years, many biomarkers relevant to the mechanisms of depression have been identified. This study uses bibliometric methods and visualization tools to analyse the literature on depression biomarkers and its hot topics, and research frontiers to provide references for future research. Methods Scientific publications related to depression biomarkers published between 2009 and 2022 were obtained from the Web of Science database. The BICOMB software was used to extract high-frequency keywords and to construct binary word-document and co-word matrices. gCLUTO was used for bicluster and visual analyses of high-frequency keywords. Further graphical visualizations were generated using R, CiteSpace and VOSviewer software. Results A total of 14,403 articles related to depression biomarkers were identified. The United States (34.81%) and China (15.68%), which together account for more than half of all publications, can be considered the research base for the field. Among institutions, the University of California, University of London, and Harvard University are among the top in terms of publication number. Three authors (Maes M, Penninx B.W.J.H., and Berk M) emerged as eminent researchers in the field. Finally, eight research hotspots for depression biomarkers were identified using reference co-citation analysis. Conclusion This study used bibliometric methods to characterize the body of literature and subject knowledge in the field of depression biomarker research. Among the core biomarkers of depression, functional magnetic resonance imaging (fMRI), cytokines, and oxidative stress are relatively well established; however, research on machine learning, metabolomics, and microRNAs holds potential for future development. We found “microRNAs” and “gut microbiota” to be the most recent burst terms in the study of depression biomarkers and the likely frontiers of future research.
... A growing literature has underscored the role of inflammation, particularly pro-inflammatory cytokines and acute phase proteins, in anxiety and PTSD [77,78]. Critically, inflammation has been shown to decrease among those who respond to pharmotherapy for depression [76]. Limited neurostimulation research in this area using animal models suggests that the effect of rTMS on depression is via effects on neuroinflammation [79]. ...
Article
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Purpose of Review Post-traumatic stress disorder (PTSD) is a prevalent problem. Despite current treatments, symptoms may persist, and neuromodulation therapies show great potential. A growing body of research suggests that transcranial magnetic stimulation (TMS) is effective as a standalone treatment for PTSD, with recent research demonstrating promising use when combined synergistically with behavioral treatments. In this review, we survey this literature including data suggesting mechanisms involved in anxiety and PTSD that may be targeted by neurostimulation. Recent Findings Evidence suggests the mechanism of action for TMS that contributes to behavioral change may be enhanced neural plasticity via increased functionality of prefrontal and subcortical/limbic structures and associated networks. Some research has demonstrated a behavioral change in PTSD and anxiety due to enhanced extinction learning or improved ability to think flexibly and reduce ruminative tendencies. Growing evidence suggests TMS may be best used as a therapeutic adjunct, at least acutely, for extinction-based exposure therapies in patients by accelerating therapy response. Summary While TMS has shown promise as a standalone intervention, augmentation with psychotherapy is one avenue of interest. Non-responders to current EBPs might particularly benefit from this sort of targeted approach, and it may shorten treatment length, which would help the successful completion of a course of therapy.
... It is seen that immune dysfunction is involved in the underlying mechanisms of many diseases such as cancer (Lindqvist et al., 2017), psychiatric (Miller et al., 2018), and neurodegenerative (Blesa et al., 2015) diseases, etc., especially cardiometabolic syndrome. ...
Conference Paper
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Turizm sektörü doğrudan, dolaylı ve uyarılmış etkileri dahil olmak üzere milyonlarca kişiye gelir yaratan bir sektördür. Gelişmekte olan ve az gelişmiş ülkelerin istihdam sorunlarının giderilmesinde önemli bir sektör olarak görülmektedir. Birden fazla sektör ile ilişkili ve emek yoğun bir sektör olması sebebiyle deturizm, kadınlara yeni istihdam alanı oluşturmakta, esnek çalışma olanakları ile işgücüne aktif katılımlarında önemli rol üstlenerek, kadınların ekonomik ve sosyal olarak güçlenmelerine katkı vermektedir. Sektörde çalışanların büyük çoğunluğu kadınlar ve gençlerdir. Oldukça karmaşık ve kırılgan bir yapısıyla turizmsektörü hem diğer sektörlerdeki gelişmelerden etkilenmekte hem de bu sektörlerdeki gelişmeleri etkilemektedir. Bu nedenle ortaya çıkan krizlerden en çok etkilenen sektörlerin başında gelmektedir. Covid-19 salgının, tüm dünyayı sarsan “1929 Ekonomik Buhran’ından” daha etkili olduğu düşünülmüştür. Salgın dünya çapında işgücü piyasasında ciddi bozulmalara neden olmuştur. Hükümetler, işçi ve işveren örgütleri salgına bağlı ortaya çıkan krizle mücadele etmek için, işleri ve gelirleri korumak için kapsam ve cömertlik açısından farklılık göstermekle birlikte birçok acil önlemler almışlardır. Alınan tedbirlere rağmen tüm ülkelerde istihdamda ciddi bozulmalar yaşamıştır. Tüm dünyada 2020 yılında 2019'a göre toplam istihdam, çalışanların işsiz kalması veya işten ayrılması sonucu 114 milyon azalmıştır. Kriz kaynaklı küresel istihdam açığının 2021'de 75 milyon ve 2022'de 23 milyon olacağı tahmin edilmektedir. Salgın öncesi 2019 yılında tüm dünyada toplam turizm istihdamının %54,2’sini kadın işgücü oluşturmuştur. Kadınların turizm sektöründe istihdam oranı 2019 yılında %31,9’dur. Salgın sonrası işgücü piyasasının dezavantajlı gruplarından kadınlarda istihdam kayıpları daha büyük olmuştur. Bu kayıplar halk sağlığı kısıtlamalarından doğrudan etkilenen turizm ve konaklama gibi sektörlerde daha şiddetli olmuştur. Getirilen kısıtlamalar nedeniyle turistik seyahatler 2020 yılında bir önceki yıla göre %74 gerilemiştir. Bu çalışmanın temel amacı 2019 yılında ortaya çıkan Covid-19 salgınının turizm sektöründeki kadın istihdamı oranına etkisini Türkiye ölçeğinde değerlendirmektir. Çalışmada kullanılan veriler Türkiye İstatistik Kurumu ile Kültür ve Turizm Bakanlığı verilerinden elde edilmiştir.
... The current study revealed higher baseline CRP and IL-6 level predicting better treatment response to SSRIs. This is in line with the study conducted by Lindqvist et al. (2017) who found that IL-6 decreased significantly in responders during the course of 8 week SSRIs treatment in MDD. This is also in line with the study conducted by Yoshimura (Yoshimura et al., 2013) who found baseline level of IL-6 was higher in the responder group than in the non-responder group to SNRIs in MDD. ...
Conference Paper
Research into psycho neuroimmunology has led to substantial advances in our understanding of the reciprocal interactions between the central nervous system and the immune system in neuropsychiatric disorders. To date, inflammation has been implicated in the pathogenesis of depression and anxiety.
... [3][4][5][6] Continued exposure to stress increases oxidative stress and produced neuroinflammation in brain of humans; which may lead to depression. 7 Chronic unpredictable mild stress (CUMS) is commonly employed model to induce depression in laboratory animals. 8 CUMS leads to anhedonia, increased anxiety-like behavior, and hyperactivity of HPA axis in rodents. ...
... Meanwhile, ROS can also activate the MAPK/ NF-κB/NLRP3 inflammation pathway [47]. Inflammation and oxidative stress are related to the pathogenesis of depression [48]. Consistent with this, our experiment observed that corticosterone could induce inflammation in PC12 cells, and SSA and AF could reverse this phenomenon by inhibiting the expression of p-p38, p-ERK, p-JNK, NF-κB, and NLRP3. ...
Article
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Background Saikosaponin A (SSA) and albiflorin (AF) are major bioactive compounds of Radix Bupleuri and Radix Paeoniae alba respectively, which possess antidepressant effects in pharmacological experiments. However, whether SSA and AF have synergistic neuroprotective effects and the synergistic mechanisms are still unknown. Methods and Results The corticosterone-induced PC12 cells apoptosis model was employed to assess the neuroprotective effects of SSA and AF, and the synergistic effect was analyzed using three mathematical models. Meanwhile, cell metabolomics was used to detect the effects on metabolite regulation of SSA and AF. Furthermore, the key metabolites, metabolic enzymes, and cellular markers were verified by ELISA and Western blotting. The results showed that the combination of SSA and AF has a synergistic neuroprotective effect. Besides, the combination could regulate more metabolites than a single agent and possessed a stronger adjustment effect on metabolites. The TCA cycle was regulated by SSA and AF via improving mitochondrial function. The purine metabolism was regulated by SSA via inhibition xanthine oxidase activity and the glutamate metabolism was regulated by AF via inhibition glutaminase activity. Moreover, the oxidative stress induced by the purine metabolism was attenuated by SSA via a reduction in the ROS level. Additionally, the inflammation induced by the oxidative stress was attenuated by the SSA and AF via inhibition of the NLRP3 protein expression. Conclusions This study for the first time demonstrated the synergistic neuroprotective effects of SSA and AF, and the synergistic mechanisms were involved in metabolic disorders regulation and neuroinflammation inhibition.
... OS is linked to the pathophysiological mechanisms underlying CAD [13][14][15][16][17][18]. Higher levels of lipid peroxidation markers, specifically 8-ISO, are found in those with cardiovascular conditions [19,20] and in healthy individuals with cardiovascular risk factors, such as smoking, hypercholesterolemia, obesity, and diabetes [21]. ...
Article
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Background: (1) Sleep disorders are prevalent in coronary artery disease (CAD) patients and predict cardiac events and prognosis. While increased oxidative stress (OS) has been associated with sleep disorders, less is known about its relationship with sleep quality. Similarly, little is known of how this relationship might change with exercise, which can improve sleep quality. Factors of sleep quality, such as sleep duration and disturbances, are also important as they predict cardiovascular diseases better than a global score alone. This study investigated whether OS was associated with self-rated sleep quality and its factors before and after completing a 24-week exercise intervention. (2) Methods: CAD patients undergoing an exercise program were recruited. OS was measured at baseline by the concentrations of early- (lipid hydroperoxides, LPH) and late-stage (8-isoprostane, 8-ISO) lipid peroxidation products and their ratio. Sleep quality was measured by the self-reported Pittsburgh Sleep Quality Index (PSQI) instrument at baseline and termination. Three sleep factors-perceived sleep quality, sleep efficiency, and daily disturbances-were derived from the PSQI. (3) Results: Among CAD patients (n = 113, 85.0% male, age = 63.7 ± 6.4 years, global PSQI = 5.8 ± 4.0), those with poor sleep (PSQI ≥ 5) had higher baseline 8-ISO levels (F(1, 111) = 6.212, p = 0.014, ηp2 = 0.053) compared to those with normal sleep. Concentrations of LPH (F(1, 105) = 0.569, p = 0.453, ηp2 = 0.005) and 8-ISO/LPH ratios (F(1, 105) = 2.173, p = 0.143, ηp2 = 0.020) did not differ between those with poor sleep and normal sleep. Among factors, perceived sleep quality was associated with 8-ISO and 8-ISO/LPH, and daily disturbances were associated with 8-ISO. (4) Conclusions: A marker of late-stage lipid peroxidation is elevated in CAD patients with poor sleep and associated with daily disturbances, but not with other factors or with sleep quality and its factors after exercise intervention.
... One study using Raman imaging indicates that animal models of TBI are associated with alterations to lipid concentrations in the brain over time, particularly elevated CHOL (Surmacki et al., 2017). Elevated reactive oxygen species (ROS) production can lead to oxidative stress, a characteristic feature of a numerous diseases associated with elevated allostatic load including TBI (Cornelius et al., 2013), major depressive disorder (MDD) (Lindqvist et al., 2017), metabolic syndrome (Furukawa et al., 2004), diabetes (Leslie and Vartak, 2020), hypertension (Guidi et al., 2020), Lupus (Nuttall et al., 2003), and PTSD (Miller et al., 2018), among other associated conditions. Each of these conditions is also associated with alterations in peripheral lipid homeostasis, particularly increased LDL CHOL and Triglycerides (TG) and reductions of many phospholipid species, like phosphatidylcholine (PC) (Demirkan et al., 2013;Hu et al., 2017). ...
Article
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Oxidative and lipid homeostasis are altered by stress and trauma and post-traumatic stress disorder (PTSD) is associated with alterations to lipid species in plasma. Stress-induced alterations to lipid oxidative and homeostasis may exacerbate PTSD pathology, but few preclinical investigations of stress-induced lipidomic changes in the brain exist. Currently available techniques for the quantification of lipid species in biological samples require tissue extraction and are limited in their ability to retrieve spatial information. Raman imaging can overcome this limitation through the quantification of lipid species in situ in minimally processed tissue slices. Here, we utilized a predator exposure and psychosocial stress (PE/PSS) model of traumatic stress to standardize Raman imaging of lipid species in the hippocampus using LC-MS based lipidomics and these data were confirmed with qRT-PCR measures of mRNA expression of relevant enzymes and transporters. Electron Paramagnetic Resonance Spectroscopy (EPR) was used to measure free radical production and an MDA assay to measure oxidized polyunsaturated fatty acids. We observed that PE/PSS is associated with increased cholesterol, altered lipid concentrations, increased free radical production and reduced oxidized polyunsaturated fats (PUFAs) in the hippocampus (HPC), indicating shifts in lipid and oxidative homeostasis in the HPC after traumatic stress.
... In humans, the expression of IDO and select cytokines (e.g., proinflammatory interleukin-6), which are generally increased in MDD patients, is attenuated with eight-weeks of SSRI treatment. [92,93] In patients with a first episode generalized anxiety disorder, 12 weeks of treatment with SSRIs similarly decreases serum pro-inflammatory cytokine levels. [94] Depression during peripartum is similarly proinflammatory, systemically and in the brain. ...
Article
Serotonin modulates vascular, immune, and neurophysiology and is dysregulated in preeclampsia. Despite biological plausibility that selective serotonin reuptake inhibitors (SSRIs) prevent preeclampsia pathophysiology, observational studies have indicated increased risk and providers may be hesitant. The objective of this meta-analysis and quality assessment was to evaluate the evidence linking SSRI use in pregnancy to preeclampsia/gestational hypertension. PubMed was searched through June 5, 2020 manually and using combinations of terms: “preeclampsia”, “serotonin”, and “SSRI”. This review followed MOOSE guidelines. Inclusion criteria were: 1) Observational cohort or population study, 2) exposure defined as SSRI use during pregnancy, 3) cases defined as preeclampsia or gestational hypertension, and 4) human participants. Studies were selected that addressed the hypothesis that gestational SSRI use modulates preeclampsia and/or gestational hypertension risk. Review Manager Web was used to synthesize study findings. Articles were read and scored (Newcastle-Ottawa Quality Assessment Scale) for quality by two independent reviewers. Publication bias was assessed using a funnel plot and the Egger test. Of 179 screened studies, nine were included. The pooled risk ratio (random effects model) was 1.43 (95% CI: 1.15-1.78, P<0.001; range 0.96-4.86). Two studies were rated as moderate quality (both with total score of 6); others were high quality. Heterogeneity was high (I2=88%) and funnel asymmetry was significant (p<0.00001). Despite evidence for increased preeclampsia risk with SSRIs, shared risk factors and other variables are poorly controlled. Depression treatment should not be withheld due to perceived gestational hypertension risk. Mechanistic evidence for serotonin modulation in preeclampsia demonstrates a need for future research.
... 64 Here, we have targeted the main pathological hallmarks of neurodegenerative diseases, oxidative stress, and neuroinflammation. 65 Consistent human data reiterated the generation of free radicals with ethanol consumption, 43,44 and such amassing precipitated cognitive impairment due to narrow anti-oxidants in the brain. 66 Ethanol has a high propensity for ROS generation and this is further validated by an elevated level of LPO along with a reduced glutathione level and which is consistent with previous findings. ...
Article
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Introduction: Several studies revealed that alcohol utilization impairs memory in adults; however, the underlying mechanism is still unclear. The production of inflammatory markers and reactive oxygen species (ROS) plays a major role in neurodegeneration, which leads to memory impairment. Therefore, targeting neuroinflammation and oxidative distress could be a useful strategy for abrogating the hallmarks of ethanol-induced neurodegeneration. Moreover, several studies have demonstrated multiple biological activities of thiazolidine derivatives including neuroprotection. Methods: In the current study, we synthesized ten (10) new thiazolidine-4-carboxylic acid derivatives (P1-P10), characterized their synthetic properties using proton nuclear magnetic resonance (1H-NMR) and carbon-13 NMR, and further investigated the neuroprotective potential of these compounds in an ethanol-induced neuroinflammation model. Results: Our results suggested altered levels of antioxidant enzymes associated with an elevated level of tumor necrosis factor-alpha (TNF-α), nuclear factor-κB (p-NF-κB), pyrin domain-containing protein 3 (NLRP3), and cyclooxygenase-2 (COX-2) in ethanol-treated animals. Ethanol treatment also led to memory impairment in rats, as assessed by behavioral tests. To further support our notion, we performed molecular docking studies, and all synthetic compounds exhibited a good binding affinity with a fair bond formation with selected targets (NF-κB, TLR4, NLRP3, and COX-2). Discussion: Overall, our results revealed that these derivatives may be beneficial in reducing neuroinflammation by acting on different stages of inflammation. Moreover, P8 and P9 treatment attenuated the neuroinflammation, oxidative stress, and memory impairment caused by ethanol.
... In schizophrenia, there is either reduction in primary antioxidants levels including superoxide dismutase (SOD), CAT and glutathione peroxidase (GPx), or a decrease in the secondary antioxidants such as glutathione, vitamins B6 (pyridoxine), B9 (folate), B12 (cobalamin), C, D, and E (Schweizer et al., 2008;. The deficiency in vitamins B6, B9 , and B12 leads to enhanced homocysteine levels resulting in decreased glutathione and vitamins C and E levels mediating oxidative insult leading to neurotoxic effects (Lindqvist et al., 2017;Mikkelsen et al., 2017). Reduced vitamin C levels induce serotonin reduction and dopamine induction but on the other hand, levels of trace elements including copper and zinc have opposite effects resulting in hyperprolactinemia mediated depression (Pohl et al., 2011). ...
... In the present study, MS, isoproterenol, and MS combined with isoproterenol caused oxidative stress, which was identified by reduced GSH levels and SOD activity in the brain and heart tissue. In addition to GSH, SOD enzymes are also involved as anti-oxidants and work via depletion of free radicals (O 2 −− and OH − ) and conversion of superoxide radicals into H 2 O 2 and oxygen (Ighodaro and Akinloye 2018;Lindqvist et al. 2017). Researchers reported that the level of SOD activity decreases in depressive disorders and MI (Metias et al. 2016;Shen et al. 2021). ...
Article
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Depression and coronary heart diseases are the common comorbid disorder affecting humans globally. The present study evaluated the effectiveness of rosmarinic acid (RA) against myocardial infarction (MI) in comorbid depression induced by maternal separation in rats. Maternal stress is one of the childhood crises that may be a potential risk factor for coronary heart disease in later part of life. As per protocol, 70-80% of pups were separated daily for 3 h between postnatal day 1 (PND1) and postnatal day 21 (PND21). Forced-swim test, sucrose preference test, and electrocardiography were performed during the experiment. Body weight was measured on PND0, PND35, and PND55. Orally rosmarinic acid (25 mg/kg and 50 mg/kg) and fluoxetine (10 mg/kg) was done from PND35 to PND55. On PND53 and PND54, isoproterenol (100 mg/kg, subcutaneously) was administered to induce myocardial infarction. On PND55, blood was collected and animals sacrificed, and plasma corticosterone, brain-derived neurotrophic factor, cardiac biomarkers, interleukine-10, and anti-oxidant parameters were measured. Rosmarinic acid and fluoxetine ameliorated the maternal separation-induced increase in immobility period, anhedonia, body weight, ST elevation, corticosterone, creatine kinase-MB (CK-MB), and lactate dehydrogenase (LDH). At the same time, both drugs elevated the tissue levels of BDNF, IL-10, glutathione, and superoxide dismutase activity. This study provides the first experimental evidence that maternal stress is an independent risk factor of cardiac abnormalities in rats. Moreover, maternal stress synergistically increases the severity of cardiac abnormalities induced by isoproterenol. Interestingly, fluoxetine and rosmarinic acid effectively ameliorated behavioral anomalies and myocardial infarction in maternally separated rats. Schematic representation of possible molecular mechanism of action of rosmarinic acid against MS-induced myocardial infarction. RA, rosmarinic acid; MS, maternal separation; PND, postnatal days; ISO, isoproterenol; BDNF, brain-derived neurotrophic factor; GSH, glutathione; SOD, superoxide dismutase; IL-10, interleukin-10; MI, myocardial infarction.
... It is clear that a number of additional systems or pathways are also thought to play a role in the pathophysiology of depression, such as oxidant-antioxidant imbalance, 135 mitochondrial dysfunction, 136,137 and circadian rhythm-related genes; 138 especially their critical interactions (e.g., interactions between the HPA and mitochondrial metabolism 139,140 ), and the reciprocal interaction between oxidative stress and inflammation. 135 We still do not fully understand the causes of depressive disorders in spite of the abundance of research on the disease and numerous hypotheses nowadays. Different researchers have performed a variety of tasks related to modality from linked and complementary perspectives, which is helpful to further our understanding of depression. ...
Article
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Major depressive disorder (MDD) is a highly prevalent and disabling disorder. Despite the many hypotheses proposed to understand the molecular pathophysiology of depression, it is still unclear. Current treatments for depression are inadequate for many individuals, because of limited effectiveness, delayed efficacy (usually two weeks), and side effects. Consequently, novel drugs with increased speed of action and effectiveness are required. Ketamine has shown to have rapid, reliable, and long‐lasting antidepressant effects in treatment‐resistant MDD patients and represent a breakthrough therapy for patients with MDD; however, concerns regarding its efficacy, potential misuse, and side effects remain. In this review, we aimed to summarize molecular mechanisms and pharmacological treatments for depression. We focused on the fast antidepressant treatment and clarified the safety, tolerability, and efficacy of ketamine and its metabolites for the MDD treatment, along with a review of the potential pharmacological mechanisms, research challenges, and future clinical prospects. This review aimed to clarify the safety, tolerability, and efficacy of ketamine and its metabolites for the treatment of major depressive disorder (MDD), along with a review of potential pharmacological mechanisms, research challenges, and future clinical prospects. Many novel hubba proteins and MDD‐risk proteins were found, indicating that the current pharmacological mechanisms were just the tip of the iceberg.
... [43] Lindqvist et al. analyzed different parameters of oxidative stress and found the differences between the levels of parameters such as TNF-α, IL-6, 8-iso-PGF2α, and 8-OHdG in the individuals having major depression and the healthy ones to be statistically significant. [44] Furthermore, the levels of markers of oxidative stress (e.g., 8-iso-PGF 2 α, 8-OHdG) and inflammation markers (e.g., IL-6) were influenced by antidepressant treatment. [5] Raza et al. described the role of DNA damage in various psychiatric disorders such as major depressive disorders, schizophrenia, and bipolar disorders, but none of the study assessed the levels of comet parameters in the major depression patients before starting and after completion of treatment with fluoxetine. ...
... [43] Lindqvist et al. analyzed different parameters of oxidative stress and found the differences between the levels of parameters such as TNF-α, IL-6, 8-iso-PGF2α, and 8-OHdG in the individuals having major depression and the healthy ones to be statistically significant. [44] Furthermore, the levels of markers of oxidative stress (e.g., 8-iso-PGF 2 α, 8-OHdG) and inflammation markers (e.g., IL-6) were influenced by antidepressant treatment. [5] Raza et al. described the role of DNA damage in various psychiatric disorders such as major depressive disorders, schizophrenia, and bipolar disorders, but none of the study assessed the levels of comet parameters in the major depression patients before starting and after completion of treatment with fluoxetine. ...
Article
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Background and aims Previous studies showed that inflammation affects depressive symptoms. Dietary fiber may be associated with inflammation and depressive symptoms. We aimed to investigate the relationship between inflammation and depressive symptoms at different levels of dietary fiber intake and to explore whether dietary fiber affects depression through inflammation. Methods A total of 8,430 National Health and Nutrition Examination Survey (NHANES) samples were collected between 2015 and 2018. Factor analysis was used to determine dietary patterns. Linear regression and logistic regression analysis were used to explore the relationship between nutrients, inflammation, and depressive symptoms, and the mediation analysis was conducted using the bootstrap method. Results Factor 3 (dietary fiber and vitamins) was inversely associated with depressive symptoms and inflammation. The upper quartile scores of the dietary inflammatory index (DII) and C-reactive protein (CRP) were associated with depressive symptoms compared with controls (DII: OR = 1.851, 95% CI: 1.267–2.705; CRP: OR = 1.737, 95% CI: 1.136–2.656). The DII score and CRP were associated with depressive symptoms in the group with low dietary fiber intake (DII: OR = 2.736, 95% CI: 1.628–4.598; CRP: OR = 2.092, 95% CI: 1.196–3.658) but not in the high dietary fiber intake group. Mediating analysis showed that CRP partially mediated the effect of dietary fiber intake on depressive symptoms (β indirect = −0.0025, 95% CI: −0.0038 to −0.0013), and the mediated proportion was 10.5%. Conclusion In this study, we found that DII scores and CRP were not associated with depressive symptoms in participants with high dietary fiber intake, and inflammation partially mediates the effect of dietary fiber on depressive symptoms.
Article
Astrocyte-derived extracellular vesicles (ADEs) allow the in vivo probing of the inflammatory status of astrocytes practical. Serum sample and ADEs were used to test the inflammatory hypothesis in 70 patients with major depressive disorder (MDD) and 70 matched healthy controls (HCs). In serum, tumor necrosis factor α (TNF-α) and interleukin (IL)-17A were significantly increased, where as IL-12p70 was significantly reduced in the MDD patients compared with HCs. In ADEs, all inflammatory markers (Interferon-γ, IL-12p70, IL-1β, IL-2, IL-4, IL-6, TNF-α, and IL-17A) except IL-10 were significantly increased in the MDD patients, the Hedge's g values of elevated inflammatory markers varied from 0.48-1.07. However, there were no differences of all inflammatory markers whether in serum or ADEs between MDD-drug free and medicated subgroups. The association of inflammatory biomarkers between ADEs and serum did not reach statistically significance after multi-comparison correction neither in the HCs nor MDD patients. The spearman coefficients between inflammatory factors and clinical characteristics in the MDD patients, such as onset age, disease course, current episode duration, and severity of depression, were nonsignificant after multi-comparison correction. In the receiver operating characteristic curves analysis, the corrected partial area under the curve (pAUC) of each inflammatory markers in ADEs ranged from 0.522 to 0.696, and the combination of these inflammatory factors achieved a high pAUC (>0.9). Our findings support the inflammatory glial hypothesis of depression, and suggests that in human ADEs could be a useful tool to probe the in vivo astrocyte status.
Article
Background Growing evidence indicates that depression is more common in people who partake in a pro-inflammatory diet. The objective of our study was to assess the association between the Dietary Inflammatory Index (DII) and depression through a cross-sectional study of the National Health and Nutrition Examination Survey from 2007 to 2018. Methods We used weighted multivariable logistic regression models with subgroup analysis to explore the relationship between DII and depression. Generalized additive models were used to test whether there was a nonlinear association. Then, we constructed a two-piece linear regression model and performed a recursive algorithm to calculate the inflection point. Results The study enrolled a total of 30,627 individuals from the United States. In the regression model with full confounding variables adjusted, the OR (95 % CI) for the association between DII and depression was 1.05 (1.04, 1.06). A J-shaped association was found between DII and depression, with a turning point of 2.74. After the turning point, the OR (95 % CI) was 1.60 (1.51, 1.69). Only the interaction in the cardiovascular disease (CVD) analysis was statistically significant. Conclusion Our study highlighted a J-shaped association between DII and depression in a nationally representative sample of adults from the United States.
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Background Mental health disorders in systemic lupus erythematosus (SLE) are gradually getting recognized; however, less is known regarding the actual structure and compositional alterations in gut microbiome and metabolism and the mechanisms of how they affect depression development in SLE patients. Methods Twenty-one SLE patients with depression (SLE-d), 17 SLE patients without depression (SLE-nd), and 32 healthy controls (HC) were included in this study. Fecal samples were collected for 16S rRNA gene sequencing and ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) based metabolomics. Results The structure of gut microbiome in the SLE-d group changed compared with that in the other two groups. The microbiome composition of SLE-d group showed decreased species richness indices, characterized by low ACE and Chao1 indices, a decrease in the ratio of phylum Firmicutes to Bacteroidetes, genus Faecalibacterium and Roseburia . A downregulation of the metabolite fexofenadine involved in bile secretion was positively correlated with the genus Faecalibacterium , Subdoligranulum and Agathobacter . Compared with the SLE-nd group, the SLE-d group had elevated serum levels of IL-2 and IL-6 and decreased BDNF. Interestingly, abundance of the genus Faecalibacterium and Roseburia was negatively correlated with IL-6, abundance of the genus Roseburia was negatively correlated with IL-2, and abundance of the genus Bacteroides was positively correlated with IL-2. Conclusion This study identified specific fecal microbes and their metabolites that may participate in the development of SLE-d. Our findings provide a new perspective for improving depression in SLE patients by regulating the gut–brain axis.
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Background Major depressive disorder (MDD) is a life-threatening, debilitating mental health condition. An important factor in the development of depression is endoplasmic reticulum stress (ERS). However, their roles in MDD have not yet been established. The goal of this study was to examine ERS and its underlying molecular mechanisms in MDD. Methods We used data from two microarray datasets (GSE98793 and GSE39653) and the GeneCards database to examine the reticulum stress-related differentially expressed genes (ERSR-DEGs) associated with MDD. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and Gene Set Variation Analysis (GSVA) were used to further investigate the function and mechanism of ERS in MDD. Moreover, we constructed protein-protein interaction (PPI) networks to identify hub genes as well as the regulatory network of microRNAs (miRNAs), transcription factors (TFs), and potential drugs related to ERSR-DEGs. CIBERSORT was then used to evaluate the immune activity of MDD samples and conduct a correlation analysis between the hub genes and immune cells. Results In total, 37 ERSR-DEGs and five hub genes were identified (NCF1, MAPK14, CASP1, CYBA, and TNF). Functional enrichment analysis revealed that ERSR-DEGs were predominantly enriched in inflammation-and immunity-related pathways, such as tumor necrosis factor signaling, NF-κB signaling, and Toll-like receptor signaling pathways. Additionally, 179 miRNAs, 25 TFs, and 15 potential drugs were tested for their interactions with the ERSR-DEGs. CIBERSORT found high proportions of Tregs, monocytes, and macrophages M0 in the MDD samples. Among these, hub genes showed a significant correlation with immune cell infiltration in patients with MDD. Conclusions NCF1, MAPK14, CASP1, CYBA, and TNF are potential ERS-related biomarkers for the diagnosis of MDD. Our research has revealed a significant correlation between immune cells and ERS-related genes with MDD. Not only did our study contribute to a better understanding of the regulatory mechanisms of ERS in underlying MDD pathology, but it also established a paradigm for future studies on ERS.
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Major depressive disorder (MDD) is the most prevalent mood disorder globally. Most antidepressants available for the treatment of MDD increase the concentration of monoamines in the synaptic cleft. However, such drugs have a high latency time to obtain benefits. Thus, new antidepressants with fast action and robust efficacy are very important. This study evaluated the effects of escitalopram, ketamine, and probiotic Bifidobacterium infantis in rats submitted to the maternal deprivation (MD). MD rats received saline, escitalopram, ketamine, or probiotic for 10, 30, or 50 days, depending on the postnatal day (PND):21, 41, and 61. Following behavior, this study examined the integrity of the blood-brain barrier (BBB) and oxidative stress markers. MD induced depressive-like behavior in females with PND21 and males with PND61. All treatments reversed depressive-like behavior in females and escitalopram and ketamine in males. MD induced an increase in the permeability of the BBB, an imbalance between oxidative stress and antioxidant defenses. Treatments regulated the oxidative damage and the integrity of the BBB induced by MD. The treatment with escitalopram, ketamine, or probiotics may prevent behavioral and neurochemical changes associated with MDD, depending on the developmental period and gender.
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Depression and anxiety are the most prevalent neuropsychiatric disorders that have emerged as global health concerns. Anxiolytic and antidepressant drugs, such as benzodiazepines, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, and tricyclics, are the first line used in treating anxiety and depression. Although these drugs lack efficacy and have a delayed response time and numerous side effects, their widespread abuse and market continue to grow. Over time, traditional practices using natural and phytochemicals as alternative therapies to chemical drugs have emerged to treat many pathological conditions, including anxiety and depression. Recent preclinical studies have demonstrated that the phenolic compound, rosmarinic acid, is effective against several neuropsychiatric disorders including anxiety and depression. In addition, rosmarinic acid showed various pharmacological effects, such as cardioprotective, hepatoprotective, lung protective, antioxidant, anti-inflammatory, and neuroprotective effects. However, the potentialities of the use of rosmarinic acid in the treatment of nervous system-related disorders, such as anxiety and depression, are less or not yet reviewed. Therefore, the purpose of this review was to present several preclinical and clinical studies, when available, from different databases investigating the effects of rosmarinic acid on anxiety and depression. These studies showed that rosmarinic acid produces advantageous effects on anxiety and depression through its powerful antioxidant and anti-inflammatory properties. This review will examine and discuss the possibilities that anxiolytic and anti-depressive effects of rosmarinic acid could be associated with its potent antioxidant and anti-inflammatory activities.
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Background Underlying inflammation is associated with an increased risk of depression in older adults. In this study, we examined the role of inflammatory biomarkers in antidepressant response in depressed older adults undergoing adjunct Tai Chi Chih (TCC) or Health education interventions. Methods Older adults aged 60 years and above with a diagnosis of major depression were randomized to 12 weeks of TCC versus Health and Wellness Education (HEW) as an adjunct therapy to their stable antidepressant treatment regimen. A panel of 19 cytokine/chemokines was measured at baseline and 12 weeks. Five factors were derived using factor analysis. General linear models were estimated to examine the change in factor scores and the association of these changes on depression remission rates, controlling for age, sex, and body mass index. Results Of the 170 randomized participants (TCC: n= 85 and HEW: n= 85), 55 TCC and 58 HEW completed the 3-month assessment. The groups did not differ at baseline in any measure. At follow-up, neither the changes in cytokine/chemokines scores nor the depression remission rate differed significantly between TCC and HEW. However, remitters and non-remitters differed significantly in changes in a factor composed of growth-regulated oncogene protein-alpha (GRO-alpha), epidermal growth factor (EGF), and soluble CD40 ligand (sCD40L). GRO-alpha and EGF levels (in both groups) were significantly increased in remitters compared to non-remitters. Conclusion Changes in certain cytokines/chemokines may accompany improvement in depressive symptoms in older adults. Future studies will need to explore the role of these molecules in remission of late-life depression.
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Depression is a debilitating psychiatric disorder impacting an individual’s quality of life. It is the most prevalent mental illness across all age categories, incurring huge socio-economic impacts. Most depression treatments currently focus on the elevation of neurotransmitters according to the monoamine hypothesis. Conventional treatments include tricyclic antidepressants (TCAs), norepinephrine–dopamine reuptake inhibitors (NDRIs), monoamine oxidase inhibitors (MAOIs), and serotonin reuptake inhibitors (SSRIs). Despite numerous pharmacological strategies utilising conventional drugs, the discovery of alternative medicines from natural products is a must for safer and beneficial brain supplement. About 30% of patients have been reported to show resistance to drug treatments coupled with functional impairment, poor quality of life, and suicidal ideation with a high relapse rate. Hence, there is an urgency for novel discoveries of safer and highly effective depression treatments. Stingless bee honey (SBH) has been proven to contain a high level of antioxidants compared to other types of honey. This is a comprehensive review of the potential use of SBH as a new candidate for antidepressants from the perspective of the monoamine, inflammatory and neurotrophin hypotheses.
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Importance: Nucleic acid damage from oxidative stress (NA-OXS) may be a molecular mechanism driving the severely increased morbidity and mortality from somatic causes in adults with psychiatric disorders. Objective: To systematically retrieve and analyze data on NA-OXS across the psychiatric disorder diagnostic spectrum. Data sources: The PubMed, Embase, and PsycINFO databases were searched from inception to November 16, 2021. A hand search of reference lists of relevant articles was also performed. Study selection: Key study inclusion criteria in this meta-analysis were as follows: adult human study population, measurement of any marker of DNA or RNA damage from oxidative stress, and either a (1) cross-sectional design comparing patients with psychiatric disorders (any diagnosis) with a control group or (2) prospective intervention. Two authors screened the studies, and 2 senior authors read the relevant articles in full and assessed them for eligibility. Data extraction and synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Two authors performed data extraction independently, and a senior coauthor was consulted in cases of disagreement. Data were synthesized with random-effects and multilevel meta-analyses. Main outcomes and measures: The predefined hypothesis was that individuals with psychiatric disorders have increased NA-OXS levels. The main outcome was the standardized mean differences (SMDs) among patients and controls in nucleic acid oxidation markers compared across diagnostic groups. Analyses were divided into combinations of biological matrices and nucleic acids. Results: Eighty-two studies fulfilled the inclusion criteria, comprising 205 patient vs control group comparisons and a total of 10 151 patient and 10 532 control observations. Overall, the data showed that patients with psychiatric disorders had higher NA-OXS levels vs controls across matrices and molecules. Pooled effect sizes ranged from moderate for urinary DNA markers (SMD = 0.44 [95% CI, 0.20-0.68]; P < .001) to very large for blood cell DNA markers (SMD = 1.12 [95% CI, 0.69-1.55; P < .001). Higher NA-OXS levels were observed among patients with dementias followed by psychotic and bipolar disorders. Sensitivity analyses excluding low-quality studies did not materially alter the results. Intervention studies were few and too heterogenous for meaningful meta-analysis. Conclusions and relevance: The results of this meta-analysis suggest that there is an association with increased NA-OXS levels in individuals across the psychiatric disorder diagnostic spectrum. NA-OXS may play a role in the somatic morbidity and mortality observed among individuals with psychiatric disorders.
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This study investigated the protective effect of quercetin against cyclophosphamide‐induced immunosuppressive indoleamine 2,3‐dioxygenase (IDO) via the mechanism of oxidative‐inflammatory stress and behavioral indices. Cyclophosphamide (CYP) was administered to male Wister rats at a dose of 100 mg/kg with or without quercetin 50 mg/kg every other day for 7 days. Experimental techniques including western blotting, immunohistochemistry analysis, and inflammatory and oxidative stress marker assays were carried out. We also conducted behavioral analyses such as open field, tail suspension, and Y‐maze tests for cognitive assessment. The results indicated that quercetin attenuated oxidative‐inflammatory stress induced by CYP in the hippocampus and cerebral cortex of male Wister rats by augmenting the activities of antioxidant enzymes and suppressing lipid peroxidation as well as inflammatory mediators such as interleukin‐6 and interferon‐γ. Concomitantly, quercetin partially prevented the alteration in brain tissue histological architecture and mitigated the activities of IDO/tryptophan 2,3‐dioxygenase (TDO) and protein expression of IDO1. This was corroborated by the IDO‐quercetin model obtained in silico, revealing a favorable inhibitory interaction between quercetin and the enzyme. Finally, the results of behavioral tests suggested that quercetin significantly prevented the depressive‐like posture of the CYP‐treated rats. Our study for the first time revealed that quercetin ameliorates the effect of CYP‐instigated IDO/TDO activities in the cerebral cortex and hippocampus via restoration of antioxidant enzymes and preventing oxidative‐inflammatory stress.
Article
Background: Major depressive disorder (MDD) is a risk factor for dementia including that caused by Alzheimer's disease (AD). Both MDD and AD have a higher prevalence in women than men, and estrogen-related processes have been implicated in this sex difference. Objective: To identify if enhanced oxidative stress and decreased expression of the memory enhancer insulin-like growth factor 2 (IGF2), each implicated separately in MDD and AD, are exaggerated in individuals with both AD and MDD compared to those with AD. Methods: Expression of target genes are determined by qPCR in postmortem hippocampus (Hip) and anterior cingulate cortex (ACC) of individuals with dementia and autopsy confirmed AD and those of AD+MDD. Results: Transcript levels of the antioxidant enzymes catalase (CAT) and superoxide dismutase 1 (SOD1), as well as IGF2 and its receptor (IGF2R) were significantly lower in the Hip and ACC of individuals with both AD and MDD compared to those with AD and no MDD. Expressions of Progestin and AdipoQ Receptor Family Member 7 (PAQR7, alias progesterone receptor alpha, mPRa) and PAQR8 (mPRβ), receptors that bind neurosteroids, were also lower in the Hip and ACC of AD+MDD samples compared to those of AD without MDD. Correlations among these transcripts revealed that estrogen receptor 2 (ESR2) and mPR β are direct or indirect regulators of the expression of the antioxidant enzymes and IGF2R. Conclusion: Reduced levels of antioxidant enzymes, decreased IGF2 expression, and diminished estrogen or membrane progesterone receptor-dependent processes might be more pronounced in the subpopulation of individuals with AD and MDD than without MDD.
Article
Infections can lead to the onset of mood disorders in adults, partly through inflammatory mechanisms. However pediatric data are lacking. The aim of this study is to evaluate the relationship between depressive disorder and seropositivity of Herpes virus infections in children. The sample group consisted of patients diagnosed with depressive disorder according to DSM‐5 diagnostic criteria and healthy volunteers, being between 11‐18 years with clinically normal mental capacity. All children completed DSM‐5‐level‐2 depression scale, DSM‐5‐level‐2 irritability scale, DSM‐5‐level‐2 sleep scale, DSM‐5‐level‐2 somatic symptoms scale. The levels of anti‐HSV1‐IgG, anti‐CMV‐IgG, anti‐EBNA, and anti‐HHV6‐IgG were examined in all participants. Patients with an antibody value above the cut‐off values specified in the test kits were evaluated as seropositive. The mean age was 15.54±1.57 years in the depression group(DG), 14.87±1.76 years in the healthy control group(CG). There were 4 boys(11.2%), 32 girls(88.8%) in the DG, 9 boys (21.9%) and 32 girls(78.04%) in the CG. There was no statistically significant difference between the groups in terms of the presence of seropositivity of HSV1, CMV, EBV and HHV6. HHV6 antibody levels were significantly higher in the DG(p=0.000). A significant positive correlation was found between HHV6 antibodies and DSM‐5 level‐2 somatic symptoms scale score. HHV6 antibody levels were found to be significantly higher in patients with existing suicidal ideation in the DG(n=13) compared to those without existing suicidal ideation in the DG(p=0.043). HHV6 persistent infections may be responsible for somatic symptoms and etiology of suicidal ideation in childhood depressive disorder. This article is protected by copyright. All rights reserved.
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Background: To study differences in oxidative stress markers and antioxidants among patients with bipolar depression (BPD) and unipolar depression (UPD). Methods: DATA SOURCES: Electronic MEDLINE/PubMed/Cochrane Library/Scopus/TripDatabase database search until 30/06/2021. STUDY SELECTION: Included were articles comparing antioxidant or oxidative stress markers between adults with BPD or UPD and healthy controls (HCs). DATA EXTRACTION: Two authors extracted data independently. Random effects meta-analysis, calculating standardized mean differences for results from ≥3 studies. Results: Oxidative stress markers reported in 40 studies –1 published repeatedly– (UPD, studies=30 n=3072; their HCs, n=2856; BPD, studies=11 n=393; their HCs, n=540; with 1 study reporting on both UPD and BPD) included thiobarbituric acid reactive substances (TBARS), antioxidant uric acid and antioxidant-enhancing enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione-peroxidase (GPX). Compared with HCs, UPD and BPD were associated with significantly higher levels of TBARS, without differences between UPD and BPD (P=0.11). Compared with HCs, UPD and BPD did not differ regarding the activity of the CAT (P=0.28), SOD (P=0.87) and GPX (P=0.25) enzymes. However, uric acid levels were significantly higher vs HCs in UPD than in BPD among adult patients (P=0.004). Results were heterogenous, which, for some parameters, decreased after stratification by the blood source (serum, plasma red blood cells, whole blood). Limitations: The main limitations are the small number of studies/participants in the BPD subgroup, and heterogeneity of the results. Summations: Both BPD and UPD may be associated with an impaired oxidative stress balance, with significantly higher uric acid levels vs. HCs in UPD than in BPD.
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The etiology of astrocyte dysfunction is not well understood even though neuronal defects have been extensively studied in a variety of neuronal degenerative diseases. Astrocyte defects could be triggered by the oxidative stress that occurs during physiological aging. Here, we provide evidence that intracellular or mitochondrial reactive oxygen species (ROS) at physiological levels can cause hippocampal (neuronal) dysfunctions. Specifically, we demonstrate that astrocyte defects occur in the hippocampal area of middle-aged Tet-mev-1 mice with the SDHC(V69E) mutation. These mice are characterized by chronic oxidative stress. Even though both young adult and middle-aged Tet-mev-1 mice overproduced MitoSOX Red-detectable mitochondrial ROS compared to age-matched wild-type C57BL/6J mice, only young adult Tet-mev-1 mice upregulated manganese and copper/zinc superoxide dismutase (Mn- and Cu/Zn-SODs) activities to eliminate the MitoSOX Red-detectable mitochondrial ROS. In contrast, middle-aged Tet-mev-1 mice accumulated both MitoSOX Red-detectable mitochondrial ROS and CM-H2 DCFDA-detectable intracellular ROS. These ROS levels appeared to be in the physiological range as shown by normal thiol and glutathione disulfide/glutathione concentrations in both young adult and middle-aged Tet-mev-1 mice relative to age-matched wild-type C57BL/6J mice. Furthermore, only middle-aged Tet-mev-1 mice showed JNK/SAPK activation and Ca(2+) overload, particularly in astrocytes. This led to decreasing levels of glial fibrillary acidic protein and S100β in the hippocampal area. Significantly, there were no pathological features such as apoptosis, amyloidosis, and lactic acidosis in neurons and astrocytes. Our findings suggest that the age-dependent physiologically relevant chronic oxidative stress caused astrocyte defects in mice with impaired mitochondrial electron transport chain functionality.
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Major depressive disorder (MDD) is associated with a significantly elevated risk of developing serious medical illnesses such as cardiovascular disease, immune impairments, infection, dementia and premature death. Previous work has demonstrated immune dysregulation in subjects with MDD. Using genome-wide transcriptional profiling and promoter-based bioinformatic strategies, we assessed leukocyte transcription factor (TF) activity in leukocytes from 20 unmedicated MDD subjects versus 20 age-, sex- and ethnicity-matched healthy controls, before initiation of antidepressant therapy, and in 17 of the MDD subjects after 8 weeks of sertraline treatment. In leukocytes from unmedicated MDD subjects, bioinformatic analysis of transcription control pathway activity indicated an increased transcriptional activity of cAMP response element-binding/activating TF (CREB/ATF) and increased activity of TFs associated with cellular responses to oxidative stress (nuclear factor erythroid-derived 2-like 2, NFE2l2 or NRF2). Eight weeks of antidepressant therapy was associated with significant reductions in Hamilton Depression Rating Scale scores and reduced activity of NRF2, but not in CREB/ATF activity. Several other transcriptional regulation pathways, including the glucocorticoid receptor (GR), nuclear factor kappa-B cells (NF-κB), early growth response proteins 1-4 (EGR1-4) and interferon-responsive TFs, showed either no significant differences as a function of disease or treatment, or activities that were opposite to those previously hypothesized to be involved in the etiology of MDD or effective treatment. Our results suggest that CREB/ATF and NRF2 signaling may contribute to MDD by activating immune cell transcriptome dynamics that ultimately influence central nervous system (CNS) motivational and affective processes via circulating mediators.
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The central nervous system is particularly sensitive to oxidative stress due to many reasons, including its high oxygen consumption even under basal conditions, high production of reactive oxygen and nitrogen species from specific neurochemical reactions, and the increased deposition of metal ions in the brain with aging. For this reason, along with inflammation, oxidative stress seems to be one of the main inducers of neurodegeneration, causing excitotoxicity, neuronal loss, and axonal damage, ultimately being now considered a key element in the onset and progression of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and hereditary spastic paraplegia. Thus, the present paper reviews the role of oxidative stress and of its mechanistic insights underlying the pathogenesis of these neurodegenerative diseases, with particular focus on current studies on its modulation as a potential and promising therapeutic strategy.
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Background: Chronic obstructive pulmonary disease (COPD) is a non-specific inflammation, which involves the airways, lung parenchyma and pulmonary vessels. The inflammation causes the activation of inflammatory cells and the release of various inflammatory mediators such as interleukin-8 (IL-8), IL-6 and tumor necoris factor alpha (TNF-a). The purpose of the present study was to measure serum IL-6, C-reactive protein (CRP) (as a positive phase reactant) and albumin level (as a negative phase reactant) in COPD patients (only due to cigarette smoking not bio-mass), non COPD smokers and healthy subjects using enzyme-linked immunosorbent assay (ELISA); we compared the differences in inflammatory factors among groups. Materials and methods: A total of 180 males were enrolled in this study and divided into three equal groups. The first group was 60 smokers who had COPD. The second group included 60 smokers without COPD and the third group consisted of people who were not smokers and did not have COPD; 5 mL of venous blood was taken from all participants and it was collected in a test tube containing anticoagulant and then centrifuged at 3000 rpm for 10 minutes. Serum was separated and used to measure the amount of IL-6, CRP and albumin. Spirometry was performed according to the criteria set by the American Thoracic Society. Results: The mean serum level of IL-6 was 83.2±7.5 pg/mL in group I, 54.9±24.3 pg/mL in group II and 46.9±10.4 pg/mL in group III. There was a significant difference among the three groups (P<0.001). The mean serum level of CRP was 28.9±14.9 mg/dL in the first group, 19.9±8.5 mg/dL in the second group and 4.2±2.3 mg/dL in the third group (P=0.02). But by controlling the confounding effects of age, this difference was not significant (P=0.49). The mean serum level of albumin was I 4.1±0.57 mg/dL in group I, 4.3±0.56 mg/dL in group II and 4.1±0.53 mg/dL in group III. There was no significant difference among the three groups in this regard (P=0.099).There was a significant inverse relationship between serum levels of IL-6 and FEV 1 (r=-0.341, P<0.001). Moreover, there was a significant inverse relationship between serum levels of IL-6 and FEV1/FVC (r=-0.309, P<0.001). Serum albumin level was not different among various stages. Level of CRP and IL6 increased as the stage of COPD got worse in smokers. Conclusion: Our study showed that serum level of IL-6 predicts development of COPD in smokers with a high sensitivity among all inflammatory factors namely CRP, IL-6, and albumin.
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The depressive state has been characterised as one of elevated inflammation, which holds promise for better understanding treatment-resistance in affective disorders as well as for future developments in treatment stratification. Aiming to investigate alterations in the inflammatory profiles of individuals with depression as putative biomarkers for clinical response, we conducted a meta-analyses examining data from 35 studies that investigated inflammation before and after treatment in depressed patients together with a measure of clinical response. There were sufficient data to analyse IL-6, TNFα and CRP. Levels of IL-6 decreased with antidepressant treatment regardless of outcome, whereas persistently elevated TNFα was associated with prospectively determined treatment resistance. Treatment non-responders tended to have higher baseline inflammation, using a composite measure of inflammatory markers. Our findings suggest that elevated levels of inflammation are contributory to treatment resistance. Combining inflammatory biomarkers might prove a useful tool to improve diagnosis and detection of treatment refractoriness, and targeting persistent inflammation in treatment-resistant depression may offer a potential target for the development of novel intervention strategies. Copyright © 2015. Published by Elsevier B.V.
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Oxidative stress plays a pathological role in the development of various diseases including diabetes, atherosclerosis, or cancer. Systemic oxidative stress results from an imbalance between oxidants derivatives production and antioxidants defenses. Reactive oxygen species (ROS) are generally considered to be detrimental for health. However, evidences have been provided that they can act as second messengers in adaptative responses to stress. Obesity represents a major risk factor for deleterious associated pathologies such as type 2 diabetes, liver, and coronary heart diseases. Many evidences regarding obesity-induced oxidative stress accumulated over the past few years based on established correlations of biomarkers or end-products of free-radical-mediated oxidative stress with body mass index. The hypothesis that oxidative stress plays a significant role in the development of metabolic disorders, especially insulin-resistance state, is supported by several studies where treatments reducing ROS production reverse metabolic alterations, notably through improvement of insulin sensitivity, hyperlipidemia, or hepatic steatosis. In this review, we will develop the mechanistic links between oxidative stress generated by adipose tissue in the context of obesity and its impact on metabolic complications development. We will also attempt to discuss potential therapeutic approaches targeting obesity-associated oxidative stress in order to prevent associated-metabolic complications.
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Objective: Major depressive disorder has been linked with inflammatory processes, but it is unclear whether individual differences in levels of inflammatory biomarkers could help match patients to treatments that are most likely to be beneficial. The authors tested the hypothesis that C-reactive protein (CRP), a commonly available marker of systemic inflammation, predicts differential response to escitalopram (a serotonin reuptake inhibitor) and nortriptyline (a norepinephrine reuptake inhibitor). Method: The hypothesis was tested in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study, a multicenter open-label randomized clinical trial. CRP was measured with a high-sensitivity method in serum samples from 241 adult men and women with major depressive disorder randomly allocated to 12-week treatment with escitalopram (N=115) or nortriptyline (N=126). The primary outcome measure was the score on the Montgomery-Åsberg Depression Rating Scale (MADRS), administered weekly. Results: CRP level at baseline differentially predicted treatment outcome with the two antidepressants (CRP-drug interaction: β=3.27, 95% CI=1.65, 4.89). For patients with low levels of CRP (<1 mg/L), improvement on the MADRS score was 3 points higher with escitalopram than with nortriptyline. For patients with higher CRP levels, improvement on the MADRS score was 3 points higher with nortriptyline than with escitalopram. CRP and its interaction with medication explained more than 10% of individual-level variance in treatment outcome. Conclusions: An easily accessible peripheral blood biomarker may contribute to improvement in outcomes of major depressive disorder by personalizing treatment choice.
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Nitro-oxidative stress (NOS) plays a fundamental role in aging, as well as in the pathogenesis of neurodegenerative disorders, and major depression (MD). The latter is a very frequent psychiatric illness characterized by accelerated aging, neurodegeneration, high comorbidity with age-related disorders, and premature mortality; all of these conditions find an explanation in an altered redox homeostasis. If aging, neurodegeneration, and major depression share a common biological base in their pathophysiology, common therapeutic tools could be investigated for the prevention and treatment of these disorders. As an example, antidepressants have been demonstrated to present neuroprotective and anti-inflammatory properties and to stimulate neurogenesis. In parallel, antioxidants that stimulate the antioxidant defense systems and interact with the monoaminergic system show an antidepressant-like activity. Further research on this topic could lead, in the near future, to the expansion of the therapeutic possibilities for the treatment of NOS-related disorders.
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In order to assess the effect of gray matter volumes and cortical thickness on antidepressant treatment response in late-life depression, the authors examined the relationship between brain regions identified a priori and Montgomery-Åsberg Depression Rating Scale (MADRS) scores over the course of an antidepressant treatment trial. In a nonrandomized prospective trial, 168 patients who were at least 60 years of age and met DSM-IV criteria for major depression underwent MRI and were enrolled in a 12-week treatment study. Exclusion criteria included cognitive impairment or severe medical disorders. The volumes or cortical thicknesses of regions of interest that differed between the depressed group and a comparison group (N=50) were determined. These regions of interest were used in analyses of the depressed group to predict antidepressant treatment outcome. Mixed-model analyses adjusting for age, education, age at depression onset, race, baseline MADRS score, scanner, and interaction with time examined predictors of MADRS scores over time. Smaller hippocampal volumes predicted a slower response to treatment. With the inclusion of white matter hyper-intensity severity and neuropsychological factor scores, the best model included hippocampal volume and cognitive processing speed to predict rate of response over time. A secondary analysis showed that hippocampal volume and frontal pole thickness differed between patients who achieved remission and those who did not. These data expand our understanding of the prediction of treatment course in late-life depression. The authors propose that the primary variables of hippocampal volume and cognitive processing speed, subsuming other contributing variables (episodic memory, executive function, language processing) predict antidepressant response.
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Background It has been suggested that depressed persons have increased oxidative stress and decreased anti-oxidant defences. 8-Hydroxy-2′-deoxyguanosine (8-OHdG) and F2-isoprostanes, measures of oxidative DNA and lipid damage respectively, are among the most reliable oxidative stress markers, but studies on their association with depression show conflicting results. This meta-analysis quantifies the association between depression and these markers and explores factors that may explain inconsistencies in the results. Methods A systematic literature search was conducted in PubMed, EMBASE and PsycINFO. Studies assessing the association of 8-OHdG or F2-isoprostanes with elevated depressive symptoms, major depressive disorder (MDD) or bipolar disorder (BD) were pooled in two random-effect models. Results The pooled effect size (Hedges’ g) for the association of depression with oxidative stress was 0.31 (p = 0.01, I2 = 75%) for 8-OHdG (10 studies, 1308 subjects) and 0.48 (p = 0.001, I2 = 73%) for F2-isoprostanes (8 studies, 2471 subjects), indicating that both markers are increased in depression. There was no indication of publication bias for either marker. The F2-isoprostane results did not differ by type of depression, biological specimen, laboratory method or quality, however subgroup analyses in the 8-OHdG studies showed significantly stronger associations in plasma/serum vs. urine samples (p < 0.01), in measurements performed with immuno-assay vs. chromatography–mass spectrometry (p < 0.01) and weaker associations in high quality studies vs. low (p = 0.02). Conclusion This meta-analysis finds that oxidative stress, as measured by 8-OHdG and F2-isoprostanes, is increased in depression. Larger-scale studies are needed to extend the evidence on oxidative stress in depression, and examine the potential impact of treatment.
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Several psychiatric disorders, including major depressive disorder (MDD), are associated with increased blood markers of oxidative stress. The relevance of this to the oxidation-sensitive hippocampus (HC) is unknown. We investigated the relationship between peripheral oxidative stress markers and HC volume in unmedicated individuals with MDD (n=16) and healthy controls (n=19). To conserve power, our primary analysis was carried out in the combined group of subjects, and secondary analyses examined each group separately. Oxidative stress markers (oxidized glutathione) and antioxidants (reduced glutathione, glutathione peroxidase, Vitamin C) were assessed, and a “total net antioxidant score” was calculated. 4-T MRI estimated total HC volume and HC subfield (CA1, CA1-CA2 transition zone, subiculum and CA3/dentate gyrus [CA3&DG]) volumes. Across groups, the antioxidant score was significantly and positively correlated with total HC volume and CA3&DG subfield volume, adjusting for age and sex. Similar relationships were observed in each individual group but missed statistical significance, likely due to type II errors, with the exception of a significant correlation between the antioxidant score and CA3&DG volume in the MDD group. These preliminary data are consistent with oxidative stress being associated with smaller total HC and CA3&DG subfield volumes.