Yingqian Zhang

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: Major depression (MDD) is linked to neuro-immune, metabolic, and oxidative stress (NIMETOX) pathways. The gut microbiome may contribute to these pathways via leaky gut and immune–metabolic processes. Aims: To identify gut microbial alterations in MDD and to quantify functional pathways and enzyme gene families and integrate these with the clinical phenome and immune–metabolic biomarkers of MDD. Methods: Shotgun metagenomics with taxonomic profiling was performed in MDD versus controls using MetaPhlAn v4.0.6, and functional profiling was conducted using HUMAnN v3.9, aligning microbial reads to species-specific pangenomes (Bowtie2 v2.5.4) followed by alignment to the UniRef90 v201901 protein database (DIAMOND v2.1.9). Results: Gut microbiome diversity, both species richness and evenness, is quite similar between MDD and controls. The top enriched taxa in the multivariate discriminant profile of MDD reflect gut dysbiosis associated with leaky gut and NIMETOX mechanisms, that is, Ruminococcus gnavus, Veillonella rogosaem, and Anaerobutyricum hallii . The top four protective taxa enriched in controls indicate an anti-inflammatory ecosystem and microbiome resilience, that is, Vescimonas coprocola , Coprococcus , Faecalibacterium prausnitzii , and Faecalibacterium parasitized . Pathway analysis indicates loss of barrier protection, antioxidants, and short-chain fatty acids, and activation of NIMETOX pathways. The differential abundance of gene families suggests that there are metabolic distinctions between both groups, indicating aberrations in purine, sugar, and protein metabolism. The gene and pathway scores explain a larger part of the variance in suicidal ideation, recurrence of illness, neurocognitive impairments, immune functions, and atherogenicity. Conclusion: The gut microbiome changes might contribute to activated peripheral NIMETOX pathways in MDD.

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.

Background: accumulating evidence suggests that Long COVID (LC) is mediated by chronic immune activation, oxidative stress, and metabolic dysregulation. These processes may impair glucose homeostasis and promote insulin resistance (IR). However, no prior meta-analysis has systematically and quantitatively evaluated IR indices and related biomarkers in LC compared with normal controls. Objectives: To systematically review and meta-analyze composite and solitary indices of IR, β-cell function, and adipokine levels in individuals with LC compared with normal controls. Methods: PubMed, SCOPUS, and Google Scholar databases were searched for relevant studies from inception to August 2025. Sixty-three eligible studies were included, comprising 12,409 participants—5,891 LC patients and 6,518 normal controls. Results: LC disease is characterized by elevated global IR (standardized mean difference, SMD = 0.395; 95% confidence intervals, CI: 0.226;0.563), Fasting insulin + C-peptide + FBG composite score (SMD = 0.605; 95% CI: 0.306;0.904) and acute + chronic glycemia composite scores (SMD = 0.424; 95% CI: 0.258;0.590). Furthermore, significant increases in HOMA-IR (SMD = 0.621; 95% CI: 0.379;0.863), Insulin (SMD = 0.488; 95% CI: 0.202;0.774), HbA1c (SMD = 0.308; 95% CI: 0.053;0.563), and fasting and random blood glucose (SMD = 0.831; 95% CI: 0.271;1.391, SMD = 0.396; 95% CI: 0.188;0.605) alongside reduced HOMA-%B and HOMA-%S were observed in LC patients versus normal controls. No publication bias observed in the results. Conclusion: The current study suggests that LC disease is characterized by persistent insulin resistance, hyperglycemia, and β-cell dysfunction, suggesting sustained metabolic disturbances beyond the acute phase

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 AP response shows that around 63.7% of MDD patients have a smoldering acute phase response with high specificity.

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.

Aims This study investigated a) whether the affective, chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), respiratory, and neurological Long COVID (LC) symptom domains are intercorrelated manifestations of an underlying construct, namely the LC phenome; and b) the predictive effects of clinical symptoms and biomarkers of the COVID-19 infectious phase on LC. Methods This cohort study included 71 LC patients who had suffered from COVID-19 six months prior. The patients complied with the LC disease criteria set forth by the World Health Organization (WHO). We used the WHO symptom list to score the LC symptoms and assessed SARS-CoV-2 positivity using real-time reverse transcription-polymerase chain reaction (RT-PCR), white blood cell counts, anion gap, alanine transaminase (ALT) levels, paraoxonase 1 (PON1) activity and genotypes, total radical trapping potential of plasma (TRAP), and nitric oxide metabolites (NOx). Results All four clinical LC subdomains are significantly intercorrelated, allowing for the extraction of a single latent construct encompassing affective, CFS/ME, respiratory, and neurological symptoms, labeled the physio-affective phenome of LC. The latter was strongly predicted by dyspnea and productive sputum, RT-PCR SARS-CoV-2 cycle threshold values, lower anion gap, and increased neutrophil percentage during the infectious phase. Other predictive biomarkers were lower ALT, TRAP, and NOx levels, and the PON1 QR192 over dominant gene model (protective). Conclusions LC may be a clinically homogeneous disease characterized by highly intercorrelated affective, CFS, neurological, and respiratory subdomains. The physio-affective phenome and its domains are strongly predicted by biomarkers of acute infection and associated inflammation and oxidative stress.