Neuronal damage and inflammatory biomarkers are associated with the affective and chronic fatigue-like symptoms due to end-stage renal disease.

BACKGROUND: Many biochemical, immunological, and neuropsychiatric changes are associated with end-stage renal disease (ESRD). Neuronal damage biomarkers such as glial fibrillary acidic protein (GFAP), neurofilament light chain (NFL), S100 calcium-binding protein B (S100B), ionized calcium-binding adaptor molecule-1 (IBA1), and myelin basic protein (MBP) are among the less-studied biomarkers of ESRD. AIM: We examined the associations between these neuro-axis biomarkers, inflammatory biomarkers, e.g., C-reactive protein (CRP), interleukin (IL-6), IL-10, and zinc, copper, and neuropsychiatric symptoms due to ERSD. METHODS: ELISA techniques were used to measure serum levels of neuronal damage biomarkers in 70 ESRD patients, and 46 healthy controls. RESULTS: ESRD patients have higher scores of depression, anxiety, fatigue, and physiosomatic symptoms than healthy controls. Aberrations in kidney function tests and the number of dialysis interventions are associated with the severity of depression, anxiety, fibro-fatigue and physiosomatic symptoms, peripheral inflammation, nestin, and NFL. Serum levels of neuronal damage biomarkers (NFL, MBP, and nestin), CRP, and interleukin (IL)-10 are elevated, and serum zinc is decreased in ESRD patients as compared with controls. The neuronal damage biomarkers NFL, nestin, S100B and MBP are associated with the severity of one or more neuropsychiatric symptom domains. Around 50 % of the variance in the neuropsychiatric symptoms is explained by NFL, nestin, S00B, copper, and an inflammatory index. CONCLUSIONS: The severity of renal dysfunction and/or the number of dialysis interventions may induce peripheral inflammation and, consequently, neurotoxicity to intermediate filament proteins, astrocytes, and the blood-brain barrier, leading to the neuropsychiatric symptoms of ESRD.

Increased AGE-RAGE axis stress in methamphetamine abuse and methamphetamine-induced psychosis: Associations with oxidative stress and increased atherogenicity.

Methamphetamine (MA)-induced psychosis (MIP) is associated with increased oxidative toxicity (especially lipid peroxidation) and lowered antioxidant defences. Advanced glycation end products (AGEs) cause oxidative stress upon ligand binding to AGE receptors (RAGEs). There is no data on whether MA use may cause AGE-RAGE stress or whether the latter is associated with MIP. This case-control study recruited 60 patients with MA use disorder and 30 normal controls and measured serum levels of oxidative stress toxicity (OSTOX, lipid peroxidation), antioxidant defences (ANTIOX), magnesium, copper, atherogenicity, AGE and soluble RAGE (sRAGE) and computed a composite reflecting AGE-RAGE axis activity. MA dependence and use were associated with elevated levels of AGE, sRAGE, OSTOX/ANTIOX, Castelli Risk Index 1 and atherogenic index of plasma. Increased sRAGE concentrations were strongly correlated with dependence severity and MA dose. Increased AGE-RAGE stress was correlated with OSTOX, OSTOX/ANTIOX and MA-induced intoxication symptoms, psychosis, hostility, excitement and formal thought disorders. The regression on AGE-RAGE, the OSTOX/ANTIOX ratio, decreased magnesium and increased copper explained 54.8% of the variance in MIP symptoms, and these biomarkers mediated the effects of increasing MA concentrations on MIP symptoms. OSTOX/ANTIOX, AGE-RAGE and insufficient magnesium were found to explain 36.0% of the variance in the atherogenicity indices. MA causes intertwined increases in AGE-RAGE axis stress and oxidative damage, which together predict the severity of MIP symptoms and increased atherogenicity.

Increased insulin resistance due to Long COVID is associated with depressive symptoms and partly predicted by the inflammatory response during acute infection.

OBJECTIVE: Some months after the remission of acute COVID-19, some individuals show depressive symptoms, which are predicted by increased peak body temperature (PBT) and decreased blood oxygen saturation (SpO2). The present study aimed to examine data on whether long COVID is associated with increased insulin resistance (IR) in association with neuroimmune and oxidative (NIO) processes during the acute infectious and long COVID phases. METHODS: This case-control, retrospective cohort study used the Homeostasis Model Assessment 2 (HOMA2) calculator© to compute ß-cell function (HOMA2%B) and insulin sensitivity (HOMA2%S) and resistance (HOMA2-IR) and administered the Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HAMD) to 86 patients with long COVID and 39 controls. RESULTS: Long COVID (3-4 months after the acute infection) is accompanied by increased HOMA2-IR, fasting blood glucose (FBG), and insulin levels; 33.7% of the patients vs. 0% of the controls had HOMA2-IR values > 1.8, suggesting IR. Increased IR was predicted by PBT during acute infection and associated with depressive symptoms above and beyond the effects of NIO pathways (nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 [NLRP3] inflammasome, myeloperoxidase [MPO], protein oxidation). There were no significant associations between increased IR and the activated NIO pathways during long COVID. CONCLUSION: Long COVID is associated with new-onset IR, which may contribute to onset of depressive symptoms due to long COVID by enhancing overall neurotoxicity.

A Causal-Pathway Phenotype of Chronic Fatigue Syndrome due to Hemodialysis in Patients with End-Stage Renal Disease.

BACKGROUND: End-stage renal disease (ESRD) is associated with fatigue and physiosomatic symptoms. OBJECTIVE: The objective of this study is to delineate the associations between severity of fatigue and physio-somatic symptoms and glomerular filtration rate, inflammatory biomarkers, and Wnt/cateninpathway proteins. METHODS: The Wnt-pathway related proteins ß-catenin, Dickkopf-related protein 1 (DKK1), R-spondin- 1, and sclerostin were measured by ELISA technique in 60 ESRD patients and 30 controls. The Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale was used to assess the severity of FF symptoms. RESULTS: ESRD is characterized by a significant increase in the total FF score, muscle tension, fatigue, sadness, sleep disorders, gastro-intestinal (GI) symptoms, and a flu-like malaise. The total-FF score was significantly correlated with serum levels of urea, creatinine, and copper (positively), and ß-catenin, eGFR, hemoglobin, albumin, and zinc (inversely). The total-FF score was associated with the number of total dialysis and weekly dialysis sessions, and these dialysis characteristics were more important in predicting FF scores than eGFR measurements. Partial Least Squares analysis showed that the FF score comprised two factors that are differently associated with biomarkers: a) 43.0% of the variance in fatigue, GI symptoms, muscle tension, sadness, and insomnia is explained by hemoglobin, albumin, zinc, ß-catenin, and R-spondin-1; and b) 22.3% of the variance in irritability, concentration and memory impairments by increased copper and cations/chloride ratio, and male sex. CONCLUSION: ESRD patients show high levels of fatigue and physio-somatic symptoms associated with hemodialysis and mediated by dialysis-induced changes in inflammatory pathways, the Wnt/catenin pathway, and copper.

In Transfusion-Dependent Thalassemia Children, Increased Iron Overload is Associated with Lower Serum Alpha-Klotho, Which is Strongly Associated with Lower Total and Ionized Calcium Concentrations.

BACKGROUND: Patients with transfusion-dependent thalassemia (TDT) show disorders in calcium metabolism. The α-Klotho protein is predominantly expressed in tissues that are involved in calcium homeostasis, and lowered levels are associated with bone disease. The aim of the study is to examine the associations between low α-Klotho status and calcium metabolism in relation to iron status in children with TDT. METHODS: Calcium, α-Klotho, parathyroid hormone (PTH), calcyphosin, vitamin D3, phosphorous, fibroblast growth factor receptor 2 (FGFR2), as well as iron and erythron biomarkers were measured in 60 children with TDT and 30 healthy control children. RESULTS: A meaningful part of TDT patients showed lowered α-Klotho levels, and those children also showed low serum total and ionized calcium concentrations. TDT patients showed increased PTH, FGFR2, and calcyphosin and lowered vitamin D3 as compared with healthy children. The α-Klotho levels were significantly correlated with total and ionized calcium (positively) and with iron overload and transfusions biomarkers (inversely). Partial Least Squares path analysis showed that 40.1% of the variance in serum total calcium could be explained by the regression on α-Klotho, vitamin D3 (both positively), and calcyphosin (inversely) and that the effects of the latter are mediated by iron overload and the number of blood transfusions. CONCLUSION: In conclusion, the iron overload in TDT and its consequences may induce lowered levels of α-Klotho which in turn may lead to lower calcium thereby explaining at least in part the effects of TDT on bone metabolism including spontaneous pathological fractures, osteoporosis, osteopenia, and skeletal deformities.

Increased insulin resistance due to long COVID is associated with depressive symptoms and partly predicted by the inflammatory response during acute infection

Objective: Some months after the remission of acute COVID-19, some individuals show depressive symptoms, which are predicted by increased peak body temperature (PBT) and decreased blood oxygen saturation (SpO2). The present study aimed to examine data on whether long COVID is associated with increased insulin resistance (IR) in association with neuroimmune and oxidative (NIO) processes during the acute infectious and long COVID phases. Methods: This case-control, retrospective cohort study used the Homeostasis Model Assessment 2 (HOMA2) calculator© to compute β-cell function (HOMA2%B) and insulin sensitivity (HOMA2%S) and resistance (HOMA2-IR) and administered the Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HAMD) to 86 patients with long COVID and 39 controls. Results: Long COVID (3-4 months after the acute infection) is accompanied by increased HOMA2-IR, fasting blood glucose (FBG), and insulin levels; 33.7% of the patients vs. 0% of the controls had HOMA2-IR values > 1.8, suggesting IR. Increased IR was predicted by PBT during acute infection and associated with depressive symptoms above and beyond the effects of NIO pathways (nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 [NLRP3] inflammasome, myeloperoxidase [MPO], protein oxidation). There were no significant associations between increased IR and the activated NIO pathways during long COVID. Conclusion: Long COVID is associated with new-onset IR, which may contribute to onset of depressive symptoms due to long COVID by enhancing overall neurotoxicity.

Increased Lipid Peroxidation and Lowered Antioxidant Defenses Predict Methamphetamine Induced Psychosis.

BACKGROUND: a significant percentage of methamphetamine (MA) dependent patients develop psychosis. The associations between oxidative pathways and MA-induced psychosis (MIP) are not well delineated. OBJECTIVE: the aim of this study is to delineate whether acute MA intoxication in MA dependent patients is accompanied by increased nitro-oxidative stress and whether the latter is associated with MIP. METHOD: we recruited 30 healthy younger males and 60 acutely intoxicated males with MA dependence and assessed severity of MA use and dependence and psychotic symptoms during intoxication, and serum oxidative toxicity (OSTOX) biomarkers including oxidized high (oxHDL) and low (oxLDL)-density lipoprotein, myeloperoxidase (MPO), malondialdehyde (MDA), and nitric oxide (NO), and antioxidant defenses (ANTIOX) including HDL-cholesterol, zinc, glutathione peroxidase (GPx), total antioxidant capacity (TAC), and catalase-1. RESULTS: a large part (50%, n = 30) of patients with MA dependence could be allocated to a cluster characterized by high psychosis ratings including delusions, suspiciousness, conceptual disorganization and difficulties abstract thinking and an increased OSTOX/ANTIOX ratio. Partial Least Squares analysis showed that 29.9% of the variance in MIP severity (a first factor extracted from psychosis, hostility, excitation, mannerism, and formal thought disorder scores) was explained by HDL, TAC and zinc (all inversely) and oxLDL (positively). MA dependence and dosing explained together 44.7% of the variance in the OSTOX/ANTIOX ratio. CONCLUSIONS: MA dependence and intoxication are associated with increased oxidative stress and lowered antioxidant defenses, both of which increase risk of MIP during acute intoxication. MA dependence is accompanied by increased atherogenicity due to lowered HDL and increased oxLDL and oxHDL.

The immune-opioid axis in prediabetes: predicting prediabetes with insulin resistance by plasma interleukin-10 and endomorphin-2 to kappa-opioid receptors ratio.

BACKGROUND: Prediabetes is characterized by a hemoglobin A1c of 5.7-6.4% and fasting blood glucose of 100-125 mg/dl. A high percentage of prediabetes subjects develop type 2 diabetes mellitus in the next years. The effects of opioid peptides and their receptors, in addition to immunological cytokines, on prediabetes are not well understood. Therefore, molecular, physiological, and clinical studies are required to link the opioid system, immune system, and insulin resistance (IR) in prediabetes. We hypothesize that opioid peptides (endomorphin-2 (EM2), and ß-endorphin (ßEP)), and their receptors (µ-opioid receptors (MOR) and κ-opioid receptors (KOR)), in addition to the inflammatory cytokines (IL-6) and anti-inflammatory cytokine (IL-10), affect IR parameters in patients with prediabetes. METHODS: Sixty prediabetes patients with IR (prediabetes+IR) and sixty prediabetes patients without IR (prediabetes-IR), in addition to 58 controls, have participated in the study. IL-6, IL-10, EM2, ßEP, MOR, and KOR were measured by the ELISA technique. RESULTS: In general, most prediabetes subjects have dyslipidemia. The IL-6, IL-10, ß-endorphin, MOR, and endomorphin-2 were higher in the prediabetes subgroups than the control group. The immune system was activated in the prediabetes in an IR-dependent manner. Prediabetes+IR can be predicted by the increased levels of IL-10, ßEP, and EM2 and by the combination of IL-10 and EM2/KOR with good sensitivity and specificity. CONCLUSION: Opioid peptides and their receptors were upregulated in patients with prediabetes, depending on the significance of IR and the immune cytokines. The intercorrelation between the immune system, EOS, and insulin in prediabetes was confirmed.

Increased zinc and albumin but lowered copper in children with transfusion-dependent thalassemia.

BACKGROUND: Measurements of copper and zinc in transfusion-dependent thalassemia (TDT) show contradictory results. AIM OF THE STUDY: To examine serum levels of these minerals in TDT in relation to iron overload indices and erythron variables. METHODS: This study recruited 60 children with TDT and 30 healthy controls aged 3-12 years old. RESULTS: Zinc was significantly higher in TDT children than in controls, while copper and the copper to zinc ratio were significantly lowered in TDT. Serum zinc was significantly associated with the number of blood transfusions and iron overload variables (including serum iron and TS%) and negatively with erythron variables (including hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin). Serum copper was significantly and negatively associated with the same iron overload and erythron variables. The copper to zinc ratio was significantly correlated with iron, TS%, ferritin, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin. Albumin levels were significantly higher in TDT children than in control children. CONCLUSION: Our results suggest that the increase in zinc in children with TDT may be explained by iron loading anemia and hemolysis and the consequent shedding of high amounts of intracellular zinc into the plasma. Increased albumin levels and treatment with Desferral may further contribute towards higher zinc levels in TDT. We suggest that the elevations in zinc in TDT are a compensatory mechanism protecting against infection, inflammation, and oxidative stress. Previous proposals for prophylactic use of zinc supplements in TDT may not be warranted.

Construction of an exposure-pathway-phenotype in children with depression due to transfusion-dependent thalassemia: Results of (un)supervised machine learning.

BACKGROUND: Transfusion dependent thalassemia (TDT) patients are treated with continued blood transfusions and show a higher prevalence of depression. TDT with consequent iron overload and inflammation is associated with increased severity of depressive symptoms in TDT children. AIM OF THE STUDY: To construct a pathway-phenotype which combines iron overload and neuro-immune biomarkers with depressive symptom subdomains in TDT children. METHODS: We measured iron status parameters (iron, ferritin, transferrin saturation percentage) and inflammatory (interleukin-1ß and tumour necrosis factor-α) biomarkers in TDT (n=111) and healthy (n=53) children and analyzed the results using machine learning. RESULTS: Cluster analysis separated TDT children with depression from those without depression and revealed two depressive subgroups one with low self-esteem and another with increased social-irritability scores. Exploratory factor analysis validated four depressive symptom dimensions as reliable constructs, namely key depressive, physiosomatic, lowered self-esteem and social-irritability dimensions. Partial Least Squares showed that 73.0% of the variance in a latent vector extracted from those four clinical subdomains, immune-inflammatory and iron overload biomarkers was explained by exposure variables including the number of blood transfusions and hospitalizations and use of deferoxamine. The exposure data, iron and immune biomarkers, and symptom subdomains are reflective manifestations of a single latent trait, which shows internal consistency reliability and predictive relevance. CONCLUSIONS: The nomological network combining exposure, pathways and behavioral phenome manifestations provides an index of overall severity and disease risk and, therefore, constitutes a new drug target, indicating that iron overload and immune activation should be targeted to treat depression due to TDT.

The Endogenous Opioid System in Schizophrenia and Treatment Resistant Schizophrenia: Increased Plasma Endomorphin 2, and κ and µ Opioid Receptors Are Associated with Interleukin-6.

BACKGROUND: activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS) plays a key role in schizophrenia (SCZ) and treatment resistant SCZ. There are only a few data on immune and endogenous opioid system (EOS) interactions in SCZ and treatment resistant SCZ. METHODS: we examined serum ß-endorphin, endomorphin-2 (EM2), mu-opioid (MOR) and kappa-opioid (KOR) receptors, and interleukin (IL)-6 and IL-10 in 60 non responders to treatment (NRTT), 55 partial RTT (PRTT) and 43 normal controls. RESULTS: serum EM2, KOR, MOR, IL-6 and IL-10 were significantly increased in SCZ as compared with controls. ß-endorphin, EM2, MOR and IL-6 were significantly higher in NRTT than in PRTT. There were significant correlations between IL-6, on the one hand, and ß-endorphin, EM2, KOR, and MOR, on the other, while IL-10 was significantly correlated with MOR only. A large part of the variance in negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation and formal thought disorders was explained by the combined effects of EM2 and MOR with or without IL-6 while increased KOR was significantly associated with all symptom dimensions. Increased MOR, KOR, EM2 and IL-6 were also associated with neurocognitive impairments including in episodic, semantic and working memory and executive functions. CONCLUSION: the EOS contributes to SCZ symptomatology, neurocognitive impairments and a non-response to treatment. In SCZ, EOS peptides/receptors may exert CIRS functions, whereas increased KOR levels may contribute to the pathophysiology of SCZ and EM2 and KOR to a non-response to treatment.

Serum Cesium, Rhenium, and Rubidium in Rheumatoid Arthritis Patients.

A considerable attention has been focused on the possible association between ultra-trace elements (UTEs) status and pathogenesis of many diseases including rheumatoid arthritis (RA). UTEs have important roles in numerous metabolic processes. Serum Cs, Rb, and Re levels in RA are not studied previously. The correlation of serum Cs, Rb, and Re levels with the well-known serological parameters, anticyclic citrullinated protein antibody (ACPA), C-reactive protein (CRP), ESR, and rheumatoid factor (RF) is also not studied previously. The present study aimed to measure the level and the correlation between serum UTEs with various blood tests results in RA patients. Serum Cs, Rb, Re, ACPA, CRP, RF, and ESR were measured in Iraqi RA patients who have a positive ACPA (ACPA > 25 U/ml) and compared with healthy individuals. There were significant elevations (p < 0.05) in serum levels of all the measured parameters as compared with those of the healthy control group except Rb and uric acid which have not been changed. Subgrouping of patients according to the results of CRP and RF leads to different results. In the low-CRP group, the high-RF subgroup showed an elevation of ACPA, Cs, and ESR in comparison with the low-RF patients. In the high-CRP group, the patients with high RF showed an increase in the levels of Cs, Rb, ESR, and ACPA. The patient group with high RF and high CRP showed more significant correlations between serum UTEs and serological tests. Serum levels of UTEs were significantly altered in RA patients. The variations in the serum levels of the measured parameters in RA need more investigation to explore the possible association between these UTEs and RA. RA subgroups, according to the results of CRP and CPA, produce more and various information than taking RA as a whole group in the estimation of UTEs.

Anti-pepsin activity of silicon dioxide nanoparticles / Actividad antipepsina de nanopartículas de dióxido de silicio / Atividade antipepsina de nanopartículas de dióxido de silício

SiO2NPs as an inhibitor of pepsin enzyme for treatment of gastro-esophageal reflux disease (GERD) were investigated. Silicon dioxide nanoparticles (pepsin coated SiO2NPs) are among the safest nanoparticles that can be used inside the human body. The activity of pepsin before and after the addition of certain amounts of the NPs to the reaction mixture was measured spectrophotometrically. Furthermore, these experiments were repeated at different temperatures, different weights of NPs, and different ionic strengths. The kinetic parameters (Km & Vmax) of the pepsin-catalyzed reactions were calculated from the Lineweaver-Burk plots. The results showed that there is a significant reduction of pepsin activity by SiO2NPs (Vmax of free pepsin = 4.82 U and Vmax of the immobilized pepsin = 2.90 U). The results also indicated that the presence of ionic strength causes remarkable reduction of pepsin activity. It can be concluded the best condition for inhibition of pepsin activity is by using a combinationof SiO2NPs and high concentration NaCl at 37 °C.

Se usaron nanopartículas de dióxido de silicio como inhibidores de la pepsina para el tratamiento del reflujo gastroesofágico (GERD). Estas nanopartículas (SiO2NPs recubiertas de pepsina) son unas de las más seguras y pueden usarse en el cuerpo humano. Se midió a través de espectrofotometría la actividad de la pepsina antes y después de añadir cierta cantidad de NPs a la mezcla reactante. Adicionalmente, se repitieron estas pruebas a diferentes temperaturas, variando el peso de las NPs y la fuerza iónica. Se calcularon los parámetros cinéticos (Km y Vmax) de las reacciones catalizadas con pepsina a través de las gráficas de Lineweaver-Burk. Los resultados mostraron que, usando SiO2NPs (Vmax de pepsina libre = 4.82 U y Vmax de pepsina inmovilizada = 2.90 U) y a través de la presencia de fuerza iónica, la actividad enzimática se reduce significativamente. Se concluye que la mejor condición para inhibir la actividad enzimática es usando una combinación de SiO2NPs y una alta concentración de NaCl a 37 °C.

Foram usadas nanopartículas de dióxido de silício como inibidores da pepsina para o tratamento do refluxo gastroesofágico (GERD). Estas nanopartículas (SiO2NPs cobertas de pepsina) são uma das mais seguras e podem usar-se no corpo humano. Foi medida a atividade da pepsina mediante espectrofotometria antes e depois de agregar certa quantidade de NPs à mistura de reação. Adicionalmente, repetiram-se estas provas a diferentes temperaturas, variando o peso das NPs e a força iónica. Foram calculados os parâmetros cinéticos (Km e Vmax) das reações catalisadas com pepsina a través das gráficas de Lineweaver-Burk. Os resultados mostraram que, usando SiO2NPs (Vmax de pepsina livre = 4.82 U e Vmax de pepsina imobilizada = 2.90 U) e a través da presença de força iónica, a atividade enzimática se reduze significativamente. Foi concluído que a melhor condição para inibir a atividade enzimática é usando uma combinação de SiO2NPs e uma alta concentração de NaCl a 37 °C.