Correction: Therapeutic effects of a walnut-derived peptide on NLRP3 inflammasome activation, synaptic plasticity, and cognitive dysfunction in T2DM mice.

Correction for 'Therapeutic effects of a walnut-derived peptide on NLRP3 inflammasome activation, synaptic plasticity, and cognitive dysfunction in T2DM mice' by Yanru Li et al., Food Funct., 2024, 15, 2295-2313, https://doi.org/10.1039/D3FO05076A.

Analysis of Ester-Producing Performance in High-Yield Ethyl Hexanoate Yeast and the Effect on Metabolites in Bio- Enhanced Daqu, the starter for Baijiu and other traditional fermented foods.

AIMS: Ethyl hexanoate, one of the key flavor compounds in Strong-flavor Baijiu. To improve the content of ethyl hexanoate in Strong-flavor Baijiu, a functional strain with high yield of ethyl hexanoate was screened and its ester-producing performance was studied. METHODS AND RESULTS: Upon identification, the strain was classified as Candida sp. and designated as ZY002. Under optimal fermentation conditions, the content of ethyl hexanoate synthesized by ZY002 can be as high as 170.56 mg·L-1. A fermentation test was carried out using the ZY002 strain bioaugmented Daqu to verify the role of the strain applied to Baijiu brewing. It was found that strain ZY002 could not only improve the moisture and alcohol contents of fermented grains but also diminish the presence of reducing sugar and crude starch. Furthermore, it notably amplified the abundance of flavor compounds. CONCLUSION: In this study, Candida sp. ZY002 with a high yield of ethyl hexanoate provided high-quality strain resources for the actual industrial production of Baijiu.

Effect of bi-enzyme hydrolysis on the properties and composition of hydrolysates of Manchurian walnut dreg protein.

Walnut dreg (WD) active peptides are an important source of dietary antioxidants; however, the products of conventional hydrolysis have limited industrial output owing to poor flavour and low bioactivity. To this end, in this study, we aimed to employ bvLAP, an aminopeptidase previously identified in our research, as well as commercially available Alcalase for bi-enzyme digestion. The flavour, antioxidant activity, and structures of products resulting from various digestion methods were compared. The results showed that the bi-enzyme digestion products had enhanced antioxidant activity, increased ß-sheet content, and reduced bitterness intensity from 9.65 to 6.93. Moreover, bi-enzyme hydrolysates showed a more diverse amino acid composition containing 1640 peptides with distinct sequences. These results demonstrate that bi-enzyme hydrolysis could be a potential process for converting WD into functional food ingredients. Additionally, our results provide new concepts that can be applied in waste processing and high-value utilisation of WD.

Therapeutic effects of a walnut-derived peptide on NLRP3 inflammasome activation, synaptic plasticity, and cognitive dysfunction in T2DM mice.

NLRP3 inflammasome activation plays a key role in the development of diabetes-induced cognitive impairment. However, strategies to inhibit NLRP3 inflammasome activation remain elusive. Herein, we evaluated the impact of a walnut-derived peptide, TWLPLPR (TW-7), on cognitive impairment in high-fat diet/streptozotocin-induced type 2 diabetes mellitus (T2DM) mice and explored its underlying mechanisms in high glucose-induced HT-22 cells. In the Morris water maze test, TW-7 alleviated cognitive deficits in mice; this was confirmed at the level of synaptic structure and dendritic spine density in the mouse hippocampus using transmission electron microscopy and Golgi staining. TW-7 increased the expression of synaptic plasticity-related proteins and suppressed the NEK7/NLRP3 inflammatory pathway, as determined by western blotting and immunofluorescence analysis. The mechanism of action of TW-7 was verified in an HT-22 cell model of high glucose-induced insulin resistance. Collectively, TW-7 could regulate T2DM neuroinflammation and synaptic function-induced cognitive impairment by inhibiting NLRP3 inflammasome activation and improving synaptic plasticity.

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.

Mechanism of Intestinal Epithelial Absorption and Electrophysiological Regulation of the Shrimp Peptide QMDDQ.

We investigated the absorption mechanism of the shrimp peptide QMDDQ in small intestines, explored its physiological function in inhibiting neuronal hyperactivity, and verified its entry into the brain in vivo to display functional activity. The everted rat sac model and a Caco-2 paracellular absorption monolayer model were used, indicating that QMDDQ has a good absorption capacity with an apparent permeability coefficient (Papp) > 1 × 10-6 cm/s and the absorption of QMDDQ was concentration-dependent. When the concentration of QMDDQ was 1 mM and the transport time was 180 min, the highest absorption concentration of QMDDQ was 41.17 ± 3.48 µM (P < 0.05). The myosin light-chain kinase (MLCK)-specific inhibitor ML-7 and activator MPA, Western blotting, and immunofluorescence results showed that QMDDQ absorption takes place by mediating the MLCK-p-MLCK-MLC signaling pathway, reversibly opening the zonula occludens-1 (ZO-1), occludin in tight junctions (TJs), upregulating claudin-2 expression, and reaching targets through blood to inhibit neuronal overactivity. Results of fluorescence imaging in vivo verified that QMDDQ could enter the brain 4 h after oral administration. The results provide a theoretical foundation for the mechanism of paracellular absorption of active peptides and a starting point for the development of functional foods for Alzheimer's disease intervention.

Walnut-Derived Peptide Improves Cognitive Impairment in Colitis Mice Induced by Dextran Sodium Sulfate via the Microbiota-Gut-Brain Axis (MGBA).

In this study, we investigated the protective mechanism of walnut-derived peptide LPLLR (LP-5) against cognitive impairment induced in a dextran sodium sulfate (DSS)-induced colitis mouse model, with emphasis on the microbiota-gut-brain axis (MGBA). The results revealed that LP-5 could improve the learning ability and memory of mice with cognitive impairment and mitigate colitis symptoms, including weight loss, bloody stools, colon shortening, and histopathological changes. Additionally, LP-5 protected the integrity of the intestinal barrier by promoting the expression of tight junction proteins (TJs) while attenuating colonic inflammation by suppressing proinflammatory cytokine and epithelial cell apoptosis. Western blotting indicated that LP-5 treatment suppressed the inflammatory NF-κB/MLCK/MLC signaling pathway activity. Furthermore, LP-5 ameliorated hippocampal neuron damage and protected blood-brain barrier (BBB) integrity by downregulating microglia marker protein Iba-1, increasing TJ protein expression, and restoring the deterioration of synaptic proteins. Importantly, 16S rRNA sequencing results indicated that LP-5 reshaped the abundance of a wide range of gut microbiota at the phylum and genus levels, with increased Prevotella and Akkermansia associated with tryptophan (TRP), 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA). These findings suggest that LP-5 could maintain intestinal barrier and BBB integrity, reverse gut dysbiosis, and improve learning and memory ability in colitis mice, providing novel insights into alterations of gut microbes in colitis and a potential new mechanism by which it causes cognitive impairment.

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.

Complement in Human Brain Health: Potential of Dietary Food in Relation to Neurodegenerative Diseases.

The complement pathway is a major component of the innate immune system, which is critical for recognizing and clearing pathogens that rapidly react to defend the body against external pathogens. Many components of this pathway are expressed throughout the brain and play a beneficial role in synaptic pruning in the developing central nervous system (CNS). However, excessive complement-mediated synaptic pruning in the aging or injured brain may play a contributing role in a wide range of neurodegenerative diseases. Complement Component 1q (C1q), an initiating recognition molecule of the classical complement pathway, can interact with a variety of ligands and perform a range of functions in physiological and pathophysiological conditions of the CNS. This review considers the function and immunomodulatory mechanisms of C1q; the emerging role of C1q on synaptic pruning in developing, aging, or pathological CNS; the relevance of C1q; the complement pathway to neurodegenerative diseases; and, finally, it summarizes the foods with beneficial effects in neurodegenerative diseases via C1q and complement pathway and highlights the need for further research to clarify these roles. This paper aims to provide references for the subsequent study of food functions related to C1q, complement, neurodegenerative diseases, and human health.

Recent advances in the metabolic engineering and physiological opportunities for microbial synthesis of L-aspartic acid family amino acids: A review.

L-aspartic acid, L-threonine, L-isoleucine, l-lysine, and L-methionine constitute the l-aspartate amino acids (AFAAs). Except for L-aspartic acid, these are essential amino acids that cannot be synthesized by humans or animals themselves. E. coli and C. glutamicum are the main model organisms for AFAA production. It is necessary to reconstitute microbial cell factories and the physiological state of industrial fermentation cells for in-depth research into strains with higher AFAA production levels and optimal growth states. Considering that the anabolic pathways of the AFAAs and engineering modifications have rarely been reviewed in the latest progress, this work reviews the central metabolic pathways of two strains and strategies for the metabolic engineering of AFAA synthetic pathways. The challenges posed by microbial physiology in AFAA production and possible strategies to address them, as well as future research directions for constructing strains with high AFAA production levels, are discussed in this review article.

Purification, Identification, Chelation Mechanism, and Calcium Absorption Activity of a Novel Calcium-Binding Peptide from Peanut (Arachis hypogaea) Protein Hydrolysate.

A novel calcium-binding peptide was purified from peanut protein hydrolysate using gel filtration chromatography and identified using HPLC-MS/MS. Its amino acid sequence was determined as Phe-Pro-Pro-Asp-Val-Ala (FPPDVA, named as FA6) with the calcium-binding capacity of 15.67 ± 0.39 mg/g. Then, the calcium chelating characteristics of FPPDVA were investigated using ultraviolet-visible absorption spectroscopy, fluorescence spectroscopy, Fourier transform infrared spectroscopy, particle size, and zeta potential. The results showed that FPPDVA interacted with calcium ions, the chelation of calcium ions induced FPPDVA to fold and form a denser structure, the calcium-binding sites may mainly involve oxygen atoms from the carboxyl residues of Asp and Ala, and Phe possessed contact energy and carbonyl residues of Val. Microstructure analysis showed that FPPDVA-calcium chelate exhibited a regularly ordered and tightly aggregated sheets or block structures. Additionally, FPPDVA-calcium chelate had good gastrointestinal digestive stability and thermal stability. The results of everted rat intestinal sac and Caco-2 cell monolayer experiments showed that FPPDVA-calcium chelate could promote calcium absorption and transport through the Cav1.3 and TRPV6 calcium channels. These data suggest that FPPDVA-calcium chelate possesses the potential to be developed and applied as calcium supplement.

Synergistic Effect of Combined Walnut Peptide and Ginseng Extracts on Memory Improvement in C57BL/6 Mice and Potential Mechanism Exploration.

This work aimed to investigate whether there are synergistic effects between walnut peptide (WNP) and ginseng extracts (GSE) treatments to ameliorate the memory impairment caused by scopolamine (SCOP). The Morris water maze trial, hippocampal neuron morphology, neurotransmitters, and synaptic ultrastructure were examined, along with brain-derived neurotrophic factor (BDNF)-related signaling pathway proteins. The results of the Morris water maze trial demonstrated that the combined administration of WNP and GSE effectively alleviated memory impairment in C57BL/6 rats caused by SCOP. Improvement in the morphology of hippocampal neurons, dendritic spines, and synaptic plasticity and upregulation of neurotransmitters AChE, ACh, ChAT, Glu, DA, and 5-HT supported the memory improvement effects of WNP + GSE. In addition, compared with the model group, WNP + GSE significantly enhanced the protein levels of VAChT, Trx-1, and the CREB/BDNF/TrkB pathway in hippocampal and PC12 cells induced by SCOP (p < 0.05). Notably, WNP + GSE boosted memory via multiple pathways, not only the BDNF/TrkB/CREB target.

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.

Athelia rolfsii Exopolysaccharide Protection Against Kidney Injury in Lead-Exposed Mice via Nrf2 Signaling Pathway.

This study aimed to explore protective efficacy of Athelia rolfsii exopolysaccharides (AEPS) to mice kidney against lead-exposed injury with a focus on the role of nuclear factor erythroid-2-related factor 2 (Nrf2) signaling pathway. Lead accumulation in the kidney induces oxidative stress which causes low antioxidant activity, abnormal pathological changes, and apoptosis. Here, the changes in lead levels in the kidney and whole blood proved that AEPS inhibited lead accumulation. It might be related to AEPS enhancing glutathione (GSH) levels and glutathione-s-transferase (GST) activities, as well as the protein abundances of multidrug resistance-associated protein 1 (MRP1) and multidrug resistance-associated protein 2 (MRP2). Moreover, AEPS increased antioxidant activity by upregulating superoxide dismutase (SOD), catalase (CAT) activities, downregulating malondialdehyde (MDA) levels. It also restored kidney function by decreasing blood urea nitrogen (BUN) and creatinine (CRE) levels in the serum. Histopathologic analysis showed that AEPS alleviated the kidney injury induced by lead, too. AEPS also showed anti-apoptosis effect by downregulating caspase-3 and bax expression and upregulating bcl-2 expression. Importantly, AEPS activated Nrf2 signaling pathway by promoting nuclear translocation of Nrf2. However, all-trans-retinoic acid (ATRA), an Nrf2 inhibitor, reversed the effects on AEPS to activation of Nrf2, enhancement of antioxidant, alleviation of kidney injury, restoration of kidney function, prevention of apoptotic, and facilitation of lead exclusion. In brief, AEPS showed kidney protective effect and facilitated lead-expulsion in an Nrf2-dependent manner.

Improving ACE inhibitory activity of hazelnut peptide modified by plastein: Physicochemical properties and action mechanism.

The plastein reaction can increase the activity of angiotensin-converting enzyme (ACE) inhibitory peptides, but the underlying mechanism is unknown. Hence, hazelnut protein hydrolysate and hazelnut peptide YLVR were used as substrate to explore the effect of plastein on physicochemical properties and the mechanism of structural change. The increase in turbidity and particle size and the decrease in free amino groups indicated that the reaction occurred via condensation. The modified products of YLVR were identified by NANO-HPLC-MS/MS, indicating that the N-terminal homologous amino acid aggregates in the plastein. Novel ACE inhibitory peptide YYLVR, YLLVR, and YYLLVR were synthesized and their inhibition rates were 66.35, 72.61, and 89.10 %, respectively, which were higher than that of YLVR (52.58 %). MD simulation showed that YYLLVR exhibited the lowest binding energies of -35.98 ± 2.30 kcal/mol to ACE. Taken together, plastein reaction is a promising strategy for inducing structural modifications to improve the activity of peptide.

Walnut-derived peptides ameliorate d-galactose-induced memory impairments in a mouse model via inhibition of MMP-9-mediated blood-brain barrier disruption.

Disruption of the blood-brain barrier (BBB) has been observed in several neurological diseases. This study explored the protective effect of the walnut-derived peptide TWLPLPR (TW-7) against d-galactose (d-gal)-induced cognitive disturbance in mice and its potential protection mechanism in ß-amyloid 25-35 (Aß25-35)-injured bEnd.3 cells. TW-7 improved the learning ability and memory of the cognitive impairment mice. Transmission electron microscopy showed that the BBB integrity in the hippocampus was restored; while immunofluorescence analysis and western blotting indicated that the protection of BBB integrity was associated with increased expression levels of tight junction (TJ) proteins. In Aß25-35-damaged bEnd.3 cells, treatment with a matrix metalloproteinase 9 (MMP-9) activator and inhibitor confirmed that TW-7 partially reduced MMP-9 expression and increased zonula occludin-1 (ZO-1) and Claudin-5 expression. Furthermore, TW-7 reduced MMP-9 levels by forming stable complexes with it and by inhibiting the NF-κB p65/iNos pathway. These data suggested that TW-7 maintains BBB integrity by inhibiting the expression and activity of MMP-9, and TW-7 improves learning and memory ability in mice.

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.