Food-derived opioid peptides frim casein and gliadin inhibit cysteine uptake with redox and epigenetic consequences

Dietary interventions like gluten-free and casein-free diets have been
reported to improve intestinal, autoimmune and neurological symptoms in
patients with a variety of conditions; however, the underlying mechanism
of benefit for such diets remains unclear. Epigenetic programming,
including CpG methylation and histone modifications, occurring during
early postnatal development can influence the risk of disease in later
life, and such programming may be modulated by nutritional factors such
as milk and wheat, especially during the transition from a solely
milk-based diet to one that includes other forms of nutrition. The
hydrolytic digestion of casein (a major milk protein) and gliadin (a
wheat-derived protein) releases peptides with opioid activity, and in
the present study, we demonstrate that these food-derived proline-rich
opioid peptides modulate cysteine uptake in cultured human neuronal and
gastrointestinal (GI) epithelial cells via activation of opioid
receptors. Decreases in cysteine uptake were associated with changes in
the intracellular antioxidant glutathione and the methyl donor S-adenosylmethionine.
Bovine and human casein-derived opioid peptides increased genome-wide
DNA methylation in the transcription start site region with a potency
order similar to their inhibition of cysteine uptake. Altered expression
of genes involved in redox and methylation homeostasis was also
observed. These results illustrate the potential of milk- and
wheat-derived peptides to exert antioxidant and epigenetic changes that
may be particularly important during the postnatal transition from
placental to GI nutrition. Differences between peptides derived from
human and bovine milk may contribute to developmental differences
between breastfed and formula-fed infants. Restricted antioxidant
capacity, caused by wheat- and milk-derived opioid peptides, may
predispose susceptible individuals to inflammation and systemic
oxidation, partly explaining the benefits of gluten-free or casein-free
diets.

PLOS Pathogens: Binding of Glutathione to Enterovirus Capsids Is Essential for Virion Morphogenesis

Enteroviruses (family of the Picornaviridae) cover a large
group of medically important human pathogens for which no antiviral
treatment is approved. Although these viruses have been extensively
studied, some aspects of the viral life cycle, in particular
morphogenesis, are yet poorly understood. We report the discovery of
TP219 as a novel inhibitor of the replication of several enteroviruses,
including coxsackievirus and poliovirus. We show that TP219 binds
directly glutathione (GSH), thereby rapidly depleting intracellular GSH
levels and that this interferes with virus morphogenesis without
affecting viral RNA replication. The inhibitory effect on assembly was
shown not to depend on an altered reducing environment. Using TP219, we
show that GSH is an essential stabilizing cofactor during the transition
of protomeric particles into pentameric particles. Sequential passaging
of coxsackievirus B3 in the presence of low GSH-levels selected for
GSH-independent mutants that harbored a surface-exposed methionine in
VP1 at the interface between two protomers. In line with this
observation, enteroviruses that already contained this surface-exposed
methionine, such as EV71, did not rely on GSH for virus morphogenesis.
Biochemical and microscopical analysis provided strong evidence for a
direct interaction between GSH and wildtype VP1 and a role for this
interaction in localizing assembly intermediates to replication sites.
Consistently, the interaction between GSH and mutant VP1 was abolished
resulting in a relocalization of the assembly intermediates to
replication sites independent from GSH. This study thus reveals GSH as a
novel stabilizing host factor essential for the production of
infectious enterovirus progeny and provides new insights into the poorly
understood process of morphogenesis.

Oxidative stress induces mitochondrial dysfunction in a subset of autistic lymphoblastoid cell lines.

There is an increasing recognition that mitochondrial dysfunction is
associated with autism spectrum disorders. However, little attention has
been given to the etiology of mitochondrial dysfunction and how
mitochondrial abnormalities might interact with other physiological
disturbances such as oxidative stress. Reserve capacity is a measure of
the ability of the mitochondria to respond to physiological stress. In
this study, we demonstrate, for the first time, that lymphoblastoid cell
lines (LCLs) derived from children with autistic disorder (AD) have an
abnormal mitochondrial reserve capacity before and after exposure to
reactive oxygen species (ROS). Ten (44%) of 22 AD LCLs exhibited
abnormally high reserve capacity at baseline and a sharp depletion of
reserve capacity when challenged with ROS. This depletion of reserve
capacity was found to be directly related to an atypical simultaneous
increase in both proton-leak respiration and adenosine
triphosphate-linked respiration in response to increased ROS in this AD
LCL subgroup. In this AD LCL subgroup, 48-hour pretreatment with
N-acetylcysteine, a glutathione precursor, prevented these abnormalities
and improved glutathione metabolism, suggesting a role for altered
glutathione metabolism associated with this type of mitochondrial
dysfunction. The results of this study suggest that a significant
subgroup of AD children may have alterations in mitochondrial function,
which could render them more vulnerable to a pro-oxidant
microenvironment as well as intrinsic and extrinsic sources of ROS such
as immune activation and pro-oxidant environmental toxins. These
findings are consistent with the notion that AD is caused by a
combination of genetic and environmental factors.

N-acetyl cysteine offers a potential therapeutic alternative in psychiatric disorders

 "Improved understanding of the roles of inflammation and oxidative stress in psychiatric disorders has generated new leads in the search for novel therapies. One such investigative compound currently in clinical trials is an amino acid, N-Acetyl Cysteine (NAC), which appears to reduce the core symptoms of bipolar disorder, schizophrenia, depression, autism and cravings in addictions including cocaine, cannabis abuse and cigarette smoking."

Glutathione Deficiency in Gclm Null Mice Results in Complex I Inhibition and Dopamine Depletion following Paraquat Administration.

Depletion of glutathione has been shown to occur in autopsied brains of patients with Parkinson's disease (PD) as well as in animal models of PD. The goal of this study was to determine if chronic GSH deficiency per se resulted in complex I inhibition and/or dopamine depletion and whether these indices were further potentiated by aging or administration of paraquat, a redox-cycling herbicide that produces a PD-like neurodegeneration model in rodents (Brooks et al. 1999; McCormack et al. 2002). Deletion of the rate-limiting GSH synthesis gene, glutamate-cysteine ligase modifier subunit (Gclm) leads to significantly lower GSH concentrations in all tissues including brain. Gclm null (Gclm-/-) mice provide a model of prolonged GSH depletion to explore the relationship between GSH, complex I inhibition and dopamine loss in vivo. Despite ~60% depletion of brain GSH in Gclm-/- mice of ages 3-5 or 14-16 months, striatal complex I activity, dopamine levels, 3-nitrotyroine/tyrosine ratios, aconitase activity and CoASH remained unchanged. Administration of paraquat (10 mg/kg, twice/week, 3 weeks) to 3-5 month old Gclm-/- mice resulted in significantly decreased aconitase activity, complex I activity and dopamine levels but not in 3-5 month old Gclm+/+ mice. Furthermore, paraquat-induced inhibition of complex I and aconitase activities in Gclm-/- mice was observed in the striatum but not cortex. The results suggest that chronic deficiency of GSH in Gclm-/- mice was not sufficient to result in complex I inhibition or dopamine depletion perhaps due to homeostatic mechanisms but required an additional oxidative stress insult as shown with paraquat exposure.

Research shows oral supplement (glutathione) increases body's storage of antioxidant

"Oral supplementation of glutathione is effective in increasing the body's stores of the antioxidant, said Penn State College of Medicine researchers in study results presented at a conference today (April 22)."

Effects of dimethyl fumarate on neuroprotection and immunomodulation.

Neuronal degeneration in multiple sclerosis has been linked to oxidative stress. Dimethyl fumarate is a promising novel oral therapeutic option shown to reduce disease activity and progression in patients with relapsing-remitting multiple sclerosis. These effects are presumed to originate from a combination of immunomodulatory and neuroprotective mechanisms. We aimed to clarify whether neuroprotective concentrations of dimethyl fumarate have immunomodulatory effects.FINDINGS:We determined time- and concentration-dependent effects of dimethyl fumarate and its metabolite monomethyl fumarate on viability in a model of endogenous neuronal oxidative stress and clarified the mechanism of action by quantitating cellular glutathione content and recycling, nuclear translocation of transcription factors, and the expression of antioxidant genes. We compared this with changes in the cytokine profiles released by stimulated splenocytes measured by ELISPOT technology and analyzed the interactions between neuronal and immune cells and neuronal function and viability in cell death assays and multi-electrode arrays. Our observations show that dimethyl fumarate causes short-lived oxidative stress, which leads to increased levels and nuclear localization of the transcription factor nuclear factor erythroid 2-related factor 2 and a subsequent increase in glutathione synthesis and recycling in neuronal cells. Concentrations that were cytoprotective in neuronal cells had no negative effects on viability of splenocytes but suppressed the production of proinflammatory cytokines in cultures from C57BL/6 and SJL mice and had no effects on neuronal activity in multi-electrode arrays.CONCLUSIONS:These results suggest that immunomodulatory concentrations of dimethyl fumarate can reduce oxidative stress without altering neuronal network activity.

Certain Features Of Autism May Be Improved By Antioxidant (N-acetyl cysteine)

The antioxidant, N-Acetylcysteine, or NAC, lowered irritability in children with autism as well as reducing the children's repetitive behaviors. The researchers emphasized that the findings must be confirmed in a larger trial before NAC can be recommended for children with autism.

Unveiling the mechanisms for decreased glutathione in individuals with HIV infection.

We examined the causes for decreased glutathione (GSH) in individuals with HIV infection. We observed lower levels of intracellular GSH in macrophages from individuals with HIV compared to healthy subjects. Further, the GSH composition found in macrophages from HIV(+) subjects heavily favors oxidized glutathione (GSSG) which lacks antioxidant activity, over free GSH which is responsible for GSH's antioxidant activity. This decrease correlated with an increase in the growth of Mycobacterium tuberculosis (M. tb) in macrophages from HIV(+) individuals. In addition, we observed increased levels of free radicals, interleukin-1 (IL-1), interleukin-17 (IL-17) and transforming growth factor-β (TGF-β) in plasma samples derived from HIV(+) individuals compared to healthy subjects. We observed decreased expression of the genes coding for enzymes responsible for de novo synthesis of GSH in macrophages derived from HIV(+) subjects using quantitative PCR (qPCR). Our results indicate that overproduction of proinflammatory cytokines in HIV(+) individuals lead to increased production of free radicals. This combined with the decreased expression of GSH synthesis enzymes leads to a depletion of free GSH and may lead in part to the loss of immune function observed in HIV patients.

Reversal of Oxidative Stress by Histamine H3 Receptor-Ligands in Experimental Models of Schizophrenia.

Schizophrenia (SCZ) is a debilitating disorder afflicting around 1% of the world population. Recent literature reveals oxidative injuries contribute enormously to the pathophysiology of SCZ alongside other psychopathological disturbances. Histamine H3R-antagonists have shown dual mechanism of action in experimental models of SCZ. Firstly it prevents oxidative stress and secondly alleviates schizophrenic symptoms, particularly the negative symptoms and cognitive deficits. In the present study, histamine H3R-antagonists used were ciproxifan (3.0 mg/kg, ip) and clobenpropit (15 mg/kg, ip) markedly controlled the elevated levels of various oxidative stress markers, for example, thiobarbituric acid reactive substance (TBARS), glutathione (GSH), superoxide dismutase, catalase, etc., as a result of augmented oxidative stress in the experimental models of SCZ such as amphetamine (0.5 mg/kg, sc) and dizocilpine (MK-801) (0.2 mg/kg, ip) induced locomotor hyperactivity, apomorphine (1.5 mg/kg, sc) induced climbing behavior and haloperidol (2.0 mg/kg, po) induced catalepsy. The results of the present study revealed that H3R-antagonists possess antioxidant activity and could serve with dual mechanism by supplementing antioxidant needs of SCZ and at the same time controlling symptoms of SCZ.

Behavioral phenotyping of glutathione-deficient mice: relevance to schizophrenia and bipolar disorder.

Redox-dysregulation represents a common pathogenic mechanism in schizophrenia (SZ) and bipolar disorder (BP). It may in part arise from a genetically compromised synthesis of glutathione (GSH), the major cellular antioxidant and redox-regulator. Allelic variants of the genes coding for the rate-limiting GSH synthesizing enzyme glutamate-cysteine-ligase modifier (GCLM) and/or catalytic (GCLC) subunit have been associated with SZ and BP. Using mice knockout (KO) for GCLM we have previously shown that impaired GSH synthesis is associated with morphological, functional and neurochemical anomalies similar to those in patients. Here we asked whether GSH deficit is also associated with SZ- and BP-relevant behavioral and cognitive anomalies. Accordingly, we subjected young adult GCLM-wildtype (WT), heterozygous and KO males to a battery of standard tests. Compared to WT, GCLM-KO mice displayed hyperlocomotion in the open field and forced swim test but normal activity in the home cage, suggesting that hyperlocomotion was selective to environmental novelty and mildly stressful situations. While spatial working memory and latent inhibition remained unaffected, KO mice showed a potentiated hyperlocomotor response to an acute amphetamine injection, impaired sensorymotor gating in the form of prepulse inhibition and altered social behavior compared to WT. These anomalies resemble important aspects of both SZ and the manic component of BP. As such our data support the notion that redox-dysregulation due to GSH deficit is implicated in both disorders. Moreover, our data propose the GCLM-KO mouse as a valuable model to study the behavioral and cognitive consequences of redox dysregulation in the context of psychiatric disease.

The Parkinsonian Mimetic, MPP+, Specifically Impairs Mitochondrial Transport in Dopamine Axons

MPP+ effects on Dopaminergic mitochondria were completely blocked by the thiol-anti-oxidant N-acetyl-cysteine or membrane-permeable glutathione.
Parkinson's disease risk factors

Parkinson's disease gene KEGG pathways including glutathione

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N-Acetyl Cysteine Effective for Bipolar Depression

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N-Acetyl Cysteine is a precursor for glutathione, a potent antioxidant that also protects oligodendrocytes.
 It also possesses antiviral and bactericidal properties: It appears to be effective in bipolar disorder and has also been used with some success in schizophrenia Refs. Glutathione deficiency is observed in many other diseases, as is oxidative stress, and the authors intend to pursue this avenue in autism.

Risk factors: Bipolar disorder : Kegg pathways in Bipolar disorder

Drug stops progression of Parkinson's disease in mice; Medication turns on critical gene, protects brain cells

 Phenylbutyrate turns on DJ-1 allowing it to activate antioxidant programmes  including glutathione synthesis. The drug is in clinical trials.
 Risk factors:  Parkinson's disease  Kegg pathways  Parkinson's 

Reduced antioxidant defense in early onset first-episode psychosis: a case-control study.

Glutathione levels were decreased in this survey: This is an important antioxidant, but it also has bactericidal and viricidal effects: There have  been a number of reports showing that the glutathione precursor N-acetyl cysteine is of benefit in schizophrenia

Risk factors:  Schizophrenia  

Kegg pathways Schizophrenia

Isolation rearing-induced deficits in sensorimotor gating and social interaction in rats are related to cortico-striatal oxidative stress, and reverse

Social stress has a number of interesting effects on the brain, including increased superoxide dismutase activity, changes in glutathione homoeostasis and increased lipid peroxidation.

The role of intracellular glutathione in progression of the Chlamydia trachomatis infection.

The role of intracellular glutathione in progressi... [Free Radic Biol Med. 2010] - PubMed result Glutathione has important bactericidal and viricidal effects against a number of pathogens

Effects of N-acetyl-cysteine treatment on glutathione depletion and a short-term spatial memory deficit in 2-cyclohexene-1-one-treated rats.

Interaction of glutathione depletion and psychotropic drug treatment in prepulse inhibition in rats and mice.

 glutathione   prepulse inhibition

Assessing oxidative pathway genes as risk factors for bipolar disorder.

Assessing oxidative pathway genes as risk factors ... [Bipolar Disord. 2010] - PubMed result