Effects of gintonin on the proliferation, migration, and tube formation of human umbilical-vein endothelial cells: involvement of lysophosphatidic-acid receptors and vascular-endothelial-growth-factor signaling

Hwang, Sung‐Hee; Lee, Byung-Hwan; Choi, Sun-Hye; Kim, Hyeonjoong; Won, Kyung Jong; Lee, Hwan Myung; Rhim, Hyewon; Kim, Hyoung‐Chun; Nah, Seung‐Yeol

doi:10.1016/j.jgr.2015.10.002

Cited by 35 publications

(36 citation statements)

References 42 publications

(73 reference statements)

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“…In the present study, the migration and tube formation of HUVECs increased significantly following the treatment with 10 and 100 µg/ml CCL. The increased movement of endothelial cells during angiogenesis was previously found to be closely linked to the formation of new blood vessels in wounds (19,20). Ashcroft et al (21) reported accelerated wound healing through a reduction of inflammation, and pro-inflammatory cytokines were shown to play a crucial role during this healing response.…”

Section: Discussionmentioning

confidence: 96%

“…Moreover, VEGFR2 has been shown to play a major role in VEGF-dependent angiogenesis (24). Additionally, IL-6 acts on a variety of organs and cell types and promotes cell growth, and its expression has been reported during wound healing (15,19,20). Furthermore, TNF-α has been implicated as an indirect angiogenic factor, and various cytokines including IL-1b have been shown to be associated with VEGF-dependent angiogenesis (10,17,18).…”

Section: Discussionmentioning

confidence: 99%

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Ameliorating effects of Cuscuta chinensis Lamak extract on hind‑limb ischemia, and angiogenic‑ or inflammatory associated factors in ovariectomized mice

et al. 2019

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Cuscuta chinensis Lamak (CCL) has traditionally been used in Korea to treat sexual disorders and skin problems. The aim of the present study was to investigate the effects of CCL extract on surgical injury-induced ischemia in the hind limbs of mice. Specifically, female C57BL/6 mice were ovariectomized, and their hind-limb vessels were ligated with surgical silk (6-0) and excised. CCL (150 or 450 mg/kg/BW) was then administered to the mice for 3 weeks, and the blood flow rate was evaluated using a laser Doppler system at -7, 0, 7, 14 and 21 days following hind-limb ischemia. The serum expression profiles of angiogenic and inflammatory mediators were measured using an antibody array, and the transcript levels were reverse transcription-quantitative polymerase chain reaction. The rate of hind limb blood flow was normalized to non-ischemic lesions and revealed to be markedly elevated at 14 and 21 days following ischemia when compared with the vehicle group. The density of capillaries in the hind limbs was also significantly increased following treatment with CCL in a dose-dependent manner. In addition, the transcriptional expression of angiogenetic factors were upregulated, whereas that of inflammatory cytokines were downregulated. Finally, vascular endothelial cell migration and tube formation were evaluated in vitro using human umbilical vein endothelial cells (HUVECs) and identified to be significantly increased following treatment with CCL. Overall, the results of the present study indicate that CCL extract exhibits therapeutic potential for the treatment of hind-limb ischemia as it promotes peripheral angiogenic and anti-inflammatory effects in mice.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Ameliorating effects of Cuscuta chinensis Lamak extract on hind‑limb ischemia, and angiogenic‑ or inflammatory associated factors in ovariectomized mice

et al. 2019

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“…Its main functional ingredients are LPAs. We have also shown that gintonin LPAs function as an LPA receptor-ligand exhibiting diverse biological effects in vitro and in vivo [4][5][6][7][8][9]. In a subsequent study, we showed that gintonin contains other bioactive lipids besides LPAs, listed in order of prevalence: linoleic acid > phosphatidic acids > LPAs > LPIs [12].…”

Section: Discussionmentioning

confidence: 82%

“…Viability of INS-1 cells was determined by a sodium 2,3,-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)-carbonyl]-2H-tetrazolium inner salt) (XTT)-based assay, as previously described, with some modifications [4,8]. Briefly, cells were seeded at 3 × 10 3 cells per well into 96-well plates.…”

Section: Cell Viabilitymentioning

confidence: 99%

“…We later demonstrated that lysophosphatidic acids (LPAs) were a major functional component of gintonin [4] and showed that gintonin could activate LPA receptors, a kind of G-protein coupled receptor (GPCR), in animal cells. We reported that gintonin exerted diverse cellular effects in vitro through LPA receptor activation, including transient intracellular calcium mobilization, morphological changes, enhancement of proliferation and migration, vascular development, and neurite retraction [5][6][7][8][9]. Gintonin has also consistently shown memory improvement, hippocampal cell proliferation, and neurodegenerative disease antagonism in animal models [5,6,[9][10][11].…”

Section: Introductionmentioning

confidence: 99%

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Ginseng Gintonin Contains Ligands for GPR40 and GPR55

et al. 2020

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Gintonin, a novel ginseng-derived glycolipoprotein complex, has an exogenous ligand for lysophosphatidic acid (LPA) receptors. However, recent lipid analysis of gintonin has shown that gintonin also contains other bioactive lipids besides LPAs, including linoleic acid and lysophosphatidylinositol (LPI). Linoleic acid, a free fatty acid, and LPI are known as ligands for the G-protein coupled receptors (GPCR), GPR40, and GPR55, respectively. We, herein, investigated whether gintonin could serve as a ligand for GPR40 and GPR55, using the insulin-secreting beta cell-derived cell line INS-1 and the human prostate cancer cell line PC-3, respectively. Gintonin dose-dependently enhanced insulin secretion from INS-1 cells. Gintonin-stimulated insulin secretion was partially inhibited by a GPR40 receptor antagonist but not an LPA1/3 receptor antagonist and was down-regulated by small interfering RNA (siRNA) against GPR40. Gintonin dose-dependently induced [Ca2+]i transients and Ca2+-dependent cell migration in PC-3 cells. Gintonin actions in PC-3 cells were attenuated by pretreatment with a GPR55 antagonist and an LPA1/3 receptor antagonist or by down-regulating GPR55 with siRNA. Taken together, these results demonstrated that gintonin-mediated insulin secretion by INS-1 cells and PC-3 cell migration were regulated by the respective activation of GPR40 and GPR55 receptors. These findings indicated that gintonin could function as a ligand for both receptors. Finally, we demonstrated that gintonin contained two more GPCR ligands, in addition to that for LPA receptors. Gintonin, with its multiple GPCR ligands, might provide the molecular basis for the multiple pharmacological actions of ginseng.

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Retracted: Paeoniflorin promotes angiogenesis and tissue regeneration in a full‐thickness cutaneous wound model through the PI3K/AKT pathway

Dong

Xiang

et al. 2020

Journal Cellular Physiology

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The treatment of wounds remains a clinical challenge because of poor angiogenesis under the wound bed, and increasingly, the patients' need for functional and aesthetically pleasing scars. For the wound healing process, new blood vessels which can deliver nutrients and oxygen to the wound area are necessary. In this study, we investigated the pro‐angiogenesis ability and mechanism in wound healing of paeoniflorin (PF), which is a traditional Chinese medicine. In our in vitro results, the ability for proliferation, migration and in vitro angiogenesis in human umbilical vein endothelial cells was promoted by coculturing with PF (1.25–5 μM). Meanwhile, molecular docking studies revealed that PF has excellent binding abilities to phosphatidylinositol‐3‐kinase (PI3K) and protein kinase B (AKT), and consistent with our western blot results, that PF suppressed PI3K and AKT phosphorylation. Furthermore, to investigate the healing effect of PF in vivo, we constructed a full‐thickness cutaneous wound model in rats. PF stimulated the cellular proliferation status, collagen matrix deposition and remodeling processes in vitro and new blood vessel formation at the wound bed resulting in efficient wound healing after intragastric administration of 10 mg·kg−1·day−1 in vivo. Overall, PF performed the pro‐angiogenetic effect in vitro and accelerating wound healing in vivo. In summary, the capacity for angiogenesis in endothelial cells could be enhanced by PF treatment via the PI3K/AKT pathway in vitro and could accelerate the wound healing process in vivo through collagen deposition and angiogenesis in regenerated tissue. This study provides evidence that application of PF represents a novel therapeutic approach for the treatment of cutaneous wounds.

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Effects of gintonin on the proliferation, migration, and tube formation of human umbilical-vein endothelial cells: involvement of lysophosphatidic-acid receptors and vascular-endothelial-growth-factor signaling

Cited by 35 publications

References 42 publications

Ameliorating effects of Cuscuta chinensis Lamak extract on hind‑limb ischemia, and angiogenic‑ or inflammatory associated factors in ovariectomized mice

Ameliorating effects of Cuscuta chinensis Lamak extract on hind‑limb ischemia, and angiogenic‑ or inflammatory associated factors in ovariectomized mice

Ginseng Gintonin Contains Ligands for GPR40 and GPR55

Retracted: Paeoniflorin promotes angiogenesis and tissue regeneration in a full‐thickness cutaneous wound model through the PI3K/AKT pathway

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