Natural regulatory IgM-mediated autoimmune responses directed against malondialdehyde regulate oxidative and nitrosative pathways and coupled with IgM responses to nitroso adducts attenuate depressive and physiosomatic symptoms at the end of term pregnancy.

AIM: We aimed to delineate the effects of immunoglobulin (Ig)M-mediated autoimmune responses directed against malondialdehyde (MDA) and nitroso (SNO) adducts on nitro-oxidative stress and depressive and physiosomatic symptoms (DPSS) at the end of term. METHODS: IgM responses to MDA, NO (nitroso) adducts formed by nitrosylation, and NO2 tyrosine formed by nitration were measured as well as hydroperoxides (ferrous oxidation xylenol orange), advanced protein oxidation products (AOPP), and NO metabolite (NOx) levels in women at the end of term pregnancy and in normal controls. RESULTS: IgM responses to MDA were significantly and inversely associated with AOPP, ferrous oxidation xylenol orange, and NOx and DPSS. IgM responses to NO adducts were significantly and inversely associated with DPSS and positively with NOx levels. There were significant associations between IgM responses to MDA, NO adducts, and NO2 tyrosine. The DPSS score was predicted by AOPP and a lifetime history of premenstrual syndrome (both positively) and IgM responses to NO adducts (inversely). Furthermore, 71.8% of the variance in the index of nitro-oxidative stress was explained by lowered IgM responses to MDA, antioxidant levels (zinc, total radical trapping parameter), and inflammatory mediators. CONCLUSION: Lowered levels of IgM responses to MDA during pregnancy are accompanied by a reduced regulation of nitro-oxidative processes thereby explaining increased oxidative and nitrosative stress biomarkers in association with DPSS. IgM responses to NO adducts, which reflect nitrosylation as a consequence of increased NO production, regulate DPSS symptoms at the end of term and are a trait marker of major depression. IgM responses to MDA are a key part of the compensatory anti-inflammatory responses system.

IgM-mediated autoimmune responses to oxidative specific epitopes, but not nitrosylated adducts, are significantly decreased in pregnancy: association with bacterial translocation, perinatal and lifetime major depression and the tryptophan catabolite (TRYCAT) pathway.

Immunoglubulin (Ig)M responses directed to oxidative specific epitopes (OSEs) and nitric oxide (NO)-adducts are significantly associated with major depression and physio-somatic symptoms. End of term serum IgM responses to OSEs and NO-adducts were assayed in pregnant women with (n = 24) and without prenatal depression (n = 25) as well as in 24 non-pregnant women. Associations of IgM/IgA responses to Gram-negative gut commensal bacteria (leaky gut index) and IgA/IgM responses to tryptophan catabolites (TRYCATs) were analyzed. IgM responses to OSEs, but not NO-adducts, were significantly reduced at the end of term. There were no significant associations between IgM responses to OSEs and perinatal depression, whilst IgM responses to NO-adducts, especially NO-cysteinyl, were significantly associated with a lifetime major depression. IgM responses to OSEs and NO-cysteinyl were significantly associated with IgA/IgM responses to Gram-negative bacteria, especially Morganella morganii, Klebsiella pneumoniae and Citrobacter koseri. IgM responses to NO-adducts and OSEs, especially malondialdehyde and myristic acid, and C-reactive protein (CRP) were inversely associated with TRYCAT pathway activity, whilst a lifetime depression and Pseudomonas putida were positively associated. The attenuation of natural IgM-mediated responses to OSEs at the end of term may indicate lowered activity of this part of the compensatory (anti-)inflammatory reflex system and may be partly explained by lowered bacterial translocation. Increased IgM responses to NO-cysteinyl is a biomarker of lifetime depression and may be induced by bacterial translocation. Natural IgM-mediated autoimmune responses, increased nitrosylation and higher CRP levels may have negative regulatory effects on the TRYCAT pathway.

In utero and early-life exposure of rats to a Wi-Fi signal: screening of immune markers in sera and gestational outcome.

An experimental approach was used to assess immunological biomarkers in the sera of young rats exposed in utero and postnatal to non-ionizing radiofrequency fields. Pregnant rats were exposed free-running, 2 h/day and 5 days/week to a 2.45 GHz Wi-Fi signal in a reverberation chamber at whole-body specific absorption rates (SAR) of 0, 0.08, 0.4, and 4 W/kg (with 10, 10, 12, and 9 rats, respectively), while cage control rats were kept in the animal facility (11 rats). Dams were exposed from days 6 to 21 of gestation and then three newborns per litter were further exposed from birth to day 35 postnatal. On day 35 after birth, all pups were sacrificed and sera collected. The screening of sera for antibodies directed against 15 different antigens related to damage and/or pathological markers was conducted using enzyme-linked immunosorbent assay (ELISA). No change in humoral response of young pups was observed, regardless of the types of biomarker and SAR levels. This study also provided some data on gestational outcome following in utero exposure to Wi-Fi signals. Mass evaluation of dams and pups and the number of pups per litter was monitored, and the genital tracts of young rats were observed for abnormalities by measuring anogenital distance. Under these experimental conditions, our observations suggest a lack of adverse effects of Wi-Fi exposure on delivery and general condition of the animals.

Frontiers in vitamin research: new antibodies, new data.

Since 2004, the anatomical distribution of vitamins in the monkey brain, studied using immunohistochemical techniques and new tools (specific antisera that discriminate different vitamins reasonably well), has been an ongoing research field. The visualization of immunoreactive structures containing vitamins (folic acid, riboflavin, thiamine, pyridoxal, and vitamin C) has recently been reported in the monkey brain (Macaca fascicularis), all these vitamins showing a restricted or very restricted distribution. Folic acid, thiamine, and riboflavin have only been observed in immunoreactive fibers, vitamin C has only been found in cell bodies (located in the primary somatosensory cortex), and pyridoxal has been found in both fibers and cell bodies. Perikarya containing pyridoxal have been observed in the paraventricular hypothalamic nucleus, the periventricular hypothalamic region, and in the supraoptic nucleus. The fibers containing vitamins are thick, smooth (without varicosities), and are of medium length or long, whereas immunoreactive cell bodies containing vitamins are round or triangular. At present, there are insufficient data to elucidate the roles played by vitamins in the brain, but the anatomical distribution of these compounds in the monkey brain provides a general idea (although imprecise and requiring much more study) about the possible functional implications of these molecules. In this sense, here the possible functional roles played by vitamins are discussed.

Amyotrophic lateral sclerosis (ALS) and extremely-low frequency (ELF) magnetic fields: a study in the SOD-1 transgenic mouse model.

There is some evidence from epidemiological studies of an association between occupational exposure to electromagnetic fields and Amyotrophic Lateral Sclerosis (ALS). Our aim was to perform, for the first time, an animal study in a controlled magnetic environment. We used the SOD-1 mouse model to assess the possible effect of ELF magnetic fields on development of the disease. Seven mice per group were exposed to 50 Hz magnetic fields at two intensities (100 and 1000 microT(rms)) before the onset of the clinical signs of ALS. Exposure lasted 7 weeks, and body weight, motor performance and life span were monitored. Our results did not reveal any evidence of a link between ELF exposure and ALS in this transgenic animal model.

Body image dissatisfaction in pregnant and non-pregnant females is strongly predicted by immune activation and mucosa-derived activation of the tryptophan catabolite (TRYCAT) pathway.

OBJECTIVES: The aim of the present study is to delineate the associations between body image dissatisfaction in pregnant women and immune-inflammatory biomarkers, i.e., C-reactive protein (CRP), zinc and IgA/IgM responses to tryptophan and tryptophan catabolites (TRYCATs). METHODS: We assessed 49 pregnant and 24 non-pregnant females and assessed Body Image Satisfaction (BIS) scores at the end of term (T1), and 2-4 days (T2) and 4-6 weeks (T3) after delivery. Subjects were divided in those with a lowered BIS score (≤ 3) versus those with a higher score. RESULTS: Logistic regression analysis showed that a lowered T1 BIS score was predicted by CRP levels and IgA responses to tryptophan (negative) and TRYCATs (positive), perinatal depression, body mass index (BMI) and age. The sum of quinolinic acid, kynurenine, 3-OH-kynurenine and 3-OH-anthranilic acid (reflecting brain quinolinic acid contents) was the single best predictor. In addition, a large part of the variance in the T1, T2 and T3 BIS scores was explained by IgA responses to tryptophan and TRYCATs, especially quinolinic acid. CONCLUSIONS: Body image dissatisfaction is strongly associated with inflammation and mucosa-derived IDO activation independently from depression, pregnancy, BMI and age. IgA responses to peripheral TRYCATs, which determine brain quinolinic acid concentrations, also predict body image dissatisfaction.

IgA/IgM Responses to Gram-Negative Bacteria are not Associated with Perinatal Depression, but with Physio-somatic Symptoms and Activation of the Tryptophan Catabolite Pathway at the End of Term and Postnatal Anxiety.

BACKGROUND: Evidence has implicated the translocation of commensal Gram-negative bacteria (Gram-B) due to leaky gut in the pathophysiology of depression and physio-somatic symptoms (e.g. fatigue, pain, irritable bowel syndrome, malaise, etc.). In addition, the leaky gut may contribute to immune- inflammatory activation and oxidative stress. This study investigated whether bacterial translocation is associated with perinatal depression and anxiety scores and with prenatal physio-somatic symptoms and immune-inflammatory biomarkers, including the tryptophan catabolite (TRYCAT) pathway. METHOD: Data were collected in pregnant women at the end of term (T1) and 4-6 weeks after delivery (T2) as well as in non-pregnant controls. We examined the associations between serum IgM/IgA responses to Gram-B at the end of term and depression (Edinburgh Postnatal Depression Scale -EPDS) and anxiety (Spielberger's State Anxiety Inventory -STAI) symptoms. RESULTS: Levels of C-reactive protein, zinc, haptoglobin, hematocrit and IgA/IgM responses to 9 TRYCATs were also measured. No significant associations of the IgA/IgM responses to Gram-B with prenatal depression and anxiety were observed. Increased IgA/IgM responses to Gram-B predict higher levels of haptoglobin, hematocrit and TRYCATs, in particular quinolinic acid and the quinolinic acid / kynurenic acid ratio. IgA responses to Gram-B were significantly lowered in pregnant women compared to age-matched non-pregnant women, while IgM responses were significantly elevated in participants with alcohol consumption. Physio-somatic symptoms at the end of term were significantly associated with IgM responses to Klebsiella pneumonia. Postnatal anxiety was significantly predicted by IgA responses to Pseudomonas aeruginosa. CONCLUSIONS: Our findings suggest that pregnancy may protect against bacterial translocation, while alcohol use may increase bacterial translocation. The results suggest that end of term mucosa-derived immune responses to Gram-B contribute to immune activation, physio-somatic symptoms at the end of term and postnatal anxiety. HIGHLIGHTS: • Immune responses to Gram - Bacteria associate with physio-somatic symptoms in pregnancy. • IgA responses to Pseudomonas aeruginosa predict anxiety symptoms after delivery. • Pregnancy may have a protective effect against bacterial translocation. • Alcohol use increases leaky gut and bacterial translocation.

IgA/IgM responses to tryptophan and tryptophan catabolites (TRYCATs) are differently associated with prenatal depression, physio-somatic symptoms at the end of term and premenstrual syndrome.

There is some evidence that lowered tryptophan and an activated tryptophan catabolite (TRYCAT) pathway play a role in depression, somatoform disorder, and postpartum blues. The aim of this study is to delineate the associations between the TRYCAT pathway and premenstrual syndrome (PMS) and perinatal depressive and physio-somatic symptoms. We examine the associations between end of term serum IgM and IgA responses to tryptophan and 9 TRYCATs in relation to zinc, C-reactive protein (CRP), and haptoglobin and prenatal physio-somatic (previously known as psychosomatic) symptoms (fatigue, back pain, muscle pain, dyspepsia, obstipation) and prenatal and postnatal depression and anxiety symptoms as measured using the Edinburgh Postnatal Depression Scale (EPDS), Hamilton Depression Rating Scale (HAMD), and Spielberger's State Anxiety Inventory (STAI). We included pregnant females with (n = 24) and without depression (n = 25) and 24 non-pregnant females. There were no significant associations between the IgA/IgM responses to tryptophan and TRYCATs and prenatal and postnatal depression/anxiety symptoms, except for lowered IgA responses to anthranilic acid in prenatal depression. A large part of the variance in IgA responses to most TRYCATs was explained by PMS and haptoglobin (positively) and CRP (inversely) levels. The IgA responses to TRYCATs were significantly increased in PMS, in particular picolinic, anthranilic, xanthurenic and kynurenic acid, and 3OH-kynurenine. Variance (62.5%) in physio-somatic symptoms at the end of term was explained by PMS, previous depressions, zinc (inversely), CRP and haptoglobin (both positively), and the IgM responses to quinolinic acid (positively), anthranilic acid, and tryptophan (both negatively). The results suggest that mucosa-derived TRYCAT pathway activation is significantly associated with PMS, but not with perinatal depression/anxiety symptoms. Physio-somatic symptoms in pregnancy have an immune-inflammatory pathophysiology. Induction of the TRYCAT pathway appears to be more related to physio-somatic than to depression symptoms.

Activated neuro-oxidative and neuro-nitrosative pathways at the end of term are associated with inflammation and physio-somatic and depression symptoms, while predicting outcome characteristics in mother and baby.

OBJECTIVES: To examine oxidative & nitrosative stress (O&NS) biomarkers at the end of term in relation to perinatal affective symptoms, neuro-immune biomarkers and pregnancy-related outcome variables. METHODS: We measured plasma advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), total radical trapping antioxidant parameter (TRAP), -sulfhydryl (-SH), peroxides (LOOH) and paraoxonase (PON)1 activity in pregnant women with and without prenatal depression and non-pregnant controls. RESULTS: Pregnancy is accompanied by significantly increased AOPP and NOx, and lowered TRAP, -SH and LOOH. Increased O&NS and lowered LOOH and -SH levels are associated with prenatal depressive and physio-somatic symptoms (fatigue, pain, dyspepsia, gastro-intestinal symptoms). Increased AOPP and NOx are significantly associated with lowered -SH, TRAP and zinc, and with increased haptoglobin and C-reactive protein levels. Increased O&NS and lowered TRAP and PON 1 activity, at the end of term predict mother (e.g. hyperpigmentation, labor duration, caesarian section, cord length, breast milk flow) and baby (e.g. sleep and feeding problems) outcome characteristics. CONCLUSIONS: Pregnancy is accompanied by interrelated signs of O&NS, lowered antioxidant defenses and activated neuro-immune pathways. Increased O&NS at the end of term is associated with perinatal depressive and physio-somatic symptoms and may predict obstetric and behavioral complications in mother and baby.

GEMSP: a new therapeutic approach to multiple sclerosis.

A new therapeutic approach called Endotherapia (GEMSP) for the treatment of Multiple Sclerosis (MS) is suggested. Endotherapia is the result of an immunopathological strategy addressing chronic incurable diseases with a multifactorial etiology. This approach combines a biomedical evaluation of circulating immunoglobulins directed against specific self-antigens and self-antigens modified by free radicals. GEMSP is a "tailor-made" combination of small molecules (fatty acids, antioxidants, radical scavengers, amino acids) linked to a non-immunogenic linear chain of poly-L.lysine (PLL). Each individual linkage or PLL derivative offers great advantages, such as an increase in the half-life of the active small molecules. GEMSP inhibits brain leukocyte infiltration and abolishes episodes of experimental autoimmune encephalomyelitis. In a clinical trial with 102 MS patients treated with GEMSP Endotherapia, 28% of them showed a worsening of their state; 20% showed a decrease in the progression of the disease; 17% showed disease stabilization; and 35% showed a reversal of the evolution of disease; i.e., an improvement in their disease state. In 72% of the cases, a positive evolution of the state of the MS patients treated with Endotherapia was observed (a decrease or stabilization of disease evolution or an improvement). Endotherapia is very safe and no side-effects were reported for GEMSP. Moreover, GEMSP showed no toxicity either in experimental animals or in humans. It seems that Endotherapia is a promising therapy for MS, with no side-effects, which should be considered in the management of long-term pathologies.

Endotherapia: a new frontier in the treatment of multiple sclerosis and other chronic diseases.

Currently, several drugs are accessible for the treatment of many chronic diseases (multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, etc.), but most of them have a large list of side effects. Here, we propose a new therapeutic approach called Endotherapia for the treatment of chronic diseases. This approach combines a biomedical evaluation of circulating immunoglobulins directed against specific self-antigens and self-antigens modified by free radicals. The therapy proposed here is a "tailor-made" combination of small molecules (e.g., fatty acids and vitamins) linked to a non-immunogenic chain of poly-L.Lysine (PLL). Each individual linkage or PLL derivative offers great advantages, such as an increase in the half-life of the active small molecules. Endotherapia also involves clinical aspects, allowing an exact diagnosis of the disease and the identification of specific circulating antibodies in the serum of patients in several clinical trials (e.g., multiple sclerosis). Endotherapia has been shown to be very safe. In summary, Endotherapia is the result of an immunopathological strategy addressing chronic incurable diseases with a multifactorial etiology. In light of the results obtained, it seems that Endotherapia is a promising therapy for chronic diseases, with no side effects, which is evidently mandatory in the management of long-term pathologies.

A new drug candidate (GEMSP) for multiple sclerosis.

GEMSP is a mixture of functional polypeptides: fatty acids linked to poly-L-Lysine (PL), antioxidants linked to PL, free radical scavengers linked to PL, and amino acids linked to PL (patent numbers 6114388 (USA) and 792167 (EU)). In this review, we update the data on this new drug reported in the literature. There is evidence suggesting that GEMSP is a good candidate for the treatment of multiple sclerosis (MS), an inflammatory and neurodegenerative disease of the central nervous system characterized by focal leukocyte inflammation, demyelization and axonal degeneration, resulting in nerve cell dysfunction. Experimental autoimmune encephalomyelitis (EAE) is the main animal model used in the study of MS, a T cell-mediated autoimmune disease of the central nervous system. EAE has many clinical and histopathological similarities to MS. In this model, preclinical studies on GEMSP have demonstrated that the drug strongly inhibits brain leukocyte infiltration and completely abolishes EAE episodes and clinical scores, and it also appears that GEMSP preserves myelin integrity. In general, treatment with the free constituents of GEMSP (not linked to the inert carrier protein) is poorly active against brain leukocyte infiltration in EAE-immunized animals. This means that free molecules (not linked to PL) exert a very poor action on such infiltration and that these molecules are either rapidly incorporated into the metabolism or are degraded. Moreover, with immunocytochemical techniques, it has been demonstrated that one component of GEMSP, the methionine compound, is stored inside the motoneurons of the ventral horn of the spinal cord. However, this component of GEMSP has not been found in the brain. The new candidate for MS therapy has shown no toxicity either in experimental animals or in humans. An open clinical trial in humans has demonstrated that GEMSP is completely safe. In addition, the approved drugs for the treatment of MS exert marked side effects, but no side effects have been reported following the administration of GEMSP. The results obtained at six months of treatment with low doses of GEMSP (0.75 mg/day) in that open clinical trial in humans were as follows: 55% of the patients maintained a stable expanded disability status scale (EDSS) value and 18% of the patients had a decreased EDSS value instead of a normal progression of 0.25 point on the mean EDSS scale. We focus our review on the following topics: 1) EAE models and clinical evaluation; 2) the synthesis of GEMSP; 3) the effects of GEMSP dosage on EAE; 4) the effects of GEMSP on brain leukocyte infiltration; 5) GEMSP inside motoneurons; 6) the role of the components of GEMSP; and 7) GEMSP in MS patients, GEMSP toxicity, and side effects. In conclusion, all the data reported indicate that GEMSP is a new potential drug candidate for the treatment of MS.

Mouse strain susceptibility to trypanosome infection: an arginase-dependent effect.

We previously reported that macrophage arginase inhibits NO-dependent trypanosome killing in vitro and in vivo. BALB/c and C57BL/6 mice are known to be susceptible and resistant to trypanosome infection, respectively. Hence, we assessed the expression and the role of inducible NO synthase (iNOS) and arginase in these two mouse strains infected with Trypanosoma brucei brucei. Arginase I and arginase II mRNA expression was higher in macrophages from infected BALB/c compared with those from C57BL/6 mice, whereas iNOS mRNA was up-regulated at the same level in both phenotypes. Similarly, arginase activity was more important in macrophages from infected BALB/c vs infected C57BL/6 mice. Moreover, increase of arginase I and arginase II mRNA levels and of macrophage arginase activity was directly induced by trypanosomes, with a higher level in BALB/c compared with C57BL/6 mice. Neither iNOS expression nor NO production was stimulated by trypanosomes in vitro. The high level of arginase activity in T. brucei brucei-infected BALB/c macrophages strongly inhibited macrophage NO production, which in turn resulted in less trypanosome killing compared with C57BL/6 macrophages. NO generation and parasite killing were restored to the same level in BALB/c and C57BL/6 macrophages when arginase was specifically inhibited with N(omega)-hydroxy-nor-L-arginine. In conclusion, host arginase represents a marker of resistance/susceptibility to trypanosome infections.