scholarly journals Lowered Antioxidant Defenses and Increased Oxidative Toxicity Are Hallmarks of Deficit Schizophrenia: Neurocognitive and Symptom Correlates

2020 ◽  
Author(s):  
Michael Maes ◽  
Sunee Sirivichayakul ◽  
Andressa Keiko Matsumoto ◽  
Anna Paula Michelin ◽  
Laura de Oliveira Semeão ◽  
...  
Keyword(s):  
Negative Symptoms ◽  
Psychomotor Retardation ◽  
Antioxidant Defenses ◽  
Paraoxonase 1 ◽  
Pon1 Activity ◽  
Lipid Hydroperoxides ◽  
Sh Groups ◽  
Deficit Schizophrenia ◽  
Immune Biomarkers ◽  
Thought Disorders

Background: There is now evidence that schizophrenia and deficit schizophrenia are neuro-immune conditions and that oxidative stress toxicity (OSTOX) may play a pathophysiological role. Aims of the study: To compare OSTOX biomarkers and antioxidant (ANTIOX) defenses in deficit versus non-deficit schizophrenia. Methods: We examined lipid hydroperoxides (LOOH), malondialdehyde (MDA), advanced oxidation protein products (AOPP), sulfhydryl (-SH) groups, paraoxonase 1 (PON1) activity and PON1 Q192R genotypes, total radical-trapping antioxidant parameter (TRAP) as well as immune biomarkers in patients with deficit (n=40) and non-deficit (n=40) schizophrenia and healthy controls (n=40). Results: Deficit schizophrenia is characterized by significantly increased levels of AOPP and lowered -SH, and PON1 activity, while no changes in the OSTOX/ANTIOX biomarkers were found in non-deficit schizophrenia. An increased OSTOX/ANTIOX ratio was significantly associated with deficit versus non-deficit schizophrenia (Odds ratio=3.15, p<0.001). Partial least squares analysis showed that 47.6% of the variance in a latent vector extracted from psychosis, excitation, hostility, mannerism, negative symptoms, psychomotor retardation, formal thought disorders, and neurocognitive test scores was explained by LOOH+AOPP, PON1 genotype + activity, CCL11, tumor necrosis factor (TNF)-α, IgA responses to neurotoxic tryptophan catabolites (TRYCATs), whereas -SH groups and IgM responses to MDA showed indirect effects mediated by OSTOX and neuro-immune biomarkers. Discussion: Our findings indicate that with increasing overall severity of schizophrenia, neuro-immune and neuro-oxidative (especially protein oxidation indicating chlorinative stress) toxicities become more prominent and together with lowered antioxidant defenses and impairments in innate immunity-associated resilience against neurotoxic processes shape a distinct nosological entity, namely deficit schizophrenia.

Deficit schizophrenia and its features are associated with PON1 Q192R genotypes and lowered paraoxonase 1 (PON1) enzymatic activity: effects on bacterial translocation

CNS Spectrums ◽  
2020 ◽  
pp. 1-10 ◽  
Author(s):  
Andressa K. Matsumoto ◽  
Michael Maes ◽  
Thitiporn Supasitthumrong ◽  
Annabel Maes ◽  
Ana P. Michelin ◽  
...  
Keyword(s):  
Negative Symptoms ◽  
Immunoglobulin A ◽  
Quorum Quenching ◽  
Psychomotor Retardation ◽  
Paraoxonase 1 ◽  
Pon1 Activity ◽  
Phenyl Acetate ◽  
Gram Negative ◽  
Deficit Schizophrenia ◽  
Thought Disorders

Abstract Background. Primary deficit schizophrenia (DS) is characterized by enduring negative symptoms and represents a qualitatively different disease entity with respect to non-deficit schizophrenia (NDS). No studies investigated the association between the enzyme paraoxonase 1 (PON1) and DS and its phenomenology. Methods. In this case-control study, Thai women and men, aged 18 to 65 years, were divided in DS (n = 40) and NDS (n = 40) and were compared to controls (n = 40). PON1 activities against 4-(chloromethyl)phenyl acetate (CMPA) and phenylacetate were determined. Moreover, subjects were genotyped for their PON1 Q192R polymorphism and immunoglobulin A (IgA) levels responses directed to Gram-negative bacteria were measured. Results. DS is significantly associated with the QQ genotype and the Q allele as compared with NDS and controls. PON1 activities are significantly and inversely associated with negative symptoms, formal thought disorders, psychomotor retardation, excitation and DS. The presence of the Q allele is associated with increased IgA responses to Pseudomonas aeruginosa, Morganella morganii, and Pseudomonas putida as compared with RR carriers. Conclusions. The PON1 Q allele and lower PON1 activities especially against CMPA are associated with DS, indicating lowered quorum quenching abilities as well as lowered defenses against lipoperoxidation and immune activation. It is suggested that lowered PON1 activity in DS constitutes an impairment in the innate immune system which together with lowered natural IgM may cause lower immune regulation thereby predisposing toward greater neurotoxic effects of immune-inflammatory, oxidative and nitrosative pathways and Gram-negative microbiota.

scholarly journals In Schizophrenia, PON1 Q192R Genotypes and/or Lowered Paraoxonase 1 (PON1) Enzymatic Activity are Significantly Associated with the Deficit Syndrome, Negative Symptoms, Formal Thought Disorders, Psychomotor Retardation, Excitation and Increased IgA Levels to Gram-Negative Microbiota

2019 ◽  
Author(s):  
Andressa Keiko Matsumoto ◽  
Michael Maes ◽  
Annabel Maes ◽  
Ana Paula Michelin ◽  
Laura de Oliveira Semeão ◽  
...  
Keyword(s):  
Negative Symptoms ◽  
Quorum Quenching ◽  
Psychomotor Retardation ◽  
Paraoxonase 1 ◽  
Pon1 Activity ◽  
Phenyl Acetate ◽  
Gram Negative ◽  
Deficit Syndrome ◽  
Deficit Schizophrenia ◽  
Thought Disorders

Background: Primary deficit schizophrenia (DS) is characterized by enduring negative symptoms and represents a qualitatively different disease entity with respect to non-deficit schizophrenia (NDS). No studies investigated the association between the enzyme paraoxonase 1 (PON1) and DS and its phenomenology. Methods: In this case-control study, Thai women and men, aged 18-65 years, were divided in DS (n=40) and NDS (n=40) and were compared to controls (n=40). PON1 activities against 4-(chloromethyl)phenyl acetate (CMPA) and phenylacetate were determined. Moreover, subjects were genotyped for their PON1 Q192R polymorphism and IgA levels responses directed to Gram-negative bacteria were measured. Results: DS is significantly associated with the QQ genotype and the Q allele as compared with NDS and controls. PON1 activities are significantly and inversely associated with negative symptoms, formal thought disorders, psychomotor retardation, excitation and DS. The presence of the Q allele is associated with increased IgA responses to Pseudomonas aeruginosa, Morganella morganii, and Pseudomonas putida as compared with RR carriers. Conclusions: The PON1 Q allele and lower PON1 activities especially against CMPA are associated with DS, indicating lowered quorum quenching abilities as well as lowered defenses against lipoperoxidation and immune activation. It is suggested that lowered PON1 activity in DS constitutes an impairment in the innate immune system which together with lowered natural IgM may cause lower immune regulation thereby predisposing towards greater neurotoxic effects of immune-inflammatory, oxidative and nitrosative pathways and Gram-negative microbiota.

Increased Levels of Plasma Tumor Necrosis Factor-α Mediate Schizophrenia Symptom Dimensions and Neurocognitive Impairments and Are Inversely Associated with Natural IgM and Paraoxonase 1 Activity

2019 ◽  
Author(s):  
Michael Maes ◽  
Sunee Sirivichayakul ◽  
Andressa Keiko Matsumoto ◽  
Annabel Maes ◽  
Ana Paula Michelin ◽  
...  
Keyword(s):  
Negative Symptoms ◽  
Cognitive Impairments ◽  
Word List ◽  
Psychomotor Retardation ◽  
Paraoxonase 1 ◽  
Necrosis Factor Alpha ◽  
Symptom Dimensions ◽  
Deficit Schizophrenia ◽  
Thought Disorders ◽  
Natural Igm

Accumulating evidence suggests that TNF-α-mediated immune-neurotoxicity contributes to cognitive impairments and the overall severity of schizophrenia (OSOS). There are no data whether peripheral IL-6 and IL-4 may affect the phenome of schizophrenia above and beyond the effects of TNF-α and whether those cytokines are regulated by lowered natural IgM to malondialdehyde (MDA) and paraoxonase 1 enzyme activity. We assessed the aforementioned biomarkers in schizophrenia patients with (n=40) and without (n=40) deficit schizophrenia and 40 healthy controls. Deficit schizophrenia was best predicted by a combination of increased IL-6 and PON1 status (QQ genotype and lowered CMPAase activity) and lowered IgM to MDA. Partial Least Squares bootstrapping shows that 41.0% of the variance in negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, and formal thought disorders was explained by increased TNF-α and PON1 status (QQ genotype and lowered CMPAase activity), lowered IL-4 and IgM to MDA as well as male sex and lowered education. We found that 47.9% of the variance in verbal fluency, word list memory, true recall, Mini-Mental State Examination, and executive functions was predicted by increased TNF-α and lowered IL-4, IgM to MDA and education. In addition, both TNF-α and IL-4 levels were significantly associated with lowered IgM to MDA, while TNF-α was correlated with PON1 status. These data provide evidence that the symptomatic (both the deficit subtype and OSOS) and cognitive impairments in schizophrenia are to a large extent mediated by the effects of immune-mediated neurotoxicity as well as lowered regulation by the innate immune system.

Schizophrenia phenomenology revisited: positive and negative symptoms are strongly related reflective manifestations of an underlying single trait indicating overall severity of schizophrenia

CNS Spectrums ◽  
2020 ◽  
pp. 1-10 ◽  
Author(s):  
Abbas F. Almulla ◽  
Hussein K. Al-Hakeim ◽  
Michael Maes
Keyword(s):  
Convergent Validity ◽  
Negative Symptoms ◽  
Discriminant Validity ◽  
Psychomotor Retardation ◽  
Future Research ◽  
Stable Phase ◽  
Deficit Schizophrenia ◽  
Latent Vector ◽  
Thought Disorders ◽  
Positive And Negative Symptoms

Abstract Background. To examine whether negative symptoms, psychosis, hostility, excitation, and mannerism (PHEM symptoms), formal thought disorders (FTD) and psychomotor retardation (PMR) are interrelated phenomena in major neurocognitive psychosis (MNP) or deficit schizophrenia and whether those domains belong to an underlying latent vector reflecting general psychopathology. Methods. In this study, we recruited 120 patients with MNP or deficit schizophrenia and 54 healthy subjects and measured the above-mentioned symptom domains. Results. In MNP, there were significant associations between negative and PHEM symptoms, FTD and PMR. A single latent trait, which is essentially unidimensional, underlies these key domains of schizophrenia and MNP and additionally shows excellent internal consistency reliability, convergent validity, and predictive relevance. Confirmatory Tedrad Analysis indicates that this latent vector fits a reflective model. The lack of discriminant validity shows that positive (and PHEM or psychotic) and negative symptoms greatly overlap and probably measure the same latent construct. Soft independent modeling of class analogy (SIMCA) shows that MNP (diagnosis based on negative symptoms) is better modeled using PHEM symptoms, FTD, and PMR than negative symptoms. Conclusions. In stable phase MNP, which is a restricted sample of the schizophrenia population, negative and PHEM symptoms, FTD and PMR belong to one underlying latent vector reflecting overall severity of schizophrenia (OSOS). The bi-dimensional concept of “positive” and “negative” symptoms cannot be validated and, therefore, future research in stable phase schizophrenia should consider that the latent phenomenon OSOS as well as its reflective manifestations are the key factors of schizophrenia phenomenology.

scholarly journals Increased Oxidative Stress Toxicity and Lowered Antioxidant Defenses in Temporal Lobe Epilepsy and Mesial Temporal Sclerosis: Associations with Psychiatric Comorbidities

2020 ◽  
Author(s):  
Michael Maes ◽  
Thitiporn Supasitthumrong ◽  
Chusak Limotai ◽  
Ana Paula Michelin ◽  
Andressa Keiko Matsumoto ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Anxiety Disorders ◽  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Negative Symptoms ◽  
Antioxidant Defenses ◽  
Mesial Temporal Sclerosis ◽  
Lipid Hydroperoxides ◽  
Psychiatric Comorbidities ◽  
Sh Groups

Oxidative stress toxicity (OSTOX), as well as lowered antioxidant defenses (ANTIOX), play a role in temporal lobe epilepsy (TLE). Nevertheless, the associations between OSTOX/ANTIOX and psychiatric comorbidities in TLE are largely unknown.Thus, this study examines plasma malondialdehyde (MDA), lipid hydroperoxides (LOOH), advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), total radical trapping antioxidant parameter (TRAP) and sulfhydryl (-SH) groups in Depression due to TLE (n=25); Anxiety Disorders due to TLE (n=27); Psychotic Disorder due to TLE (n=25); “pure TLE” (n=27); and healthy controls (n=40).TLE and mesial temporal sclerosis (MTS) were characterized by significant increases in OSTOX (MDA, AOPP, LOOH) and lowered ANTIOX (-SH groups, TRAP). The discrimination of pure TLE from controls yielded a significant area under the ROC curve for MDA (0.999), AOPP (0.851), -SH groups (0.899) and the OSTOX/ANTIOX ratio (0.996). Seizure frequency is significantly associated with increased MDA and lowered LOOH and NOx levels. Increased MDA was associated with the severity of depressive and physiosomatic symptoms, whilst increased AOPP levels predicted suicidal ideation. Depression and anxiety disorders co-occurring with TLE showed significantly lower MDA levels than TLE without any comorbidities. The psychotic and negative symptoms of TLE are associated with increased MDA levels and excitation with increased LOOH and lowered TRAP levels.These results indicate that oxidative stress toxicity especially protein oxidation and aldehyde formation coupled with lowered -SH groups play a key role in the pathophysiology of TLE/MTS. Increased aldehyde formation also impacts psychopathology, psychosis, as well as negative and depressive symptoms.

scholarly journals How to Construct a Bottom-Up Nomothetic Network Model and Disclose Novel Nosological Classes by Integrating Risk Resilience and Adverse Outcome Pathways with the Phenome of Schizophrenia

2020 ◽  
Vol 10 (9) ◽  
pp. 645 ◽  
Author(s):  
Michael Maes ◽  
Aristo Vojdani ◽  
Piotr Galecki ◽  
Buranee Kanchanatawan
Keyword(s):  
Negative Symptoms ◽  
Adverse Outcome ◽  
Psychomotor Retardation ◽  
Oxidative Stress Biomarkers ◽  
Case Definitions ◽  
Current Case ◽  
Bottom Up ◽  
Thought Disorders ◽  
Using Data ◽  
Adverse Outcome Pathways

Current case definitions of schizophrenia (DSM-5, ICD), made through a consensus among experts, are not cross-validated and lack construct reliability validity. The aim of this paper is to explain how to use bottom-up pattern recognition approaches to construct a reliable and replicable nomothetic network reflecting the direct effects of risk resilience (RR) factors, and direct and mediated effects of both RR and adverse outcome pathways (AOPs) on the schizophrenia phenome. This study was conducted using data from 40 healthy controls and 80 patients with schizophrenia. Using partial least squares (PLS) analysis, we found that 39.7% of the variance in the phenomenome (lowered self-reported quality of life) was explained by the unified effects of AOPs (IgA to tryptophan catabolites, LPS, and the paracellular pathway, cytokines, and oxidative stress biomarkers), the cognitome (memory and executive deficits), and symptomatome (negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, formal thought disorders); 55.8% of the variance in the symptomatome was explained by a single trait extracted from AOPs and the cognitome; and 22.0% of the variance in the latter was explained by the RR (Q192R polymorphism and CMPAase activity, natural IgM, and IgM levels to zonulin). There were significant total effects (direct + mediated) of RR and AOPs on the symptomatome and the phenomenome. In the current study, we built a reliable nomothetic network that reflects the associations between RR, AOPs, and the phenome of schizophrenia and discovered new diagnostic subclasses of schizophrenia based on unified RR, AOPs, and phenome scores.

scholarly journals The Role of Immune and Oxidative Pathways in Menstrual-Cycle Associated Depressive, Physio-Somatic, Breast and Anxiety Symptoms: Modulation by Sex Hormones

2020 ◽  
Author(s):  
Chutima Roomruangwong ◽  
Andressa Keiko Matsumoto ◽  
Ana Paula Michelin ◽  
Laura de Oliveira Semeão ◽  
João Victor de Lima Pedrão ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Menstrual Cycle ◽  
Sex Hormones ◽  
Rating Scale ◽  
Antioxidant Defenses ◽  
Complement C3 ◽  
Phenyl Acetate ◽  
Lipid Hydroperoxides ◽  
Sh Groups ◽  
Radical Trapping

Objective: To examine whether 1) immune and nitro-oxidative stress (IO&NS) biomarkers are associated with premenstrual syndrome (PMS); and 2) changes in IO&NS biomarkers during the menstrual cycle (MC) are associated with PMS symptoms and plasma estradiol and progesterone. Methods: Forty-one women completed the Daily Record of Severity of Problems (DRSP) rating scale during 28 consecutive days and MC Associated Syndrome (MCAS) was diagnosed when the summed DRSP score during the MC is > 0.666 percentile. We assayed plasma levels of complement C3 and C4, highly sensitive C-reactive protein (hsCRP), haptoglobin (Hp), advanced oxidation protein products (AOPP), lipid hydroperoxides (LOOH), nitric oxide metabolites (NOx), total radical-trapping antioxidant parameter (TRAP), sulfhydryl (-SH) groups and the activity of paraoxonase (PON)1 at days 7 (D7), 14 (D14), 21 (D21) and 28 (D28) of the MC. Results: All biomarkers, except hsCRP, showed significant alterations during the MC. Arylesterase (AREase) was lowered at D28, while LOOH increased at D14 and C4 at D21 in women with MCAS. The total DRSP score was predicted by the combined effects of C4 (positively) and AREase and malondialdehyde (MDA) (both inversely associated). Progesterone lowered levels of LOOH, AOPP and C3 and estradiol lowered levels of Hp while both sex hormones increased 4-(chloromethyl)phenyl acetate (CMPA)ase and AREase activities and levels of -SH groups. Conclusion: PMS/MCAS is not accompanied by a peripheral inflammatory response. Lowered MDA and antioxidant defenses and increased C4 may play a role in MC-associated symptoms while sex hormones may have a protective effect against oxidative stress toxicity.

scholarly journals Chronic Fatigue and Fibromyalgia Symptoms are Key Components of Deficit Schizophrenia and are Strongly Associated with Activated Immune-Inflammatory Pathways

2019 ◽  
Author(s):  
Abbas Almulla ◽  
Hussein Al-Hakeim ◽  
Mokhlad Abed ◽  
André Carvalho ◽  
Michael Maes
Keyword(s):  
Convergent Validity ◽  
Rating Scale ◽  
Somatic Symptoms ◽  
Internal Consistency Reliability ◽  
Chronic Fatigue ◽  
Psychomotor Retardation ◽  
Deficit Schizophrenia ◽  
Thought Disorders ◽  
Symptom Domains

A subset of patients with schizophrenia experience physio-somatic symptoms reminiscent of chronic fatigue and fibromyalgia. In schizophrenia, these symptoms contribute to impaired quality of life, and are strongly related to neuro-cognitive deficits, and increased IgA responses to tryptophan catabolites. Negative and PHEM (psychosis, hostility, excitation, mannerism) symptoms, psychomotor retardation (PMR) and formal thought disorders, appear to be manifestations of a single trait reflecting overall severity of schizophrenia (OSOS). In this study, 120 patients with deficit schizophrenia (DEFSCZ) and 54 healthy subjects were assessed with the FibroFatigue (FF) rating scale, and the above-mentioned symptom domains as well as neuro-cognitive tests and biomarkers were measured. In DEFSCZ, there were robust associations between the FF score and all above-mentioned symptom domains, and impairments in semantic and episodic memory and executive functions. Furthermore, the FF score loaded highly on an OSOS latent vector (LV), which showed adequate convergent validity, internal consistency reliability and predictive relevance and fitted a reflective model. Soft Independent Modelling of Class Analogy (SIMCA) showed that the FF items discriminated DEFSCZ from controls with an overall accuracy of 100%. Interleukin IL-1β, IL-1 receptor antagonist (sIL-1RA), tumour necrosis factor (TNF)-α and CCL-11 (eotaxin) explained 66.8% of the variance in the FF score and 59.4% of the variance in OSOS. In conclusion, these data show that physio-somatic symptoms are a core component of the phenomenology of DEFSCZ and are largely mediated by neurotoxic effects of activated immune pathways, including aberrations in CCL-11, IL-1β and TNF-α signalling.

scholarly journals How to Construct a Bottom-up Nomothetic Network Model and Disclose Novel Nosological Classes by Integrating Risk Resilience and Adverse Outcome Pathways with the Phenome of Schizophrenia

2020 ◽  
Author(s):  
Michael Maes ◽  
Aristo Vodjani ◽  
Piotr Galecki ◽  
Buranee Kanchanatawan
Keyword(s):  
Negative Symptoms ◽  
Adverse Outcome ◽  
Psychomotor Retardation ◽  
Oxidative Stress Biomarkers ◽  
Case Definitions ◽  
Current Case ◽  
Bottom Up ◽  
Thought Disorders ◽  
Using Data ◽  
Adverse Outcome Pathways

Current case definitions of schizophrenia (DSM-5, ICD), made through a consensus among experts, are not cross-validated and lack construct reliability validity. The aim of this paper is to explain how to use bottom-up pattern recognition approaches to construct a reliable and replicable nomothetic network reflecting the direct effects of risk resilience (RR) factors, and direct and mediated effects of both RR and adverse outcome pathways (AOPs) on the schizophrenia phenome. This study was conducted using data of 40 healthy controls and 80 patients with schizophrenia. Using partial least Squares (PLS) analysis, we found that 39.7% of the variance in the phenomenome (lowered self-reported quality of life) was explained by the unified effects of AOPs (IgA to tryptophan catabolites, LPS, and the paracellular pathway, cytokines, and oxidative stress biomarkers), the cognitome (memory and executive deficits), and symptomatome (negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, formal thought disorders); 55.8% of the variance in the symptomatome was explained by a single trait extracted from AOPs and the cognitome; and 22.0% of the variance in the latter was explained by the RR (Q192R polymorphism and CMPAaase activity, natural IgM, and IgM levels to zonulin). There were significant total effects (direct + mediated) of RR and AOPs on the symptomatome and phenomenome. In the current study, we built a reliable nomothetic network that reflects the associations between RR, AOPs, and the phenome of schizophrenia and discovered new diagnostic subclasses of schizophrenia based on unified RR, AOPs, and phenome scores.

scholarly journals Tratment With Folic Acid Increases Paraoxonase 1 Activity Thereby Improving Chronic Kidney Disease

2020 ◽  
Author(s):  
Andressa Matsumoto ◽  
Michael Maes ◽  
Ana Paula Michelin ◽  
Kamila Bonifácio ◽  
Laura Semeão ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Folic Acid ◽  
Kidney Disease ◽  
Antioxidant Defenses ◽  
Paraoxonase 1 ◽  
Pon1 Activity ◽  
Renal Disease Progression ◽  
Ckd Stage ◽  
Before And After

Introduction: Increased oxidative stress, including elevated homocysteine (Hcy) plasma levels, and lowered levels of antioxidants participate in the pathophysiology and progression of chronic kidney disease (CKD). Paraoxonase (PON)1 activity and folic acid are antioxidants which play a role in Hcy metabolism. However, there are no data whether, in CKD, treatment with folic acid improves glomerular filtration rate (GFR) through effects on PON1 activity and Hcy concentrations. Methods: In the current study, we determined PON1 genotypes and activity, Hcy and estimated GFR (eGFR) both before and after treatment with folic acid (5 mg/d) versus no treatment during three consecutive months in 113 outpatients with CKD classified into stages 4, 3b and 3a. Results: PON1 CMPAase and AREase activities were significantly lower in patients allocated to CKD stage 4 as compared with stages 3b and 3a. Treatment with folic acid significantly improved eGFR and increased levels of CMPAase and AREase in patients allocated to classes 4 and 3b, but not 3a. The improvement of eGFR was associated with increased CMPAase and AREase activities, while the latter were associated with increased levels of folic acid. Treatment with folic acid significantly reduced plasma Hcy levels and the Hcy/PON1 activity ratio. The effects of folic acid increasing PON1 activities were not mediated by changes in Hcy. Discussion: Treatment of CKD patients in early/intermediate stages of CKD patients improves oxidative stress by rebalancing the prooxidant (Hcy) / antioxidant (PON1 activities) ratio. Treatment with folic acid significantly improves eGFR and these effects are mediated via increased PON1 activities. Treatment with folic acid in phase G3b and G4 may reduce renal disease progression by enhancing antioxidant defenses.

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