Background: Contrary to the negative acute-phase protein (APP) response, there is no consistent correlation between serum pentameric C-reactive protein (pCRP) and major depression (MDD). Monomeric CRP (mCRP), a dissociation product of pCRP under immune-inflammatory conditions, exhibits pro-inflammatory effects; however, it has not been investigated in MDD or its subtypes, major dysmood disorder (MDMD) and simple dysmood disorder (SDMD). Objective: To examine serum mCRP, albumin, transferrin, M1 macrophage and Thelper-17 immune profiles, and adverse childhood experiences (ACEs) in MDD, MDMD and SDMD. Methods: Seventy-nine MDMD patients, 30 SDMD patients, and 40 controls were included. Serum mCRP was measured by ELISA; albumin, transferrin, and pCRP by biochemical assays; and cytokines using Luminex technology. Results: MDMD patients showed significantly higher mCRP compared with SDMD and controls, while both patient groups exhibited reduced albumin and transferrin. Combining mCRP with albumin and transferrin showed an adequate accuracy for MDD (area under the ROC Curve = 0.793). Adding IL-17A and ACEs improved accuracy (ROC = 0.855). Serum mCRP levels are additionally associated with pCRP, M1 macrophage profile, body mass index, and ACEs. Up to 36.6% of the variance in overall severity of depression was explained by mCRP, T-helper-17 profile, ACEs (all positively), albumin and transferrin (both inversely). Conclusion: Future research in MDD should employ mCRP rather than pCRP as a biomarker of depression/MDMD. Combining mCRP with biomarkers of the negative acute-phase response identified 63.7% of MDD patients with a smouldering acute-phase response, with a specificity of 82.1%. We recommend to assess mCRP rather than pCRP in MDD studies.

Introduction: Anxiety disorders continue to prevail as the most prevalent cluster of mental disorders following the COVID-19 pandemic, exhibiting substantial detrimental effects on individuals’ overall well-being and functioning. Even after a search spanning over a decade for novel anxiolytic compounds, none have been approved, resulting in the current anxiolytic medications being effective only for a specific subset of patients. Consequently, researchers are investigating everyday nutrients as potential alternatives to conventional medicines. Our prior study analyzed the antianxiety and memory-enhancing properties of the combination of Walnut Peptide (WP) and Casein Peptide (CP) in zebrafish.Methods and Results: Based on this work, our current research further validates their effects in mice models exhibiting elevated anxiety levels through a combination of gavage oral administration. Our results demonstrated that at 170 + 300 mg human dose, the WP + CP combination significantly improved performances in relevant behavioral assessments related to anxiety and memory. Furthermore, our analysis revealed that the combination restores neurotransmitter dysfunction observed while monitoring Serotonin, gamma-aminobutyric acid (GABA), dopamine (DA), and acetylcholine (ACh) levels. This supplementation also elevated the expression of brain-derived neurotrophic factor mRNA, indicating protective effects against the neurological stresses of anxiety. Additionally, there were strong correlations among behavioral indicators, BDNF (brain-derived neurotrophic factor), and numerous neurotransmitters.Conclusion: Hence, our findings propose that the WP + CP combination holds promise as a treatment for anxiety disorder. Besides, supplementary applications are feasible when produced as powdered dietary supplements or added to common foods like powder, yogurt, or milk.

Background: Major depressive disorder (MDD) is associated with neuro-immune – metabolic – oxidative (NIMETOX) pathways. Aims: To examine the connections among NIMETOX pathways in outpatient MDD (OMDD) with and without metabolic syndrome (MetS); and to determine the prevalence of NIMETOX aberrations in a cohort of OMDD patients. Methods: We included 67 healthy controls and 66 OMDD patients and we assessed various NIMETOX pathways. Results: We successfully identified a subgroup of individuals with aberrations in NIMETOX pathways, including diminished lecithin-cholesterol acyltransferase (LCAT), paraoxonase 1 (PON1) activity, and reverse cholesterol transport (RCT) activities, and elevated atherogenicity, differentially expressed immune networks, and advanced oxidation protein products (AOPP). A large part of the variance (around 44%) in atherogenicity indices was associated with AOPP, fasting blood glucose (FBG), PON1 activity, and immune activation. LCAT activity was positively correlated with PON1 activity and negatively with FBG, AOPP and immune activation. RCT was positively related with the PON1 R/R 192 genotype and negatively with FBG and immune activation. A larger part of the variance in the overall severity of OMDD (50.4%), suicidal behaviors (27.7%), and neuroticism (42.1%) was positively associated with adverse childhood experiences and NIMETOX pathways, including AOPP, immune-related neurotoxicity, FBG, insulin, and atherogenicity, and inversely with immune-related neuroprotection. Conclusions: Many OMDD patients (78.8%) show aberrations in NIMETOX pathways. The features of OMDD, including severity of illness, neuroticism, and suicidal behaviors, are caused by intertwined NIMETOX pathways that may exert additional effects depending on whether MetS is present or not.

Anxiety disorders are the most common mental disorders and, without proper treatment, may lead to severe conditions: e.g., somatic disorders or permanent damage to central nervous system. Although there are drugs in clinical trials, this study focuses on exploring the efficacy of nutrients in treating these diseases. We built different zebrafish models and screened several nutrient combinations for their antianxiety, antioxidant, neuro-protecting, and memory-improving activities. Our results showed that the combinations of nutrients (e.g., Walnut Peptides + Theanine at 14.2 + 33.3 μg/ml) have similar or better activities than the positive control drugs. In addition, we discovered that the effects of the nutrients in the above four aspects were universal and highly related. This study is noteworthy as it suggested that nutrients could be healthier and greener drug alternatives and provide similar or better universal treatments for anxiety and related conditions.

Current state-of-the-art neuroimmune, metabolic, and oxidative stress (NIMETOX) knowledge that has been developed in clinical major depressive disorder (MDD) research over the past three decades is explored in this review. Between 1990 and 2000, the acute phase of severe MDD was characterized by the activation of T helper (Th)1 cells and M1 macrophages, leading to immune dysregulation that affects nutritional immunity and alters protein, tryptophan, iron, and lipid metabolism. The latter comprises lower high-density lipoprotein cholesterol, reverse cholesterol transport (RCT), ω3 polyunsaturated fatty acids, heightened lipid peroxidation and atherogenicity. Additionally, immune alterations regulate stress-responsive systems and modify the biological basis of depressive symptoms through neurotoxic effects and reduced neuroprotection. The incremental information acquired from 2000 to 2026 revealed that the acute phase of severe MDD is characterized by immune sensitization, imbalances between the compensatory immunoregulatory system (CIRS) and the immune-inflammatory response system (IRS) and that there are multiple interactions between increased atherogenicity, metabolic syndrome, oxidative stress, and lower antioxidant activity and RCT. Additionally, the NIMETOX pathway may be fuelled by increased expression of TLR4 and NF-κB intracellular signaling driven by increased lipopolysaccharides, lipids, and oxidatively modified epitopes. This paper presents evidence that peripheral NIMETOX pathways may lead to neuroinflammation, microglial activation, and neuronal damage and that increased lipid load impairs these central pathways. This paper assesses the field’s future advancements by conducting a comprehensive examination of the reviewed knowledge base, deep phenotyping, panomics methodologies, and machine learning techniques, including the nomothetic precision approach.

Background Multiple sclerosis (MS) is a chronic autoimmune disorder affecting the central nervous system (CNS). Reactivation of Human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) is observed in MS. Objectives This study investigates immunoglobulins (Ig)G, IgM, and IgA directed against EBV nuclear antigen EBNA-366-406, HHV-6 and EBV deoxyuridine-triphosphatase (dUTPase), and different immune profiles in 58 patients with relapsing remitting MS (RRMS) compared to 60 healthy controls. Methods We employed enzyme-linked immunosorbent assays (ELISA) to measure the immunoglobulins to viral antigens. Multiplex immunoassays were used to measure cytokines, chemokines and growth factor levels that were used to compute immune profiles, including M1 macrophage, T helper (Th)-1, Th-17, and overall immune activation. We assessed disabilities using the Expanded Disability Status Scale (EDSS) and disease progression using the Multiple Sclerosis Severity Score (MSSS). Results IgG/IgA/IgM directed to the three viral antigens were significantly higher in RRMS than in controls. RRMS was significantly discriminated from controls by using IgG and IgM against HHV-6 dUTPase, yielding an accuracy of 91.5% (sensitivity=87.3% and specificity=95.2%). Neural network analysis showed that using IgG to EBV-dUTPase, IgM to EBV-dUTPase, and immune profiles yielded an area under the ROC curve of 1 and a predictive accuracy of 97.1%. There were strong associations between IgG/IgM responses to HHV-6 and EBV-dUTPases and the EDSS/MSSS scores and aberrations in M1, Th-17, profiles, and overall immune activation. Conclusions HHV-6 and EBV reactivation play a key role in RRMS and these effects are mediated by activation of cytokine profiles.