Apelin-APJ effects of ginsenoside-Rb1 depending on hypoxia-induced factor 1α in hypoxia neonatal cardiomyocytes

Apelin/APJ signaling in hypoxia-related diseases

“…Consistent with the previous studies, hypoxia is able to promote BMSCs proliferation through apelin/APJ/autophagy signaling pathway [37] .. Consistently, the apelin/APJ system is a mediator of the anti-apoptosis effect of ginsenoside-Rb1 in hypoxic neonatal A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 6 cardiomyocytes (Table 1) [21] .…”

“…In the myocardium and cardiomyocytes, the level of apelin is markedly augmented by exposure to hypoxia or treatment with desferrioxamine (DFO, prolyl hydroxylase inhibitor).However, the overexpression of apelin by hypoxia is restrained to the IPAS (a HIF inhibitor) [19][20][21][22] . Some studies also have suggested that the expression of apelin is enhanced in endothelial cells and endothelial progenitor cells (EPCs) as well as vascular smooth muscle cells (VSMCs) during a hypoxic phase in vitro, whereas the knockdown of HIF-1α…”

“…In addition, apelin protects against ischemic brain injury by activating the PI3K/AKT-dependent manner. Eyries et.al [15] Casals et.al [19] Ronkainen et.al [20] Kong et.al [21] Cox et.al [22] Sheikh et.al [23] Zhang et.al [24] Glassford et.al [25] Geiger et.al [26] Kunduzova et.al [27] Sorli et.al [28 ] Heo et.al [29] Masri et.al [30] Han et.al [31] Wang et.al [32] Lu et.al [33] Andersen et.al [34] Melgar et.al [35] Kerkela et.al [36] Li et.al [37] Poirier et.al [38] Yang et.al [39] Loewen et.al [40] MEECs, Kasai et.al [41] Zhang et.al [52] Zeng et.al [59] Zhang et.al [74] Michailido u et.al [86] cardiomyocytes ROP patients…”

Cellular stress response mechanisms as therapeutic targets of ginsenosides

“…Ginsenosides exhibit different activities on HIF‐1α and its downstream genes under distinct pathological conditions. For example, HIF‐1α levels were upregulated by Rg1 in neonatal rat brains following hypoxia/ischemia injury and rat heart tissue, as well as by Rb1 in hypoxia neonatal cardiomyocytes . However, HIF‐1α expression is downregulated by Rg3 in several cancer cell lines, including human ovarian cancer cells (e.g., SKOV3 and 3AO, bone marrow stromal cells isolated from acute leukemia patients, and human esophageal carcinoma cells [i.e., EC109, TE1, and KYSE170]) and two tumor mice models, including Lewis lung cancer cell xenografted mice and SKOV3 cells xenografted into nude mice .…”

“…HIF‐1α is regulated by ginsenosides through several mechanisms (Fig. ), including (1) the upregulation of HIF‐1α by Rb1 was completely abolished by 3‐(5′‐hydroxymethyl‐2′‐furyl)‐1‐benzylindazole (YC‐1), which was shown to block the de novo synthesis of HIF‐1α through the inactivation of PI3K/Akt/mTOR pathway, accelerate the degradation of HIF‐1α, or block murine double minute 2 (Mdm2); (2) the Rg3‐mediated downregulation of HIF‐1α was reversed by inhibiting the phosphorylation of Akt and ERK1/2; and (3) HIF‐1α degradation was enhanced by Rg3 by activating the ubiquitin–proteasome pathway in a proline hydroxylase 1 (PHD1)‐von Hippel‐Lindau protein (VHL) dependent manner …”