Gypenoside XLIX

Gypenoside XLIX is a multifunctional bioactive compound that can be isolated from Gynostemma pentaphyllum, with a K_a value of 1.58 μM for its binding to SIRT1. Gypenoside XLIX acts as a PPAR-α agonist. It inhibits the activation of TLR4-mediated NF-κB signaling pathway by activating the Sirt1/Nrf2 signaling pathway, reduces ROS accumulation, and alleviates hepatic inflammatory injury in mice with sepsis-induced liver disease. Gypenoside XLIX targets SIRT1 to block YAP-NLRP3 activation and improve sepsis-induced cardiomyopathy. Gypenoside XLIX inhibits apoptosis (Apoptosis), pyroptosis (Pyroptosis), autophagy (Autophagy), lipid peroxidation, pro-inflammatory cytokines and anti-inflammatory cytokines. Gypenoside XLIX alleviates sepsis-induced splenic injury by inhibiting inflammation and oxidative stress, and mitigates sepsis-associated encephalopathy by targeting PPAR-α. Gypenoside XLIX prevents acute kidney injury by inhibiting IGFBP7/IGF1R-mediated programmed cell death and inflammation. Gypenoside XLIX inhibits the expression and activity of vascular cell adhesion molecule-1 in cytokine-induced human endothelial cells. Gypenoside XLIX is applicable to research related to acute liver injury, lung injury, cardiomyopathy, acute splenic injury, sepsis-associated encephalopathy, acute kidney injury, atherosclerosis and chronic inflammation^{[1][2][3][4][5][6][7]}. In Vitro:Gypenoside XLIX (0-80 μM) reduces the viability of RAW264.7 cells at concentrations of 10, 20, 40, and 80 μM, while exerts no significant effect at 5 μM^[1].
Gypenoside XLIX (40 μM) inhibits the LPS (HY-D1056)-activated NF-κB signaling pathway in RAW264.7 cells by reducing the levels of P-IκBα and P-P65 and restoring the level of IκBα, and activates PPAR-α in LPS-stimulated RAW264.7 cells by upregulating the protein level of PPAR-α^[1].
Gypenoside XLIX (40 μM; 1 h pre-incubation) activates the antioxidant Nrf2 pathway in LPS-stimulated RAW264.7 cells by upregulating the protein levels of Nrf2, HO-1 and NQO1, thereby alleviating oxidative stress^[1].
Gypenoside XLIX (40 μM; 1 h pre-incubation) inhibits the NLRP3 inflammasome pathway and alleviates pyroptosis in LPS-stimulated RAW264.7 cells by reducing the protein levels of NLRP3, ASC, Caspase1 P20, GSDMD and IL-1β^[1].
Gypenoside XLIX (32 μM; 12 h) activates the Sirt1/Nrf2 signaling pathway, reduces ROS production, and inhibits NLRP3 inflammasome activation in LPS/ATP (HY-B2176)-stimulated MLE-12 cells^[2].
Gypenoside XLIX (3.125-100 μM) binds directly to recombinant SIRT1 protein with high affinity, with a K_d value of 1.58 μM measured by SPR, and stabilizes SIRT1 protein in H9C2 rat cardiomyocytes against heat-induced degradation^[3].
Gypenoside XLIX (40 μM; 24 h) alleviates LPS-induced inflammation and oxidative stress in H9C2 rat cardiomyocytes in a SIRT1-dependent manner, reduces the expression of proinflammatory cytokines, the levels of oxidative stress markers and the activation of NLRP3 inflammasome, and promotes the phosphorylation, deacetylation and proteasomal degradation of YAP in cells^[3].
Gypenoside XLIX (40 μM) promotes post-transcriptional proteasomal degradation of NLRP3 in YAP-overexpressing H9C2 rat cardiomyocytes by enhancing K27-linked ubiquitination, and reverses YAP-induced upregulation of NLRP3^[3].
Gypenoside XLIX (20-40 μM) reduces the viability of mouse microglial BV-2 cells^[5].
Gypenoside XLIX (10 μM; 12 h) reduces the production of NO and ROS in LPS-stimulated mouse microglial BV-2 cells, upregulates the expression of PPAR-α in cells, and inhibits the activation of p38 and JNK MAPK pathways, and this effect is partially dependent on the activation of PPAR-α^[5].
Gypenoside XLIX (10 μM; 12 h) reduces the expression of inflammatory proteins iNOS, COX-2 and TLR4 in LPS-stimulated mouse microglial BV-2 cells, and activates the Nrf2/Keap1 oxidative stress response pathway in cells, an effect that depends on the activation of PPAR-α^[5].
Gypenoside XLIX (10 μM; 12 h) reduces the apoptosis level of LPS-stimulated mouse microglial BV-2 cells by regulating the expression of apoptotic proteins, and this effect depends on the activation of PPAR-α^[5].
Gypenoside XLIX (0-256 μM; 24 h) restores the viability of HK2 cells treated with Cisplatin (HY-17394)^[6].
Gypenoside XLIX (0-128 μM; 24 h) reduces the increases in KIM-1 protein and KIM-1 mRNA levels induced by Cisplatin or hypoxia/reoxygenation (H/R) in HK2 cells, decreases proinflammatory cytokine production and NF-κB activation, and inhibits necroptosis and apoptosis^[6].
Gypenoside XLIX (64 μM; overnight pre-incubation) activates the IGF pathway in Cisplatin-treated HK2 cells by reducing the expression of IGFBP7 and its binding to IGF1R^[6].
Gypenoside XLIX (10-300 μM; 0.5-24 h) inhibits TNF-α-induced VCAM-1 promoter activity (IC₅₀ = 186.8 μM), mRNA expression, total protein expression, and surface VCAM-1 expression in human umbilical vein endothelial cells (HUVECs) via a PPAR-α-dependent pathway^[7]. In Vivo:Gypenoside XLIX (40 mg/kg; i.p.; single dose/daily; 4 days) significantly alleviates cecal ligation and puncture (CLP)-induced acute liver injury in mice by activating the Sirt1/Nrf2 signaling pathway to inhibit the NF-κB/PPAR-α/NLRP3 pathway, thereby improving liver dysfunction, attenuating inflammatory responses, oxidative stress, lipid accumulation, pyroptosis, mitochondrial pathway apoptosis, and excessive mitophagy^[1][2].
Gypenoside XLIX (10-40 mg/kg; i.p.; daily; 5 days) dose-dependently alleviates sepsis-induced cardiomyopathy, with the 40 mg/kg dose exerting the most significant therapeutic effects, including an 80% survival rate, reduced levels of inflammation and oxidative stress, restored cardiac function, and inhibition of the YAP-NLRP3 pathway via activation of SIRT1^[3].
Gypenoside XLIX (20 mg/kg; i.p.; daily; 4 days) significantly alleviates CLP-induced acute splenic inflammation and oxidative stress in male BALB/c mice with sepsis by reducing ROS and MDA levels, enhancing antioxidant enzyme activity, and regulating the expression of pro-inflammatory and anti-inflammatory mediators^[4].
Gypenoside XLIX (40 mg/kg; i.p.; daily; 5 days) alleviates sepsis-associated encephalopathy in CLP-induced C57BL/6 mice via activating PPAR-α, increases the survival rate to 73.33%, and simultaneously attenuates neuroinflammation, oxidative stress, cell apoptosis and blood-brain barrier damage, as well as restores cognitive function^[5].
Gypenoside XLIX (25-100 mg/kg; i.p.; daily; 3 days) significantly protects male C57BL/6 mice against cisplatin- and renal ischemia-reperfusion-induced acute kidney injury (AKI) by inhibiting renal inflammation, necroptosis, apoptosis, and dysregulation of the IGFBP7/IGF1R pathway, while it also markedly reduces serum creatinine, blood urea nitrogen (BUN), renal tubular injury scores, and the levels of pro-inflammatory and cell death markers^[6].