Construction of a Zn(II)-Eu(III) Nanoring with Temperature-Dependent Luminescence for the Qualitative and Quantitative Detection of Neopterin as an Inflammatory Marker.

A nine-metal Zn(II)-Eu(III) nanoring 1 with a diameter of about 2.3 nm was constructed by the use of a long-chain Schiff base ligand. It shows a luminescence response to neopterin (Neo) through the enhancement of lanthanide emission with high selectivity and sensitivity, which can be used to quantitatively analyze the concentrations of Neo in fetal calf serum and urine. The luminescence sensing of 1 to Neo is temperature-dependent, and it displays more obvious response behavior at lower temperatures. Filter paper strips bearing 1 can be used to qualitatively detect Neo by the color change from chartreuse to red under a UV lamp. The limit of detection is as low as 3.77 × 10-2 nM.

Role of neopterin as an inflammatory biomarker in congestive heart failure with insights on effect of drug therapies on its level.

Inflammation has a major role in the pathogenesis of heart failure (HF). It triggers a cascade that leads to the release of pro-inflammatory cytokines which in turn cause cardiac hypertrophy, fibrosis, apoptosis, negative inotorpy and leukocyte recruitment which worsen the condition. Neopterin is an inflammatory biomarker which is released as a response to macrophage activation. Levels of neopterin are elevated in conditions which has an immunological component such as autoimmune disease, viral and bacterial infections and malignancy. Neopterin levels were found to be elevated in patients with HF. This is due to the fact that inflammation takes place during the development of the condition. Studies demonstrated that neopterin can be used as a biomarker for diagnosing HF, determining severity of the disease and monitoring its progression. Neopterin levels were higher in patients with New York Heart Association classification (NYHA) III-IV more than class I-II. Moreover, neopterin levels correlated well with morbidity and mortality. It has been suggested that neopterin be monitored levels to determine effectiveness of HF treatment options.

Following the Clues: Usefulness of Biomarkers of Neuroinflammation and Neurodegeneration in the Investigation of HTLV-1-Associated Myelopathy Progression.

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease due to axonal damage of the corticospinal secondary to an inflammatory response against infected T-cells. In the present work, we aimed to evaluate biomarkers of neurodegeneration and neuroinflammation in the definition of HAM/TSP prognosis. Neurofilament light (NfL) and phosphorylated heavy (pNfH) chains, total Tau protein, cellular prion protein (PrPc), inflammatory chemokines, and neopterin were quantified in paired cerebrospinal fluid (CSF) and serum samples from HAM/TSP patients (n=21), HTLV-1 asymptomatic carriers (AC) (n=13), and HTLV-1 seronegative individuals with non-inflammatory non-degenerative neurological disease (normal-pressure hydrocephalus) (n=9) as a control group. HTLV-1 proviral load in peripheral blood mononuclear cells and the expression of chemokine receptors CCR4, CCR5, and CXCR3 in infected CD4+ T-cells (HTLV-1 Tax+ cells) were also assessed. CSF levels of Tau, NfL, and pNfH were similar between groups, but PrPc and neopterin were elevated in HAM/TSP patients. Most individuals in the control group and all HTLV-1 AC had CSF/serum neopterin ratio < 1.0, and two-thirds of HAM/TSP patients had ratio values > 1.0, which positively correlated with the speed of disease progression and pNfH levels, indicating active neuroinflammation. HAM/TSP patients showed high serum levels of CXCR3-binding chemokines (CXCL9, CXCL10, and CXCL11) and elevated CSF levels of CCL2, CCL3, CCL4, CCL17, CXCL5, CXCL10, and CXCL11. Indeed, CXCL10 concentration in CSF of HAM/TSP patients was 5.8-fold and 8.7-fold higher in than in HTLV-1 AC and controls, respectively, and correlated with CSF cell counts. HAM/TSP patients with typical/rapid disease progression had CSF/serum CXCL10 ratio > 1.0 and a higher frequency of CXCR3+Tax+CD4+ T-cells in blood, which indicated a positive gradient for the migration of infected cells and infiltration into the central nervous system. In conclusion, the slow progression of HAM/TSP abrogates the usefulness of biomarkers of neuronal injury for the disease prognosis. Thus, markers of inflammation provide stronger evidence for HAM/TSP progression, particularly the CSF/serum neopterin ratio, which may contribute to overcome differences between laboratory assays.

Targeting interferon-γ in hyperinflammation: opportunities and challenges.

Interferon-γ (IFNγ) is a pleiotropic cytokine with multiple effects on the inflammatory response and on innate and adaptive immunity. Overproduction of IFNγ underlies several, potentially fatal, hyperinflammatory or immune-mediated diseases. Several data from animal models and/or from translational research in patients point to a role of IFNγ in hyperinflammatory diseases, such as primary haemophagocytic lymphohistiocytosis, various forms of secondary haemophagocytic lymphohistiocytosis, including macrophage activation syndrome, and cytokine release syndrome, all of which are often managed by rheumatologists or in consultation with rheumatologists. Given the effects of IFNγ on B cells and T follicular helper cells, a role for IFNγ in systemic lupus erythematosus pathogenesis is emerging. To improve our understanding of the role of IFNγ in human disease, IFNγ-related biomarkers that are relevant for the management of hyperinflammatory diseases are progressively being identified and studied, especially because circulating levels of IFNγ do not always reflect its overproduction in tissue. These biomarkers include STAT1 (specifically the phosphorylated form), neopterin and the chemokine CXCL9. IFNγ-neutralizing agents have shown efficacy in the treatment of primary haemophagocytic lymphohistiocytosis in clinical trials and initial promising results have been obtained in various forms of secondary haemophagocytic lymphohistiocytosis, including macrophage activation syndrome. In clinical practice, there is a growing body of evidence supporting the usefulness of circulating CXCL9 levels as a biomarker reflecting IFNγ production.

Neurofilament Light in CSF and Plasma Is a Marker of Neuronal Damage in HTLV-1-Associated Myelopathy and Correlates With Neuroinflammation.

BACKGROUND AND OBJECTIVES: To evaluate the usefulness of CSF and plasma neurofilament light (Nf-L) as a biomarker for human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy (HAM). METHODS: Nf-L, CXCL10, and neopterin were measured by ELISA in 83 CSF samples obtained from 49 individuals living with HTLV-1/2. Plasma Nf-L was also measured by single molecule array. Results were correlated with duration of disease, age, mobility, CSF cell counts, CSF protein, and HTLV-1 proviral load. RESULTS: Nf-L was detected in all CSF samples (median [range] = 575 [791.8-2,349] pg/mL) and positively correlated with markers of inflammation (CXCL10 (r = 0.733), neopterin (r = 0.499), cell count (r = 0.403), and protein levels (r = 0.693) in CSF; p < 0.0015). There was an inverse correlation between Nf-L and duration of disease (r = -0.584, p < 0.0001). Wheelchair-dependent patients had high concentrations of markers of inflammation and neuronal damage. Concentrations of CXCL10, neopterin, and Nf-L remained elevated in follow-up samples (mean follow-up 5.2 years). Nf-L in plasma correlated with concentration of Nf-L, neopterin, CXCL10, and protein in CSF. CONCLUSIONS: Nf-L in plasma and CSF has potential to be used as a biomarker of disease activity in HAM. Neuronal damage seems to be more intense early in disease but persists long term. Wheelchair-dependent patients have ongoing neuroinflammation.

Effect of Helicobacter Pylori on Plasma Metabolic Phenotype in Patients With Gastric Cancer.

BACKGROUND: Although Helicobacter pylori (Hp) as high risk factor for gastric cancer have been investigated from human trial, present data is inadequate to explain the effect of Hp on the changes of metabolic phenotype of gastric cancer in different stages. PURPOSE: Herein, plasma of human superficial gastritis (Hp negative and positive), early gastric cancer and advanced gastric cancer analyzed by UPLC-HDMS metabolomics can not only reveal metabolic phenotype changes in patients with gastric cancer of different degrees (30 Hp negative, 30 Hp positive, 20 early gastric cancer patients, and 10 advanced gastric cancer patients), but also auxiliarily diagnose gastric cancer. RESULTS: Combined with multivariate statistical analysis, the results represented biomarkers different from Hp negative, Hp positive, and the alterations of metabolic phenotype of gastric cancer patients. Forty-three metabolites are involved in amino acid metabolism, and lipid and fatty acid metabolism pathways in the process of cancer occurrence, especially 2 biomarkers glycerophosphocholine and neopterin, were screened in this study. Neopterin was consistently increased with gastric cancer progression and glycerophosphocholine tended to consistently decrease from Hp negative to advanced gastric cancer. CONCLUSION: This method could be used for the development of rapid targeted methods for biomarker identification and a potential diagnosis of gastric cancer.

Pharmacodynamic biomarkers of long-term interferon beta-1a therapy in REFLEX and REFLEXION.

This post-hoc analysis evaluated candidate biomarkers of long-term efficacy of subcutaneous interferon beta-1a (sc IFN ß-1a) in REFLEX/REFLEXION studies of clinically isolated syndrome. Samples from 507 REFLEX and 287 REFLEXION study participants were analyzed. All investigated biomarkers were significantly upregulated 1.5-4-fold in response to sc IFN ß-1a treatment versus baseline (p ≤ 0.008). The validity of MX1, 2'5'OAS, and IL-1RA as biomarkers of response to sc IFN ß-1a was confirmed in this large patient cohort, with biomarkers consistently upregulated in a dose-dependent manner. Neopterin, TRAIL, and IP-10 were confirmed as biomarkers associated with long-term sc IFN ß-1a treatment efficacy over 5 years.

Preoperative inflammatory mediators and postoperative delirium: systematic review and meta-analysis.

BACKGROUND: Postoperative delirium has eluded attempts to define its complex aetiology and describe specific risk factors. The role of neuroinflammation as a risk factor, determined by measuring blood levels of preoperative 'innate' inflammatory mediator levels, has been investigated. However, results have been conflicting. We conducted a systematic review and meta-analysis of the evidence on associations between preoperative blood levels of inflammatory mediators and postoperative delirium in the older person. Influence of type of surgery was also assessed. METHODS: Original, low risk of bias studies, published in peer-reviewed journals, which fulfilled the eligibility criteria were included. Seventeen articles fulfilled study criteria. Data extraction, synthesis, and risk of bias analysis were guided by Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and quality in prognostic studies guidelines. Meta-analyses used a random-effects model. Inflammatory mediators included C-reactive protein, interleukin-6, -8, and -10, tumour necrosis factor-α, insulin-like growth factor-1, cortisol, and neopterin. Surgical groups were cardiac, noncardiac, and hip fracture. RESULTS: Higher preoperative interleukin-6 was associated with postoperative delirium with a standardised mean difference (95% confidence interval) of 0.33 (0.11-0.56) and P=0.003. Higher neopterin was also associated with postoperative delirium. CONCLUSIONS: The association of preoperative blood levels of inflammatory mediators with postoperative delirium may be influenced by the type of surgery and the specific mediator. The potential modulating effect of type of surgery, intrinsic brain vulnerability, and the complex interactions between inflammatory mediators and binding proteins will need to be considered in future studies. CLINICAL TRIAL REGISTRATION: CRD42019159471 (PROSPERO).

Vascular Endothelial Growth Factor (VEGF) and Neopterin Levels in Children with Steroid-sensitive and Steroid-resistant Nephrotic Syndrome.

BACKGROUND: The most common glomerular disease in children is nephrotic syndrome. Steroid-resistant nephrotic syndrome tends to have a worse disease course, which bears a significant risk of chronic kidney disease in children. OBJECTIVE: To compare VEGF and neopterin levels between children with steroid-sensitive nephrotic syndrome (SSNS), steroid-resistant nephrotic syndrome (SRNS), and also healthy (control) children. METHODS: This cross-sectional study was conducted at H. Adam Malik General Hospital, Indonesia from January to December 2018. There were 160 children aged 1 to 8 years with confirmed nephrotic syndrome and without end-stage renal disease and systemic diseases, divided into SSNS, SRNS, and control groups. Data regarding age, gender, urine albumin creatinine ratio (UACR), serum albumin, total cholesterol, urea, creatinine, VEGF, and neopterin levels were collected. A p-value of less than 0.05 is considered statistically significant. RESULTS: There were no differences between groups in gender (p = 0.269) and age (p = 0.375), but there was significant difference of UACR, albumin level, total cholesterol level, and VEGF level between groups, (all p< 0.001). There was a moderate positive correlation between VEGF level and UACR (r(158) = 0.439, p< 0.001) and a moderate negative correlation between neopterin level and albumin level (r(158)= -0.312, p = 0.005). CONCLUSION: There were no differences in serum VEGF and neopterin levels between steroid-sensitive and steroid-resistant nephrotic syndrome groups. Serum VEGF level was positively correlated with UACR while serum neopterin level was negatively correlated with serum albumin level.

The potential role of neopterin in Covid-19: a new perspective.

Neopterin (NPT) is a member of pteridines group, synthesized by macrophages when stimulated by interferon gamma (INF-γ). NPT is regarded as a macrophage stimulation indicator, marker of cellular immune activation and T helper 1 (Th1) type 1 immune response. Here, we aimed to provide a view point on the NPT features and role in Covid-19. Serum NPT level is regarded as an independent prognostic factor for Covid-19 severity, with levels starting to increase from the 3rd day of SARS-CoV-2 infection, being associated with severe dyspnea, longer hospitalization period and complications. Also, early raise of NPT reflects monocytes/macrophages activation before antibody immune response, despite the NPT level may also remain high in Covid-19 patients or at the end of incubation period before the onset of clinical symptoms. On the other hand, NPT attenuates the activity of macrophage foam cells and is linked to endothelial inflammation through inhibition of adhesion molecules and monocytes migration. However, NPT also exerts anti-inflammatory and antioxidant effects by suppressing NF-κB signaling and NLRP3 inflammasomes. NPT can be viewed as a protective compensatory mechanism to counterpoise hyper-inflammation, oxidative stress, and associated organ damage.

Elevated levels of neopterin and pentraxin 3 in patients with rheumatoid arthritis.

OBJECTIVES: As a systemic inflammatory disease, rheumatoid arthritis (RA) is the most common inflammatory arthritis in the population and there is no specific diagnostic marker in laboratory tests. The purpose of the study was to determine whether serum neopterin and pentraxin 3 (PTX3) levels may be a marker of increased inflammation in RA patients. MATERIALS AND METHODS: The study were consist of 30 RA patients and 30 healthy controls who were admitted to the department of rheumatology. Blood specimens were taken from both group, and the levels of neopterin were analyzed by chromatography method (HPLC) and the PTX 3 levels were measured by enzyme-linked immunosorbent assay (ELISA). All data and demographic characteristics of participants were also recorded. RESULTS: Serum neopterin and PTX 3 levels of the patient group (25.99 ± 7.24 ng/mL and 4.19 ± 1.01 ng/dL, respectively) was higher than the control group (9.55 ± 0.74 ng/mL and 2.23 ± 0.39 ng/dL, respectively). These results were remarkable significant (p<0.01). No statistically significant correlation was found between age-PTX 3, age-neopterin and PTX 3-neopterin parameters in the patient group. In the control group, a significant negative correlation was found between age and PTX 3 (p<0.05), and a positive correlation between neopterin and PTX 3. CONCLUSIONS: Consequently, the serum neopterin and PTX 3 levels were higher in RA patients as compared to the healthy individuals. Our study suggest that there is a relation between neopterin and PTX 3 levels with RA patients. These findings suggest that neopterin and PTX 3 are important markers in the monitoring of RA disease.

Salivary neopterin and related pterins: their comparison to those in plasma and changes in individuals.

Neopterin (NP), biopterin (BP) and monapterin (MP) exist in saliva. The physiological role of salivary NP as well as the pathophysiological role of increased NP in the immune-activated state has been unclear. Saliva is a characteristic specimen different from other body fluids. In this study, we analysed salivary NP and related pterin compounds, BP and MP and revealed some of its feature. High-performance liquid chromatography (HPLC) analysis of saliva and plasma obtained from 26 volunteers revealed that salivary NP existed mostly in its fully oxidized form. The results suggested that salivary NP as well as BP would mostly originate from the oral cavity, perhaps the salivary glands, and that salivary NP levels might not reflect those in the plasma. We also found that a gender difference existed in correlations between concentrations of salivary total concentrations of NP (tNP) and BP (tBP). HPLC analysis of saliva obtained from 5 volunteers revealed that the concentrations of salivary tNP as well as tBP fluctuated in an irregular fashion in various individuals. MP, a diastereomer of NP, might have come from oral cavity NP itself or its precursor. These results indicated that the nature of salivary NP might be different from that of NP in the blood or urine.

The usefulness of biomarkers in diagnosis of asbestos-induced malignant pleural mesothelioma.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is a malignant tumor that is associated mostly with asbestos exposure. The present study was to evaluates the diagnostic value of neopterin, periostin, YKL-40, Tenascin-C (TNC), and Indolamine 2,3-dioxygenase (IDO) as noninvasive markers of malign pleural mesothelioma. METHODS: Included in the study were 30 patients diagnosed with malign pleural mesothelioma, and 25 people as a control group. Biomarker levels were determined using an enzyme immunoassay . A Mann-Whitney U test and Spearman correlation methods were used for the statistical analysis. RESULTS: All evaluated biomarkers were found to be significantly higher in the MPM group than in the control group (p < 0.05). There was no effect of such variables as gender, age or MPMsubtype on the parameters (p > 0.05) in the patient group. All biomarkers were positively correlated with each other (p < 0.001). CONCLUSIONS: The current non-invasive biomarkers that can be used in the diagnosis of MPM yielded significant results and can make important contributions to the early diagnosis of MPM.

Sapropterin (BH4) Aggravates Autoimmune Encephalomyelitis in Mice.

Depletion of the enzyme cofactor, tetrahydrobiopterin (BH4), in T-cells was shown to prevent their proliferation upon receptor stimulation in models of allergic inflammation in mice, suggesting that BH4 drives autoimmunity. Hence, the clinically available BH4 drug (sapropterin) might increase the risk of autoimmune diseases. The present study assessed the implications for multiple sclerosis (MS) as an exemplary CNS autoimmune disease. Plasma levels of biopterin were persistently low in MS patients and tended to be lower with high Expanded Disability Status Scale (EDSS). Instead, the bypass product, neopterin, was increased. The deregulation suggested that BH4 replenishment might further drive the immune response or beneficially restore the BH4 balances. To answer this question, mice were treated with sapropterin in immunization-evoked autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. Sapropterin-treated mice had higher EAE disease scores associated with higher numbers of T-cells infiltrating the spinal cord, but normal T-cell subpopulations in spleen and blood. Mechanistically, sapropterin treatment was associated with increased plasma levels of long-chain ceramides and low levels of the poly-unsaturated fatty acid, linolenic acid (FA18:3). These lipid changes are known to contribute to disruptions of the blood-brain barrier in EAE mice. Indeed, RNA data analyses revealed upregulations of genes involved in ceramide synthesis in brain endothelial cells of EAE mice (LASS6/CERS6, LASS3/CERS3, UGCG, ELOVL6, and ELOVL4). The results support the view that BH4 fortifies autoimmune CNS disease, mechanistically involving lipid deregulations that are known to contribute to the EAE pathology.

Neopterin in the Evolution from Obesity to Prediabetes and Newly Diagnosed Type 2 Diabetes.

Background: Neopterin, marker of cellular immunity and oxidative stress, is mainly produced by activated macrophages. It could play a crucial role in the development of insulin resistance (IR) and type 2 diabetes (T2D). The aim of this study was to investigate the circulating levels of neopterin in different stages of glucose dysregulation from obesity through prediabetes to newly diagnosed diabetes. Methods: Neopterin levels were determined using a commercially available human enzyme-linked immunosorbent assay kit. The homeostasis model assessment of IR was used as an index to assess IR. Results: The sample consisted of 163 subjects with mean age 52.5 ± 11.3 years, divided in three age- and body mass index (BMI)-matched groups-obesity, prediabetes, and diabetes. The control group consisted of 42 healthy individuals. Neopterin levels were significantly higher in patients with obesity and/or prediabetes and newly diagnosed diabetes than those in the control group, respectively (4.14 ± 2.51; 4.04 ± 2.80 and 2.17 ± 1.93 vs. 0.87 ± 0.84; P < 0.05). Correlation analysis showed that the level of neopterin positively correlated with BMI, waist, waist-to-stature ratio, waist-to-hip ratio, fasting glucose, and triglycerides. Receiver operating characteristic analysis established neopterin suitable for distinguishing subjects with obesity [area under the curve (AUC) = 0.83; P < 0.001] and carbohydrate disturbances (AUC = 0.59; P < 0.05) from those without these conditions. Neopterin ≥0.47 ng/mL have an odds ratio (OR) of 2.71 for development of dysglycemia, whereas threshold value of neopterin ≥0.56 ng/mL shows an OR of 5.94 for development of obesity. Conclusion: The levels of neopterin were increased in patients with obesity and carbohydrate disturbances. Further studies will elucidate the role of the biomarker in development of T2D and its complications.

Comparison of serum cytokine profiles in macrophage activation syndrome complicating different background rheumatic diseases in children.

OBJECTIVES: To compare the cytokines involved in the development of macrophage activation syndrome (MAS) in different background rheumatic diseases and to identify serum biomarkers for MAS diagnosis. METHODS: Serum neopterin, IL-6, IL-18 and soluble TNF receptor (sTNFR) type I (sTNFR-I) and type II (sTNFR-II) levels were determined using ELISA in 12 patients with SLE, including five with MAS; 12 patients with JDM, including four with MAS; 75 patients with Kawasaki disease (KD), including six with MAS; and 179 patients with systemic JIA (s-JIA), including 43 with MAS. These results were compared with the clinical features of MAS. RESULTS: Serum neopterin, IL-18 and sTNFR-II levels were significantly higher during the MAS phase than during the active phase in patients with all diseases. Furthermore, serum sTNFR-I levels were significantly higher during the MAS phase than during the active phase in patients with SLE, KD and s-JIA. Receiver operating characteristic (ROC) curve analysis revealed that serum sTNFR-I levels for SLE, serum IL-18 levels for JDM, and serum sTNFR-II levels for KD and s-JIA had the highest areas under the ROC curve. Serum levels of these cytokines were significantly and positively correlated with serum ferritin levels. CONCLUSIONS: Overproduction of IFN-γ, IL-18 and TNF-α might be closely related to the development of MAS. Serum levels of sTNFR-I for SLE, IL-18 for JDM, and sTNFR-II for KD and s-JIA might be useful diagnostic markers for the transition from active phase to MAS.

The prognostic role of neopterin in COVID-19 patients.

In Coronavirus disease-2019 (COVID-19) cases, hyper inflammation is associated with the severity of the disease. High levels of circulating cytokines were reported in severe COVID-19 patients. Neopterin produced by macrophages on stimulation with interferon-gamma, which is an important cytokine in the antiviral immune response, hence it can be used to predict the severity of disease in COVID-19 cases. In this study, it was aimed to determine the prognostic value of the neopterin for the prediction of severe disease in patients with COVID-19. This single-center, prospective study was conducted in hospitalized COVID-19 patients and healthy volunteers. Severe and mild COVID-19 cases were compared in terms of clinical and laboratory findings as well as serum neopterin levels on hospital admission. To assess the prognostic utility of neopterin between the severe and mild COVID-19 groups, a receiver-operating characteristic (ROC) curve was generated, and the area under the curve (AUC) was calculated. The median serum neopterin level was four times higher in COVID-19 patients than the healthy controls (46 vs. 12 nmol/L; p < .001). The AUC value of serum neopterin was 0.914 (95% confidence interval, 0.85-0.97). The sensitivity and specificity of serum neopterin for the cut-off value of 90 nmol/L to identify severe COVID-19 cases were 100% and 76%, respectively. Serum neopterin levels on hospitalization were significantly higher in severe COVID-19 disease than mild COVID-19 patients. Neopterin levels can be used as an early prognostic biomarker for COVID-19 on admission.

Serum neopterin levels in relation to mild and severe COVID-19.

BACKGROUND: The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, is rapidly spreading worldwide. There is limited information about prognostic markers that could help clinicians to identify COVID-19 patients with a poor prognosis. Serum levels of the immune activation marker neopterin has shown to be of prognostic value in patients with SARS. The aim of this study was to investigate whether serum neopterin is associated with the severity of COVID-19. METHODS: We included 34 patients with confirmed COVID-19 between March 3 and March 30, 2020. Fifteen patients had mild disease and did not require hospitalization, whereas 19 patients developed severe COVID-19 requiring intensive care. Concentrations of serum neopterin, tryptophan, and kynurenine were measured at and repeatedly after inclusion. RESULTS: We found a more than two-fold higher mean concentration of neopterin in severely ill patients (mean value 42.0 nmol/L (SD 18.2)) compared to patients with mild symptoms (16.9 nmol/L (SD 11.0)). All of the severe cases had elevated neopterin concentrations (> 9.1 nmol/L) at the initial sampling with values ranging from 17.2 to 86.7 nmol/L. In comparison, 10 of 15 patients with mild disease had neopterin levels above 9.1 nmol/L, with concentrations in the range from 4.9 to 31.6 nmol/L. Neopterin levels gradually decreased during the course of COVID-19, but severe cases maintained elevated levels for a longer period. Moreover, lower levels of tryptophan and higher levels of kynurenine, indicating an increased tryptophan catabolism, were seen in the group with severe cases. CONCLUSIONS: In conclusion, we found that serum neopterin levels are associated with the severity of COVID-19. Our findings suggest that neopterin could be used as a prognostic marker, but further studies are needed to elucidate how it can be used in the clinic.

Neopterin serum level does not reflect the disease activity in rheumatoid arthritis: A systematic review and meta-analysis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease caused by established chronic inflammation. Neopterin levels have extensively been considered as a marker of immune activation during inflammation. In this study, we performed a systematic evaluation and meta-analysis to elucidate the overall relationship between neopterin concentration and RA disease activity. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, a systematic review was conducted using PubMed, Google Scholar, Web of Science, and Scopus from 2000 to August 2020. The Newcastle-Ottawa scale was used to assess the quality of eligible studies. The effect size (ES) and corresponding 95% confidence intervals (CIs) were calculated to evaluate this association. A total of 15 studies out of 98 met our inclusion criteria. The pooled analysis found that patients with RA had high level of neopterin; however, no statistically significant association was found between neopterin levels with high, intermediate, and low diseases activity score (DAS)-28 (ES =11.18, 95% CI: 6.02 to 16.34, and I2 = 91.8%; and ES = 8.57, 95% CI: 6.41 to 10.37, and I2 = 99.5%; and ES =12.45, 95% CI: -1.68 to 26.58, and I2 = 99.0%, respectively). Our results indicated that the neopterin concentration does not seem to have any substantial impact on the RA disease activity.

Neopterin and biopterin levels and tryptophan degradation in patients with diabetes.

This study aimed to evaluate the possible changes of neopterin, biopterin levels and tryptophan degradation in diabetes and to compare the results within diabetes groups and with healthy subjects. Diabetes mellitus patients and healthy controls were recruited the study. Patients were further subgrouped according to their drug therapy. Serum neopterin concentrations were detected by ELISA. Urinary neopterin, biopterin, serum tryptophan (Trp) and kynurenine (Kyn) levels were detected by HPLC. There was no difference between controls and diabetes patients in serum neopterin, urinary neopterin and biopterin levels (p > 0.05, all). Serum Trp and Kyn levels were significantly different in type 1 diabetes (T1DM) patients compared to controls (p < 0.05, both). Serum neopterin levels were significantly higher in type 2 diabetes patients (T2DM) compared to T1DM (p < 0.05). Urinary biopterin levels of T2DM patients using both metformin and vildagliptin were significantly higher than T1DM patients (p < 0.05). The correlations between serum neopterin and urinary neopterin, Kyn and Kyn/Trp were statistically significant in control and patient groups (p < 0.05, all). The study showed that Kyn/Trp was altered in diabetes patients due to immune modulation. On the other hand, although xenobiotic exposure may change pteridine levels, metformin and/or vildagliptin use in T2DM patients did not have any effect on the measured parameters.