While synbiotic interventions show promise in alleviating food allergy (FA), targeted optimization of probiotic-prebiotic combinations for enhanced immunomodulatory metabolite production remains insufficiently explored. This study constructed a novel synbiotic containing five human milk oligosaccharides (5-HMOs), Bifidobacterium bifidum R0071, bovine whey protein hydrolysate, and tryptophan, which demonstrated efficient production of indole-3-lactic acid (ILA) in vitro. In an ovalbumin (OVA)-induced FA mouse model, the synbiotic significantly alleviated allergic symptoms, reduced OVA-sIgE levels, restored Th2/Th17 immune balance, improved intestinal barrier integrity, and activated the aryl hydrocarbon receptor. 16S rRNA sequencing revealed that this synbiotic treatment enriched beneficial gut bacteria, including Bifidobacterium, Akkermansia, and Lactobacillus johnsonii. Targeted metabolomics confirmed elevated intestinal ILA levels, which were closely correlated with the alleviation of FA. Collectively, these findings demonstrate that the 5-HMOs synbiotic alleviates FA by modulating the gut microbiota and enhancing ILA production, offering novel insights into the targeted development of synbiotic-based interventions against FA.

One new cassane diterpenoid(1) and six known compounds(2-7) were isolated from the 95% ethanol extract of fresh Caesalpinia decapetala pods by silica gel column chromatography, gel filtration chromatography, and semi-preparative HPLC. Compound 1 was identified as a highly oxidized cassane diterpenoid, and its absolute configuration was determined by comprehensive spectroscopic analysis and electronic circular dichroism(ECD) calculations, being named caesalpin L. The known compounds were characterized as caesalsappanin K(2), bonducellin(3), 4-hydroxy-3,5-dimethoxybenzaldehyde(4), thellungianin C(5), p-hydroxybenzoyl coumaric acid anhydride(6), and gallic acid(7). Compounds 2 and 4-7 were obtained from this plant species for the first time. The anti-inflammatory activity of compounds 1 and 2 was comparable to that of the positive control.

In this study, a technique that combines supercritical fluid extraction with ethanol extraction was employed to effectively fractionate egg yolk extracts into non-polar and polar lipids. By utilizing feature based molecular networking (FBMN) and MS-DIAL database search, 35 glycerolipids were identified in the supercritical extract (SE), and 70 glycerophospholipids in the ethanol extract (EE). Following the identification of lipids, a heatmap was generated using R software to visualize the abundance of lipids across both fractions. The results indicated that glycerolipids in SE primarily included C18:1, C16:0, and C18:2 fatty acids. In contrast, the glycerophospholipids present in EE exhibited a significant proportion of polyunsaturated fatty acids, notably docosahexaenoic acid (DHA, C22:6) and arachidonic acid (C20:4). Further analysis using GC-MS revealed that the combined content of DHA and arachidonic acid in EE exceeded 10 %. Moreover, EE exhibited potent antiinflammatory activities, whereas SE showed significant analgesic effects in zebrafish model.

Introduction:Depression is a mental illness closely associated with neurological damage and is characterised by high rates of suicide and mood changes. As a traditional medicinal plant, Rosa roxburghii Tratt has been widely used since ancient times in the Miao and Dong regions of Southwest China for the relief of sleep disorders, indigestion, anti-inflammation, neurasthenia and neuroprotection. The total triterpenes of R. roxburghii were previously found to have certain neuroprotective effects, and whether Kaji-ichigoside F1 (KF1), as its main ingredient, plays a relevant pharmacological role needs to be further investigated. Methods:Establishment of mouse depression model and BV2 microglia inflammation model using intraperitoneal injection of LPS in mice and LPS stimulated-BV2 microglia, respectively. The antidepressant effects of KF1 were evaluated by forced swim test (FST), sucrose preference test (SPT), tail suspension test (TST) and open field test (OFT). The number of Nissl bodies and apoptotic positive cells in the CA1 region of the hippocampus was observed by Nissl and TUNEL staining. Then, the levels of TNFα, PPAR-γ, TGF-β, and IL-6 cytokines were tested by ELISA kits. Finally, the molecular mechanisms were investigated by Western blotting (WB) and immunofluorescence in vivo and in vitro. Results:KF1 dramatically ameliorated LPS-induced depressive like behaviors, neuronal damage, apoptosis, and suppressed the levels of pro-inflammatory cytokines in the serum and hippocampus of mice. Our vitro experiment also showed KF1 significantly reduced cell viability and attenuated apoptosis in LPS-induced BV2 microglia, decreased the mean fluorescence intensity of Caspase-1, TNFα, NF-κB, IL-1β, NLRP3, and Keap1. However, the mean fluorescence intensity of GCLC, GCLM, GST, SOD1, HO-1, and Nrf2 were significantly increased. Finally, Western blot analysis showed that KF1 suppressing the expression of NF-κB/NLRP3 signaling pathway and activating PPARγ/CX3CR1/Nrf2 signaling pathway both in vivo and in vitro. Conclusion:In conclusion, these results suggest that KF1 is an effective alleviator of LPS-induced depression-like effects in vivo and in vitro. These effects were associated with activating PPARγ/CX3CR1/Nrf2 signaling, and suppressing NF-κB/NLRP3 signaling pathways.

Gray mold, caused by Botrytis cinerea, is a prominent postharvest disease that significantly diminishes the commercial value of strawberries. This study aimed to reveal the effects and potential mechanism of collaborative treatment with natamycin and potassium sorbate (SNPS) on enhancing gray mold resistance by regulating phenylpropanoid metabolism in strawberry fruit. All strawberries were first inoculated with a suspension of B. cinerea conidia, air dried and then the two experimental groups received injections of 10 mu L SNPS (1 of minimal inhibitory concentration, MIC) and SNPS (3 of MIC) respectively, with distilled water as control. Strawberries treated with SNPS exhibited a significant reduction of 70 % and 50 % in disease incidence and lesion diameter after 3 days, respectively, compared to untreated samples. SNPS treatment also inhibited weight loss, and maintained high hardness and the contents of total soluble solids, anthocyanin and ascorbic acid. SNPS treatment activated Phenylalanine Ammonia-lyase, cinnamic acid-4-hydroxylase and 4-coumaric acid- CoA ligase, and also promoted the accumulation of total phenols, total flavonoids, and lignin. Moreover, strawberry fruit treated with SNPS inducer the accumulation of disease-course related proteins compared to the control. SNPS treatment effectively inhibit gray mold infection in strawberries by activating the phenylpropanoid metabolism pathways and disease process-related protein accumulation.

Eleven sesquiterpenoids were isolated from the petroleum ether and ethyl acetate extracted fraction of 95% ethanol extract of fresh Centipeda minima by using modern chromatographic separation techniques such as silica gel, MCI, gel, and semi-preparative liquid chromatography. Their structures were identified using spectroscopy and nuclear magnetic resonance(NMR) calculation as minimin A(1), brevilin A(2), minimolide L(3), minimolide A(4), minimolide B(5), arnicolide D(6), microhelenin C(7), 2β-hydroxyl-2,3-dihydrogen-6-O-angeloylplenolin(8), 11α,13-dihydroarnifolin(9),(1S,2R,5R,6S,7S,8S,10R)-6-hydroxy-2-ethoxy-4-oxopseudoguai-11(13)-en-12,8-olide(10), and pulchellin-2-O-isovalerate(11), among which compound 1 was a new compound, and compounds 9-11 were isolated from Centipeda for the first time. The evaluation results of in vitro anti-inflammatory activity showed that compounds 1-11 possessed significant anti-inflammatory activity, with IC_(50) values ranging from(0.13±0.03) to(13.11±0.17) μmol·L~(-1).

BackgroundNon-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by the excessive accumulation of lipids as a pathological feature. Previous studies have demonstrated that Rosa roxburghii Tratt. fruit vinegar (RFV) played an important role in intervening in obesity and related complications by regulating the intestinal microbiota in high-fat diet mice.MethodsThis study investigated the mechanisms by which RFV improves NAFLD from multiple perspectives. Potential targets were predicted by network pharmacology and molecular docking analyses. Intestinal microbial communities were detected and analyzed using 16S rRNA gene sequencing technology. Liver metabolites were detected and analyzed using ultra high performance liquid chromatography quadrupole-exactive high field-X mass spectrometer (UHPLC-Q-Exactive HF-X) and Progenesis QI software. Hepatic protein expression levels were detected and quantified using Western blotting analysis and gray-value analysis, respectively.ResultsThe results indicated that, RFV could improve the diversity of intestinal microbiota in NAFLD mice, reduce the ratio of Firmicutes to Bacteroidetes (F/B), and reverse the relative abundance of differential bacteria genera related to lipid accumulation and energy metabolism. The intestinal microbiota was correlated with the levels of lipid metabolism and oxidative stress in the serum and liver of mice with NAFLD. The primary bacteria genera involved were Allobaculum, Faecalibaculum, Dubosiella, Blautia, and unclassified_f_Lachnospiraceae. A total of 441 liver metabolites were identified in NAFLD mice and participating in 21 metabolic pathways. Glycerophospholipid metabolism may be an important pathway regulating NAFLD by RFV. Phosphatidylcholines (PC) and lysophosphatidylcholinergic (LPC) metabolites were significantly regulated by RFV and had significant correlation with differential microbiota. RFV may improve NAFLD by regulating lipid synthesis in the adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK) pathway. Western blotting analysis showed that, RFV could activate the AMPK phosphorylation, and reduce the expression of fatty acid synthase (FASN) and sterol regulatory element-binding protein 1 (SREBP-1c), resulting in the inhibition of fatty acids de novo synthesis and lipid accumulation.ConclusionAs a functional food, RFV has been proven to be effective in improving NAFLD. The underlying mechanisms involve the modulation of the intestinal microbiota and metabolites balance, and regulation on lipid disorders through AMPK signaling pathway.

Addressing the uncontrolled spread and increase in antibiotic resistance in methicillin-resistant Staphylococcus aureus (MRSA) will require new control strategies, particularly to improve the safety of food. Our results revealed the efficacy of theaflavin-3,3′-digallate (TFBG), which is a novel polyphenol derived from tea, in targeting the key regulatory protein multiple gene regulator A (MgrA) in S. aureus. Through fluorescence anisotropy, we showed that the half maximal inhibitory concentration (IC50) of TFBG was 26.76 μg/mL. TFBG uniquely counters S. aureus by regulating its virulence factors and adhesion processes rather than by killing the bacteria directly. This compound alters the expression of key virulence factors and modulates the transcription levels of genes related to adhesion in S. aureus, ultimately reducing the bacteria’s ability to adhere to fibrinogen and its hemolytic activity. Our assays confirmed that TFBG directly interacts with the MgrA protein in MRSA, and we identified critical binding sites. Our in vivo studies highlighted the potent efficacy of TFBG. TFBG administration is an innovative approach to improve food safety by diminishing MRSA virulence and reducing its pathogenicity.

Alzheimer's disease is defined pathologically by the irregular buildup of senile plaques, neurofibrillary tangles, and associated neuroinflammation. As aging progresses, senescent cells gradually accumulate and significantly contribute to brain dysfunction; however, the precise mechanisms driving aging remain unclear. In the current study, ABT263, a potent senolytic drug, was administered orally to APP/PS1 mice (n = 16) for five days per cycle throughout the course of two cycles, and their behavioral tests in the Morris water maze were evaluated. Using mouse hippocampal tissue, senescence-related gene expression and SASP-associated protein expression were assessed using biochemical tests and immunohistochemical labeling. The Morris water maze test results indicated that ABT263 alleviated spatial memory impairment and reduced amyloid-beta (A beta) accumulation in APP/PS1 mice. Additionally, ABT263 treatment led to a decline in senescence-associated beta-galactosidase activity, p16 senescence-related gene expression, and the expression of SASP-associated proteins, including IL-6, IL-8, and MMP-1. Further investigation revealed that ABT263 enhanced the phosphorylation levels of phosphatidylinositol-3 kinase (PI3K) (Tyr458), serine/threonine kinase AKT (S473), and glycogen synthase kinase-3 beta (GSK-3 beta) (Ser9) in APP/PS1 mice. Our results showed that ABT263 protected neurons against A beta pathology, reduced the accumulation of senescent cells, and improved cognitive decline by enhancing PI3K/AKT/GSK-3 activity.

Aim: Hyperphosphorylated tau plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Whether mammalian target of rapamycin (mTOR) directly interacts with the Tau protein at Ser214, Ser356 and Thr231 is not clear. This study aimed to investigate whether mTOR-regulated tau phosphorylation disrupts mitochondrial dynamics and function and whether rapamycin, an mTOR inhibitor, can modulate tau phosphorylation levels and attenuate AD-related alterations. Methods: Adeno-associated virus (AAV) vectors were used to intracranially deliver the TauS214E/T231E/S356E (Tau3E) variant into 2-month-old C57BL/6 mice. The mice were intraperitoneally administered the mTOR inhibitor rapamycin for one week, followed by assessment via the Morris water maze test. Western blot analysis, immunofluorescence staining, and flow cytometry were employed to measure the expression levels of mTOR, p70S6K, and tau; mitochondrial dynamics; and reactive oxygen species (ROS) in HT22 cells and a mouse model overexpressing Tau3E, as well as in postmortem brain tissues from AD patients. Results: p-mTORS2448 colocalized with p-TauSer214, p-TauSer356, and p-TauThr231 in the hippocampal CA3 region of AD patients. HT22 cells and C57BL/6 mice overexpressing Tau3E presented elevated levels of p-mTOR, downstream target p-p70S6K, and ROS production; mitochondrial fragmentation; and p-TauSer214, p-TauSer356, and p-TauThr231. Rapamycin treatment partially mitigated the cognitive and molecular alterations in Tau3E mice. Conclusion: This study revealed a causal link between Tau phosphorylation at Ser214, Ser356, and p-Thr231 and mTOR upregulation and downstream impairments in ROS, mitochondrial dysfunction and cognitive function. Treatment using mTOR inhibitor rapamycin (i.p.) can alleviate impairment, reduce p-Tau and restore mitochondrial homeostasis, neuronal loss and cognitive impairment in mice. ### Competing Interest Statement The authors have declared no competing interest.

Agrocybe cylindracea dietary fiber (ADF) contains 95% water-insoluble dietary fiber, resulting in poor application performance. To address this issue, ADF was modified by four methods (cellulase, sodium hydroxide, high-temperature, and Lactobacillus fermentation) in this paper. By comparing the physicochemical properties, microstructures, monosaccharide compositions, and functional characteristics (antioxidant and α-glucosidase inhibitory activities in vitro) of all modified ADF samples, the optimal modification method was selected. Results showed that sodium hydroxide treatment was deemed the most effective modification method for ADF, as alkali-treated ADF (ADF-A) revealed a higher oil-holding capacity (2.02 g/g), swelling capacity (8.38 mL/g), cholesterol adsorption (6.79 mg/g), and α-glucosidase inhibitory activity (more than 70% at 0.4–0.6 mg/mL) than the other modified samples. The looser microstructure in ADF-A might be attributed to molecular rearrangement and spatial structure disruption, which resulted in smaller molecular sizes and decreased viscosity, hence improving ADF’s physicochemical and functional qualities. All these findings indicate the greater application potential of modified ADF products in food and weight-loss industries, providing a comprehensive reference for the industrial application of ADF.

Alzheimer's disease is characterized by abnormal β-amyloid and tau accumulation, mitochondrial dysfunction, oxidative stress, and synaptic dysfunction. Here, we aimed to assess the mechanisms and signalling pathways in the neuroprotective effect of gastrodin, a phenolic glycoside, on murine neuroblastoma N2a cells expressing human Swedish mutant APP (N2a/APP). We found that gastrodin increased the levels of presynaptic-SNAP, synaptophysin, and postsynaptic-PSD95 and reduced phospho-tau Ser396, APP and Aβ1-42 levels in N2a/APP cells. Gastrodin treatment reduced reactive oxygen species generation, lipid peroxidation, mitochondrial fragmentation and DNA oxidation; restored mitochondrial membrane potential and intracellular ATP production. Upregulated phospho-GSK-3β and reduced phospho-ERK and phospho-JNK were involved in the protective effect of gastrodin. In conclusion, we demonstrated the neuroprotective effect of gastrodin in the N2a/APP cell line by ameliorating the impairment on synaptic and mitochondrial function, reducing tau phosphorylation, Aβ1-42 levels as well as reactive oxygen species generation. These results provide new mechanistic insights into the potential effect of gastrodin in the treatment of Alzheimer’s disease.

Background: Depression is a common and recurrent neuropsychiatric disorder. Recent studies have shown that the N-methyl-d-aspartate (NMDA) receptor (NMDAR) is involved in the pathophysiology of depression. Previous studies have found that Kaji-ichigoside F1 (KF1) has a protective effect against NMDA-induced neurotoxicity. However, the antidepressant mechanism of KF1 has not been confirmed yet. Purpose: In the present study, we aimed to evaluate the rapid antidepressant activity of KF1 and explore the underlying mechanism. Study design: First, we explored the effect of KF1 on NMDA-induced hippocampal neurons and the underlying mechanism. Second, depression was induced in C57BL/6 mice via chronic unpredictable mild stress (CUMS), and the immediate and persistent depression-like behavior was evaluated using the forced swimming test (FST) after a single administration of KF1. Third, the contributions of NMDA signaling to the antidepressant effect of KF1 were investigated using pharmacological interventions. Fourth, CUMS mice were treated with KF1 for 21 days, and then their depression-like behaviors and the underlying mechanism were further explored. Methods: The FST was used to evaluate immediate and persistent depression-like behavior after a single administration of KF1 with or without NMDA pretreatment. The effect of KF1 on depressive-like behavior was investigated in CUMS mice by treating them with KF1 once daily for 21 days through the sucrose preference test, FST, open field test, and tail suspension test. Then, the effects of KF1 on the morphology and molecular and functional phenotypes of primary neuronal cells and hippocampus of mice were investigated by hematoxylin-eosin staining, Nissl staining, propidium iodide staining, TUNEL staining, Ca2+ imaging, JC-1 staining, ELISA, immunofluorescence analysis, RT-PCR, and Western blot. Results: KF1 could effectively improve cellular viability, reduce apoptosis, inhibit the release of LDH and Ca2+, and increase the mitochondrial membrane potential and the number of dendritic spines numbers in hippocampal neurons. Moreover, behavioral tests showed that KF1 exerted acute and sustained antidepressant-like effects by reducing Glu-levels and ameliorating neuronal damage in the hippocampus. Additionally, in vivo and in vitro experiments revealed that PSD95, Syn1, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and brain-derived neurotrophic factor (BDNF) were upregulated at the protein level, and BDNF and AMPA were upregulated at the mRNA level. NR1 and NR2A showed the opposite trend. Conclusion: These results confirm that KF1 exerts rapid antidepressant effects mainly by activating the AMPA-BDNF-mTOR pathway and inhibiting the NMDAR-CaMKII alpha pathway. This study serves as a new reference for discovering rapid antidepressants.

BACKGROUND:Ulcerative colitis (UC) refers to an idiopathic chronic inflammatory bowel disease that starts with inflammation of the intestinal mucosa. Dietary fiber plays a crucial role in maintaining the normal architecture of the intestinal mucosa. In this study, the protective effect and potential mechanism of soluble dietary fiber from Rosa roxburghii Tratt residue (SDFR) on dextran sulfate sodium (DSS)-induced UC mice were explored. RESULTS:The results revealed that SDFR could ameliorate body weight loss and pathological injury, improve the structure and crypt destruction in colon in DSS-induced mice. Moreover, the levels of NO, IL-1β, TNF-α, MPO and protein expression of iNOS and COX-2 were decreased after administration of SDFR. Notably, nontargeted metabolomics analysis indicated that there were significant differences in 51 potential metabolites in serum between the DSS and control groups. SDFR intervention could regulate aberrant alterations of these metabolites and mitigate UC via regulating metabolic pathways, including arachidonic acid and glycerophospholipid metabolism. CONCLUSION:This study provides novel evidence that SDFR could be used as a potential modulator to relieve UC. Also, the results provide a theoretical basis for the utilization of byproducts in Rosa roxburghii Tratt fruit processing. © 2024 Society of Chemical Industry.

Cinnamigones A–C, three undescribed highly oxidized guaiane-type sesquiterpenes were isolated from the fruits of Cinnamomum migao. Cinnamigone A (1), structurally artemisinin-like, is a natural 1,2,4-trioxane caged endoperoxide with an unprecedented tetracyclic 6/6/7/5 ring system. Compounds 2–3 are classic guaiane sesquiterpene featuring different epoxy units. Guaiol (4) is considered to be the precursor of 1–3 in the biosynthesis pathway hypothesis. The planar structures and configurations of cinnamigones A–C were elucidated by spectral analysis, HRESIMS, X-ray crystallography and ECD calculations. Evaluation of the neuroprotective activity of 1–3 on N-methyl-ᴅaspartate (NMDA) toxicity was demonstrated that compounds 1–2 exhibited moderate neuroprotective activity against NMDA-induced neurotoxicity.

Insects rely on odorant-binding proteins (OBPs) for chemical perception, making OBPs a promising target for studying attractants and repellents of pests, such as Bemisia tabaci. However, no reports have reported using B. tabaci OBPs (BtOBPs) as pesticide screening targets. To fill this gap, we obtained BtOBP8 through prokaryotic expression and purification. Then, we confirmed its identity using western blotting and mass spectrometry. Next, we used the sitting drop and hanging drop methods to screen its crystal conditions. Using microscale thermophoresis and isothermal titration calorimetry, we identified the highest affinity ligand, 3l, from 30 compounds. Furthermore, point mutation techniques identified Val119 as a key amino acid residue in binding 31 to BtOBP8. Finally, we tested the bioactivity of B. tabaci Mediterranean and found that 3l more effectively inhibits the bioactivity of B. tabaci MED than imidacloprid. This study presents a new approach for developing green insecticides specific to B. tabaci MED by targeting OBPs. Conclusively, identifying and targeting specific OBPs can create more targeted and effective pest control strategies without relying on toxic chemicals.

Alzheimer’s disease (AD) is featured by abnormal β-amyloid (Aβ) deposition, neurofibrillary tangle formation, downstream mitochondrial dysfunction, oxidative stress, and synaptic loss. Gastrodin, a phenolic glycoside, has shown neuroprotective effect and used in the treatment of a range of brain diseases. Here we aim to assess the mechanisms and signaling pathways involved in the neuroprotective effect of gastrodin in murine neuroblastoma N2a cells expressing human Swedish mutant amyloid precursor protein (N2a/APP). The levels of pre- and postsynaptic proteins, amyloid precursor protein C-terminal fragments (APP-CTFs), levels of tau, glycogen synthase kinase-3 β (GSK-3β), extracellular regulated kinase (ERK), and c-Jun N-terminal Kinase (JNK) were assessed by Western blotting. Flow cytometry assays for mitochondrial membrane potential (JC1) and reactive oxidative stress, as well as immunofluorescence staining for lipid peroxidation (4◻hydroxynonenal) and DNA oxidation (8◻hydroxy◻2’◻deoxyguanosine), were performed. We found that gastrodin treatment increased the levels of presynaptic SNAP25, synaptophysin, and postsynaptic PSD95, reduced phosphorylated tau protein Ser396, and APP-CTFs in N2a/APP cells. In addition, gastrodin reduced the levels of reactive oxygen species generation, lipid peroxidation, and DNA oxidation, reestablished mitochondrial membrane potential. Upregulated levels of phosphorylated-GSK-3β, reduced levels of phosphorylated-ERK, and phosphorylated-JNK were involved the protective effect of gastrodin. In conclusion, we demonstrated a neuroprotective effect of gastrodin in N2a/APP cell line.

Alzheimer’s disease is characterized by abnormal β-amyloid (Aβ) plaque accumulation, tau hyperphosphorylation, reactive oxidative stress, mitochondrial dysfunction and synaptic loss. Myricetin, a dietary flavonoid, has been shown to have neuroprotective effects in vitro and in vivo. Here, we aimed to elucidate the mechanism and pathways involved in myricetin’s protective effect on the toxicity induced by the Aβ42 oligomer. Neuronal SH-SY5Y cells were pretreated with myricetin before incubation with Aβ42 oligomer. The levels of pre- and postsynaptic proteins, mitochondrial division and fusion proteins, glycogen synthase kinase-3 β (GSK-3β) and extracellular regulated kinase (ERK) 1/2 were assessed by Western blotting. Flow cytometry assays for mitochondrial membrane potential (JC1) and reactive oxidative stress, as well immunofluorescence staining for lipid peroxidation (4-HNE) and DNA oxidation (8-OHdG), were performed. We found that myricetin prevented Aβ42 oligomer-induced tau phosphorylation and the reduction in pre/postsynaptic proteins. In addition, myricetin reduced reactive oxygen species generation, lipid peroxidation, and DNA oxidation induced by the Aβ42 oligomer. Moreover, myricetin prevented the Aβ42 oligomer-induced reduction in mitochondrial fusion proteins (mitofusin-1, mitofusin-2), fission protein (dynamin-related protein 1) phosphorylation, and mitochondrial membrane potential via the associated GSK-3β and ERK 1/2 signaling pathways. In conclusion, this study provides new insight into the neuroprotective mechanism of myricetin against Aβ42 oligomer-induced toxicity.

A range of novel 1-phenyl-benzopyrrolizidin-3-one derivatives were synthesized and evaluated for neuroprotective effects against N-methyl-D-aspartate (NMDA)-induced injury in PC12 cells. Interestingly, derivatives that 1-phenyl moiety bearing electron-donating group, especially benzyloxy, and the trans-forms exhibited better protective activity against NMDA-induced neurotoxicity. Compound 11 m demonstrated the best neuroprotective potency and shown a dose-dependent prevention. The increased intracellular calcium (Ca2+) influx caused by NMDA in PC12 cells was reversed in the case of compound 11 m pretreatment at 15 mu M. These results suggested that the synthesized 1-phenyl-benzopyrrolizidin-3-one derivatives exerted neuroprotective effect on NMDA-induced excitotoxicity in PC12 cells associated with inhibition of Ca2+ overload and can be further optimized for the development of neuroprotective agents.

Kaji-ichigoside F1 (KF1), a natural oleanane-type triterpenoid saponin, is the main active constituent from Rosa roxburghii. In the southwest regions of China, particularly in Guizhou Province, this plant was used as a Miao ethnic medicine to prevent and treat dyspepsia, dysentery, hypoimmunity, and neurasthenia. In the present study, the neuroprotective effect of KF1 was evaluated against N-methyl-D-aspartate (NMDA)-induced neurotoxicity in vivo and in vitro. An NMDA-induced PC12 cell neurotoxicity assay showed that KF1 effectively improved cellular viability, inhibited the release of lactate dehydrogenase (LDH), and reduced cell apoptosis. Furthermore, KF1-treated NMDA-induced excitotoxicity mice displayed a remarkable capacity for improving spatial learning memory in the Y-maze and Morris water maze tests. In addition, KF1 increased the levels of the neurotransmitters 5-hydroxytryptamine, dopamine, and monoamine oxidase and reduced the calcium ion concentration in the hippocampus of mice. Hematoxylin and eosin and Nissl staining indicated that KF1 effectively reduced the impairment of neurons. Furthermore, Western blot assays showed that KF1 decreased NMDAR1 expression. In contrast, the NMDAR2B (NR2B), glutamate receptor (AMPA), TrkB, protein kinase B (AKT), mammalian target of rapamycin (mTOR), PSD95, and synapsin 1 were upregulated in NMDA-induced PC12 cells and an animal model. These results suggest that KF1 has a remarkable protective effect against NMDA-induced neurotoxicity, which is directly related to the regulation of the NMDA receptor and the activation of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) and BDNF/AKT/mTOR signaling pathways.