New Horizons for the Study of Dietary Fiber and Health: A Review.

Dietary fibre has been consumed for centuries with known health benefits, but defining dietary fibre is a real challenge. From a functional perspective, dietary fibre is described as supporting laxation, attenuating blood glucose responses and assisting with cholesterol lowering. The problem is different types of dietary fibre have different effects, and new effects are increasingly observed, such as the influence on gut microbiota. Thus, a single definition may need to be described in more generic terms. Rather than being bound by a few functional definitions, we may need to embrace the possibilities of new horizons, and derive a working definition of dietary fibre based on a set of conceptual principles, rather than the limited definitions we have to date. To begin this process, a review of individual fibre types and their physiological effects would be helpful. Dietary fibre is a complex group of substances, and there is a growing interest in specific effects linked to fibre type. Different fractions of dietary fibre have different physiological properties, yet there is a paucity of literature covering the effects of all fibres. This paper describes a range of individual fibre types and identifies gaps in the literature which may expose new directions for a working definition of dietary fibre.

Effect of Nrf2 activators on release of glutathione, cysteinylglycine and homocysteine by human U373 astroglial cells.

Neurons rely on the release and subsequent cleavage of GSH to cysteinylglycine (CysGly) by astrocytes in order to maintain optimal intracellular GSH levels. In neurodegenerative diseases characterised by oxidative stress, neurons need an optimal GSH supply to defend themselves against free radicals released from activated microglia and astroglia. The rate of GSH synthesis is controlled largely by the activity of γ-glutamyl cysteine ligase. Expression of γ-glutamyl cysteine ligase and of the Xc- system, which facilitates cystine uptake, is regulated by the redox-sensitive transcription factor, nuclear factor erythroid-2-related factor 2 (Nrf2). Compounds that can activate the Nrf2-ARE pathway, referred to as 'Nrf2 activators' are receiving growing attention due to their potential as GSH-boosting drugs. This study compares four known Nrf2 activators, R-α-Lipoic acid (LA), tert-butylhydroquinone (TBHQ), sulforaphane (SFN) and Polygonum cuspidatum extract containing 50% resveratrol (PC-Res) for their effects on astroglial release of GSH and CysGly. GSH levels increased dose-dependently in response to all four drugs. Sulforaphane produced the most potent effect, increasing GSH by up to 2.4-fold. PC-Res increased GSH up to 1.6-fold, followed by TBHQ (1.5-fold) and LA (1.4-fold). GSH is processed by the ectoenzyme, γ-glutamyl transpeptidase, to form CysGly. Once again, SFN produced the most potent effect, increasing CysGly by up to 1.7-fold, compared to control cells. TBHQ and PC-Res both induced fold increases of 1.3, followed by LA with a fold increase of 1.2. The results from the present study showed that sulforaphane, followed by lipoic acid, resveratrol and Polygonum multiflorum were all identified as potent "GSH and Cys-Gly boosters".

Chronic inflammation alters production and release of glutathione and related thiols in human U373 astroglial cells.

Neurons rely on glutathione (GSH) and its degradation product cysteinylglycine released by astrocytes to maintain their antioxidant defences. This is particularly important under conditions of inflammation and oxidative stress, as observed in many neurodegenerative diseases including Alzheimer's disease (AD). The effects of inflammatory activation on intracellular GSH content and the extracellular thiol profile (including cysteinylglycine and homocysteine) of astrocytes were investigated. U373 astroglial cells exposed to IL-1ß and TNF-α for up to 96 h showed a dose-dependent increase in IL-6 release, indicative of increasing pro-inflammatory cellular activation. With increasing concentrations of IL-1ß and TNF-α (0.01-1 ng/ml), an increase in both intracellular and extracellular GSH levels was observed, followed by a return to control levels in response to higher concentrations of IL-1ß and TNF-α. Extracellular levels of cysteinylglycine decreased in response to all concentrations of IL-1ß and TNF-α. In contrast, levels of the neurotoxic thiol homocysteine increased in a dose-dependent manner to IL-1ß and TNF-α-induced activation. Our results suggest that chronically activated astrocytes in the brain might fail to adequately maintain GSH substrate delivery to neurons, thus promoting neuronal vulnerability. They might also explain the elevated levels of homocysteine found in the brains and serum of patients with AD.

Activated astroglia during chronic inflammation in Alzheimer's disease--do they neglect their neurosupportive roles?

Alzheimer's disease (AD) is a neurodegenerative disorder, characterized histopathologically by the extracellular deposition of beta-amyloid peptide in senile plaques, as well as intracellular neurofibrillary tangles (NFT) of hyperphosphorylated tau protein, extensive neuronal loss and synaptic changes in the hippocampus and cerebral cortex. In addition, the AD brain shows chronic inflammation characterized by an abundance of reactive astrocytes and activated microglia. In the healthy brain, astrocytes provide essential services for brain homeostasis and neuronal function, including metabolic support for neurons in the form of lactate, glutamate uptake and conversion into glutamine, and synthesis of glutathione and its precursors. In AD, a large body of evidence now suggests that by transforming from a basal to a reactive state, astrocytes neglect their neurosupportive functions, thus rendering neurons vulnerable to neurotoxins including pro-inflammatory cytokines and reactive oxygen species. This review will explain the normal functions of astrocytes, and how these cells might be activated to turn into inflammatory cells, actively contributing to neurodegeneration and neglecting their neurosupportive roles ("neuro-neglect hypothesis"). Furthermore, it is proposed that astrocytes might be promising target of therapeutic intervention for Alzheimer's disease, if these compromised functions can be normalized with pharmacological agents that are specifically designed to return astrocytes to a quiescent phenotype or supplement factors which activated astrocytes lack to produce.

Activated astrocytes: a therapeutic target in Alzheimer's disease?

Astrocytes become activated in Alzheimer's disease, contributing to and reinforcing an inflammatory cascade. A large body of evidence suggests that by transforming from a basal to a reactive state, astrocytes neglect their neurosupportive functions, thus rendering neurons vulnerable to neurotoxins, including proinflammatory cytokines and reactive oxygen species. This review highlights three important astrocytic functions that may be impaired in neurodegenerative diseases such as Alzheimer's disease. These are: the uptake of glucose and release of lactate; the uptake of glutamate and release of glutamine; and the uptake of glutathione precursors and release of glutathione. Astrocytes could become promising targets of therapeutic intervention for Alzheimer's disease, if these compromised functions can be normalized with pharmacological agents that are specifically designed to return astrocytes to a quiescent phenotype or to supplement any factors that activated astrocytes fail to produce.