A further examination of growth factors, T helper 1 polarization, and the gut microbiome in major depression: Associations with reoccurrence of illness, cognitive functions, suicidal behaviors, and quality of life.

Growth factors, T helper (Th)1 polarization, and the microbiome are involved in the pathophysiology of major depression (MDD). It remains unclear whether the combination of these three pathways could enhance the accuracy of predicting the features of MDD, including recurrence of illness (ROI), suicidal behaviors and the phenome. We measured serum stem cell factor (SCF), stem cell growth factor (SCGF), stromal cell-derived factor-1 (SDF-1), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), macrophage-colony stimulating factor (M-CSF) and vascular endothelial growth factor (VEGF), the ratio of serum Th1/Th2 cytokines (zTh1-zTh2), and the abundances of gut microbiome taxa by analyzing stool samples using 16S rDNA sequencing from 32 MDD patients and 37 healthy controls. The results show that serum SCF is significantly lower and VEGF increased in MDD. Adverse childhood experiences (ACE) and ROI are significantly associated with lowered SCF and increasing VEGF. Lifetime and current suicidal behaviors are strongly predicted (63.5%) by an increased VEGF/SCF ratio, Th1 polarization, a gut microbiome enterotype indicating gut dysbiosis, and lowered abundance of Dorea and Faecalobacterium. Around 80.5% of the variance in the phenome's severity is explained by ROI, ACEs, and lowered Parabacteroides distasonis and Clostridium IV abundances. A large part of the variance in health-related quality of life (54.1%) is explained by the VEGF/SCF ratio, Th1 polarization, ACE, and male sex. In conclusion, key features of MDD are largely predicted by the cumulative effects of ACE, Th1 polarization, aberrations in growth factors and the gut microbiome with increased pathobionts but lowered beneficial symbionts.

Increased malondialdehyde and nitric oxide formation, lowered total radical trapping capacity coupled with psychological stressors are strongly associated with the phenome of first-episode mild depression in undergraduate students.

Undergraduate students are frequently afflicted by major depressive disorder (MDD). Oxidative and nitrosative stress (O&NS) has been implicated in the pathophysiology of MDD. There is no information regarding whether mild outpatient MDD (SDMD) and first episode SDMD (FE-SDMD) are accompanied by O&NS. The current study compared lipid hydroperoxides (LOOH), malondialdehyde (MDA), advanced protein oxidation products, nitric oxide metabolites (NOx), thiol groups, plasma total antioxidant potential (TRAP), and paraoxonase 1 activities among SDMD and FE-SDMD patients versus healthy controls. We found that SDMD and FE-SDMD exhibit elevated MDA and NOx, and decreased TRAP and LOOH as compared with controls. There was a significant and positive correlation between O&NS biomarkers and adverse childhood experiences (ACEs), and negative life events (NLEs). O&NS pathways, NLEs and ACEs accounted for 51.7 % of the variance in the phenome of depression, and O&NS and NLS explained 42.9 % of the variance in brooding. Overall, these results indicate that SDMD and FE-SDMD are characterized by reduced total antioxidant defenses and increased aldehyde and NOx production. The combined effects of oxidative and psychological stressors are substantially associated with the manifestation of SDMD.

T cell activation and lowered T regulatory cell numbers are key processes in severe major depressive disorder: Effects of recurrence of illness and adverse childhood experiences.

BACKGROUND: Major depressive disorder (MDD) is characterized by increased T helper (Th)1 polarization, T cell activation (e.g., CD71+ and CD40L+), and cannabinoid receptor type 2 bearing CD20+ B cells; and lower T regulatory (Treg) numbers. AIMS: To delineate the effects of adverse childhood experiences (ACEs) and recurrence of illness (ROI) on activated T and CB2-bearing B populations, and Tregs, including FoxP3 + CD152+, FoxP3 + GARP+, and FoxP3 + CB1+ cells. METHODS: We measured ROI, ACEs, the number of activated T cells, Tregs, and CD20 + CB2+ B cells, in 30 MDD patients and 20 healthy controls. RESULTS: A larger part of the variance in the depression phenome (40.8 %) was explained by increased CD20 + CB2+ and activated T cells, and lowered Tregs. ROI and lifetime suicidal behaviors were significantly and positively associated with CD20 + CB2+, CD3 + CD71+, CD3 + CD40L+, CD4 + CD71+, CD4 + CD40L+, and CD4HLADR+ numbers. ROI was significantly correlated with CD8 + CD40L+ numbers. The sum of ACEs was significantly associated with CD20 + CB2+, CD3 + CD40L+, CD4 + 40 L+ numbers, T cell activation (positively) and Treg (inversely) indices. One replicable latent vector could be extracted from activated T cells, lifetime and current suicidal behaviors, number of depressive episodes, and severity of depression, and 48.8 % of its variance was explained by ACEs. CONCLUSIONS: ACE-induced activation of T effector and cytotoxic cells and B cells with autoimmune potential, coupled with lowered Treg numbers are a key component of depression. The findings indicate that increasing ROI, the phenome of depression and suicidal behaviors, are caused by autoimmune processes, which are the consequence of ACEs and increasing sensitization of immune responses.

Reactivation of herpesvirus type 6 and IgA/IgM-mediated responses to activin-A underpin long COVID, including affective symptoms and chronic fatigue syndrome.

BACKGROUND: Persistent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), reactivation of dormant viruses, and immune-oxidative responses are involved in long COVID. OBJECTIVES: To investigate whether long COVID and depressive, anxiety, and chronic fatigue syndrome (CFS) symptoms are associated with IgA/IgM/IgG to SARS-CoV-2, human herpesvirus type 6 (HHV-6), Epstein-Barr Virus (EBV), and immune-oxidative biomarkers. METHODS: We examined 90 long COVID patients and ninety healthy controls. We measured serum IgA/IgM/IgG against HHV-6 and EBV and their deoxyuridine 5'-triphosphate nucleotidohydrolase (duTPase), SARS-CoV-2, and activin-A, C-reactive protein (CRP), advanced oxidation protein products (AOPP), and insulin resistance (HOMA2-IR). RESULTS: Long COVID patients showed significant elevations in IgG/IgM-SARS-CoV-2, IgG/IgM-HHV-6, and HHV-6-duTPase, IgA/IgM-activin-A, CRP, AOPP, and HOMA2-IR. Neural network analysis yielded a highly significant predictive accuracy of 80.6% for the long COVID diagnosis (sensitivity: 78.9%, specificity: 81.8%, area under the ROC curve = 0.876); the topmost predictors were as follows: IGA-activin-A, IgG-HHV-6, IgM-HHV-6-duTPase, IgG-SARS-CoV-2, and IgM-HHV-6 (all positively) and a factor extracted from all IgA levels to all viral antigens (inversely). The top 5 predictors of affective symptoms due to long COVID were IgM-HHV-6-duTPase, IgG-HHV-6, CRP, education, IgA-activin-A (predictive accuracy of r = 0.636). The top 5 predictors of CFS due to long COVID were in descending order: CRP, IgG-HHV-6-duTPase, IgM-activin-A, IgM-SARS-CoV-2, and IgA-activin-A (predictive accuracy: r = 0.709). CONCLUSION: Reactivation of HHV-6, SARS-CoV-2 persistence, and autoimmune reactions to activin-A combined with activated immune-oxidative pathways play a major role in the pathophysiology of long COVID as well as the severity of its affective symptoms and CFS.

In major dysmood disorder, physiosomatic, chronic fatigue and fibromyalgia symptoms are driven by immune activation and increased immune-associated neurotoxicity.

Major depressive disorder (MDD) is accompanied by activated neuro-immune pathways, increased physiosomatic and chronic fatigue-fibromyalgia (FF) symptoms. The most severe MDD phenotype, namely major dysmood disorder (MDMD), is associated with adverse childhood experiences (ACEs) and negative life events (NLEs) which induce cytokines/chemokines/growth factors. To delineate the impact of ACE + NLEs on physiosomatic and FF symptoms in first episode (FE)-MDMD, and examine whether these effects are mediated by immune profiles. ACEs, NLEs, physiosomatic and FF symptoms, and 48 cytokines/chemokines/growth factors were measured in 64 FE-MDMD patients and 32 normal controls. Physiosomatic, FF and gastro-intestinal symptoms belong to the same factor as depression, anxiety, melancholia, and insomnia. The first factor extracted from these seven domains is labeled the physio-affective phenome of depression. A part (59.0%) of the variance in physiosomatic symptoms is explained by the independent effects of interleukin (IL)-16 and IL-8 (positively), CCL3 and IL-1 receptor antagonist (inversely correlated). A part (46.5%) of the variance in physiosomatic (59.0%) symptoms is explained by the independent effects of interleukin (IL)-16, TNF-related apoptosis-inducing ligand (TRAIL) (positively) and combined activities of negative immunoregulatory cytokines (inversely associated). Partial least squares analysis shows that ACE + NLEs exert a substantial influence on the physio-affective phenome which are partly mediated by an immune network composed of interleukin-16, CCL27, TRAIL, macrophage-colony stimulating factor, and stem cell growth factor. The physiosomatic and FF symptoms of FE-MDMD are partly caused by immune-associated neurotoxicity due to T helper (Th)-1 polarization and M1 macrophage activation and relative lowered compensatory immunoregulatory protection.

Adverse childhood experiences and recent negative events are associated with activated immune and growth factor pathways, the phenome of first episode major depression and suicidal behaviors.

This research assessed the effects of adverse childhood experiences (ACEs) and negative life events (NLEs) on forty-eight cytokines/chemokines/growth factors, in 71 FE-MDMD patients and forty heathy controls. ACEs are highly significantly associated with the classical M1 macrophage, T helper (Th)-1, Th-1 polarization, IRS, and neurotoxicity immune profiles, and not with the alternative M2, and Th-2 immune profiles. There are highly significant correlations between ACEs and NLEs and different cytokines/chemokines/growth factors, especially with interleukin (IL)-16, CCL27, stem cell growth factor, and platelet-derived growth factor. Partial Least Squares analysis showed that 62.3 % of the variance in the depression phenome (based on severity of depression, anxiety and suicidal behaviors) was explained by the regression on IL-4 (p = 0.001, inversely), the sum of ACEs + NLEs (p < 0.0001), and a vector extracted from 10 cytokines/chemokines/growth factors (p < 0.0001; both positively associated). The latter partially mediated (p < 0.0001) the effects of ACE + NLEs on the depression phenome. In conclusion, part of the effects of ACEs and NLEs on the depression phenome is mediated via activation of immune and growth factor networks. These pathways have a stronger impact in subjects with lowered activities of the compensatory immune-regulatory system.

Towards a major methodological shift in depression research by assessing continuous scores of recurrence of illness, lifetime and current suicidal behaviors and phenome features.

BACKGROUND: The binary major depressive disorder (MDD) diagnosis is inadequate and should never be used in research. AIMS: The study's objective is to explicate our novel precision nomothetic strategy for constructing depression models based on adverse childhood experiences (ACEs), lifetime and current phenome, and biomarker (atherogenicity indices) scores. METHODS: This study assessed recurrence of illness (ROI: namely recurrence of depressive episodes and suicidal behaviors, SBs), lifetime and current SBs and the phenome of depression, neuroticism, dysthymia, anxiety disorders, and lipid biomarkers including apolipoprotein (Apo)A, ApoB, free cholesterol and cholesteryl esters, triglycerides, high density lipoprotein cholesterol in 67 normal controls and 66 MDD patients. We computed atherogenic and reverse cholesterol transport indices. RESULTS: We were able to extract one factor from a) the lifetime phenome of depression comprising ROI, and traits such as neuroticism, dysthymia and anxiety disorders, and b) the phenome of the acute phase (based on depression, anxiety and quality of life scores). PLS analysis showed that 55.7 % of the variance in the lifetime + current phenome factor was explained by increased atherogenicity, neglect and sexual abuse, while atherogenicity partially mediated the effects of neglect. Cluster analysis generated a cluster of patients with major dysmood disorder, which was externally validated by increased atherogenicity and characterized by increased scores of all clinical features. CONCLUSIONS: The outcome of depression should not be represented as a binary variable (MDD or not), but rather as multiple dimensional scores based on biomarkers, ROI, subclinical depression traits, and lifetime and current phenome scores including SBs.

Nutrient patterns and risk of diabetes mellitus type 2: a case-control study.

BACKGROUNDS: Although the significance of diet in preventing or managing diabetes complications is highlighted in current literature, there is insufficient evidence regarding the correlation between nutrient patterns and these complications. The objective of this case-control study is to investigate this relationship by analyzing the dietary intake of nutrients in participants with and without type 2 diabetes (T2D). METHODS: A case-control study was conducted at the Tabriz Center of Metabolism and Endocrinology to investigate the relationship between nutrient patterns and type 2 diabetes (T2D). The study enrolled 225 newly diagnosed cases of T2D and 225 controls. The dietary intake of nutrients was assessed using a validated semi-quantitative food frequency questionnaire (FFQ). Principal component analysis using Varimax rotation was used to obtain nutrient patterns. Logistic regression analysis was performed to estimate the risk of T2D. RESULTS: The participants' mean (SD) age and BMI were 39.8 (8.8) years and 27.8 (3.6) kg/m2, respectively. The results identified three major nutrient patterns. The first nutrient pattern was characterized by high consumption of sucrose, animal protein, vitamin E, vitamin B1, vitamin B12, calcium, phosphorus, zinc, and potassium. The second nutrient pattern included fiber, plant protein, vitamin D, Riboflavin, Vitamin B5, copper, and Magnesium. The third nutrient pattern was characterized by fiber, plant protein, vitamin A, riboflavin, vitamin C, calcium, and potassium. Individuals in the highest tertile of nutrient pattern 3 (NP3) had a lower risk of T2D compared to those in the lowest tertile after adjusting for confounders. The odds ratio was 0.52 with a 95% confidence interval of 0.30-0.89 and a P_trend of 0.039. CONCLUSION: This study found that conforming to a nutrient pattern consisting of plant protein, vitamin C, vitamin A, vitamin B2, potassium, and calcium is linked to a lower likelihood of developing T2D.The initial results suggest that following a nutrient pattern that includes these nutrients may reduce the risk of T2D. However, further research is required to confirm the relationship between nutrient patterns and T2D.

Neuroprotective effects of riluzole in Alzheimer's disease: A comprehensive review.

BACKGROUND: Despite several hundred clinical trials of drugs that initially showed promise, there has been limited clinical improvement in Alzheimer's disease (AD). This may be attributed to the existence of at least 25 abnormal cellular pathways that underlie the disease. It is improbable for a single drug to address all or most of these pathways, thus even drugs that show promise when administered alone are unlikely to produce significant results. According to previous studies, eight drugs, namely, dantrolene, erythropoietin, lithium, memantine, minocycline, piracetam, riluzole, and silymarin, have been found to target multiple pathways that are involved in the development of AD. Among these drugs, riluzole is currently indicated for the treatment of medical conditions in both adult patients and children and has gained increased attention from scientists due to its potential in the excitotoxic hypothesis of neurodegenerative diseases. OBJECTIVE: The aim of this study was to investigate the effects of drugs on AD based on cellular and molecular mechanisms. METHODS: The literature search for this study utilized the Scopus, ScienceDirect, PubMed, and Google Scholar databases to identify relevant articles. RESULTS: Riluzole exerts its effects in AD through diverse pathways including the inhibition of voltage-dependent sodium and calcium channels, blocking AMPA and NMDA receptors and inhibiting the release of glutamic acid release and stimulation of EAAT1-EAAT2. CONCLUSION: In this review article, we aimed to review the neuroprotective properties of riluzole, a glutamate modulator, in AD, which could benefit patients with the disease.

A comprehensive review on Ellagic acid in breast cancer treatment: From cellular effects to molecular mechanisms of action.

Globally, breast cancer (BC) is the leading cause of cancer-related deaths in women. Hence, developing a therapeutic plan to overcome the disease is crucial. Numerous factors such as endogenous hormones and environmental factors may play a role in the pathophysiology of BC. Regarding the multi-modality treatment of BC, natural compounds like ellagic acid (EA) received has received increased interest in antitumor efficacy with lower adverse effects. Based on the results of this comprehensive review, EA has multiple effects on BC cells including (1) suppresses the growth of BC cells by arresting the cell cycle in the G0/G1 phase, (2) suppresses migration, invasion, and metastatic, (3) stimulates apoptosis in MCF-7 cells via TGF-ß/Smad3 signaling axis, (4) inhibits CDK6 that is important in cell cycle regulation, (5) binds to ACTN4 and induces its degradation via the ubiquitin-proteasome pathway, inducing decreased cell motility and invasion in BC cells, (6) inhibits the PI3K/AKT pathway, and (7) inhibits angiogenesis-associated activities including proliferation (reduces VEGFR-2 tyrosine kinase activity). In conclusion, EA exhibits anticancer activity through various molecular mechanisms that influence key cellular processes like apoptosis, cell cycle, angiogenesis, and metastasis in BC. However, further researches are essential to fully elucidate its molecular targets and implications for clinical applications.

The tryptophan catabolite or kynurenine pathway in autism spectrum disorder; a systematic review and meta-analysis.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social communication and interaction, as well as rigid and unchanging interests and behaviors. Several studies have reported that activated immune-inflammatory and nitro-oxidative pathways are accompanied by depletion of plasma tryptophan (TRP), increased competing amino acid (CAAs) levels, and activation of the TRP catabolite (TRYCAT) pathway. This study aims to systematically review and meta-analyze data on peripheral TRP, CAAs, TRYCAT pathway activity, and individual TRYCATs, including kynurenine (KYN) and kynurenic acid (KA) levels, in the blood and urine of ASD patients. After extensively searching PubMed, Google Scholar, and SciFinder, a total of 25 full-text papers were included in the analysis, with a total of 6653 participants (3557 people with ASD and 3096 healthy controls). Our results indicate that blood TRP and the TRP/CAAs ratio were not significantly different between ASD patients and controls (standardized mean difference, SMD = -0.227, 95% confidence interval, CI: -0.540; 0.085, and SMD = 0.158, 95% CI: -0.042; 0.359), respectively. The KYN/TRP ratio showed no significant difference between ASD and controls (SMD = 0.001, 95% CI: -0.169; 0.171). Blood KYN and KA levels were not significantly changed in ASD. Moreover, there were no significant differences in urine TRP, KYN, and KA levels between ASD and controls. We could not establish increases in neurotoxic TRYCATs in ASD. In conclusion, this study demonstrates no abnormalities in peripheral blood TRP metabolism, indoleamine 2,3-dioxygenase enzyme (IDO) activity, or TRYCAT production in ASD. Reduced TRP availability and elevated neurotoxic TRYCAT levels are not substantial contributors to ASD's pathophysiology.

Conjugated linoleic acid and glucosamine supplements may prevent bone loss in aging by regulating the RANKL/RANK/OPG pathway.

The skeleton is a living organ that undergoes constant changes, including bone formation and resorption. It is affected by various diseases, such as osteoporosis, osteopenia, and osteomalacia. Nowadays, several methods are applied to protect bone health, including the use of hormonal and non-hormonal medications and supplements. However, certain drugs like glucocorticoids, thiazolidinediones, heparin, anticonvulsants, chemotherapy, and proton pump inhibitors can endanger bone health and cause bone loss. New studies are exploring the use of supplements, such as conjugated linoleic acid (CLA) and glucosamine, with fewer side effects during treatment. Various mechanisms have been proposed for the effects of CLA and glucosamine on bone structure, both direct and indirect. One mechanism that deserves special attention is the regulatory effect of RANKL/RANK/OPG on bone turnover. The RANKL/RANK/OPG pathway is considered a motive for osteoclast maturation and bone resorption. The cytokine system, consisting of the receptor activator of the nuclear factor (NF)-kB ligand (RANKL), its receptor RANK, and its decoy receptor, osteoprotegerin (OPG), plays a vital role in bone turnover. Over the past few years, researchers have observed the impact of CLA and glucosamine on the RANKL/RANK/OPG mechanism of bone turnover. However, no comprehensive study has been published on these supplements and their mechanism. To address this gap in knowledge, we have critically reviewed their potential effects. This review aims to assist in developing efficient treatment strategies and focusing future studies on these supplements.

Melatonin in Chemo/Radiation Therapy; Implications for Normal Tissues Sparing and Tumor Suppression: An Updated Review.

Resistance to therapy and the toxicity of normal tissue are the major problems for efficacy associated with chemotherapy and radiotherapy. Drug resistance is responsible for most cases of mortality associated with cancer. Furthermore, their side effects can decrease the quality of life for surviving patients. An enhancement in the tumor response to therapy and alleviation of toxic effects remain unsolved challenges. One of the interesting topics is the administration of agents with low toxicity to protect normal tissues and/or sensitize cancers to chemo/radiotherapy. Melatonin is a natural body hormone that is known as a multitasking molecule. Although it has antioxidant properties, a large number of experiments have uncovered interesting effects of melatonin that can increase the therapeutic efficacy of chemo/radiation therapy. Melatonin can enhance anticancer therapy efficacy through various mechanisms, cells such as the immune system, and modulation of cell cycle and death pathways, tumor suppressor genes, and also through suppression of some drug resistance mediators. However, melatonin may protect normal tissues through the suppression of inflammation, fibrosis, and massive oxidative stress in normal cells and tissues. In this review, we will discuss the distinct effects of melatonin on both tumors and normal tissues. We review how melatonin may enhance radio/chemosensitivity of tumors while protecting normal tissues such as the lung, heart, gastrointestinal system, reproductive system, brain, liver, and kidney.

T helper-1 activation via interleukin-16 is a key phenomenon in the acute phase of severe, first-episode major depressive disorder and suicidal behaviors.

BACKGROUND: Immune-inflammatory pathways in major depressive disorder are confined to the major dysmood disorder (MDMD) phenotype (Maes et al., 2022). No studies have addressed the immune profile of first episode MDMD (FE-MDMD). METHODS: This study investigated the immune profiles of 71 patients with the acute phase of first-episode major depressive disorder (FE-MDMD) and 40 healthy controls. We measured 48 cytokines/chemokines/growth factors, classical M1, alternative M2, T helper (Th)-1, Th-2, and Th-17 phenotypes, immune-inflammatory response system (IRS), compensatory immunoregulatory system (CIRS), and neuro-immunotoxicity profiles. RESULTS: FE-MDMD patients show significantly activated M1, M2, Th-1, IRS, CIRS, and neurotoxicity, but not Th-2 or Th-17, profiles compared to controls. FE-MDMD is accompanied by Th-1 polarization, while there are no changes in M1/M2 or IRS/CIRS ratios. The top single indicator of FE-MDMD was by far interleukin (IL)-16, followed at a distance by TRAIL, IL-2R, tumor necrosis factor (TNF)-ß. The severity of depression and anxiety was strongly associated with IRS (positively) and Th-2 (inversely) profiles, whereas suicidal behavior was associated with M1 activation. Around 56-60% of the variance in depression, anxiety, and suicidal behavior scores was explained by IL-16, platelet-derived growth factor (PDGF) (both positively), and IL-1 receptor antagonist (inversely). Increased neurotoxicity is mainly driven by IL-16, TNF-α, TRAIL, IL-6, and chemokine (CCL2, CCL11, CXCL1, CXCL10) signaling. Antidepressant-treated patients show an increased IRS/CIRS ratio as compared with drug-naïve FE-MDMD patients. CONCLUSIONS: FE-MDMD is accompanied by positive regulation of the IRS mainly driven by Th-1 polarization and T cell activation (via binding of IL-16 to CD4), and TNF, chemokine, and growth factor signaling.

Increased AGE-RAGE axis stress in methamphetamine abuse and methamphetamine-induced psychosis: Associations with oxidative stress and increased atherogenicity.

Methamphetamine (MA)-induced psychosis (MIP) is associated with increased oxidative toxicity (especially lipid peroxidation) and lowered antioxidant defences. Advanced glycation end products (AGEs) cause oxidative stress upon ligand binding to AGE receptors (RAGEs). There is no data on whether MA use may cause AGE-RAGE stress or whether the latter is associated with MIP. This case-control study recruited 60 patients with MA use disorder and 30 normal controls and measured serum levels of oxidative stress toxicity (OSTOX, lipid peroxidation), antioxidant defences (ANTIOX), magnesium, copper, atherogenicity, AGE and soluble RAGE (sRAGE) and computed a composite reflecting AGE-RAGE axis activity. MA dependence and use were associated with elevated levels of AGE, sRAGE, OSTOX/ANTIOX, Castelli Risk Index 1 and atherogenic index of plasma. Increased sRAGE concentrations were strongly correlated with dependence severity and MA dose. Increased AGE-RAGE stress was correlated with OSTOX, OSTOX/ANTIOX and MA-induced intoxication symptoms, psychosis, hostility, excitement and formal thought disorders. The regression on AGE-RAGE, the OSTOX/ANTIOX ratio, decreased magnesium and increased copper explained 54.8% of the variance in MIP symptoms, and these biomarkers mediated the effects of increasing MA concentrations on MIP symptoms. OSTOX/ANTIOX, AGE-RAGE and insufficient magnesium were found to explain 36.0% of the variance in the atherogenicity indices. MA causes intertwined increases in AGE-RAGE axis stress and oxidative damage, which together predict the severity of MIP symptoms and increased atherogenicity.

The potential role of interleukins and interferons in ovarian cancer.

Ovarian cancer poses significant challenges and remains a highly lethal disease with limited treatment options. In the context of ovarian cancer, interleukins (ILs) and interferons (IFNs), important cytokines that play crucial roles in regulating the immune system, have emerged as significant factors influencing its development. This article provides a comprehensive review of the involvement of various ILs, including those from the IL-1 family, IL-2 family, IL-6 family, IL-8 family, IL-10 family, and IL-17 family, in ovarian cancer. The focus is on their impact on tumor growth, metastasis, and their role in evading immune responses within the tumor microenvironment. Additionally, the article conducts an in-depth examination of the oncogenic or antitumor roles of each IL in the context of ovarian cancer pathogenesis and progression. Besides, we elucidated the enhancements in the treatment of ovarian cancer through the utilization of type-I IFN and type-II IFN. Recent research has shed light on the intricate mechanisms through which specific ILs and IFNs contribute to the advancement of the disease. By incorporating recent findings, this review also seeks to inspire further investigations into unexplored mechanisms, fostering ongoing research to develop more effective therapeutic strategies for ovarian cancer. Moreover, through an in-depth analysis of IL- and IFN-associated clinical trials, we have highlighted their promising potential of in the treatment of ovarian cancer. These clinical trials serve to reinforce the significant outlook for utilizing ILs and IFNs as therapeutic agents in combating this disease.

Role of T and B lymphocyte cannabinoid type 1 and 2 receptors in major depression and suicidal behaviours.

Early flow cytometry studies revealed T cell activation in major depressive disorder (MDD). MDD is characterised by activation of the immune-inflammatory response system (IRS) and the compensatory immunoregulatory system (CIRS), including deficits in T regulatory (Treg) cells. This study examines the number of cannabinoid type 1 (CB1) and type 2 (CB2) receptor-bearing T/B lymphocytes in MDD, and the effects of in vitro cannabidiol (CBD) administration on CB1/CB2-bearing immunocytes. Using flow cytometry, we determined the percentage of CD20+CB2+, CD3+CB2+, CD4+CB2+, CD8+CB2+ and FoxP3+CB1+ cells in 19 healthy controls and 29 MDD patients in 5 conditions: baseline, stimulation with anti-CD3/CD28 with or without 0.1 µg/mL, 1.0 µg/mL, or 10.0 µg/mL CBD. CB2+ was significantly higher in CD20+ than CD3+ and CD4+ and CD 8+ cells. Stimulation with anti-CD3/CD8 increases the number of CB2-bearing CD3+, CD4+ and CD8+ cells, as well as CB1-bearing FoxP3+ cells. There was an inverse association between the number of reduced CD4+ CB2+ and IRS profiles, including M1 macrophage, T helper-(Th)-1 and Th-17 phenotypes. MDD is characterised by lowered basal FoxP3+ CB1+% and higher CD20+ CB2+%. 33.2% of the variance in the depression phenome (including severity of depression, anxiety and current suicidal behaviours) is explained by CD20+ CB2+ % (positively) and CD3+ CB2+% (inversely). All five immune cell populations were significantly increased by 10 µg/mL of CBD administration. Reductions in FoxP3+ CB1+% and CD3+ /CD4+ CB2+% contribute to deficits in immune homoeostasis in MDD, while increased CD20+CB2+% may contribute to the pathophysiology of MDD by activating T-independent humoral immunity.

Anxiety due to Long COVID is partially driven by activation of the tryptophan catabolite (TRYCAT) pathway.

This study examines whether activation of the tryptophan catabolite (TRYCAT) pathway is associated with anxiety symptoms due to Long COVID. We selected 90 participants, 60 Long COVID patients and 30 individuals without any symptoms following acute COVID-19 infection. Using cluster analysis and the Hamilton Anxiety Rating scale (HAMA) score, the pure HAMA anxiety score, serum tryptophan (TRP) and kynurenine (KYN), the KYN/TRP ratio (all measured during Long COVID), and oxygen saturation (SpO2) (measured during the acute phase of COVID-19), we were able to classify Long COVID patients into two distinct clusters with an adequate silhouette cohesion and separation index (0.58): cluster 1 (n = 61) and cluster 2 (n = 29). Cluster 2 patients had lower SpO2 and TRP levels, as well as higher KYN, KYN/TRP ratio, and HAMA scores than cluster 1. Regression analysis revealed that the KYN/TRP ratio explained 14.4 % of the variance in the HAMA score (F = 14.81, df = 1/88, p = 0.001). In addition, regression analysis revealed that SpO2 partially explained the variance in serum TRP (r = 0.396, p = 0.005), KYN/TRP ratio (r = - 0.248, p = 0.018), and the HAMA score (r = - 0.279, p = 0.008). The current data imply that decreased SpO2 during the acute phase of COVID-19 infection is predictive of anxiety caused by Long COVID. Our data reveal that around 32 % of Long COVID patients have elevated IDO activity in association with elevated anxiety.

Reverse cholesterol transport and lipid peroxidation biomarkers in major depression and bipolar disorder: A systematic review and meta-analysis.

BACKGROUND: Major depression (MDD) and bipolar disorder (BD) are linked to immune activation, increased oxidative stress, and lower antioxidant defenses. OBJECTIVES: To systematically review and meta-analyze all data concerning biomarkers of reverse cholesterol transport (RCT), lipid-associated antioxidants, lipid peroxidation products, and autoimmune responses to oxidatively modified lipid epitopes in MDD and BD. METHODS: Databases including PubMed, Google scholar and SciFinder were searched to identify eligible studies from inception to January 10th, 2023. Guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. RESULTS: The current meta-analysis included 176 studies (60 BD and 116 MDD) and examined 34,051 participants, namely 17,094 with affective disorders and 16,957 healthy controls. Patients with MDD and BD showed a) significantly decreased RCT (mainly lowered high-density lipoprotein cholesterol and paraoxonase 1); b) lowered lipid soluble vitamins (including vitamin A, D, and coenzyme Q10); c) increased lipid peroxidation and aldehyde formation, mainly increased malondialdehyde (MDA), 4-hydroxynonenal, peroxides, and 8-isoprostanes; and d) Immunoglobulin (Ig)G responses to oxidized low-density lipoprotein and IgM responses to MDA. The ratio of all lipid peroxidation biomarkers/all lipid-associated antioxidant defenses was significantly increased in MDD (standardized mean difference or SMD = 0.433; 95% confidence intervals (CI): 0.312; 0.554) and BD (SMD = 0.653; CI: 0.501-0.806). This ratio was significantly greater in BD than MDD (p = 0.027). CONCLUSION: In MDD/BD, lowered RCT, a key antioxidant and anti-inflammatory pathway, may drive increased lipid peroxidation, aldehyde formation, and autoimmune responses to oxidative specific epitopes, which all together cause increased immune-inflammatory responses and neuro-affective toxicity.