Walnut-Derived Peptides Ameliorate Scopolamine-Induced Memory Impairments in a Mouse Model via Activation of Peroxisome Proliferator-Activated Receptor γ-Mediated Excitotoxicity.

We investigated the protective effect of walnut peptides and YVPFPLP (YP-7) on scopolamine-induced memory impairment in mice and ß-amyloid (Aß)-induced excitotoxic injury in primary hippocampal neurons, respectively. Additionally, the protective mechanism of YP-7 on neuronal excitotoxicity was explored. Mouse behavioral and hippocampal slice morphology experiments indicate that YP-7 improves the learning and memory abilities of cognitively impaired mice and protects synaptic integrity. Immunofluorescence, western blotting, and electrophysiological experiments on primary hippocampal neurons indicate that YP-7 inhibits neuronal damage caused by excessive excitation of neurons induced by Aß. HT-22 cell treatment with peroxisome proliferator-activated receptor γ (PPARγ) activators and inhibitors showed that YP-7 activates PPARγ expression and maintains normal neuronal function by forming stable complexes with PPARγ to inhibit the extracellular regulated protein kinase pathway. Therefore, YP-7 can ameliorate glutamate-induced excitotoxicity and maintain neuronal signaling. This provides a theoretical basis for active peptides to ameliorate excitotoxicity and the development of functional foods.

Novel strategy to the characterization and enhance the glycemic control properties of walnut-derived peptides via zinc chelation.

This study aimed to utilize zinc coordination to promote the hypoglycemic and antioxidant properties of walnut-derived peptides, such as walnut protein hydrolysate (WPH) and Leu-Pro-Leu-Leu-Arg (LPLLR, LP5), of which LP5 was previously identified from WPH. The optimal conditions for the chelation were a peptide-to-zinc ratio of 6:1, pH of 9, duration of 50 min, and temperature of 50 °C. The WPH-Zn and LP5-Zn complexes increased the α-glucosidase inhibition, α-amylase inhibition, and antioxidant activity more than WPH and LP5 (p < 0.05). In particular, the antioxidant activity of WPH-Zn was superior to LP5-Zn. This is attributable to the WPH containing more aromatic amino acids, carboxylate groups and the imidazole groups, which implies its capacity to potentially coordinate with Zn2+ to form the WPH-Zn complex. Moreover, particle size, zeta potential, and scanning electron microscope indicated that the chelation of Zn2+ by peptides led to intramolecular and intermolecular folding and aggregation.

Food-Derived Peptides: Beneficial CNS Effects and Cross-BBB Transmission Strategies.

Food-derived peptides, as dietary supplements, have significant effects on promoting brain health and relieving central nervous system (CNS) diseases. However, the blood-brain barrier (BBB) greatly limits their in-brain bioavailability. Thus, overcoming the BBB to target the CNS is a major challenge for bioactive peptides in the prevention and treatment of CNS diseases. This review discusses improvement in the neuroprotective function of food-derived active peptides in CNS diseases, as well as the source of BBB penetrating peptides (BBB-shuttles) and the mechanism of transmembrane transport. Notably, this review also discusses various peptide modification methods to overcome the low permeability and stability of the BBB. Lipification, glycosylation, introduction of disulfide bonds, and cyclization are effective strategies for improving the penetration efficiency of peptides through the BBB. This review provides a new prospective for improving their neuroprotective function and developing treatments to delay or even prevent CNS diseases.

Plant-Derived Epi-Nutraceuticals as Potential Broad-Spectrum Anti-Viral Agents.

Although the COVID-19 pandemic appears to be diminishing, the emergence of SARS-CoV-2 variants represents a threat to humans due to their inherent transmissibility, immunological evasion, virulence, and invulnerability to existing therapies. The COVID-19 pandemic affected more than 500 million people and caused over 6 million deaths. Vaccines are essential, but in circumstances in which vaccination is not accessible or in individuals with compromised immune systems, drugs can provide additional protection. Targeting host signaling pathways is recommended due to their genomic stability and resistance barriers. Moreover, targeting host factors allows us to develop compounds that are effective against different viral variants as well as against newly emerging virus strains. In recent years, the globe has experienced climate change, which may contribute to the emergence and spread of infectious diseases through a variety of factors. Warmer temperatures and changing precipitation patterns can increase the geographic range of disease-carrying vectors, increasing the risk of diseases spreading to new areas. Climate change may also affect vector behavior, leading to a longer breeding season and more breeding sites for disease vectors. Climate change may also disrupt ecosystems, bringing humans closer to wildlife that transmits zoonotic diseases. All the above factors may accelerate the emergence of new viral epidemics. Plant-derived products, which have been used in traditional medicine for treating pathological conditions, offer structurally novel therapeutic compounds, including those with anti-viral activity. In addition, plant-derived bioactive substances might serve as the ideal basis for developing sustainable/efficient/cost-effective anti-viral alternatives. Interest in herbal antiviral products has increased. More than 50% of approved drugs originate from herbal sources. Plant-derived compounds offer diverse structures and bioactive molecules that are candidates for new drug development. Combining these therapies with conventional drugs could improve patient outcomes. Epigenetics modifications in the genome can affect gene expression without altering DNA sequences. Host cells can use epigenetic gene regulation as a mechanism to silence incoming viral DNA molecules, while viruses recruit cellular epitranscriptomic (covalent modifications of RNAs) modifiers to increase the translational efficiency and transcript stability of viral transcripts to enhance viral gene expression and replication. Moreover, viruses manipulate host cells' epigenetic machinery to ensure productive viral infections. Environmental factors, such as natural products, may influence epigenetic modifications. In this review, we explore the potential of plant-derived substances as epigenetic modifiers for broad-spectrum anti-viral activity, reviewing their modulation processes and anti-viral effects on DNA and RNA viruses, as well as addressing future research objectives in this rapidly emerging field.

Insights into the Hippocampus Proteomics Reveal Epigenetic Properties of Walnut-Derived Peptides in a Low-Grade Neuroinflammation Model.

Epigenetic mechanisms that dysregulate gene expressions may play a significant role in the development of neurological disorders. However, whether peptides can modulate epigenetic mechanisms remains elusive. This work aimed to investigate the impact of pretreatment with walnut-derived peptides─WHP and YVLLPSPK─on DNA methylation in a low-grade neuroinflammation model. The enriched KEGG pathways included oxidative phosphorylation, riboflavin metabolism, ribosome, and pyrimidine metabolism, which are associated with methylation modification by oral administration of YVLLPSPK in mice with scopolamine-induced cognitive deficits. Furthermore, when THP-1 cells (human acute monocytic leukemia cell line) were exposed to lipopolysaccharide (LPS)-induced inflammation responses, both WHP and YVLLPSPK markedly inhibited the level of Il-6 to 2.05 ± 0.76 and 1.29 ± 0.19 (p < 0.05) and also declined the mRNA expression of Mcp-1 to 1.64 ± 0.02 and 3.29 ± 1.21 (p < 0.01), respectively. Meanwhile, YVLLPSPK decreased the activities of DNA methyltransferases (DNMTs) to 1.03 ± 0.02 and 1.20 ± 0.31 (p < 0.05) based on Dnmt3b and Tet2, respectively. The results indicated that YVLLPSPK modulated DNA methylation in embryonic and neural precursor cells in creating new methylation patterns. Further trials are needed to assess the mechanisms underlying DNA methylation changes through peptides in the pathophysiology of neurological disorders.

Walnut-Derived Peptides Promote Autophagy via the Activation of AMPK/mTOR/ULK1 Pathway to Ameliorate Hyperglycemia in Type 2 Diabetic Mice.

Autophagy flux plays a significant protective role in type 2 diabetes mellitus (T2DM). However, the mechanisms by which autophagy mediates insulin resistance (IR) to ameliorate T2DM remain unclear. This study explored the hypoglycemic effects and mechanisms of walnut-derived peptides (fraction 3-10 kDa and LP5) in streptozotocin and high-fat-diet-induced T2DM mice. Findings revealed that walnut-derived peptides reduced the levels of blood glucose and FINS and ameliorated IR and dyslipidemia. They also increased SOD and GSH-PX activities and inhibited the secretion of TNF-α, IL-6, and IL-1ß. Additionally, they increased the levels of ATP, COX, SDH, and MMP of liver mitochondria. Western blotting indicated that walnut-derived peptides up-regulated LC3-II/LC3-I and Beclin-1 expression, while they down-regulated p62 expression, which may be associated with the activation of the AMPK/mTOR/ULK1 pathway. Finally, the AMPK activator (AICAR) and inhibitor (Compound C) were used to verify that LP5 could activate autophagy through the AMPK/mTOR/ULK1 pathway in IR HepG2 cells.

Hypoglycemic Effect of Exopolysaccharide from Lactiplantibacillus plantarum JLAU103 on Streptozotocin and High-Fat Diet-Induced Type 2 Diabetic Mice.

Two doses (300 mg/kg bw and 600 mg/kg bw) of the Lactiplantibacillus plantarum JLAU103 exopolysaccharide (EPS103) were orally administered to a type 2 diabetic (T2DM) mouse model induced by streptozotocin and a high-fat diet. The hypoglycemic, hypolipidemic and neuroprotective effects of EPS103 on T2DM mice were evaluated. The results indicated that administration of EPS103 could alleviate insulin resistance, reduce the levels of fasting blood glucose, glycosylated hemoglobin A1c, leptin and fasting serum insulin, improve glucose tolerance, protect pancreas and liver, and modulate blood lipid disorders. EPS103 promoted hepatic glycogen synthesis by upregulating the phosphorylation of GSK3ß. Meanwhile, it upregulated the phosphorylation of IRS-1, PI3K and Akt, as well as the expression of IRS-2 and GLUT4, and downregulated the expression of PEPCK, G6Pase and PGC-1α, indicating that EPS103 promotes the uptake and transport of glucose and inhibits gluconeogenesis, which might be related to the activation of the IRS-1/PI3K/Akt pathway. Additionally, EPS103 can protect against brain nerve damage through improving oxidative stress injury, restoring the expression of IRS-2, alleviating neuronal apoptosis and inhibiting inflammation in the hippocampus of T2DM mice. Taken together, our results demonstrated that EPS103 may be a potential therapeutic agent for the treatment of T2DM.

Advances on the Antioxidant Peptides from Nuts: A Narrow Review.

Antioxidant peptides extracted from natural foods have been studied for their potential use in the development of additives, nutraceuticals, and therapeutic agents. Nut proteins are considered an excellent source of plant-derived proteins for the human diet, due to their high protein content and digestibility of up to 86.22%. Furthermore, compared with grain and soybean proteins, nut proteins have a special amino acid composition, which makes their protein structure different, and promotes their disparate functional characteristics and great bioactivity potential. This review presents the most remarkable studies on antioxidant peptides from nuts, to gain insights into feasible production methods, different evaluation indexes within in vivo or in vitro systems, high bioavailability, and the complex structure-activity relationship resulting from the particularity of their protein structure and amino acid composition. Previously published studies mainly focused on the effects of the production methods/processes of nut-derived peptides on antioxidant activity, and proved that nut-extracted antioxidant peptides can resist the degradation of acid, alkali, and gastrointestinal enzymes, have high antioxidant activity in vitro and in vivo, and also have the potential to cross small intestinal epithelial cells in a stable and integral manner. However, the structure-activity relationship of antioxidant peptides from nuts has not been fully established, and the structure information of antioxidant peptides obtained from various nut protein sources is still unclear. The findings presented in this review can be used to provide the theoretical basis for the design and production of nut-derived antioxidant peptides.

Neuroprotective effects of fermented yak milk-derived peptide LYLKPR on H2O2-injured HT-22 cells.

This study explored the neuroprotective effect of the peptide LYLKPR derived from fermented yak milk by Lactiplantibacillus plantarum JLAU103 on H2O2-injured HT-22 cells. Peptide LYLKPR showed good stability in the simulated gastrointestinal tract and strong penetrating ability of the blood-brain barrier (BBB) in vitro. LYLKPR could activate the Nrf2/Keap-1/HO-1 pathway, increase the activities of SOD and CAT, and reduce the levels of ROS and MDA in HT-22 cells. In addition, LYLKPR controlled the activation of the NLRP3 inflammasome by inhibiting the oxidative stress, ultimately preventing the cleavage of pro-IL-18 and pro-IL-1ß by caspase-1, and reducing the level of intracellular mature IL-18 by 29.08%. Based on the molecular docking verification, LYLKPR could effectively bind to the Keap-1 protein, and directly inhibit the inflammasome to significantly increase intracellular BDNF, synaptophysin, and PSD95, and protect synaptic function. Collectively, LYLKPR ameliorated oxidative stress-mediated neuronal injury by inhibiting the NLRP3 inflammasome via modulation of the Nrf2/Keap-1/HO-1 pathway.

Insights into the hippocampus proteome and phosphorylation modification alterations in C57BL/6 revealed the memory improvement mechanisms of a walnut-derived peptide.

This work aimed to explore the underlying mechanisms of memory improvement effects of a walnut derived peptide WNP-10. The morris water maze test, combined with ultrastructural observation, hematoxylin and eosin and Nissl staining showed that WNP-10 significantly improved the learning and memory capability of the scopolamine-injured mice. The four-dimensional label-free quantification proteomics analysis identified 88 differentially expressed proteins in the WNP-10-treated group compared with scopolamine-induced impairment group. Pathway enrichment analysis and western blotting demonstrated that the WNP-10 can regulate the phosphatidylinositol-3-phosphate 5-kinase, cathepsin L, N-acetylgalactosamine 6-sulfate sulfatase and AP-3 complex subunit mu-1 expression to affect inositol phosphate metabolism, thereby maintaining lysosome homeostasis in scopolamine-injured mice. Notably, the results of phosphoproteomics demonstrated that WNP-10 administration resulted in the increased phosphorylation of phosphatidylinositol-3-phosphate 5-kinase. These findings provide novel insights into the underlying mechanism of memory improvement of walnut peptides.

Pine nut antioxidant peptides ameliorate the memory impairment in a scopolamine-induced mouse model via SIRT3-induced synaptic plasticity.

This study aimed to investigate the effects of a pine nut albumin hydrolysate (fraction <3 kDa) and of its short peptide derivative, Trp-Tyr-Pro-Gly-Lys (WYPGK), on synaptic plasticity and memory function in scopolamine-induced memory-impaired mice, as well as the potential underlying mechanism in PC12 cells. In the scopolamine-induced mouse model, the results revealed that the fraction <3 kDa and WYPGK enhanced synaptic plasticity and improved learning and memory function. H&E and Nissl staining analysis showed that the damage in hippocampal neurons was decreased. Golgi staining and transmission electron microscopy further revealed that the enhanced synaptic plasticity was associated with increased dendritic spine abundance and synaptic density. In an H2O2-induced PC12 cell model, treatment with mitochondrial sirtuin 3 (SIRT3) inhibitor and inducer molecules confirmed that the <3 kDa fraction and WYPGK activated SIRT3, leading to the decrease in Ace-SOD2 acetylation and increasing the expression of SYP, SYN-1, SNAP25, and PSD95, thus enhancing synaptic plasticity. The <3 kDa fraction and WYPGK also activated the ERK/CREB pathway and upregulated the expression of brain-derived neurotrophic factor. Our results show that fraction <3 kDa and WYPGK improve learning and memory ability through SIRT3-induced synaptic plasticity in vitro and in vivo.

Nutrigenomics of Dietary Lipids.

Dietary lipids have a major role in nutrition, not only for their fuel value, but also as essential and bioactive nutrients. This narrative review aims to describe the current evidence on nutrigenomic effects of dietary lipids. Firstly, the different chemical and biological properties of fatty acids contained both in plant- and animal-based food are illustrated. A description of lipid bioavailability, bioaccessibility, and lipotoxicity is provided, together with an overview of the modulatory role of lipids as pro- or anti-inflammatory agents. Current findings concerning the metabolic impact of lipids on gene expression, epigenome, and gut microbiome in animal and human studies are summarized. Finally, the effect of the individual's genetic make-up on lipid metabolism is described. The main goal is to provide an overview about the interaction between dietary lipids and the genome, by identifying and discussing recent scientific evidence, recognizing strengths and weaknesses, to address future investigations and fill the gaps in the current knowledge on metabolic impact of dietary fats on health.

Walnut-Derived Peptide Activates PINK1 via the NRF2/KEAP1/HO-1 Pathway, Promotes Mitophagy, and Alleviates Learning and Memory Impairments in a Mice Model.

Mitophagy has a pivotal protective function in the pathogenesis of neurological disorders. However, the mechanism of its modulation remains elusive, especially in PINK1-mediated mitophagy. Here, we investigated the neuroprotective effects of a walnut-derived peptide, YVLLPSPK, against scopolamine-induced cognitive deficits in mice and explored the underlying PINK1-mediated mitophagy mechanisms in H2O2-treated HT-22 cells. Using the Morris water maze, we showed that YVLLPSPK relieved the cognitive deficiency by alleviating oxidative stress. Mitochondrial morphology was observed in mice hippocampal tissues using transmission electron microscopy (TEM). Both Western blot and immunofluorescence analysis illustrated YVLLPSPK promoted the expression of mitophagy-related proteins and activated the NRF2/KEAP1/HO-1 pathway. Subsequently, an NRF2 inhibitor (ML385) was used to verify the contribution of the YVLLPSPK-regulated NRF2/KEAP1/HO-1 pathway in PINK1-mediated mitophagy in H2O2-treated HT-22 cells. These data suggested that YVLLPSPK improved learning and memory in scopolamine-induced cognitive-impaired mice through a mechanism associated with PINK1-mediated mitophagy via the NRF2/KEAP1/HO-1 pathway.

Neuroprotection by Walnut-Derived Peptides through Autophagy Promotion via Akt/mTOR Signaling Pathway against Oxidative Stress in PC12 Cells.

Natural-derived peptides are effective substances in attenuating oxidative stress. However, their specific mechanisms have not been fully elucidated, especially in peptide-mediated autophagy. In the present study, TWLPLPR, YVLLPSPK, and KVPPLLY, novel peptides from Juglans mandshurica Maxim, prevented reactive oxygen species (ROS) production, elevated glutathione peroxidase (GSH-Px) activity and adenosine 5'-triphosphate (ATP) levels, and ameliorated apoptosis in Aß25-35 (at a concentration of 50 µM for 24 h)-induced PC12 cells (P < 0.01). Both western blot and immunofluorescence analysis illustrated that the peptides regulated Akt/mTOR signaling through p-Akt (Ser473) and p-mTOR (S2481) and promoted autophagy by increasing the levels of LC3-II/LC3-I and Beclin-1 while lowering p62 expression (P < 0.01). The autophagy inhibitor (3-methyladenine, 3-MA) and inducer (rapamycin, RAPA) were combined used to confirm the contribution of peptide-regulated autophagy in antioxidative effects. Moreover, the peptides increased the levels of LAMP1, LAMP2, and Cathepsin D (P < 0.05) and promoted the fusion with lysosomes to form autolysosomes, accelerating ROS removal. These data suggested that walnut-derived peptides regulated oxidative stress by promoting autophagy in the Aß25-35-induced PC12 cells.

A machine learning methodology for reliability evaluation of complex chemical production systems.

System reliability evaluation is very important for safe operation and sustainable development of complex chemical production systems. This paper proposes a hybrid model for the reliability evaluation of chemical production systems. First, the influential factors in system reliability are categorized into five aspects: Man, Machine, Material, Management and Environment (4M1E), each of which represents a component subsystem of a complex chemical production process. Second, the Support Vector Machine (SVM) algorithm is used to develop machine learning models for the reliability evaluation of each subsystem, during which Particle Swarm Optimization (PSO) is applied for model parameter optimization. Third, the Random Forest (RF) algorithm is employed to correlate the reliability of the five subsystems with the reliability of the corresponding whole chemical production system. Then, Markov Chain Residual error Correction (MCRC) is adopted to improve the predictive accuracy of the machine learning model. The efficacy of the proposed hybrid model is tested on a case study, and the results indicate that the proposed model is capable of delivering satisfactory prediction results.

Potential mechanisms mediating the protective effects of a peptide from walnut (Juglans mandshurica Maxim.) against hydrogen peroxide induced neurotoxicity in PC12 cells.

Amelioration of oxidative stress has been the main approach to improve neurodegenerative disorders. In the present study, a walnut peptide with a strong capacity of scavenging reactive oxygen species (ROS) was purified and identified as EVSGPGLSPN by SEC, RP-HPLC, and HPLC-MS/MS. Treatment with EVSGPGLSPN could significantly (P < 0.05) reduce ROS generation, and increase cell viability, and superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-px) activities in a dose-dependent manner in hydrogen peroxide induced PC12 cells. Western blot and immunofluorescence analysis showed that EVSGPGLSPN suppressed the expression of IKKß and p65 to inhibit NF-κB pathway activation, attenuating the neurotoxic cascade by overexpression of IL-1ß and TNF-α. Moreover, EVSGPGLSPN inhibited apoptosis by suppressing the expression of cytochrome C, caspase-9, caspase-3, and PARP. Additionally, it also up-regulated the expression of p-CREB and synaptophysin in oxidatively damaged PC12 cells. Thus, EVSGPGLSPN may protect against hydrogen peroxide induced neurotoxicity by enhancing the activity of antioxidant enzymes and blocking the NF-κB/caspase pathways.

Antioxidant hydrolyzed peptides from Manchurian walnut (Juglans mandshurica Maxim.) attenuate scopolamine-induced memory impairment in mice.

BACKGROUND: Walnut protein, which is obtained as a by-product of oil expression, has not been used efficiently. Although walnuts are beneficial for cognitive functioning, the potential of their protein composition in strengthening learning and memory functions remains unknown. In this study, the inhibition of memory impairment by the Manchurian walnut hydrolyzed peptide (MWHP) was evaluated. RESULTS: Small-molecular-weight MWHP (<3 kDa) achieved the optimal antioxidative activity. Therefore, MWHP (<3 kDa) was subjected to the following mice trials to evaluate its attenuation effect on memory impairment. In the Morris water maze test, MWHP shortened the total path for searching the platform, reduced the escape latency, and increased the dwelling distance and time in the coverage zone. MWHP also prolonged the latency and diminished errors in the passive avoidance response tests. These behavioral tests demonstrated that MWHP could inhibit scopolamine-induced memory impairment. MWHP improved memory by reducing oxidative stress, inhibiting apoptosis, regulating neurotransmitter functions, maintaining hippocampal CA3 pyramidal neurons, and increasing calmodulin-dependent protein kinase II levels in brain tissues. CONCLUSION: Experimental results proved that MWHP exhibits potential in improving memory and should be used to develop novel functional food. © 2018 Society of Chemical Industry.