Panax Notoginseng Saponins: A Review of Its Mechanisms of Antidepressant or Anxiolytic Effects and Network Analysis on Phytochemistry and Pharmacology.

Uncovering the effect and mechanism of Panax notoginseng saponins on metabolic syndrome by network pharmacology strategy

Recent research has indicated that Panax notoginseng saponins (PNS) extracted from the radix of Panax notoginseng (Burkill) F. H. Chen exert antidepressant effects. This study aimed to assess the antidepressive effects of ginsenoside Rg1 and PNS in a depression model induced by chronic unpredictable mild stress (CUMS). Over a period of three weeks, rats were administered ginsenoside Rg1 at a dose of 30 mg/kg and PNS at dosages ranging from 100 to 200 mg/kg body weight per day. To assess how ginsenoside Rg1 and PNS influence depression-like behaviours in rats, various assessments were conducted, including coat state evaluation, forced swim test, and elevated plus maze test. The levels of cortisol and testosterone in serum samples were analysed using the liquid chromatography-electrospray ionisation tandem mass spectrometry (LC-ESI-MS/MS) method. LC-ESI-MS/MS method provides precise and accurate results. The lower limit of quantification values for cortisol and testosterone were determined as 100 and 2 pg/mL, respectively. Our data demonstrated that both ginsenoside Rg1 and PNS significantly reversed depression-like behaviour in rats by improving coat condition, reducing immobility time in the forced swim test, and increasing time spent in the open arms of the elevated plus maze test. Furthermore, ginsenoside Rg1 and PNS exhibited a regulatory effect on cortisol and testosterone levels in plasma. These findings suggest that ginsenoside Rg1 and PNS may be potential antidepressants in clinical treatment.

Based on metabolomics,the metabolites of larvae zebrafish with overdose of Panax notoginseng saponins( PNS) were compared with those in normal group of larvae zebrafish to investigate the possible toxicity mechanism of overdose PNS in larvae zebrafish. An experimental animal model of long-term toxicity induced by PNS overdose was established by administering 1-6 dpf at low,medium and high doses of PNS,respectively. The ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry( UPLC-Q-TOF-MS) technique was combined with principal component analysis( PCA) and orthogonal partial least squares discriminant analysis( OPLS-DA) to screen and identify biomarkers associated with toxicity,and then the MetaboAnalyst database was used to analyze metabolism-related pathways. The results showed that the metabolites of each group could be distinguished distinctly,and they deviated more from the normal group in a time and dose dependent manner. Twenty-nine potential biomarkers related to toxicity( VIP>1,P<0. 05) were identified preliminarily,mainly involving six metabolic pathways. From the metabonomics point of view,the toxicity mechanism of overdose PNS may be related to the disorders of lipid metabolism,amino acid metabolism and energy metabolism.

To investigate the effects and possible mechanism of Panax Notoginseng saponins (PNS) on oxidative stress-induced damage and apoptosis in bone marrow stromal cells (BMSCs). BMSCs were isolated and cultured from 2-month-old New Zealand rabbits by the density gradient centrifugation combined with adherent method. The third passage cells were used for subsequent experiments. Oxidative stress was induced in cultured BMSCs by H(2)O(2) (0.1 mmol/L). BMSCs were pretreated with 25-200 μg/mL PNS for 4 h before H(2)O(2) treatment. Proliferation of BMSCs was observed using MTT assay. Alkaline phosphatase (ALP) activity, as an index of early osteoblastic differentiation, was determined with an ALP assay kit. Flow cytometry was used to observe the apoptosis of BMSCs by staining with annexinV-FITC/propidium iodide. Oxidative stress level was examined by reactive oxygen species (ROS) assay. The protein expressions of Bax, Bcl-2 and Caspase-3 in BMSCs were analyzed by Western blotting. PNS had different concentration-dependent effects on proliferation and osteoblast differentiation of BMSCs induced by H(2)O(2). A PNS concentration of 100 μg/mL was determined as the optimal effective concentration. PNS markedly attenuated H(2)O(2)-induced apoptosis rate from 41.91% to 14.67% (P<0.01). PNS significantly decreased ROS level induced by H(2)O(2) (P<0.01). Furthermore, pretreatment with PNS significantly reversed H(2)O(2)-induced inhibition of Bcl-2 expression and augmentation of Bax and Caspase-3 expression (P<0.01). PNS had a protective effect on oxidative stress-induced damage and apoptosis in cultured rabbit BMSCs through scavenging ROS and regulating the Bcl-2/Bax pathway.

To investigate the mechanism of Panax notoginseng saponins (PNS), an effective component extracted from Panax notoginseng, on atherosclerotic plaque angiogenesis in atherosclerosis-prone apolipoprotein E-knockout (ApoE-KO) mice fed with high-fat, high-cholesterol diet. Twenty ApoE-KO mice were divided into two groups, the model group and the PNS group. Ten normal C57BL/6J mice were used as a control group. PNS (60 mg/kg) was orally administered daily for 12 weeks in the PNS group. The ratio of plaque area to vessel area was examined by histological staining. The tissue sample of aortic root was used to detect the CD34 and vascular endothelial growth factor (VEGF) expression areas by immunohistochemistry. The expression of VEGF and nicotinamide adenine dinucleotide phosphate oxidase subunit 4 (NOX4) were measured by reverse transcription polymerase chain reaction and Western blotting respectively. After treatment with PNS, the plaque areas were decreased (P<0.05). CD34 expressing areas and VEGF expression areas in plaques were significantly decreased (P<0.05). Meanwhile, VEGF and NOX4 mRNA expression were decreased after treatment with PNS. VEGF and NOX4 protein expression were also decreased by about 72% and 63%, respectively (P<0.01). PNS, which decreases VEGF and NOX4 expression, could alleviate plaque angiogenesis and attenuate atherosclerosis.

Evaluating the protective mechanism of panax notoginseng saponins against oxidative stress damage by quantifying the biomechanical properties of single cell

Inhibiting adhesion events by Panax notoginseng saponins and Ginsenoside Rb1 protecting arteries via activation of Nrf2 and suppression of p38 – VCAM-1 signal pathway

Objective To investigate the effect of combined treatment with panax notoginseng saponins (PNS) and aminoguanidine (AG) on oxidative stress in kidney of diabetic rats as well as possible mechanism. Methods The rat diabetic model was induced by intraperitoneal injection of STZ in the left lower abdomen of the rats. A total of 48 model rats were randomly divided into diabetic group (n=12), PNS treatment group (n=12), AG treatment group (n=12), and PNS+ AG treatment group (n=12). Another 12 rats were used as normal controls. Serum and renal cortex superoxide dismutase (SOD) and malondialdehyde (MDA) were measured by colorimetric assay. Advanced glycation end products (AGEs) were determined by spectrum law of fluorescence in the 4 and 8 weeks. The mean glomerular area (MGA) and mean glomerular volume (MGV) were measured by image analysis system. The changes of the blood glucose levels, urine amount, urine albumen, the renal function, body weight (BW), kidney weight (KW) and KW to BW ratio were observed. Results In comparison with the diabetic group, AGEs(F=36.017, P<0.01; F=8.213, P<0.01) and MDA(F=8.683, P<0.01; F=14.615, P<0.01) in serum and renal cortex, creatinine clearance rate (F=7.233, P<0.01), MGA(F=24.317, P<0.01), MGV(F=26.145, P<0.01), urinary excretion of protein(F=17.108, P<0.05), KW(F=5.182, P<0.05) and KW to BW ratio(F=50.169, P<0.01) were decreased significantly in the PNS+ AG treatment group , and SOD(F=6.260, P<0.01; F=7.666, P<0.01)in serum and renal cortex and BW were increased significantly (F=10.449, P<0.05). Decreased serum MDA was observed in PNS+ AG treatment group compared with AG treatment group(F=8.683, P<0.05), although renal cortex MDA was significantly lower than that of PNS treatment group and AG treatment group(F=14.615, P<0.05). Serum AGEs was decreased significantly in PNS+ AG treatment group compared with AG or PNS treatment group (F=36.017, P<0.01 or ﹤0.05), and renal cortex AGEs was significantly lower than that of AG or PNS treatment group(F=8.213, P<0.05). At 8 weeks, lower MGA(F=24.317, P<0.05)and MGV(F=26.145, P<0.05)were found in the PNS+ AG treatment group. Conclusion Combined treatment with PNS and AG may possess renoprotective effect on STZ-induced diabetic rats, and the possible mechanism could be associated with reduced oxidative stress and inhibited overproduction of AGEs in renal tissue. Key words: Diabetic nephropathy; Panax notoginseng saponins; Aminoguanidine; Oxidative stress; Nonenzymatic glycosylation

Panax notoginseng saponins (PNS), the principal constituents derived from Panax notoginseng, have been extensively used for treating cardiocerebral vascular diseases in China and other Asian countries. The main effects of PNS were anti-inflammatory properties, inhibition of platelet aggregation, improvement of blood flow and insulin resistance, and so on. This study was carried out to explore the effects of PNS on macrophage polarization under hyperglycemic conditions. Human acute monocyte leukemia cell line THP-1 cells were induced into macrophages with Phorbol ester (PMA). Macrophages were then divided into five groups as follows: control (5.5mMol/l glucose), hyperglycemia group (15mMol/l glucose), hyperglycemia plus low-dose PNS (20ug/ml), hyperglycemia plus moderate-dose PNS (40ug/ml), and hyperglycemia plus high-dose PNS (60ug/ml). After 48-hour cell culture, the percentages of M1- and M2-polarized macrophages were measured by flow cytometry analysis. Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) was used to evaluate the Ym1 and arginase 1 expression in macrophages. Protein expression of arginase 1, NF-κB p50, p65, and inhibitor of κB (IκB) alpha phosphorylation in macrophages was identified with Western blotting. PNS, especially the high-dose PNS, remarkably increased M2 phenotype ratio in macrophages cultured with hyperglycemia, and the mRNA expression of Ym1 and arginase 1 in macrophages was also upregulated. Meanwhile, PNS remarkably increased the protein expression of arginase 1 and decreased IκB-alpha phosphorylation and subunits of NF-κB p50 and p65 from macrophages in culture medium with hyperglycemia. Taken together, our work demonstrated that PNS promote macrophages to transform M2 phenotype under hyperglycemic conditions through downregulating NF-κB signaling pathway.

Mechanism of Panax notoginseng saponins modulation of miR-214-3p/NR1I3 affecting the pharmacodynamics and pharmacokinetics of warfarin

Objective To investigate the effects on extravascular lung water (EVLW) and mechanism by Panax notoginseng saponins (PNS) in intestinal ischeamia reperfusion (Ⅱ/R) induced acute lung injury (ALI) rat model.Methods Forty-eight Wistar rats were randomly assigned into four groups:(①sham-operated group,laparotomy without Ⅱ/R ( n =12);②sham+PNS group,identical to group one except for PNS treatment ( n =12) ;③Ⅱ/R group,one hour of intestinal ischemia followed by three hours of reperfusion ( n =12) ; ④Ⅱ/R + PNS group,injection of 100 mg/kg PNS,intravenously,15 minutes before reperfusion ( n =12).The effects of PNS administration on lung tissue histology,index of EVLW (EVLWI),expression of αENaC mRNA and protein,PaO2/FiO2 and PaCO2 were examined.Results Compared with Ⅱ/R group,pulmonary parenchymal damages and EVLWI were significantly reduced in Ⅱ/R + PNS group.The expressions of αENaC mRNA and protein in lung tissue were increased by PNS treatment.In addition,PaO2/FiO2 was improved remarkably in the Ⅱ/R+ PNS group compared with the Ⅱ/R group.Conclusions Administration of PNS berore reperfusion injury decreases EVLW of rat with ALI induced by Ⅱ/R,and this is partly attributable to prevention the decreases of expression of αENaC mRNA and protein. Key words: Panax notoginseng saponins; Acute lung injury; Extravascular lung water; Epithelialsodium channel

To explore protective mechanism of Panax notoginseng saponins (PNS) on rat hemorrhagic shock model in recovery stage. 72 Wistar rats were selected and divided into control group, model group and PNS group with 24 rats in each group. 200 mg/kg PNS was injected intravenously at 60 min of hemorrhagic shock stage in PNS groups. Changes of endotoxin, MPO, IL-6, SOD, MDA and TNF α were observed at 30 and 120 min of recovery stage by ELISA; water content of lung and intestine was detected; HE staining was applied to observe morphological change of intestinal mucosa, kidney, liver and lung; western blot was used to detect intercellular adhesion molecule-1 (ICAM-1) level in lung tissue and intestine tissue. At 30 min and 120 min of recovery stage, MDA, MPO, endotoxin, TNF α and IL-6 levels significantly increased in model group compared with control group, however SOD level significantly decreased, the difference was statistically significant (P < 0.05); PNS dose-dependently decreased MDA, MPO, endotoxin, TNF α and IL-6 levels, and increased SOD level, which was statistically significant (P < 0.05); In results of water content detection, water content in lung tissue and intestine tissue was significantly higher than in control group, however, after being treated with PNS, the water content was significantly decreased; HE staining showed the morphologic change of lung tissue cells; Western blot showed that in lung tissue and intestine tissue, ICAM-1 level in model group was significantly higher than in control group, and it was lower in PNS group than in model group. PNS can increase SOD activity, decrease levels of MDA, endotoxin and MPO, decrease expression of TNF α and IL-6, and decrease water content in lung tissue and intestine tissue. Thus, PNS is protective to rat hemorrhagic shock model by anti oxidative stress and anti-inflammatory pathways, and ICAM-1 may play an important role in the mechanism.

RETRACTED: Borneol enhances the protective effect against cerebral ischemia/ reperfusion injury by promoting the access of astragaloside IV and the components of Panax notoginseng saponins into the brain

To investigate the mechanisms of Panax notoginseng saponins (PNS) in treating coronary heart disease (CHD) by integrating gene interaction network and functional enrichment analysis. Text mining was used to get CHD and PNS associated genes. Gene-gene interaction networks of CHD and PNS were built by the GeneMANIA Cytoscape plugin. Advanced Network Merge Cytoscape plugin was used to analyze the two networks. Their functions were analyzed by gene functional enrichment analysis via DAVID Bioinformatics. Joint subnetwork of CHD network and PNS network was identifified by network analysis. The 11 genes of the joint subnetwork were the direct targets of PNS in CHD network and enriched in cytokine-cytokine receptor interaction pathway. PNS could affect other 85 genes by the gene-gene interaction of joint subnetwork and these genes were enriched in other 7 pathways. The direct mechanisms of PNS in treating CHD by targeting cytokines to relieve the inflflammation and the indirect mechanisms of PNS in treating CHD by affecting other 7 pathways through the interaction of joint subnetwork of PNS and CHD network. The genes in the 7 pathways could be potential targets for the immunologic adjuvant, anticoagulant, hypolipidemic, anti-platelet and anti-hypertrophic activities of PNS. The key mechanisms of PNS in treating CHD could be anticoagulant and hypolipidemic which are indicated by analyzing biological functions of hubs in the merged network.

Renal fibrosis is related to impaired kidney function and can eventually lead to end-stage renal disease, for which no effective treatment is available. Panax notoginseng saponins (PNS), as a commonly used traditional Chinese medicine, is considered a possible alternative for the treatment of fibrosis. The purpose of the present study was to investigate the effects and possible mechanisms of PNS on renal fibrosis. HK-2 cells were used to induce renal fibrosis cell model by lipopolysaccharide (LPS), and the cytotoxicity of PNS on HK-2 cells was investigated. Cell damage, pyroptosis, and fibrosis were analyzed to investigate the effects of PNS on LPS-induced HK-2 cells. NLRP3 agonist Nigericin was used further to explore the inhibitory effect of PNS on LPS-induced pyroptosis so as to clarify the possible mechanism of PNS on renal fibrosis. PNS had no cytotoxicity on HK-2 cells, and could reduce the apoptosis and the release of lactate dehydrogenase (LDH) and inflammatory cytokines of LPS-induced HK-2 cells, showing an alleviating effect on cell damage. PNS also reduced the expression of pyroptosis proteins NLRP3, IL-1β, IL-18, and Caspase-1, as well as fibrosis proteins α-SMA, collagen Ⅰ and p-Smad3/Smad3, which showed an inhibitory effect on LPS-induced pyroptosis and fibrosis. In addition, LPS-induced cell damage, pyroptosis, and fibrosis were aggravated after Nigericin treatment, while PNS alleviated the aggravation caused by Nigericin. PNS inhibits pyroptosis by inhibiting the activation of NLRP3 inflammasome in LPS-induced HK-2 cells, which ultimately alleviates renal fibrosis and plays a good role in the treatment of kidney diseases.