A dramatic increase in aging populations and low birth rates rapidly drive aging societies and increase aging-associated neurodegenerative diseases. However, functional food or medicinal formulations to prevent geriatric brain disorders are not readily available. Panax ginseng is a candidate, since ginseng has long-been consumed as a rejuvenating agent. However, the underlying molecular mechanisms and the components of ginseng that are responsible for brain rejuvenation and human longevity are unknown. Accumulating evidence shows that gintonin is a candidate for the anti-aging ingredient of ginseng, especially in brain senescence. Gintonin, a glycolipoprotein complex, contains three lipid-derived G protein-coupled receptor ligands: lysophosphatidic acids (LPAs), lysophosphatidylinositols (LPIs), and linoleic acid (LA). LPA, LPI, and LA act on six LPA receptor subtypes, GPR55, and GPR40, respectively. These G protein-coupled receptors are distributed within the nervous and non-nervous systems of the human body. Gintonin-enriched fraction (GEF) exhibits anti-brain senescence and effects against disorders such as Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD). Oral administration of gintonin in animal models of d-galactose-induced brain aging, AD, HD, and PD restored cognitive and motor functions. The underlying molecular mechanisms of gintonin-mediated anti-brain aging and anti-neurodegenerative diseases include neurogenesis, autophagy stimulation, anti-apoptosis, anti-oxidative stress, and anti-inflammatory activities. This review describes the characteristics of gintonin and GEF, and how gintonin exerts its effects on brain aging and brain associated-neurodegenerative diseases. Finally, we describe how GEF can be applied to improve the quality of life of senior citizens in aging societies.

Gintonin, newly extracted from ginseng, is a glycoprotein that acts as an exogenous lysophosphatidic acid (LPA) receptor ligand. This study aimed to demonstrate the in vivo preventive effects of gintonin on gastric damage. ICR mice were randomly assigned to five groups: a normal group (received saline, 0.1 mL/10 g, p.o.); a control group (administered 0.3 M HCl/ethanol, 0.1 mL/10 g, p.o.) or indomethacin (30 mg/kg, p.o.); gintonin at two different doses (50 mg/kg or 100 mg/kg, p.o.) with either 0.3 M HCl/ethanol or indomethacin; and a positive control (Ranitidine, 40 mg/kg, p.o.). After gastric ulcer induction, the gastric tissue was examined to calculate the ulcer index. The expression of gastric damage markers, such as tumor necrosis factor (TNF)-α, cyclooxygenase 2 (COX-2), and LPA2 and LPA5 receptors, were measured by Western blotting. Interleukin-6 (IL-6) and prostaglandin E2 (PGE2) levels were measured by enzyme-linked immunosorbent assay. The platelet endothelial cell adhesion molecule (PECAM-1), Evans blue, and occludin levels in gastric tissues were measured using immunofluorescence analysis. Both HCl/ethanol- and indomethacin-induced gastric ulcers showed increased TNF-α, IL-6, Evans blue permeation, and PECAM-1, and decreased COX-2, PGE2, occludin, and LPA5 receptor expression levels. However, oral administration of gintonin alleviated the gastric ulcer index induced by HCl/ethanol and indomethacin in a dose-dependent manner. Gintonin suppressed TNF-α and IL-6 expression, but increased COX-2 expression and PGE2 levels in mouse gastric tissues. Gintonin intake also increased LPA5 receptor expression in mouse gastric tissues. These results indicate that gintonin can play a role in gastric protection against gastric damage induced by HCl/ethanol or indomethacin.

Epidermal growth factor (EGF) receptor activation and related downstream signaling pathways are known to be one of the major mechanisms of the proliferation and migration of keratinocytes. The heparin-binding EGF-like growth factor (HB-EGF) binds to EGF receptors and stimulates keratinocyte proliferation and migration. Gintonin, a novel ginseng compound, is a lysophosphatidic acid (LPA) receptor ligand. Gintonin has skin-wound-healing effects. However, the underlying mechanisms for these gintonin actions remain unclear. In this study, we aimed to elucidate the involvement of EGFRs in gintonin-induced wound repair in HaCaT keratinocytes. In this study, a water-soluble tetrazolium salt-based assay, a modified Boyden chamber migration assay, and immunoblotting were performed. Gintonin increased EGF receptor activation in HaCaT cells. However, the gintonin-induced phosphorylation of the EGF receptor was markedly reduced via treatment with the LPA inhibitor Ki16425 or the EGF receptor inhibitor erlotinib. Gintonin-enhanced proliferation and migration were blocked by the EGF receptor inhibitors (erlotinib and AG1478). Additionally, gintonin stimulated the expression and release of HB-EGF in HaCaT cells. EGF receptor inhibitors blocked gintonin-enhanced HB-EGF expression. These results indicate that the wound-healing effects of gintonin are closely related to the collaboration between EGF receptor activation and HB-EGF release-mediated downstream signaling pathways.

Background: Recently, gintonin and gintonin-enriched fraction (GEF) have been isolated from ginseng, a herbal medicine. Gintonin induces [Ca2+](i) transition in cultured hippocampal neurons and stimulates acetylcholine release through LPA receptor activation. Oral administration of GEF is linked to hippocampus-dependent cognitive enhancement and other neuroprotective effects; however, effects of its long-term administration on hippocampal gene expression remains unknown. Here, we used next-generation sequence (NGS) analysis to examine changes in hippocampal gene expressions after long-term oral administration of GEF. Methods: C57BL/6 mice were divided into three groups: control group, GEF50 (GEF 50 mg/kg, p.o.), and GEF100 (GEF 100 mg/kg, p.o.). After 22 days, total RNA was extracted from mouse hippocampal tissues. NGS was used for gene expression profiling; quantitative-real-time PCR and western blot were performed to quantify the changes in specific genes and to confirm the protein expression levels in treatment groups. Results: NGS analysis screened a total of 23,282 genes, analyzing 11-related categories. We focused on the neurogenesis category, which includes four genes for candidate markers: choline acetyltransferase (ChAT) gene, beta(3)-adrenergic receptor (Adrb3) gene, and corticotrophin-releasing hormone (Crh) gene, and tryptophan 2,3-dioxygenase (Tdo2) gene. Real-time PCR showed a marked overexpression of ChAT, Adrb3, and Crh genes, while reduced expression of Tdo2. Western blot analysis also confirmed increased ChAT and decreased Tdo2 protein levels. Conclusion: We found that GEF affects mouse hippocampal gene expressions, associated with memory, cognitive, anti-stress and anti-anxiety functions, and neurodegeneration at differential degree, that might explain the genetic bases of GEF-mediated neuroprotective effects. (C) 2020 Korea Institute of Oriental Medicine. Publishing services by Elsevier B.V.

Gintonin-enriched fraction (GEF), a bioactive glycolipoprotein derived from Panax ginseng is known for its potential as a natural anti-inflammatory agent. Keratinocytes are closely related to the development and progression of various inflammatory skin conditions. However, the effect of GEF on inflammation-related responses in keratinocytes remains unclear. This study aimed to investigate whether GEF modulates key inflammatory responses in keratinocytes stimulated by tumor necrosis factor (TNF)-α. The effect of GEF on biological activities in TNF-α-stimulated keratinocytes (HaCaT cells) was evaluated using water-soluble tetrazolium salt, enzyme-linked immunosorbent, immunostaining, and immunoblotting assays. In TNF-α-stimulated HaCaT cells, GEF attenuated reactive oxygen species production, nitric oxide release, and inducible nitric oxide synthase expression. Moreover, GEF reduced the release of interleukin (IL)-6 and RANTES, while increasing the release of IL-10 in TNF-α-exposed HaCaT cells. Additionally, GEF treatment resulted in reduced cyclooxygenase-2 expression and prostaglandin E₂ release and inhibited TNF-α-induced translocation of nuclear factor-κB in HaCaT cells. Furthermore, TNF-α and IL-6 levels in ultraviolet B-irradiated HaCaT cells were reduced by GEF treatment. These findings indicated that GEF exerts anti-inflammatory effects on keratinocytes. This study provides a basis for the development of novel therapeutic approaches for the prevention and treatment of inflammatory skin disorders.