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Objective To propose a new hypothesis that GABAergic dysfunction in excitatory and inhibitory (E/I) imbalance drives the pathogenesis of Alzheimer's disease (AD). Background Synaptic dysfunction and E/I imbalance emerge decades before the appearance of cognitive decline in AD patients, which contribute to neurodegeneration. Initially, E/I imbalance was thought to occur first, due to dysfunction of the glutamatergic and cholinergic systems. However, new evidence has demonstrated that the GABAergic system, the counterpart of E/I balance and the major inhibitory neurotransmitter system in the central nervous system, is altered enormously and that this contributes to E/I imbalance and further AD pathogenesis. New hypothesis Alterations to the GABAergic system, induced by multiple AD pathogenic or risk factors, contribute to E/I imbalance and AD pathogenesis. Major challenges for the hypothesis This GABAergic hypothesis accounts for many critical questions and common challenges confronting a new hypothesis of AD pathogenesis. More specifically, it explains why amyloid beta (Aβ), β-secretase (BACE1), apolipoprotein E4 gene (APOE e4), hyperactive glia cells, contributes to AD pathogenesis and why age and sex are the risk factors of AD. GABAergic dysfunction promotes the spread of Aβ pathology throughout the AD brain and associated cognitive impairments, and the induction of dysfunction induced by these varied risk factors shares this common neurobiology leading to E/I imbalance. In turn, some of these factors exacerbate GABAergic dysfunction and E/I imbalance. Moreover, the GABAergic system modulates various brain functions and thus, the GABAergic hypothesis accounts for nonamnestic manifestations. Furthermore, corrections of E/I balance through manipulation of GABAergic functions have shown positive outcomes in preclinical and clinical studies, suggesting the potential of the GABAergic system as a therapeutic target in AD. Linkage to other major theories Dysfunction of the GABAergic system is induced by multiple critical signaling pathways, which include the existing major theories of AD pathogenesis, such as the Aβ and neuroinflammation hypotheses. In a new perspective, this GABAergic hypothesis accounts for the E/I imbalance and related excitotoxicity, which contribute to cognitive decline and AD pathogenesis. Therefore, the GABAergic system could be a key target to restore, at least partially, the E/I balance and cognitive function in AD patients.

This study is for the first time to explore the possible effects of dietary tryptophan (Trp) on structural integrity and the related signalling factor gene expression in the gill of young grass carp (Ctenopharyngodon idella). Fish were fed with six different experimental diets containing graded levels of Trp at 0.7 (control), 1.7, 3.1, 4.0, 5.2 and 6.1 g kg(-1) diet for 8 weeks. The results firstly demonstrated that Trp deficiency or excess caused increases in reactive oxygen species (ROS) contents, and severe oxidative damage (lipid peroxidation and protein oxidation) in the gill of fish, and those negative effects could be reversed by optimal Trp levels. Secondly, compared with the optimal Trp levels, Trp deficiency could cause decreases in the mRNA levels of the barrier functional proteins (occludin, zonula occludens-1, claudin-c, and -3) and increases in the mRNA levels of the pore-formation proteins (claudin-12 and -15) mRNA levels in the gill of fish, and those were reversed by the optimal levels of Trp. The negative effects of Trp deficiency on those tight junction protein gene expression might be partly related to the increases in the mRNA levels of pro-inflammatory cytokines and related signalling factors (tumor necrosis factor α, interleukin 8, interleukin 1β and transcription factor-κB) and decreases in the mRNA levels of anti-inflammatory cytokines and related signalling factors [interleukin 10, transforming growth factor-β1, nuclear inhibitor factor κBα (iκBα), target of rapamyc and ribosome protein S6 kinase 1 (S6K1)] in the gill of fish. In addition, optimal dietary Trp protected the gill of fish against its deficiency-caused increases in the mRNA levels of the apoptosis signalling (caspase-3, caspase-8, caspase-9) and decreases in anti-superoxide radicals capacity, anti-hydroxyl radical capacity, glutathione contents and the activities of Cu/Zn superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione-S-transferase (GST) in the gill of fish. Additionally, compared with the Trp deficiency, optimal Trp up-regulated the mRNA levels of SOD, CAT, GPx, GR and GST, which might be partly ascribed to the up-regulation of the NF-E2-related factor 2 (Nrf2) mRNA levels and the down-regulation of Kelch-like-ECH-associated protein 1 (Keap1) mRNA levels in the gill of fish. Interestingly, excessive Trp caused similar results with its deficiency. Collectively, Trp deficiency or excess could cause antioxidant system disruption and change tight junction protein transcription abundances, which were partly related to the signalling factors, NF-κB p65, TOR, caspase-(3,8,9) and Nrf2, in fish gill, those could be blocked by the optimal Trp levels.

Buckwheat is a kind cereal mainly grown in cold plateau and mountainous districts. The seeds and food production made from buckwheat demonstrated great nutritional value and protective effects towards various kinds of disease. In this review, the antibacterial, trypsin inhibiting, antitumor, hypocholesterol, hypotensive and antidiabetic effects of buckwheat proteins and their enzyme hydrolysates were summarized and discussed. Many naturally occurring peptides isolated from buckwheat seeds are certified to be multiple functional compounds, such as buckwheat antimicrobial peptides, trypsin inhibitors, antitumor proteins, hypotensive peptides and antioxidant peptides. Besides its trypsin inhibiting activity upon proteases, buckwheat trypsin inhibitors also revealed antimicrobial activity towards fungi, Gram-positive and Gram-negative bacteria and antitumor activity against various kinds of cancer cells. The antitumor effects and the trypsin inhibiting activity are related with the special active site of the peptide molecules, while the hypolipidemic property and the hypotensive activity are most probably associating with the unique amino acids composition of buckwheat proteins, for the reason that the hydrolyzed small peptides still possess the relevant activity. Buckwheat peptides show prospective application in function food area and traditional medicine research. And structure–activity relationship of peptides attracts much more interests in recent years.

Flesh quality, muscle antioxidant status and related signalling molecule expressions were investigated in young grass carp fed six levels of tryptophan (Trp) for 8 weeks. The results indicated that fish fed 0.7 (deficiency) and 6.1g Trp g/kg (excess) diets exhibited lower muscle water-holding capacity, tenderness, cathepsin activity, protein levels, lipids and collagen contents. Optimal Trp reversed these negative effects, which were related to enhanced glutathione (GSH) content and glutathione peroxidase (GPx) activities regulated at gene transcription levels, rather than to superoxide dismutase (SOD) or catalase (CAT). The expression of signalling molecules [Kelch-like ECH-associated protein 1, target of rapamycin (TOR) and ribosomal S6 protein kinase 1] involved in the NF-E2-related factor 2 (Nrf2) pathway revealed a potential method of Trp-enhanced antioxidant defence. Collectively, the present study indicated that appropriate Trp levels improved flesh quality partly related to the enhancement of antioxidant ability through Nrf2 and TOR signalling.

The present research evaluated the effects of dietary tryptophan (Trp) on growth performance, intestinal mucosa] immune, barrier function and antioxidant capacity and gene expression of young grass carp (Ctenophatyngodon idella). Fish were fed six different experimental diets containing graded levels of Trp at 0.7(control), 1.7, 3.1, 4.0, 52 and 6.1 g kg(-1) diet for 8 weeks. The results showed that Trp supplementation significantly enhanced the percent weight gain (PWG), feed intake and feed efficiency (P < 0.05), and decreased the plasma ammonia content (PAC) (P < 0.05). After the 8-week feeding trail, an environmental copper exposure trail was conducted for 4 days. Results from the copper exposure trail showed that dietary Trp enhanced the lysozyme, acid phosphatase activities and complement 3 contents in the intestine of young grass carp (P < 0.05). In addition, Trp supplementation increased the copper/zinc superoxide dismutase (SOD1), glutathione peroxidase (GPx) activities and glutathione contents (P < 0.05), and decreased the protein carbonyl and malondialdehyde contents (P < 0.05). Furthermore, the relative gene expression levels of interleukin 10, transforming growth factor-beta 1, occludin, zonula occludens 1, claudin-b, -c, and 3, SOD1, GPx and NF-E2-related factor 2 in the intestine were significantly up-regulated with increasing of dietary Trp up to a certain level (P < 0.05). Conversely, the mRNA levels of tumor necrosis factor a, interleukin 8, target of rapamycin, Kelch-like-ECH-associated protein 1, claudin-12 and -15a in the intestine were significantly down-regulated by Trp (P < 0.05). Collectively, appropriate dietary Trp level improves fish growth, intestinal immune response, barrier function and antioxidant status, and regulated the mRNA levels of related signal molecules of young grass carp. Based on the quadratic regression analysis of the PWG and PAC, the dietary Trp requirement of young grass carp (287-699 g) was estimated to be 3.81 g kg(-1) diet (12.7 g kg(-1) protein) and 3.89 g kg(-1) diet (13.0 g kg(-1) protein), respectively. (C) 2014 Elsevier Ltd. All rights reserved.