Mood disorders affect over 300 million individuals worldwide, often characterized by their chronic and refractory nature, posing significant threats to patient life. There has been a notable increase in mood disorders among American adolescents and young adults, with a rising number of suicide attempts and fatalities, highlighting a growing association between mood disorders and suicidal outcomes. Dysregulation within the neuroimmune-endocrine system is now recognized as one of the fundamental biological mechanisms underlying mood and mood disorders. Lysophosphatidic acid (LPA), a novel mediator of mood behavior, induces anxiety-like and depression-like phenotypes through its receptors LPA1 and LPA5, regulating synaptic neurotransmission and plasticity. Consequently, LPA has garnered substantial interest in the study of mood regulation. This study aimed to elucidate the molecular mechanisms of lysophosphatidic acid and its receptors, along with LPA receptor ligands, in mood regulation and to explore their potential therapeutic efficacy in treating mood disorders. A comprehensive literature search was conducted using the PubMed and Web of Science databases, identifying 208 articles through keyword searches up to June 2024. After excluding duplicates, irrelevant publications, and those restricted by open access limitations, 21 scientific papers were included in this review. The findings indicate that LPA/LPA receptor modulation could be beneficial in treating mood disorders, suggesting that pharmacological agents or gintonin, an extract from ginseng, may serve as effective therapeutic strategies. This study opens new avenues for future research into how lysophosphatidic acid and its receptors, as well as lysophosphatidic acid receptor ligands, influence emotional behavior in animals and humans.

The objective of the study is to estimate the potential of gintonin, as an immune enhancing agent through natural killer cell (NK cell) activity in cyclophosphamide (CY)-induced immunosuppressive animals. Accumulated results reveals that, gintonin attenuated CY-induced immunosuppression and it might modulate NK cell activity to boost the immunity.

UNASSIGNED: Gintonin is a new material of ginseng that acts through the ginseng-derived lysophosphatidic acid (LPA) receptor ligand. The gintonin-enriched fraction (GEF) inhibits amyloid plaque accumulation in the cortex and hippocampus, improves cognitive dysfunction by increasing acetylcholine levels, and promoted hippocampal neurogenesis in an animal model of Alzheimer\'s disease. We evaluated the effect of the GEF on the cognitive performance of subjects with subjective memory impairment (SMI).
UNASSIGNED: In this eight-week, randomized, assessor- and participant-blinded, placebo-controlled study, participants with SMI were assigned to three groups receiving placebo, GEF 300 mg/day or GEF 600 mg/day. The Korean versions of the Alzheimer\'s Disease Assessment Scale (K-ADAS), Mini-Mental State Examination (K-MMSE), and Stroop color-word test (K-SCWT) were also evaluated along with the safety profiles.
UNASSIGNED: One hundred thirty-six participants completed the study. After eight weeks, we analyzed intergroup differences in primary or secondary outcome score changes. When we compared the GEF group with the placebo group, we observed significant improvements in the K-ADAS and K-SCWT scores. The GEF group did not show a significant improvement in K-MMSE and BDI scores compared to the placebo group. No adverse events were observed in the gintonin and placebo groups for eight weeks.
UNASSIGNED: The GEF is safe and effective in improving subjective cognitive impairment related to both the K-ADAS and K-SCWT in this study. However, further large-scale and randomized controlled studies are warranted to secure other cognitive function tests besides the K-ADAS and K-SCWT, and to confirm the findings of the current study.

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.

Epithelial-to-mesenchymal transition (EM transition) is a process wherein epithelial cells lose their intrinsic characteristics and cell-cell junctions and differentiate into a mesenchymal phenotype. EM transition is an important feature of cancer invasion and metastasis. In this study, we aimed to investigate the inhibitory effect of gintonin (GT), an ingredient of ginseng, on EM transition using A549 cells. The proliferation of A549 cells was enhanced following treatment with 50, 75, and 100 μg/mL of GT. GT affected EM transition-induced gene and protein expression, specifically that of vimentin (Vim), N-cadherin (N-cad), zinc finger E-box-binding homeobox 1, and Twist in A549 cells. Furthermore, the transforming growth factor beta 1 (TGF-β1)-induced phosphorylation of Smad2 and Smad3 was suppressed by GT treatment. Immunofluorescence staining also showed that GT treatment decreased the TGF-β1-induced expression of Vim and N-cad in A549 cells. Therefore, GT may be used to suppress cancer cell metastasis via maintenance of the cell-cell junction\'s integrity. However, further studies are required to pave the way for its translation into clinical application in cancer therapeutics.

Ginseng is one of the traditional herbal medicines for tonic. Gintonin is a new material derived from white/red ginseng and its lysophosphatidic acids (LPAs) play as a ligand for G protein-coupled LPA receptors. Korean red ginseng marc (KRGM) is a by-product after the KRG processes. We developed a low-cost/high-efficiency method for KRGM gintonin production. We further studied the KRGM gintonin-mediated anti-skin aging effects under UVB exposure using human dermal fibroblasts (HDFs). KRGM gintonin yield is about 8%. KRGM gintonin contains a high amount of LPA C18:2, lysophosphatidylcholine (LPC), and phosphatidylcholine (PC), which is similar to white ginseng gintonin. KRGM gintonin induced [Ca2+]i transient via LPA1/3 receptors and increased cell viability/proliferation under UVB exposure. The underlying mechanisms of these results are associated with the antioxidant action of KRGM gintonin. KRGM gintonin attenuated UVB-induced cell senescence by inhibiting cellular β-galactosidase overexpression and facilitated wound healing. These results indicate that KRGM can be a novel bioresource of KRGM gintonin, which can be industrially utilized as new material for skin nutrition and/or skin healthcare.

UNASSIGNED: Ginseng contains three active components: ginsenosides, gintonin, and polysaccharides. After the separation of 1 of the 3 ingredient fractions, other fractions are usually discarded as waste. In this study, we developed a simple and effective method, called the ginpolin protocol, to separate gintonin-enriched fraction (GEF), ginseng polysaccharide fraction (GPF), and crude ginseng saponin fraction (cGSF).
UNASSIGNED: Dried ginseng (1 kg) was extracted using 70% ethanol (EtOH). The extract was water fractionated to obtain a water-insoluble precipitate (GEF). The upper layer after GEF separation was precipitated with 80% EtOH for GPF preparation, and the remaining upper layer was vacuum dried to obtain cGSF.
UNASSIGNED: The yields of GEF, GPF, and cGSF were 14.8, 54.2, and 185.3 g, respectively, from 333 g EtOH extract. We quantified the active ingredients of 3 fractions: L-arginine, galacturonic acid, ginsenosides, glucuronic acid, lysophosphatidic acid (LPA), phosphatidic acid (PA), and polyphenols. The order of the LPA, PA, and polyphenol content was GEF > cGSF > GPF. The order of L-arginine and galacturonic acid was GPF >> GEF = cGSF. Interestingly, GEF contained a high amount of ginsenoside Rb1, whereas cGSF contained more ginsenoside Rg1. GEF and cGSF, but not GPF, induced intracellular [Ca2+]i transient with antiplatelet activity. The order of antioxidant activity was GPF > GEF = cGSF. Immunological activities (related to nitric oxide production, phagocytosis, and IL-6 and TNF-α release) were, in order, GPF > GEF = cGSF. The neuroprotective ability (against reactive oxygen species) order was GEF > cGSP > GPF.
UNASSIGNED: We developed a novel ginpolin protocol to isolate 3 fractions in batches and determined that each fraction has distinct biological effects.

UNASSIGNED: Gintonin (GT), a Panax ginseng-derived lysophosphatidic acid receptor (LPAR) ligand, has positive effects in cultured or animal models for Parkinson\'s disease, Huntington\'s disease, and so on. However, the potential therapeutic value of GT in treating epilepsy has not yet been reported.
UNASSIGNED: Effects of GT on epileptic seizure (seizure) in kainic acid [KA, 55mg/kg, intraperitoneal (i.p.)]-induced model of mice, excitotoxic (hippocampal) cell death in KA [0.2 μg, intracerebroventricular (i.c.v.)]-induced model of mice, and levels of proinflammatory mediators in lipopolysaccharide (LPS)-induced BV2 cells were investigated.
UNASSIGNED: An i.p. injection of KA into mice produced typical seizure. However, it was significantly alleviated by oral administration of GT in a dose-dependent manner. An i.c.v. injection of KA produced typical hippocampal cell death, whereas it was significantly ameliorated by administration of GT, which was related to reduced levels of neuroglial (microglia and astrocyte) activation and proinflammatory cytokines/enzymes expression as well as increased level of the Nrf2-antioxidant response via the upregulation of LPAR 1/3 in the hippocampus. However, these positive effects of GT were neutralized by an i.p. injection of Ki16425, an antagonist of LPA1-3. GT also reduced protein expression level of inducible nitric-oxide synthase, a representative proinflammatory enzyme, in LPS-induced BV2 cells. Treatment with conditioned medium clearly reduced cultured HT-22 cell death.
UNASSIGNED: Taken together, these results suggest that GT may suppress KA-induced seizures and excitotoxic events in the hippocampus through its anti-inflammatory and antioxidant activities by activating LPA signaling. Thus, GT has a therapeutic potential to treat epilepsy.

Gintonin, a glycolipid protein conjugated with lysophosphatidic acid (LPA), is a newly identified compound extracted from Korean ginseng. LPA receptor isotypes exhibit high affinity for gintonin and mediate intracellular calcium signaling in various animal cell models. In this study, we found that gintonin induced the activation of Akt and cAMP-response element binding protein (CREB) in mouse striatal neurons, and chronic treatment with gintonin potently induced dendritic growth and filopodia formation. Gintonin-induced Akt/CREB activation and dendritic development were significantly impaired by LPA receptor (LPAR1/3) inhibition with Ki16425. Intriguingly, prolonged treatment with gintonin ameliorated the reduction in dendritic formation caused by Shank3 and Slitrk5 deficiency in the striatal neurons. In addition, gintonin and brain-derived neurotrophic factor (BDNF) had a synergistic effect on AKT/CREB activation and dendritic growth at suboptimal concentrations. These findings imply that gintonin-stimulated LPA receptors play a role in dendritic growth in striatal neurons and that they may act synergistically with BDNF, which is known to play a role in dendritogenesis.