The ethanolic extract of peanut shell attenuates the depressive-like behaviors of mice through modulation of inflammation and gut microbiota.

Peanut shell is an agricultural byproduct being wasted on a large scale, which is in urgent need to be recycled. To fully utilize its pharmacological ingredients, e.g. luteolin, eriodyctiol, and 5,7-dihydroxychromone, we evaluated the curative effect of ethanol extract deriving from peanut shell (PSE) in treating chronic unpredictable mild stress (CUMS)-induced depressive mice. The chronic stress lasted for 10 weeks, and PSE at 100-900 mg/kg/day was gavaged to mice in the last 2 weeks of modeling. The depressive behaviors were assessed by analyses of sucrose preference, tail suspension, and forced swimming. The brain injury was demonstrated by Hematoxylin and Eosin (H&E), Nissl body, and TdT-mediated dUTP nick end labeling (TUNEL) stainings in the mouse hippocampus. Biochemical indicators were analyzed, including levels of neurotrophic factors, neurotransmitters, stress hormones, and inflammatory mediators. The feces were collected for the 16S rDNA sequencing of gut microbiome. Administration of PSE improved the sucrose water consumption of depressive mice, while it decreased the immobile time in tail suspension and forced swimming tests. Meanwhile, the anti-depressive effect of PSE was supported by ameliorated histochemical staining, increased levels of neurotrophic factors and neurotransmitters, as well as down-regulated stress hormones. Furthermore, the treatment of PSE was able to mitigate the levels of inflammatory cytokines in brain, serum, and small intestine. Besides, the tight junction proteins, e.g., occludin and ZO-1, of gut showed elevated expressions, which coincided with the elevated abundance and diversity of gut microbiota upon PSE treatment. This study validated the therapeutic efficacy of PSE in fighting against depression, as well as its modulatory action on inflammation and gut microbiota, which promoted the recycling of this agricultural waste to be health supplements of added value.

Flavonoids from Seabuckthorn (Hippophae rhamnoides L.) mimic neurotrophic functions in inducing neurite outgrowth in cultured neurons: Signaling via PI3K/Akt and ERK pathways.

BACKGROUND: Various brain disorders, including neurodegenerative diseases and major depressive disorders, threaten an increasing number of patients. Seabuckthorn, a fruit from Hippophae rhamnoides L., is an example of "medicine food homology". The fruit has enriched flavonoids that reported to have benefits in treating cognitive disorders. However, the studies on potential functions of Seabuckthorn and/or its flavonoid-enriched fraction in treating neurodegenerative disorders are limited. PURPOSE: This study aimed to determine the ability and mechanism of the flavonoid-enriched fraction of Seabuckthorn (named as SBF) in mimicking the neurotrophic functions in inducing neurite outgrowth of cultured neurons. METHODS: Cultured PC12 cell line, SH-SY5Y cell line and primary neurons (cortical and hippocampal neurons isolated from E17-19 SD rat embryos) were the employed models to evaluate SBF in inducing neurite outgrowth by comparing to the effects of NGF and BDNF. Immuno-fluorescence staining was applied to identify the morphological change during the neuronal differentiation. Luciferase assay was utilized for analyzing the transcriptional regulation of neurofilaments and cAMP/CREB-mediated gene. Western blot assay was conducted to demonstrate the expressions of neurofilaments and phosphorylated proteins. RESULTS: The application of SBF induced neuronal cell differentiation, and this differentiating activation was blocked by the inhibitors of PI3K/Akt and ERK pathways. Additionally, SBF showed synergy with neurotrophic factors in stimulating the neurite outgrowth of cultured neurons. Moreover, the major flavonoids within SBF, i.e., isorhamnetin, quercetin and kaempferol, could account for the neurotrophic activities of SBF. CONCLUSION: Seabuckthorn flavonoids mimicked neurotrophic functions in inducing neuronal cell differentiation via activating PI3K/Akt and ERK pathways. The results suggest the beneficial functions of Seabuckthorn as a potential health food supplement in treating various brain disorders, e.g., neurodegenerative diseases.

The neurotrophic activities of brain-derived neurotrophic factor are potentiated by binding with apigenin, a common flavone in vegetables, in stimulating the receptor signaling.

AIMS: We aimed to identify the neurotrophic activities of apigenin (4',5,7-trihydroxyflavone) via its coordination with brain-derived neurotrophic factor (BNDF) and an elevated signaling of tyrosine kinase receptor B (Trk B receptor). METHODS: The direct binding of apigenin to BDNF was validated by ultrafiltration and biacore assay. Neurogenesis, triggered by apigenin and/or BDNF, was determined in cultured SH-SY5Y cells and rat cortical neurons. The amyloid-beta (Aß)25-35 -induced cellular stress was revealed by propidium iodide staining, mitochondrial membrane potential, bioenergetic analysis, and formation of reactive oxygen species levels. Activation of Trk B signaling was tested by western blotting. RESULTS: Apigenin and BDNF synergistically maintained the cell viability and promoted neurite outgrowth of cultured neurons. In addition, the BDNF-induced neurogenesis of cultured neurons was markedly potentiated by applied apigenin, including the induced expressions of neurofilaments, PSD-95 and synaptotagmin. Moreover, the synergy of apigenin and BDNF alleviated the (Aß)25-35 -induced cytotoxicity and mitochondrial dysfunction. The synergy could be accounted by phosphorylation of Trk B receptor, and which was fully blocked by a Trk inhibitor K252a. CONCLUSION: Apigenin potentiates the neurotrophic activities of BDNF through direct binding, which may serve as a possible treatment for its curative efficiency in neurodegenerative diseases and depression.

A Herbal Mixture of Sesami Semen Nigrum and Longan Arillus Induces Neurite Outgrowth in Cultured Neurons and Shows Anti-Depression in Chronic Mild Stress-Induced Rats.

Medicinal food homology is referring to a group of food itself being considered as herbal medicine without a boundary of usage. Under the guidance of this food/medicine principle, the current study aims to develop anti-depressant from this food/medicine catalog. The herbal mixture of Sesami Semen Nigrum and Longan Arillus was evaluated in cultured PC12 rat pheochromocytoma cells, rat primary cortical neurons, and in chronic mild stress (CMS)-induced depressive rat model. The combination of two ethanolic extracts of Sesami Semen Nigrum and Longan Arillus in 1 : 1 ratio mimicked the function of nerve growth factor (NGF) and synergistically induced neurite outgrowth of PC12 cells. Besides, the expression and phosphorylation of tropomyosin receptor kinase A (TrkA) of the cultured cells were also elevated. This neurotrophic activity of herbal mixture was further supported by the increased expressions of biomarkers for neurogenesis and synaptogenesis in cortical neurons. Moreover, the depressed rats were soothed by the intake of herbal mixture, showing improved performance in behavior tests, as well as reversed levels of neurotransmitters and neurotrophic factors. Our results provide a new way to make full use of the current food/medicine resources, as to accelerate the development of therapeutics for depression.