Publications

Contents, Vol. 179, 1989

The tryptophan catabolite or kynurenine pathway in COVID-19 and critical COVID-19: a systematic review and meta-analysis

Abstract Background: Coronavirus disease 2019 (COVID-19) is accompanied by activated immune-inflammatory pathways and oxidative stress, which both may induce indoleamine-2,3-dioxygenase (IDO), a key enzyme of the tryptophan (TRP) catabolite (TRYCAT) pathway. The aim of the current study was to systematically review and meta-analyze the TRYCAT pathway status including levels of TRP and kynurenine (KYN) and IDO activity, as assessed using the KYN/TRP ratio. Methods: This systematic review was performed in December 2021 and searched data in PubMed, Google Scholar, and Web of sciences. In our meta-analysis we included 14 articles which examine TRP and TRYCATs in COVID-19 patients versus non-COVID-19 controls, and severe/critical versus mild/moderate COVID-19. Overall, the analysis was performed on 1269 individuals, namely 794 COVID-19 patients and 475 controls. Results: The results show a significant (p <0.0001) increase in the KYN/TRP ratio (standardized mean difference, SMD=1.099, 95% confidence interval, CI: 0.714; 1.484) and KYN (SMD= 1.123, 95% CI: 0.730;1.516) and significantly lower TRP ((SMD= -1.002, 95%CI: -1.738; -0.266) in COVID-19 versus controls. The KYN/TRP ratio (SMD= 0.945, 95%CI: 0.629; 1.262) and KYN (SMD= 0.806, 95%CI: 0.462; 1.149) were also significantly (p <0.001) higher and TRP lower (SMD= -0.909, 95% CI: -1.569; -0.249) in severe/critical versus mild/moderate COVID-19. No significant difference was detected in the kynurenic acid (KA)/KYN ratio and KA between COVID-19 patients and controls. Conclusions: Our results indicate increased activity of the IDO enzyme in COVID-19 and in severe/critical patients. The TRYCAT pathway is probably implicated in the pathophysiology and progression of COVID-19 and may signal a worse outcome of the disease.

Low serum somatomedin-C in protein deficiency: relationship with changes in liver somatogenic and lactogenic binding sites

Effects of buspirone on plasma prolactin and cortisol levels in major depressed and normal subjects

Impaired Social Skills as a Key Component of Clinical Depression: Associations with Severity of Illness, Self-Esteem, Family Functional Health Satisfaction, and Personality Features

Background: Social skills deficits are present in 43.3% of major depressed patients and significantly impact health-related quality of life. However, studies concerning social deficits as state-dependent markers of depression are limited. Objective: To delineate the effects of severity of depression, personality characteristics, family support satisfaction and self-esteem on social skills in clinical depression. Methods: We recruited 150 patients with major depressive disorder or persistent depressive disorder and assessed 1) Beck Depression Inventory-II (BDI-II), 2) Social Skill Inventory (SSI), 3) Family Adaptation, Partnership, Growth, Affection, Resolve (APGAR) Questionnaire 4) Rosenberg Self-Esteem Scale (RSES) and 5) Maudsley Personal Inventory (MPI). Results: Social skills deficits were significantly associated with female gender, age < 40 years, depression severity, introvert / neurotic personality, and lowered family support satisfaction and self-esteem. A large part of the variance (47.2%) in social skills deficits was predicted by satisfaction of family support, introvert personality, and low self-esteem. Exploratory Factor Analysis showed that a bifactorial model best fitted the data with a) a general factor loading highly on BDI-II, SSI emotional and social, APGAR, RSES, MPI_introvert and MPI_neurotic scores, and b) a single-group factor loading on both SSI, RSES, and MPI introvert scores. Conclusion: In clinical depression, social skills deficits covary with increasing severity of depression and thus constitute a state marker of depression, and independently from severity of depression covary with introvert personality features. As such, remission of social skills deficits may emerge as a novel objective for the treatment of depression and prevention of new episodes.

Serum Interleukin Levels and Insulin Resistance in Major Depressive Disorder

Major depressive disorder (MDD) has been associated with inflammatory processes, including increased cytokine levels, even in individuals who are otherwise physically healthy, while some MDD patients may show insulin resistance (IR).However, correlations between cytokines and IR parameters have not been studied extensively in MDD. In the present study, we measured IL-1β, IL-4, IFN-γ, TGF-β1, insulin and glucose in 63 MDD patients and 27 healthy controls. The associations between cytokine levels and IR were examined.The results revealed a significant increase (p<0.05) in serum levels of IL-1β, IL-4, IFN-γ, TGF-β1, insulin, insulin/glucose ratio, and insulin resistance (HOMA2IR) in MDD patients as compared with controls. There was a significant correlation between HOMA2IR with both IFN-γ (ρ=0.289, p<0.05) and TGF-β1 (ρ=0.364, p<0.05).The present study further confirms that MDD is accompanied by activation of the immune system with significant elevations in the levels of four cytokines. These results indicate stimulation of the immune system and increased IR and modulation of IR by increased cytokine levels in MDD. These findings show that immune activation and associated IR are a new drug target in depression.

The Microbiota-Gut-Immune-Glia (MGIG) Axis in Major Depression

Dietary Protein Restriction Decreases Insulin-Like Growth Factor I Independent of Insulin and Liver Growth Hormone Binding*

To determine the role of hypoinsulinemia and liver somatogenic (GH) receptors in growth retardation and decreased serum insulin-like growth factor I (IGF-I) levels during protein restriction, we have used a rat model where the effects of a low protein intake on body weight (BW), serum IGF-I concentration, and liver GH binding could be evaluated in the presence of low or high insulin concentrations. Two days after being made diabetic with streptozotocin (60 mg/kg BW), 6-week-old female rats (nine per group) were begun on a low (5%) or normal (15%) protein diet, without or with insulin supplementation (3 U lente daily). Nondiabetic rats fed both diets were used as controls (nine per group). In the nondiabetic animals, 7 days of protein restriction reduced BW gain by 50% (P less than 0.001), serum insulin by 44% (P less than 0.025), and serum IGF-I concentrations by 28% (P less than 0.001) without significantly changing liver GH binding. By day 9, BW was decreased in the diabetic animals by 12%, serum insulin by 80%, serum IGF-I by 55%, and liver GH binding by 62%; these effects were similar in the 5% and 15% protein-fed rats (P less than 0.001 vs. the corresponding controls). In the diabetes fed the normal diet, insulin treatment restored BW gain, serum IGF-I, and liver GH binding to normal values. In contrast, in the diabetics fed a protein-restricted diet and treated with insulin, BW gain and serum IGF-I concentrations remained low, similar to those in the malnourished controls. This diet-induced growth attenuation was observed despite high circulating insulin (2-3 times normal values), appropriate glucose control (63 +/- 9 mg/dl), and near restoration of liver GH binding. We conclude that while both protein restriction and diabetes attenuate growth and reduce IGF-I concentrations, the effects of protein restriction are independent of the effects of insulin and probably act by alteration of postreceptor mechanisms.

Advancements in the molecular understanding of major depressive disorder uncovering novel targets with therapeutic promise: focus on recurrence of illness

The future of recurrent MDD therapeutics resides in multi-targeting the ROI-associated pathways with NIMETOX-guided interventions aimed at attenuating immune sensitization, rectifying metabolic dysfunction, reducing oxidative toxicity, and concurrently restoring neuroplasticity. The development of such integrative therapies is an urgent imperative if we are to alter the natural trajectory of recurrent depression.

The cytokine, chemokine, and growth factor network of prenatal depression

Abstract Background Neuro-immune pathways are engaged in antenatal and postpartum depression. Aims: To determine if immune profiles influence the severity of prenatal depression above and beyond the effects of adverse childhood experiences (ACE), premenstrual syndrome (PMS) and current psychological stressors. Methods Using the Bio-Plex Pro human cytokine 27-plex test kit, we assayed M1 macrophage, T helper (Th)-1, Th-2, Th-17, growth factor, chemokine, T cell growth immune profiles as well as indicators of the immune inflammatory response system (IRS) and compensatory immunoregulatory system (CIRS) in 120 pregnant females in the early (&lt;16 weeks) and late (&gt; 24 weeks) pregnancy. The Edinburgh Postnatal Depression Scale (EPDS) was used to assess severity of antenatal depression. Results Cluster analyses showed that the combined effects of ACE, relationship dissatisfaction, unwanted pregnancy, PMS, and upregulated M1, Th-1, Th-2 and IRS immune profiles and the ensuing early depressive symptoms shape a stress-immune-depression phenotypic class. Elevated IL-4, IL-6, IL-8, IL-12p70, IL-15, IL-17 and GM-CSF are the primary cytokines associated with this new phenotypic class. All immune profiles (except CIRS) were significantly associated with the early EPDS score, independent of the effects of psychological variables and PMS. There was a shift in immune profiles from early to late pregnancy, with an increase in the IRS/CIRS ratio. The late EPDS score was predicted by the early EPDS score, adverse experiences, and immune profiles, mainly the Th-2 and Th-17 phenotypes. Conclusions Activated immune phenotypes contribute to early and late perinatal depressive symptoms above and beyond the effects of psychological stressors and PMS.

Recognizing the Leaky Gut as a Trans-diagnostic Target for Neuroimmune Disorders Using Clinical Chemistry and Molecular Immunology Assays

Increased intestinal permeability with heightened translocation of Gramnegative bacteria, also known as "leaky gut", is associated with the pathophysiology of neuroimmune disorders, such as Major Depressive Disorder (MDD), Chronic Fatigue Syndrome (CSF) and (deficit) schizophrenia, as well as with general medical disorders, including irritable bowel syndrome. This review aims to summarize clinical biochemistry and molecular immunology tests that may aid in the recognition of leaky gut in clinical practice.We searched online libraries, including PubMed/MEDLINE, Google Scholar and Scopus, with the key words "diagnosis" or "biomarkers" and "leaky gut", "bacterial translocation", and "intestinal permeability" and focused on papers describing tests that may aid in the clinical recognition of leaky gut.To evaluate tight junction barrier integrity, serum IgG/IgA/IgM responses to occludin and zonulin and IgA responses to actomyosin should be evaluated. The presence of cytotoxic bacterial products in serum can be evaluated using IgA/IgM responses to sonicated samples of common Gram-negative gut commensal bacteria and assays of serum lipopolysaccharides (LPSs) and other bacterial toxins, including cytolethal distenting toxin, subunit B. Major factors associated with increased gut permeability, including gut dysbiosis and yeast overgrowth, use of NSAIDs and alcohol, food hypersensitivities (IgE-mediated), food intolerances (IgG-mediated), small bacterial overgrowth (SIBO), systemic inflammation, psychosocial stressors, some infections (e.g., HIV) and dietary patterns, should be assessed. Stool samples can be used to assay gut dysbiosis, gut inflammation and decreased mucosal defenses using assays of fecal growth of bacteria, yeast and fungi and stool assays of calprotectin, secretory IgA, β-defensin, α- antitrypsin, lysozyme and lactoferrin. Blood and breath tests should be used to exclude common causes of increased gut permeability, namely, food hypersensitivities and intolerances, SIBO, lactose intolerance and fructose malabsorption.Here, we propose strategies to recognize "leaky gut" in a clinical setting using the most adequate clinical chemistry and molecular immunology assays.

&lt;strong&gt;Wnt/β-Catenin Pathway Proteins in End-Stage Renal Disease&lt;/strong&gt;&lt;strong&gt; &lt;/strong&gt;

Background. Wnt-pathway proteins play a vital role in kidney development and defects in the Wnt-pathway are associated with kidney disorders. However, the knowledge on the role of Wnt/&amp;beta;-catenin pathway proteins in end-stage renal disease (ESRD) is limited.Aim of the study. To delineate the association of ESRD and Wnt-proteins including the agonistR-spondin 1, the transducer &amp;beta;-catenin and the antagonists Dickkopf-related protein 1 (DKK1) and sclerostin.Methods. Serum Wnt-pathway proteins levels were measured by ELISA, while other biochemicals were measured spectrophotometrically in 60 ESRD patients and 30 normal controls.Results. DKK1 and sclerostin were significantly higher in ESRD than in controls, and &amp;beta;-catenin and the catenin + R-Sponin-1 / DKK1 + sclerostin ratio, reflecting the ratio of agonist and transducer on antagonists (AT/ANTA), were significantly lower in ESRD. Logistic regression analysis showed that ESRD was significantly predicted by increased levels of DDK1 and sclerostin and lowered &amp;beta;-catenin (p&amp;lt;0.001). eGFR was significantly associated with DKK1 and sclerostin (inversely), &amp;beta;-catenin (positively) and the AT/ANTA ratio (r=0.468, p&amp;lt;0.001). DKK1 levels were significantly and positively correlated with urea, creatinine, and copper. DKK1 and sclerostin were inversely associated with hemoglobin and packet cell volume. Catenin was significantly negatively associated with copper, urea and creatinine.Conclusion. Wnt/&amp;beta;-catenin pathway proteins show significant alterations in ESRD, indicating significantly increased levels of antagonists and, therefore, attenuated Wnt/&amp;beta;-catenin pathway activity. The latter is associated with lowered eGFR and increased serum copper levels. Wnt/&amp;beta;-catenin pathway proteins are possible drug targets to treat ESRD or its consequences.

Letters to the Editor

No abstract is provided for this article.

Clinical subtypes of unipolar depression: Part I. A validation of the vital and nonvital clusters

Decreased platelet alpha-2 adrenoceptor density in major depression: effects of tricyclic antidepressants and fluoxetine

Adjunctive minocycline for major depressive disorder: A sub-study exploring peripheral immune-inflammatory markers and associated treatment response

Adjunctive minocycline shows promise in treating affective and psychotic disorders; however, the therapeutic mechanism remains unclear. Identifying relevant biomarkers may enhance the efficacy of novel adjunctive treatment candidates. We thus investigated the peripheral immune-inflammatory profile in a randomized controlled trial (RCT) of minocycline in major depressive disorder (MDD).This sub-study investigated serum samples from a RCT evaluating minocycline (200 mg/day, 12 weeks) in addition to treatment as usual for MDD (ACTRN12612000283875). Of the original sample (N = 71), serum assays were conducted in 47 participants (placebo n = 24; minocycline n = 23) targeting an array of 46 immune-inflammatory analytes including cytokines, chemokines, and acute-phase reactants. General estimating equations (GEE) were used to assess whether analyte concentration at baseline (effect modification) and change in analytes (change association) influenced change in Montgomery-Åsberg Depression Rating Scale (MADRS) score over time. The Benjamini-Hochberg approach was applied when adjusting for false discovery rates (FDR).GEE models revealed several interaction effects. After adjusting for FDR several change association-models survived correction. However, no such models remained significant for effect modification. Three-way group × time × marker interactions were significant for complement C3 (B = -10.46, 95%CI [-16.832, -4.095], q = 0.019) and IL-1Ra (B = -9.008, 95%CI [-15.26, -2.751], q = 0.036). Two-way group × biomarker interactions were significant for ICAM-1/CD54 (B = -0.387, 95%CI [-0.513, -0.26], q < 0.001) and IL-8/CXCL8 (B = -4.586, 95%CI [-7.698, -1.475], q = 0.036) indicating that increases in the serum concentration of these analytes were associated with an improvement in MADRS scores in the minocycline group (compared with placebo).Change in complement C3, IL-1Ra, IL-8/CXCL8, and ICAM-1 may be associated with greater change in depressive scores following adjunctive minocycline treatment in MDD. Further investigations are needed to assess the utility of these biomarkers.

Association between immune activation and early depressive symptoms in cancer patients treated with interleukin-2-based therapy

Is dynapenia associated with the onset and persistence of depressive and anxiety symptoms among older adults? Findings from the Irish longitudinal study on ageing

Objectives The aim of the current study was to assess the associations between dynapenia and the onset and persistence of depression and anxiety among older adults.Methods This prospective cohort study enrolled community-living older adults (N = 5271; 51.1% females) aged ≥ 50 years (mean age = 63.2, standard deviation = 9.0) from The Irish Longitudinal Study on Aging (TILDA), Ireland. At baseline, participants completed a handgrip assessment. Depression was defined by a score ≥ 16 in the Center of Epidemiology Studies Depression (CES-D) tool and anxiety was considered when participants scored ≥ 8 on the anxiety section of the Hospital Anxiety and Depression Scale (HADS). Outcomes were incident and persistent depression and anxiety at two years follow-up. Multivariable logistic regression models were built for each outcome.Results After controlling for age, sex, education, marital status, employment status, smoking, body mass index, number of chronic conditions, physical activity, and cognitive function, low handgrip strength indicative of dyapenia (< 30 Kg for men and < 20 Kg for women) was associated with a greater likelihood for incident depressive (OR = 1.44; 95%CI: 1.08–1.92) as well as for persistent depressive (OR = 1.61; 95% CI: 1.01–2.58) and anxiety (OR = 1.61; 95% CI: 1.20–2.14) symptoms.Conclusions Dynapenia was associated with a higher odds of developing depressive symptoms as well as a greater likelihood to persistent depressive and anxiety symptoms among older adults. Our data suggest that interventions targeting muscle strength may prevent the onset of late-life depression and also may hold promise as novel therapeutic opportunities for depression and anxiety in later life.