Increased percentage of HLA-DR T cells in untreated juvenile dermatomyositis.

This study investigates HLA-DR expression on activated T cells and serum neopterin levels in Juvenile Dermatomyositis (JDM) children pre- and post-treatment. Sixty-nine JDM children (less than 18 years) were included. Elevated HLA-DR+ T cells (>7 %) were observed in 19 % of untreated cases. Post-treatment, mean HLA-DR+ T cells decreased from 5.1 to 2.9 (P < 0.001), and serum neopterin levels declined from 19.3 to 9.1 nmol/L (P < 0.0001). A positive correlation between serum neopterin and HLA-DR T cell percentage was observed (r = 0.39, P = 0.01). Intravenous steroid treatment exhibited a 47.4 % improvement in HLA-DR+ T cells and a 50.5 % reduction in serum neopterin levels, in contrast to 14.8 % and 34.1 % in the oral steroid group. In conclusion, treatment, particularly with IV steroids, significantly improved HLA-DR+ T cells percentage and neopterin levels. A correlation between HLA-DR+ T cells percentage and serum neopterin was noted in untreated JDM patients.

Neopterin, 7,8-dihydroneopterin, total neopterin levels and their ratio in periodontitis: New dilemma.

OBJECTIVE: Determine the saliva and serum levels of neopterin (NP) and 7,8-dihydroneopterin (7,8NP) in periodontitis patients and to reveal the relationship of these data with clinical periodontal parameters. MATERIALS AND METHODS: Twenty-three patients with stage III/grade B periodontitis and 23 periodontally healthy individuals were included. Clinical periodontal measurements were recorded (plaque index, pocket depth, clinical attachment loss & bleeding on probing). Saliva and serum levels of NP and 7,8NP were analyzed by high-performance liquid chromatography. RESULTS: Saliva NP, 7,8NP and Total Neopterin (TNP) levels were significantly elevated in the periodontitis than the control group (p < 0.001).ROC analyses of saliva NP, 7,8NP and TNP yielded areas under the curves of 0.873-0.938 for discriminating periodontitis from health, and saliva TNP was found the most accurate biomarker (AUC = 0.938).There was no significant difference among the periodontitis and control groups for saliva TNP/NP and TNP/7,8NP ratios and serum NP, 7,8NP and TNP levels (p > 0.05). CONCLUSION: Increased saliva TNP, NP and 7,8NP levels in periodontitis may suggest these biomarkers are regulating immune activation and oxidative stress mechanism in periodontal inflammation. Additionally, together with these results, equivalence of the TNP/NP ratio in intergroups may suggest that the effects of immune activation and oxidative stress mechanisms are equal in the periodontitis.

Serum neopterin and orexin-A levels in different stages of diabetic retinopathy.

CLINICAL RELEVANCE: Retinopathy is one of the most common microvascular complications of diabetes mellitus and is the leading cause of vision loss in the working middle-aged population. BACKGROUND: This study aimed to investigate the value of neopterin and orexin-A levels in patients with diabetes mellitus with different stages of diabetic retinopathy and without diabetic retinopathy and to compare those findings with results from healthy individuals without diabetes mellitus. METHODS: In total, 65 patients with type 2 diabetes mellitus and 22 healthy individuals without diabetes mellitus were enrolled in this prospective study. The participants were separated into four subgroups. The first subgroup included 25 patients without diabetic retinopathy, the second subgroup included 20 patients non-proliferative diabetic retinopathy, the third subgroup included 20 patients with proliferative diabetic retinopathy, and the fourth subgroup included 22 healthy individuals without diabetes mellitus as controls. Serum neopterin and orexin-A levels were analysed and compared among the groups. RESULTS: The age and gender of the participants between the four subgroups were not statistically significantly different (p > 0.05). The mean neopterin levels were significantly higher in patients included in the diabetes mellitus subgroups compared with the controls (p < 0.001). Neopterin levels significantly increased as diabetic retinopathy progressed within the diabetes mellitus subgroups. Mean orexin-A levels were significantly lower in the diabetes mellitus subgroups compared with the controls (p < 0.001); however, orexin-A levels were not significantly different within the diabetes mellitus subgroups (p > 0.05). CONCLUSION: Patients with diabetes mellitus have higher serum neopterin and lower serum orexin-A levels compared with healthy individuals without diabetes mellitus. Moreover, serum neopterin levels increase with progression of diabetic retinopathy.

CRP/Neopterin Ratio and Neuropsychiatric Symptoms in Patients with Different Forms of Pneumonia: Results of a Pilot Study.

BACKGROUND: Pneumonia is one of the most common infectious diseases, mostly caused by viruses or bacteria. In response to bacteria or viruses which are different but which also are partly overlapping, innate and adaptive immune responses are induced, which can be quantified using the determination of specific biomarkers. Among these, C-reactive protein (CRP) has been established as a marker of innate immune function, whereas Neopterin, which is mainly produced upon stimulation with interferon-gamma, reflects cellular immune activation. AIM: We investigated inflammation markers in patients with microbiologically confirmed viral or bacterial pneumonia, and studied the potential of CRP, Neopterin, and the CRP/Neopterin ratio to distinguish between viral and bacterial pathogenesis. Furthermore, we examined, how often neuropsychiatric symptoms occur in patients suffering from different kinds of pneumonia. PATIENTS AND METHOD: A total of 194 patients diagnosed with either coronavirus disease 2019 (COVID-19) (n = 63), bacterial pneumonia (n = 58), Influenza infection (n = 10), Influenza and a bacterial superinfection (n = 9), and COVID-19 patients with a bacterial superinfection (n = 54) were included in our pilot study. Clinical as well as laboratory parameters were determined shortly after admission. RESULTS: We found significantly higher CRP/Neopterin ratios in patients with bacterial pneumonia (median: 0.34) and lower CRP/Neopterin ratios in patients hospitalized with COVID-19 infection (median: 0.03; p < 0.001). Both in men and in women, the CRP/Neopterin ratio was able to distinguish between viral and bacterial pathogens, but also was able to detect bacterial super-infection (BSI) in subjects with initial viral pneumonia (p < 0.001). Patients with BSI presented with significantly lower CRP/Neopterin ratios (median 0.08) than patients with bacterial infection only (median 0.34; p < 0.001). Interestingly, COVID-19 patients had a decreased physical functioning (as reflected in the ECOG score) and a higher frequency of fatigue (84.1%) and neurological symptoms (54.8%) than patients with pneumonia, due to other underlying pathogens. Patients that reported fatigue during viral and bacterial pneumonia presented with lower CRP concentrations than patients without it. CONCLUSIONS: The CRP/Neopterin ratio is useful to differentiate between viral and bacterial pathogenesis. The occurrence of neuropsychiatric symptoms in pneumonia appears to depend on the kind of pathogen causing the infection. Lower CRP concentrations at admission appear to be related to fatigue during acute viral and bacterial infection.

The clinical significance of neopterin and NT-pro BNP in chronic heart failure: a systematic review.

BACKGROUND: Biomarkers emerged as powerful adjuncts to conventional clinical care in heart failure (HF). The aim of this study is to evaluate neopterin and NT-pro BNP as diagnostic and prognostic biomarkers in HF. METHODS: A systematic search was conducted in six electronic databases from inception to July 24th, 2022. Independent reviewers screened the title, abstract and full text then data extraction and critical appraisal of included studies were performed. RESULTS: A total of eleven studies were included. Neopterin and NT-pro BNP levels were elevated in HF patients as compared to control. Moreover, within HF patients, levels of biomarkers were significantly higher in patients with advanced HF and more severe disease state. Patients who suffered cardiovascular adverse events had high levels of biomarkers. Two studies assessed the effect of treatment on biomarkers levels, showed that levels of neopterin and/or NT-pro BNP decreased with treatment. Studies confirmed the potential of relying on neopterin and NT-pro BNP as diagnostic and prognostic biomarkers in HF in addition to assessing disease severity. CONCLUSION: Biomarkers levels correlate with disease severity and could be used as diagnostic and prognostic biomarkers in HF. Further research is needed for a definitive conclusion about using these biomarkers to determine the efficacy of therapy.

Exploring S100A8/A9, Neopterin, and MMP3 in Familial Mediterranean Fever.

Familial mediterranean fever (FMF) is characterized by inflammatory attacks due to overactivation of pyrin inflammasome. This study aimed to investigate the reliability of S100A8/A9, neopterin, and matrix metalloproteinase 3 (MMP3) at monitoring subclinical inflammation and disease activity, and at differentiating FMF attacks from appendicitis, the most common misdiagnosis among FMF patients. Blood samples (n=75), comprising from FMF patients during an attack (n=20), the same FMF patients during the attack-free period (n=14), patients with appendicitis (n=24), and healthy volunteers (n=17) were obtained. Duplicate determinations of S100A8/A9, neopterin, and MMP-3 levels were conducted using the enzyme-linked immunosorbent assay (ELISA). FMF patients with and without attack and patients with appendicitis had significantly elevated S100A8/A9 levels compared to healthy volunteers (p-values: <0.001, 0.036, 0.002, respectively). Patients with appendicitis and FMF patients with and without attack had significantly increased serum neopterin levels compared to healthy volunteers (p-value: <0.001). MMP3 levels were significantly higher among patients with appendicitis and FMF patients during attack compared to healthy controls (p-values: <0.001, 0.001). Serum levels of S100A8/A9, neopterin, and MMP3 were increased significantly during attacks compared to attack-free periods among FMF patients (p-values: 0.03, 0.047, 0.007). S100A8/A9 emerges as a valuable marker for monitoring disease activity. Neopterin and S100A8/A9 might help physicians to monitor subclinical inflammation during the attack-free periods of FMF patients. MMP3 might aid in diagnosing FMF attacks when distinguishing between attack and attack-free periods is challenging.

Exploring oxidative stress, immunological and metabolic biomarkers in dairy cows with postpartum pyometra.

Pyometra is a prevalent and severe infectious disease that affects the reproductive systems of cattle worldwide. This study's main goal was to investigate the biomarkers for oxidative stress (OS), adiponectin, leptin and neopterin (NPT) in cows suffering from postpartum pyometra. The study also aimed to determine which bacteria were most commonly implicated in the development of the disease. A total of 74 cows with pyometra were examined and compared to a control group of healthy cows (n = 20). In comparison to the healthy control and post-treatment groups, the pyometra group showed higher mean values of leptin, adiponectin and malondialdehyde (MDA). In contrast, the glutathione (GSH) and superoxide dismutase (SOD) mean values were lower in the pyometra group as compared to the post-treatment and control groups. NPT levels in the post-treatment groups were lower than those in cows with pyometra but comparable to the healthy control group (p > .05). When compared to the other biomarkers, NPT, leptin and adiponectin showed higher sensitivity and specificity in identifying pyometra cases (AUC ≥0.99). The predominant bacterial isolates from the ptomtra-affected cows consisted of Escherichia coli (N = 29; 39.2%), Arcanobacterium pyogenes (N = 27; 36.5%) and Fusobacterium necrophorum (N = 13; 17.6%). Mixed infection was determined in nine samples (12.2%). Conclusively, OS, adiponectin, leptin and NPT play crucial roles in comprehending the development of postpartum pyometra in cows and have the potential to serve as biomarkers for the disease.

Neopterin as a potential prognostic and predictive biomarker in metastatic renal cell carcinoma treated with immune checkpoint inhibitors.

INTRODUCTION: Immunotherapy represents a significant and essential component of renal carcinoma therapy (RCC), but the selection of an optimal regimen for an individual patient remains unclear. Despite significant improvements in therapeutic options for RCC, predictive biomarkers for immunotherapeutic agents remain elusive. Neopterin is a biomarker of cell-mediated immune response, with concentrations increased in different disorders, including cancer. High neopterin levels herald, in general, a poor prognosis. AREAS COVERED: This review briefly overviews the contemporary clinical data on biomarkers in metastatic RCC therapy, focusing on neopterin. EXPERT OPINION: Elevated neopterin levels have been observed in tumors of different primary locations. Research indicates that neopterin may serve as a potential biomarker for assessing the inflammatory status associated with certain cancers. However, it is necessary to interpret neopterin levels in the context of a comprehensive clinical evaluation, as elevated neopterin alone is not specific to cancer and can be influenced by other factors, including comorbid conditions. Neopterin has also been identified as a prognostic biomarker. An increasing neopterin level in serum and urine is associated with advanced cancer, but the role as a potential predictor of response to immunotherapy has yet to be established. A reliable biomarker for optimal therapy selection in metastatic RCC is still putative.

Elevated NET, Calprotectin, and Neopterin Levels Discriminate between Disease Activity in COVID-19, as Evidenced by Need for Hospitalization among Patients in Northern Italy.

Coronavirus disease 2019 (COVID-19) displays clinical heterogeneity, but little information is available for patients with mild or very early disease. We aimed to characterize biomarkers that are useful for discriminating the hospitalization risk in a COVID-19 cohort from Northern Italy during the first pandemic wave. We enrolled and followed for four weeks 76 symptomatic SARS-CoV-2 positive patients and age/sex-matched healthy controls. Patients with mild disease were discharged (n.42), and the remaining patients were hospitalized (n.34). Blood was collected before any anti-inflammatory/immunosuppressive therapy and assessed for soluble C5b-9/C5a, H3-neutrophil extracellular traps (NETs), calprotectin, and DNase plasma levels via ELISA and a panel of proinflammatory cytokines via ELLA. Calprotectin and NET levels discriminate between hospitalized and non-hospitalized patients, while DNase negatively correlates with NET levels; there are positive correlations between calprotectin and both NET and neopterin levels. Neopterin levels increase in patients at the beginning of the disease and do so more in hospitalized than non-hospitalized patients. C5a and sC5b-9, and other acute phase proteins, correlate with neopterin, calprotectin, and DNase. Both NET and neopterin levels negatively correlate with platelet count. We show that calprotectin, NETs, and neopterin are important proinflammatory parameters potentially useful for discriminating between COVID-19 patients at risk of hospitalization.

Neopterin in patients with COPD, asthma, and ACO: association with endothelial and lung functions.

BACKGROUND AND OBJECTIVE: Endothelial dysfunction has been widely recognized in chronic airway diseases, including chronic obstructive pulmonary disease (COPD) and asthma; however, it remains unclear in asthma-COPD overlap (ACO). Neopterin (NP), a metabolite of guanosine triphosphate, is a novel biomarker for identifying the increased risk of adverse cardiovascular events. This study aims to investigate the association of NP with endothelial dysfunction and impaired lung function in COPD, asthma, and ACO patients. METHODS: A total of 77 subjects were prospectively recruited. All the participants underwent lung function test, endothelial function evaluation, including pulse wave velocity (PWV) and flow-mediated dilation (FMD), and blood sample detection. Moreover, the effect of NP on endothelial cells (ECs) in anoxic environments was assessed in vitro. RESULTS: Endothelial function was significantly decreased in the COPD and ACO patients compared with that in the healthy controls (P < 0.05). Forced expiratory volume in 1 s (FEV1) was negatively correlated with PWV and positively correlated with FMD (P < 0.05). NP was significantly increased in patients with chronic respiratory diseases compared with that in the control group, with COPD being the highest, followed by asthma, and ACO as the last (P < 0.05). The plasma level of NP exhibited negative correlations with FEV1 and positive correlations with PWV (P < 0.05). In vitro, a high level of NP increased the reactive oxygen species (ROS) and decreased the mitochondrial membrane potential (ΔΨm) of ECs dose-dependently in a hypoxic environment (P < 0.05). CONCLUSION: NP was related to disease severity of chronic airway diseases and involved in the pathogenesis of endothelial dysfunction. A high NP level may contribute to endothelial dysfunction by increasing the oxidative stress of ECs dose-dependently in a hypoxic environment. Our findings may provide a novel evaluation and therapeutic target for endothelial dysfunction related to chronic airway diseases.

Multicenter, randomized, double-blind, placebo-controlled phase 3 study of mogamulizumab with open-label extension study in a minimum number of patients with human T-cell leukemia virus type-1-associated myelopathy.

Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neurodegenerative disease. This multicenter, randomized phase 3 study evaluated the efficacy and safety of 0.3 mg/kg intravenous mogamulizumab, a monoclonal antibody targeting-CC chemokine receptor 4, every 12 weeks in HAM/TSP patients. This study comprised a 24-week double-blind, placebo-controlled period, 24-week open-label period, and extension treatment period. The primary endpoint was the proportion of patients with a ≥ 1-grade improvement in the Osame motor disability score (OMDS). Secondary endpoints were changes in HTLV-1 proviral load, 10-m timed walk, cerebrospinal fluid (CSF) neopterin levels, and safety. The exploratory endpoint was CSF chemokine C-X-C motif ligand 10 (CXCL10) levels. Thirty-four and 33 patients were randomized to mogamulizumab and placebo arms, respectively. At the end of the double-blind period, no significant difference was found in the OMDS improvement rate or other secondary efficacy endpoints assessing motor activities. However, the mogamulizumab arm showed a significant decrease in HTLV-1 proviral load (- 59.39 ± 29.91% vs. placebo 2.32 ± 36.31%) and CSF neopterin (p < 0.001)/CXCL10 levels (p = 0.004). The baseline OMDS pattern and the 60-80% HTLV-1 proviral load reduction were sustained through the open-label and extension treatment periods. Although a higher incidence of rash (69.2%) was reported, the safety profile was similar compared with a previous phase 1/2a study. We found no significant difference in clinical benefit; however, mogamulizumab may provide long-term clinical benefit by preventing disease progression, as CSF neopterin/CXCL10 levels are associated with long-term prognosis in HAM/TSP.Clinical Trial Registration Number: NCT03191526 (registered date: 6-June-2017).

Neopterin, kynurenine metabolites, and indexes related to vitamin B6 are associated with post-stroke cognitive impairment: The Nor-COAST study.

BACKGROUND AND AIMS: We have previously shown that systemic inflammation was associated with post-stroke cognitive impairment (PSCI). Because neopterin, kynurenine pathway (KP) metabolites, and B6 vitamers are linked to inflammation, in our study we investigated whether those biomarkers were associated with PSCI. MATERIAL AND METHODS: The Norwegian Cognitive Impairment After Stroke study is a prospective multicenter cohort study of patients with acute stroke recruited from May 2015 through March 2017. Plasma samples of 422 participants (59 % male) with ischemic stroke from the index hospital stay and 3 months post-stroke were available for analyses of neopterin, KP metabolites, and B6 vitamers using liquid chromatography-tandem mass spectrometry. Mixed linear regression analyses adjusted for age, sex, and creatinine, were used to assess whether there were associations between those biomarkers and cognitive outcomes, measured by the Montreal Cognitive Assessment scale (MoCA) at 3-, 18-, and 36-month follow-up. RESULTS: Participants had a mean (SD) age of 72 (12) years, with a mean (SD) National Institutes of HealthStroke Scale score of 2.7 (3.6) at Day 1. Higher baseline values of quinolinic acid, PAr (i.e., an inflammatory marker based on vitamin B6 metabolites), and HKr (i.e., a marker of functional vitamin B6 status based on selected KP metabolites) were associated with lower MoCA score at 3, 18, and 36 months post-stroke (p < 0.01). Higher baseline concentrations of neopterin and 3-hydroxykynurenine were associated with lower MoCA scores at 18 and 36 months, and higher concentrations of xanthurenic acid were associated with higher MoCA score at 36 months (p < 0.01). At 3 months post-stroke, higher concentrations of neopterin and lower values of pyridoxal 5́-phosphate were associated with lower MoCA scores at 18- and 36-month follow-up, while lower concentrations of picolinic acid were associated with a lower MoCA score at 36 months (p < 0.01). CONCLUSION: Biomarkers and metabolites of systemic inflammation, including biomarkers of cellular immune activation, indexes of vitamin B6 homeostasis, and several neuroactive metabolites of the KP pathway, were associated with PSCI. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02650531.

Host single nucleotide polymorphisms and biomarkers of neuronal damage and inflammation in people living with HIV.

OBJECTIVES: Blood-brain barrier impairment is frequent in people living with human immunodeficiency virus (PLWHIV), affecting the penetration of target cells and antiretrovirals into the central nervous system, through transporters (e.g. ABCB1), leading to neuroinflammation. This study aimed to identify variants of genes encoding transporters able to predict neuroinflammation biomarker levels. METHODS: Cerebrospinal fluid (CSF) and plasma samples were obtained from PLWHIV. The CSF biomarkers were quantified by commercial assays. Genetic variants were evaluated through real-time polymerase chain reaction (PCR). RESULTS: A total of 107 PLWHIV (163 samples) were included in the study: 79% were male, median age was 48.5 years, CD4% was 25%, and HIV-associated neurocognitive disorder (HAND) was observed in 17.8%. The ABCB1 2677G>T genetic variant showed a different allelic distribution according to the clinical group (P = 0.026). In linear regression analyses, HIV-related central nervous system disorders, ABCG2 1194+928CC genotype, log viral load, CSF-to-serum albumin ratio, ß-1,42 levels, and CSF proteins were retained in the final model as factors independently associated with CSF neopterin levels; CSF proteins and integrase inhibitor use were associated with CSF tau level in the multivariate model. Phospho-tau regression analysis reported the ABCB1 2677GT/TT genotype and CSF proteins as predictors in the final model; sex, protease inhibitors, neopterin, and ABCB1 2677 GT/ TT genotype were predictors in the multivariate regression for ß-1,42. CONCLUSIONS: For the first time, pharmacogenetic and clinical features were found to be predictors of neuro-inflammation biomarkers.

Modulation of cell-mediated immunity during pregnancy in wild bonobos.

During pregnancy, the mammalian immune system must simultaneously protect against pathogens while being accommodating to the foreign fetal tissues. Our current understanding of this immune modulation derives predominantly from industrialized human populations and laboratory animals. However, their environments differ considerably from the pathogen-rich, resource-scarce environments in which pregnancy and the immune system co-evolved. For a better understanding of immune modulation during pregnancy in challenging environments, we measured urinary neopterin, a biomarker of cell-mediated immune responses, in 10 wild female bonobos (Pan paniscus) before, during and after pregnancy. Bonobos, sharing evolutionary roots and pregnancy characteristics with humans, serve as an ideal model for such investigation. Despite distinct environments, we hypothesized that cell-mediated immune modulation during pregnancy is similar between bonobos and humans. As predicted, neopterin levels were higher during than outside of pregnancy, and highest in the third trimester, with a significant decline post-partum. Our findings suggest shared mechanisms of cell-mediated immune modulation during pregnancy in bonobos and humans that are robust despite distinct environmental conditions. We propose that these patterns indicate shared immunological processes during pregnancy among hominins, and possibly other primates. This finding enhances our understanding of reproductive immunology.

Evaluation of inflammatory biomarkers and vitamins in hospitalized patients with SARS-CoV-2 infection and post-COVID syndrome.

OBJECTIVES: Concentrations of neopterin, kynurenine and kynurenine/tryptophan ratios predict prognosis and the need for oxygen therapy in patients hospitalized for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The aims of the present study were to evaluate the changes of these biomarkers early in the course of infection, the association with the prior coronavirus disease (COVID-19) vaccination and therapeutic administration of Anti-SARS-CoV-2 monoclonal antibodies, investigation of other potential biomarkers including neuropilin, 8-hydroxy-2-deoxyguanosine and 8-hydroxyguanosine in patients hospitalized with SARS-CoV-2 infection and an assessment of these biomarkers and vitamins A, E and D in patients with post-COVID syndrome. METHODS: Urine and blood samples were obtained on the 1st to the 4th day and 4th to 7th day from 108 patients hospitalized with COVID-19. Chromatography tandem mass spectrometry methods were used to analyse neopterin, kynurenine, tryptophan, liposoluble vitamins, and DNA damage biomarkers. RESULTS: A statistically significant decrease of neopterin, kynurenine and kynurenine/tryptophan ratios was observed on after 4th to 7th day of hospitalization, and concentrations of these biomarkers were increased in patients with poor prognosis and subsequent post-COVID syndrome. The concentrations of remaining biomarker and vitamins were not associated with outcomes, although markedly decreased concentrations of vitamin A, E and D were noted. CONCLUSIONS: The concentrations of neopterin, kynurenine and kynurenine/tryptophan ratios decrease during the course of infection SARS-CoV-2 and are associated with the post-COVID syndrome. No other prognostic biomarkers were identified.

Adjunctive silymarin supplementation and its effects on disease severity, oxidative stress, and inflammation in patients with Alzheimer's disease.

BACKGROUND: Brain tissue in Alzheimer's patients is exposed to oxidative stress. Silymarin is an adjunct drug that has anti-inflammatory and antioxidant properties. OBJECTIVE: This study aimed to evaluate the effect of silymarin on biomarkers of oxidative stress, inflammation, and disease severity in Alzheimer's patients. METHODS: This randomized, single-blind clinical trial study was performed on 33 patients with Alzheimer's disease (AD) whose disease was confirmed by DSM-5 criteria and by brain imaging. Patients in the case group received three 250 mg silymarin capsules daily (each containing 150 mg silymarin), as an adjunctive medication in addition to the routine medication regimen. In the placebo group (control), patients received the same amount of placebo. All patients underwent Mini Mental State Exam (MMSE) and a panel of blood tests including malondialdehyde, neopterin, catalase, paraoxonase-1, total oxidative status, and total antioxidant capacity to reevaluate the changes pre/postintervention at the end of the trimester. RESULTS: The catalase and MDA serum levels after the adjunctive silymarin treatment decreased significantly (Catalasebefore silymarin = 9.29 ± 7.02 vs Catalaseafter silymarin = 5.32 ± 2.97, p = 0.007 and MDAbefore silymarin = 4.29 ± 1.90 vs MDAafter silymarin = 1.66 ± 0.84, p < 0.001) while MMSE increased notably (MMSEbefore silymarin = 10.39 ± 6.42 vs MMSEafter silymarin = 13.37 ± 6.81, p < 0.001). CONCLUSION: Silymarin can be effective as an adjunct drug and a powerful antioxidant in reducing oxidative stress and improving the course of AD.

Enhanced expression of neopterin in valve tissue of bicuspid aortic stenosis.

Background: Aortic valve stenosis (AS) occurs in bicuspid aortic valve (BAV) patients at a relatively young age compared to tricuspid aortic valve (TAV) patients. However, the underlying cause of this phenomenon remains unknown. Neopterin, which is a by-product of the guanosine triphosphate (GTP) pathway, enhances the oxidative potential of reactive oxygen species. To clarify the role of neopterin in the aortic valve, we immunohistochemically studied the presence of neopterin in aortic valve specimens from patients with AS harboring either TAV or BAV. Methods: Frozen aortic valve samples were surgically obtained from 68 patients with severe AS with TAV (n=34) and BAV (n=34). Normal aortic valves were obtained from cadavers who died of non-cardiovascular causes as controls (n=9). Samples were immunohistochemically stained with antibodies against smooth muscle cells, macrophages, T lymphocytes, neopterin, and 4-hydroxy-2-nonenal (4-HNE). Results: Quantitative analysis showed that the percentage of macrophages, 4-HNE- and neopterin-positive macrophage score, and the number of T lymphocytes were significantly higher in BAV patients than in TAV patients (macrophages, P=0.013; T lymphocytes, P=0.011; neopterin, P<0.001; 4-HNE, P=0.008). Double immunostaining for neopterin and macrophages demonstrated that most neopterin-positive cells were macrophages in BAV patients. Conclusions: Neopterin accumulation in macrophages may increase oxidative stress and contribute to the early onset of AS in BAV.

The kynurenine and serotonin pathway, neopterin and biopterin in depressed children and adolescents: an impact of omega-3 fatty acids, and association with markers related to depressive disorder. A randomized, blinded, prospective study.

Depressive disorder is a severe mental condition. In addition to genetic factors, immunological-inflammatory factors, oxidative stress, and disturbances in neurotransmitter metabolism, kynurenine and serotonin pathways may play a role. The exact mechanisms, especially in depressed children and adolescents, are not fully understood. Our primary hypothesis was whether the metabolites of tryptophan degradation in children and adolescents with depressive disorder might be influenced by omega-3 FAs compared to omega-6 FAs during a 12-week supplementation. A secondary hypothesis was to investigate whether tryptophan metabolites in children and adolescents are associated with markers of inflammatory response, oxidative stress, cortisol, and the serum omega-6/omega-3 FA ratio. Metabolites of tryptophan degradation and pteridines, neopterin, and biopterin in urine were analyzed with an HPLC system. Surprisingly, omega-3 FAs stimulated both kynurenine (kynurenine/tryptophan ratio) and serotonin (5-hydroxytryptophan) pathways, whereas omega-6 FAs only increased the kynurenine/tryptophan ratio. Neopterin and biopterin were not different from the healthy controls. Biopterin increased after omega-3 FA supplementation. Serotonin was positively correlated with lipoperoxidation and a marker of oxidative protein damage. Of the monitored tryptophan metabolites, only 5-hydroxyindolacetic acid was positively correlated with the severity of depression, total cholesterol, and negatively with brain-derived neurotrophic factor and glutathione peroxidase. In conclusion, in children and adolescents, both supplemented FAs stimulated the kynurenine pathway (kynurenine/tryptophan ratio) and kynurenine formation. However, the serotonin pathway (5-hydroxytryptophan) was stimulated only by omega-3 FA. Tryptophan metabolism is associated with oxidative stress, inflammation, total cholesterol, and cortisol. We are the first to point out the association between the kynurenine pathway (KYN/TRP ratio) and the omega-6/omega-3 FA ratio. The metabolite 5-HIAA could play a role in the pathophysiology of depressive disorder in children and adolescents. Clinical Trial Registration: https://www.isrctn.com/ISRCTN81655012, identifier ISRCTN81655012.

Quantification of Enteric Dysfunction in Cystic Fibrosis: Inter- and Intraindividual Variability.

OBJECTIVES: To test the utility of various biomarkers as indicators of gut dysfunction in cystic fibrosis (CF) and determine whether intraindividual variations in these measures are repeatable over short intervals and whether interindividual variations correlate with clinical outcomes. STUDY DESIGN: We performed a cross-sectional, limited longitudinal study of children with CF aged 1-21 years who provided blood and stool samples at 2 or 3 visits, 2 weeks and 3 months apart, which were assayed for markers of intestinal inflammation (fecal calprotectin [fCal], lipocalin-2 [fLcn2], neopterin), and permeability (plasma lipopolysaccharide [LPS] antibodies, LPS-binding protein) by enzyme immunoassays. Control specimens were obtained from children without CF who had undergone esophagogastroduodenoscopy and had no evidence of gut inflammation. RESULTS: Twenty-six of 29 participants with CF completed the study. Sixty-nine stools (57 case/12 control) and 76 plasmas (60 case/16 control) were analyzed. LPS antibody had reliable intraindividual stability. fCal, fLcn2, and neopterin were significantly greater in CF than in control samples. fCal was negatively correlated with 3-month interval change (Δ) in weight-for-age z-score, body mass index/weight-for-length z-score, and forced expiratory volume in 1 second. fLcn2 was negatively correlated with FEV1 but not with anthropometrics. No marker correlated with Δbody mass index/weight-for-length z-score or ΔFEV1. CONCLUSIONS: fLcn2 is elevated in people with CF and might predict worse interval pulmonary function. Expanded studies are warranted to test if fLcn2 correlates with changes in additional outcomes.