Ruscogenin

J Pharmacol Sci. 2008 Oct;108(2):198-205.

Possible mechanism of the anti-inflammatory activity of ruscogenin: role of intercellular adhesion molecule-1 and nuclear factor-kappaB.[Pubmed: 18946195]

Ruscogenin (RUS), first isolated from Ruscus aculeatus, also a major steroidal sapogenin of traditional Chinese herb Radix Ophiopogon japonicus, has been found to exert significant anti-inflammatory and anti-thrombotic activities.
METHODS AND RESULTS:
Our previous studies suggested that Ruscogenin remarkably inhibited adhesion of leukocytes to a human umbilical vein endothelial cell line (ECV304) injured by tumor necrosis factor-alpha (TNF-alpha) in a concentration-dependent manner. Yet the underlying mechanisms remain unclear. In this study, the in vivo effects of Ruscogenin on leukocyte migration and celiac prostaglandin E(2) (PGE(2)) level induced by zymosan A were studied in mice. Furthermore, the effects of Ruscogenin on TNF-alpha-induced intercellular adhesion molecule-1 (ICAM-1) expression and nuclear factor-kappaB (NF-kappaB) activation were also investigated under consideration of their key roles in leukocyte recruitment. The results showed that Ruscogenin significantly suppressed zymosan A-evoked peritoneal total leukocyte migration in mice in a dose-dependent manner, while it had no obvious effect on PGE(2) content in peritoneal exudant. Ruscogenin also inhibited TNF-alpha-induced over expression of ICAM-1 both at the mRNA and protein levels and suppressed NF-kappaB activation considerably by decreasing NF-kappaB p65 translocation and DNA binding activity.
CONCLUSIONS:
These findings provide some new insights that may explain the possible molecular mechanism of Ruscogenin and Radix Ophiopogon japonicus for the inhibition of endothelial responses to cytokines during inflammatory and vascular disorders.

Biomed Res Int. 2014;2014:652680.

Ruscogenin ameliorates experimental nonalcoholic steatohepatitis via suppressing lipogenesis and inflammatory pathway.[Pubmed: 25136608]

The aim of the study was to investigate the protective effects of Ruscogenin, a major steroid sapogenin in Ophiopogon japonicus, on experimental models of nonalcoholic steatohepatitis.
METHODS AND RESULTS:
HepG2 cells were exposed to 300 μmol/l palmitic acid (PA) for 24 h with the preincubation of Ruscogenin for another 24 h. Ruscogenin (10.0 μmol/l) had inhibitory effects on PA-induced triglyceride accumulation and inflammatory markers in HepG2 cells. Male golden hamsters were randomly divided into five groups fed a normal diet, a high-fat diet (HFD), or a HFD supplemented with Ruscogenin (0.3, 1.0, or 3.0 mg/kg/day) by gavage once daily for 8 weeks. Ruscogenin alleviated dyslipidemia, liver steatosis, and necroinflammation and reversed plasma markers of metabolic syndrome in HFD-fed hamsters. Hepatic mRNA levels involved in fatty acid oxidation were increased in Ruscogenin-treated HFD-fed hamsters. Conversely, Ruscogenin decreased expression of genes involved in hepatic lipogenesis. Gene expression of inflammatory cytokines, chemoattractive mediator, nuclear transcription factor-(NF-) κB, and α-smooth muscle actin were increased in the HFD group, which were attenuated by Ruscogenin.
CONCLUSIONS:
Ruscogenin may attenuate HFD-induced steatohepatitis through downregulation of NF-κB-mediated inflammatory responses, reducing hepatic lipogenic gene expression, and upregulating proteins in β-oxidation pathway.

Int J Mol Sci . 2016 Aug 29;17(9):1418.

Ruscogenin Attenuates Cerebral Ischemia-Induced Blood-Brain Barrier Dysfunction by Suppressing TXNIP/NLRP3 Inflammasome Activation and the MAPK Pathway[Pubmed: 27589720]

Abstract Ruscogenin, an important steroid sapogenin derived from Ophiopogon japonicus, has been shown to inhibit cerebral ischemic injury. However, its potential molecular action on blood-brain barrier (BBB) dysfunction after stroke remains unclear. This study aimed to investigate the effects of Ruscogenin on BBB dysfunction and the underlying mechanisms in middle cerebral artery occlusion/reperfusion (MCAO/R)-injured mice and oxygen-glucose deprivation/reoxygenation (OGD/R)-injured mouse brain microvascular endothelial cells (bEnd.3). The results demonstrated that administration of Ruscogenin (10 mg/kg) decreased the brain infarction and edema, improved neurological deficits, increased cerebral brain flow (CBF), ameliorated histopathological damage, reduced evans blue (EB) leakage and upregulated the expression of tight junctions (TJs) in MCAO/R-injured mice. Meanwhile, Ruscogenin (0.1-10 μM) treatment increased cell viability and trans-endothelial electrical resistance (TEER) value, decreased sodium fluorescein leakage, and modulated the TJs expression in OGD/R-induced bEnd.3 cells. Moreover, Ruscogenin also inhibited the expression of interleukin-1β (IL-1β) and caspase-1, and markedly suppressed the expression of Nucleotide-binding domain (NOD)-like receptor family, pyrin domain containing 3 (NLRP3) and thiredoxin-interactive protein (TXNIP) in vivo and in vitro. Furthermore, Ruscogenin decreased reactive oxygen species (ROS) generation and inhibited the mitogen-activated protein kinase (MAPK) pathway in OGD/R-induced bEnd.3 cells. Our findings provide some new insights into its potential application for the prevention and treatment of ischemic stroke. Keywords: MAPK; blood-brain barrier; inflammasome; ischemic stroke; Ruscogenin.

Eur J Pharmacol. 2013 Aug 15;714(1-3):303-11.

Ruscogenin reduces cerebral ischemic injury via NF-κB-mediated inflammatory pathway in the mouse model of experimental stroke.[Pubmed: 23911884]

Transient cerebral ischemia initiates a complex series of inflammatory events, which has been associated with an increase in behavioral deficits and secondary brain damage. Ruscogenin is a major steroid sapogenin in the traditional Chinese herb Ophiopogon japonicus that have multiple bioactivities. Recent studies have demonstrated that Ruscogenin is involved in down-regulation of intercellular adhesion molecule-1 (ICAM-1) and nuclear factor-κB (NF-κB) activation in anti-inflammatory pathways.
METHODS AND RESULTS:
We hypothesized that Ruscogenin protects against brain ischemia by inhibiting NF-κB-mediated inflammatory pathway. To test this hypothesis, adult male mice (C57BL/6 strain) were pretreated with Ruscogenin and then subjected to transient middle cerebral artery occlusion (MCAO)/reperfusion. After 1 h MCAO and 24 h reperfusion, neurological deficit, infarct sizes, and brain water content were measured. Ruscogenin markedly decreased the infarct size, improved neurological deficits and reduced brain water content after MCAO. The activation of NF-κB Signaling pathway was observed after 1h of ischemia and 1h of reperfusion, and Ruscogenin significantly inhibited NF-κB p65 expression, phosphorylation and translocation from cytosol to nucleus at this time point in a dose-dependent manner. NF-κB DNA binding activity, and the expression of NF-κB target genes, including ICAM-1, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), were also suppressed by Ruscogenin pretreatment after 1 h MCAO and 24 h reperfusion.
CONCLUSIONS:
The results indicated that Ruscogenin protected the brain against ischemic damage caused by MCAO, and this effect may be through downregulation of NF-κB-mediated inflammatory responses.

J. Steroid Biochem., 2015, 154:85-93.

Ruscogenin suppresses mouse neutrophil activation: Involvement of protein kinase A pathway.[Reference: WebLink]

Ruscogenin, a natural steroidal sapogenin, presents in both food and medicinal plants. It has been found to exert significant anti-inflammatory activities.
METHODS AND RESULTS:
Considering that activation of neutrophil is a key feature of inflammatory diseases, this study was performed to investigate the inhibitory effect of Ruscogenin and its underlying mechanisms responsible for neutrophil activation. Moreover, Ruscogenin inhibited phosphorylation of protein kinase B (Akt), p38 mitogen-activated protein kinase (p38MAPK), extracellular signal-regulated kinase 1 and 2 (ERK1/2), and c-Jun N-terminal kinase (JNK). In addition, the inhibitory effects of Ruscogenin on superoxide production and the phosphorylation of Akt, p38MAPK, and ERK1/2 were reversed by PKA inhibitor (H89), suggesting a PKA-dependent mechanism.
CONCLUSIONS:
In summary, our data suggest that Ruscogenin inhibits activation of neutrophil through cPLA2, PAK, Akt, MAPKs, cAMP, and PKA signaling pathways. Increased PKA activity is associated with suppression of the phosphorylation of Akt, p38MAPK, and ERK1/2 pathways.

Int Immunopharmacol. 2012 Jan;12(1):88-93.

Ruscogenin inhibits lipopolysaccharide-induced acute lung injury in mice: involvement of tissue factor, inducible NO synthase and nuclear factor (NF)-κB.[Pubmed: 22079591 ]

Acute lung injury is still a significant clinical problem with a high mortality rate and there are few effective therapies in clinic.
METHODS AND RESULTS:
Here, we studied the inhibitory effect of Ruscogenin, an anti-inflammatory and anti-thrombotic natural product, on lipopolysaccharide (LPS)-induced acute lung injury in mice basing on our previous studies. The results showed that a single oral administration of Ruscogenin significantly decreased lung wet to dry weight (W/D) ratio at doses of 0.3, 1.0 and 3.0 mg/kg 1 h prior to LPS challenge (30 mg/kg, intravenous injection). Histopathological changes such as pulmonary edema, coagulation and infiltration of inflammatory cells were also attenuated by Ruscogenin. In addition, Ruscogenin markedly decreased LPS-induced myeloperoxidase (MPO) activity and nitrate/nitrite content, and also downregulated expression of tissue factor (TF), inducible NO synthase (iNOS) and nuclear factor (NF)-κB p-p65 (Ser 536) in the lung tissue at three doses. Furthermore, Ruscogenin reduced plasma TF procoagulant activity and nitrate/nitrite content in LPS-induced ALI mice.
CONCLUSIONS:
These findings confirmed that Ruscogenin significantly attenuate LPS-induced acute lung injury via inhibiting expressions of TF and iNOS and NF-κB p65 activation, indicating it as a potential therapeutic agent for ALI or sepsis.