Notoginsenoside R1: A systematic review of its pharmacological properties.

Notoginsenoside R1 is one of major bioactive compounds extracted from Panax notoginseng (Burk.) dry roots and rhizomes of F.H. Chen, which has been increasingly used for enhancing cognition and physical health worldwide. The objective of this study was to review the pharmacological effects of notoginsenoside R1 in a systematic manner. We performed searches on databases including MEDLINE (Pubmed), Google Scholar and Web of Science, the System for Information on to select the original research publications reporting the biological and pharmacological effects of notoginsenoside R1 from in vitro and in vivo studies regardless of publication language and study design. Notoginsenoside R1 exhibited potent characteristics of neuroprotective, anti-inflammatory, anti-apoptosis and anti-ischemia-reperfusion injury properties etc. The cytotoxic effects of notoginsenoside R1 were dependent on different types of cell lines. Other pharmacological effects including accumulation of lipopolysac chaired-induced microcirculation, endothelial injury, hypoxia-reoxygenation injury effects have been mentioned, but the results were considerably diverged. A higher quality of evidence on clinical trial studies is highly recommended to confirm the efficacy of notoginsenoside R1.

Sleep deprivation (SD) may cause serious neural injury in the central nervous system, leading to impairment of learning and memory. Melatonin receptor 1A (MTNR1A) plays an important role in the sleep regulation upon activation by melatonin. The present study aimed to investigate if notoginsenoside R1 (NGR1), an active compound isolated from Panax notoginseng, could alleviate neural injury, thus improve impaired learning and memory of SD mice, as well as to explore its underlying action mechanism through modulating MTNR1A. Our results showed that NGR1 administration improved the impaired learning and memory of SD mice. NGR1 prevented the morphological damage and the accumulation of autophagosomes in the hippocampus of SD mice. At the molecular level, NGR1 reversed the expressions of proteins involved in autophagy and apoptosis, such as beclin-1, LC3B, p62, Bcl-2, Bax, and cleaved-caspase 3. Furthermore, the effect of NGR1 was found to be closely related with the MTNR1A-mediated PI3K/Akt/mTOR signaling pathway. On HT-22 cells induced by autophagy inducer rapamycin, NGR1 markedly attenuated excessive autophagy and apoptosis, and the alleviative effect was abolished by the MTNR1A inhibitor. Taken together, NGR1 was shown to alleviate the impaired learning and memory of SD mice, and its function might be exerted through reduction of excessive autophagy and apoptosis of hippocampal neurons by regulating the MTNR1A-mediated PI3K/Akt/mTOR signaling pathway.

Atopic dermatitis (AD) is a highly pruritic chronic inflammatory skin disease. Notoginsenoside R1 (NGR1), a unique ingredient of P. notoginseng which is a well-known medicinal herb for its long history of use in traditional Chinese medicine, has been identified to have various biologically active properties that include anti-inflammatory effects. However, the effects of NGR1 on AD remain unclear. Therefore, this study aimed to investigate the effect and mechanism of NGR1 on the in vitro cell model of AD induced by LPS stimulation. RAW264.7 cells were stimulated with 1 μg/ml LPS to establish the in vitro cell inflammation model of AD. RAW264.7 cells were treated with various concentrations of NGR1 (0.1, 1, and 10 μM); then, an MTT assay was performed to determine the cell viability. An ELISA assay detected the levels of pro-inflammatory cytokines (interleukin-1β, IL-1β; interleukin-6, IL-6; tumor necrosis factor-α, TNF-α). Additionally, NO production was measured using a nitrate/nitrite assay kit. Results indicated that LPS induced increases in the levels of TNFα, IL-1β, IL-6, and NO production was significantly reduced by NGR1 treatment in a dose-dependent manner. Further, NGR1 treatment inhibited the activation of the NF-κB pathway, and the NLRP3 inflammasome in LPS stimulated RAW264.7 macrophages. The study data indicated that NGR1 might relieve atopic dermatitis via inhibiting inflammation through suppressing the NF-κB signaling pathway and NLRP3 inflammasome activation.

Context: Notoginsenoside R1 (NGR1) is the main component with cardiovascular activity in Panax notoginseng (Burk.) F. H. Chen, an herbal medicine that is widely used to enhance blood circulation and dissipate blood stasis.Objective: The objective of this study is to investigate NGR1's effects on CYP1A2, CYP2C11, CYP2D1, and CYP3A1/2 activities in rats in vivo through the use of the Cytochrome P450 (CYP450) probe drugs.Materials and methods: After pretreatment with NGR1 or physiological saline, the rats were administered intraperitoneally with a mixture solution of cocktail probe drugs containing caffeine (10 mg/kg), tolbutamide (15 mg/kg), metoprolol (20 mg/kg), and dapsone (10 mg/kg). The bloods were then collected at a set of time-points for the ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) analysis.Results: NGR1 was shown to exhibit an inhibitory effect on CYP1A2 by increased caffeine Cmax (43.13%, p < 0.01) and AUC0 − ∞ (40.57%, p < 0.01), and decreased CL/F (62.16%, p < 0.01) in the NGR1-treated group compared with those of the control group, but no significant changes in pharmacokinetic parameters of tolbutamide, metoprolol, and dapsone were observed between the two groups, indicating that NGR1 had no effects on rat CYP2C11, CYP2D1, and CYP3A1/2.Discussion and conclusion: When NGR1 is co-administered with drugs that are metabolized by CYP1A2, the pertinent potential herb–drug interactions should be monitored.

Prolonged exposure to high-intensity light can harm macula vision, particularly affecting the function of Müller cells and cone photoreceptors. Panax notoginseng saponins (PNS) have valuable pharmacological effects on cerebrovascular, neurological, and microcirculatory health. Notoginsenoside R1 (NGR1), derived from PNS, shows potential for treating vascular or ischemia-reperfusion-related retinal issues; however, its impact on cone cells and the functional vision profile is not well understood. This study aimed to explore the effect and efficacy of NGR1 on retinal photodamage in vivo in mice. In a mouse model, high-intensity light causes significant photoreceptor damage, increases the production of pro-inflammatory factors, promotes Müller cell gliosis, and remarkably reduces the content of M- and S-opsin in cones, resulting in the abnormal and dysfunctional mislocalization of cone-opsin protein trafficking. Our data demonstrated that NGR1 orally administered improved ERG amplitude, visual acuity, and visual contrast sensitivity function compared to the vehicle group. It also preserved S- and M-cone density, mitigated abnormal trafficking of cone opsin protein, inhibited Müller cell gliosis, and reduced retinal inflammation. Therefore, NGR1 may serve as a valuable traditional complementary therapeutic or nutraceutical component for enhancing functional vision and supporting the health of Müller and cone cells in the macula.

Comparison of Notoginsenoside R1 and TPO on Thrombopoiesis in Irradiated Mice.

Alzheimer's disease (AD) is the most common type of age‑related dementia, and causes progressive memory degradation, neuronal loss and brain atrophy. The pathological hallmarks of AD consist of amyloid‑β (Aβ) plaque accumulation and abnormal neurofibrillary tangles. Amyloid fibrils are constructed from Aβ peptides, which are recognized to assemble into toxic oligomers and exert cytotoxicity. The fibrillar Aβ‑protein fragment 25‑35 (Aβ25‑35) induces local inflammation, thereby exacerbating neuronal apoptosis. Notoginsenoside R1 (NGR1), one of the primary bioactive ingredients isolated from Panaxnotoginseng, exhibits effective anti‑inflammatory and anti‑oxidative activities. However, NGR1 pharmacotherapies targeting Aβ‑induced inflammation and cell injury cascade remain to be elucidated. The present study investigated the effect and mechanism of NGR1 in Aβ25‑35‑treated PC12 cells. NGR1 doses between 250 and 1,000µg/ml significantly increased cell viability suppressed by 20µM Aβ25‑35 peptide treatment. Notably, the present study demonstrated that Aβ25‑35 peptide‑induced sphingosine kinase 1 (SphK1) signaling activation was reduced after NGR1 treatment, further inhibiting the downstream NF‑κB inflammatory signaling pathway. In addition, administration of SphK1 inhibitor II (SKI‑II), a SphK1 inhibitor, also significantly reduced Aβ25‑35 peptide‑induced apoptosis and the ratio of NF‑κB p‑p65/p65. Furthermore, SphK1 knockdown in PC12 cells using small interfering RNA alleviated Aβ‑induced cell apoptosis and inflammation, suggesting a pivotal role of SphK1 signaling in the anti‑inflammatory effect of NGR1. In summary, NGR1 alleviated inflammation and apoptosis stimulated by Aβ25‑35 by inhibiting the SphK1/NF‑κB signaling pathway and may be a promising agent for future AD treatment.

In this study we investigated a possible counteracting activity notoginsenoside R1 (NG-R1) on lipopolysaccharide (LPS)-induced effects in vitro and in vivo. The upregulation of plasminogen activator inhibitor-1 (PAI-1) antigen due to LPS (1 microgram/mL for 12 hours) in human umbilical vein endothelial cells (HUVECs) was prevented when the cells were incubated simultaneously with 100 micrograms/mL NG-R1 (PAI-1 antigen: LPS-treated cells, 969 +/- 54 ng/10(5) cells; control cells, 370 +/- 15 ng/10(5) cells; LPS + NG-R1-treated cells, 469 +/- 29 ng/10(5) cells; n = 6). The 2.5- and 3.4-fold (2.2- and 3.2-kb) increases in PAI-1 mRNA levels induced by LPS (1 microgram/mL for 6 hours) were reduced to 1.4- and 2.6-fold increases in the presence of both LPS and 100 micrograms/mL NG-R1. LPS-induced tissue factor (TF) activity in HUVECs was also counteracted when the cells were coincubated with both LPS and 100 micrograms/mL NG-R1 for 6 hours (TF activity: LPS-treated cells, 88.6 +/- 6.5 mU/10(6) cells; control cells, 0.7 +/- 0.01 mU/10(6) cells; LPS + NG-R1-treated cells, 56.0 +/- 1.9 mU/10(6) cells). The 26-fold increase in TF mRNA levels induced by LPS (1 microgram/mL for 2 hours) was reduced to a 13-fold increase in the presence of both LPS and 100 micrograms/mL NG-R1. PAI activity levels in the plasma of mice 4 hours after injection of LPS (10 ng/g body wt) increased 2.3-fold compared with a control group. In contrast, PAI activity from LPS + NG-R1 (1 microgram/g body wt NG-R1)-treated animals was at control level (PAI-1 activity: LPS-treated group, 11.3 +/- 3.1 U/mL; control group, 4.9 +/- 0.3 U/mL; LPS + NG-R1-treated group, 4.3 +/- 1.0 U/mL; n = 5 to 8). The production of TNF-alpha induced by 1 microgram/mL LPS by cultured human whole-blood cells was inhibited by 46% when the cells were incubated together with 100 micrograms/mL NG-R1. NG-R1 protected mice from the lethal effects of LPS. The 78% lethality induced by LPS/galactosamine was reduced to 23% when NG-R1 was administered simultaneously (P < .01 by chi 2 test). To extend this study to inflammatory cells, the effect of NG-R1 on LPS stimulation of the monocytic cell line THP-1 was investigated. NG-R1 inhibited the LPS-induced degradation of I kappa B-alpha and superinduced LPS-induced I kappa B-alpha mRNA, indicating that the effect of NG-R1 is not restricted to endothelial cells and is at least in part mediated by interference with the NF-kappa B/I kappa B-alpha pathway.

For ages, botanical medicine has been used in the treatment of diabetes mellitus (DM). Notoginsenoside R1 (NGR1), a Panax notoginseng (Burkill) F.H.Chen metabolite, has been documented to possess antidiabetic action in vivo. However, its precise molecular mechanism of action is not clear. We evaluated NGR1's effects on blood glucose in vivo and then evaluated in vitro whether NGR1 has effects on insulin secretion and the probable molecular pathways involved in NGR1-induced insulin secretion. Diabetes was induced in mice by streptozotocin. Glucose tolerance test was performed before and after NGR1 was administered intraperitoneally to diabetic animals for 4 weeks. Static and perifusion experiments were performed using isolated female BALB/c mouse islets. Preproinsulin (Ins) mRNA expression was measured using q-PCR. Protein expression of PI3K/Akt pathway was assessed using the fully automated Wes™ capillary-based protein electrophoresis. Treatment of diabetic mice with NGR1 improved their glucose intolerance. In vitro, NGR1 increased insulin secretion in a concentration-dependent manner. NGR1 initiated the secretion of insulin at 2mM glucose and augmented glucose-stimulated insulin secretion which was sustained throughout NGR1 perifusion. NGR1-induced insulin secretion was not altered by a voltage gated calcium channel blocker or protein kinase A inhibitor. NGR1 did not significantly modulate Ins mRNA expression. However, NGR1 significantly increased the levels of phospho-Akt and phopho-p-85. In conclusion, this study has shown that NGR1 ameliorates hyperglycemia in diabetic mice. NGR1 has a direct insulin secretagogue activity on mouse islets, stimulates insulin secretion at both basal and postprandial glucose concentrations, and activates PI3K/Akt pathway to induce insulin secretion. These results suggest that NGR1 may provide an alternative therapy to manage DM.

Among other Chinese herb drugs, Panax notoginseng is used to treat cardiovascular diseases. To elucidate any possible effects of this drug on the hemostatic system in vitro, we analyzed the influence of one of its major active constituents on fibrinolytic parameters of cultured human umbilical vein endothelial cells (HUVECs). When confluent cultures of HUVECs (passages 2 to 3) were conditioned with purified notoginsenoside R1 (NR1), a dose- (0.01 to 100 micrograms NR1/mL) and time-dependent increase in tissue-type plasminogen activator (TPA) synthesis was observed, which was significant from 0.1 microgram NR1/mL and from 6 hours of incubation with 100 micrograms NR1/mL on. TPA antigen increased from 3.9 +/- 0.2 ng per 10(5) cells per 24 hours to 8.0 +/- 0.5 ng per 10(5) cells per 24 hours on addition of 100 micrograms NR1/mL. In contrast, no change in urokinase-type plasminogen activator and plasminogen activator inhibitor-1 (PAI-1) antigen synthesis was seen. There was also no effect of NR1 on PAI-1 deposition in the extracellular matrix. As judged from fibrin autography and reverse fibrin autography, TPA activity and TPA-PAI-1 complexes reached a maximal stimulation of more than threefold and twofold, respectively, at a concentration of 100 micrograms NR1/mL in conditioned media. On the contrary, NR1 induced a more than fivefold decrease in PAI-1 activity at the same concentration of NR1 in conditioned media. On Northern blot analysis of RNA obtained from NR1-stimulated and control HUVECs, NR1 induced a significant increase in TPA mRNA (192% of control value at 100 micrograms NR1/mL) while PAI-1 mRNA remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Panax notoginseng (PN) root is a renowned nutritional supplement, health food additive, and traditional medicine that maintains homeostasis within the human microcirculatory system. Notoginsenoside R1 (NG-R1), an active compound derived from PN root, has been reported to possess various pharmacological activities, including anti-inflammatory, antioxidant, anticancer, antimicrobial, and angiogenic effects. However, NG-R1's pharmacokinetic properties and pharmacological activities have not been systematically elucidated. In this paper, the pharmacokinetic properties of NG-R1, its pharmacological effects, mechanisms of actions, and structure-activity relationship have been reviewed. Notably, NG-R1 inhibits tumor necrosis factor α (TNF-α) expression, enhances the expression of nuclear factor erythroid 2-related factor 2 (NRF2), and enhances the expression of vascular endothelial growth factor receptor (VEGFR). The pharmacological effects of NG-R1 are associated with the modulation of several signaling pathways, such as mitogen-activated protein kinase (MAPK)/nuclear factor κ-B (NF-κB), NRF2/antioxidant response element (ARE), Wnt/β-catenin, and phosphoinositide-3 kinase (PI3K)/protein kinase B (AKT). NG-R1 offers potentially protective effects against numerous diseases, including cardiovascular, neurological, renal, pulmonary, bone, and diabetes-related conditions. Although the pharmacological activities and diverse effects of NG-R1 have been demonstrated in various diseases, its clinical applications are limited by poor bioavailability. Several strategies have been explored to improve the pharmacokinetic profile of NG-R1, making it a promising candidate for drug development.

Ginsenoside Rh1 is one of major bioactive compounds extracted from red ginseng, which has been increasingly used for enhancing cognition and physical health worldwide. The objective of this study was to review the pharmacological effects of ginsenoside Rh1 in a systematic manner. We performed searches on eight electronic databases including MEDLINE (Pubmed), Scopus, Google Scholar, POPLINE, Global Health Library, Virtual Health Library, the System for Information on Grey Literature in Europe, and the New York Academy of Medicine Grey Literature Report to select the original research publications reporting the biological and pharmacological effects of ginsenoside Rh1 from in vitro and in vivo studies regardless of publication language and study design. Upon applying the inclusion and exclusion criteria, we included a total of 57 studies for our systemic review. Ginsenoside Rh1 exhibited the potent characteristics of anti-inflammatory, antioxidant, immunomodulatory effects, and positive effects on the nervous system. The cytotoxic effects of ginsenoside Rh1 were dependent on different types of cell lines. Other pharmacological effects including estrogenic, enzymatic, anti-microorganism activities, and cardiovascular effects have been mentioned, but the results were considerably diverged. A higher quality of evidence on clinical trial studies is highly recommended to confirm the consistent efficacy of ginsenoside Rh1.

Growing evidence have probed a stimulatory influence of Notoginsenoside R1 (NGR1) with osteoblastic probability. miR-23a plays a crucial role in osteoblast differentiation. Whereas whether there exists a miRs-related mechanism by which NGR1 promotes preosteoblast differentiation remains unexplored. We pre-treated MC3T3-E1 with NGR1 to anatomize Runx-2 and Osx expression as well as ALP activity. Phosphorylation of regulators was evaluated by Western blot. SB203580 and Ruxolitinib were used to reduce the phosphorylation of regulators. The effects of NGR1 on miR-23a were verified by qRT-PCR. We analyzed the expression of Runx-2 and Osx, ALP activity as well as phosphorylation of regulators in MC3T3-E1 stimulated with NGR1 and transfected with miR-23a inhibitor. We found that NGR1 enhanced Runx-2 and Osx expression as well as ALP activity in a concentration-dependent manner. NGR1 might exhibit an efficacious promotion on Runx-2, Osx and ALP activity by increased phosphorylation of MAPK, JAK1, and STAT3. NGR1 resulted in miR-23a overexpression which positively modulated Runx-2 and Osx expression as well as ALP activity. Our results showed that miR-23a inhibitor reduced the phosphorylation of MAPK, JAK1 and STAT3 in MC3T3-E1 pre-treated with NGR1. In conclusion, NGR1 exhibited an efficacious promotion on preosteoblast differentiation by up-regulating miR-23a through MAPK and JAK1/STAT3 pathways. Highlights: NGR1 induces MC3T3-E1 differentiation; miR-23a is positively regulated by NGR1; NGR1 regulates MAPK/JAK1/STAT3 through miR-23a.

Estrogen receptors (ERs) are important for preventing endotoxin-induced myocardial dysfunction. Therefore, plant-derived phytoestrogens, which target ERs may also affect endotoxin-induced toxicity in cardiomyocytes. Our previous study revealed that notoginsenoside-R1 (NG-R1), a predominant phytoestrogen from Panax notoginseng, protects against cardiac dysfunction. However, the effects of NG-R1 on cardiomyocytes and the precise cellular/molecular mechanisms underlying its action remain to be elucidated. In the present study, pretreatment with NG-R1 suppressed the lipopolysaccharide (LPS)-induced degradation of inhibitor of nuclear factor-κB (NF-κB) α, the activation of NF-κB and caspase-3, and the subsequent myocardial inflammatory and apoptotic responses in H9c2 cardiomyocytes. An increase in the mRNA and protein expression of ERα was also observed in the NG-R1-treated cardiomyocytes. However, the expression pattern of ERβ remained unaltered. Furthermore, the cardioprotective properties of NG-R1 against LPS-induced apoptosis and the inflammatory response in cardiomyocytes were attenuated by ICI 182780, a non-selective ERα antagonist, and methyl-piperidino-pyrazole, a selective ERα antagonist. These findings suggested that NG-R1 reduced endotoxin-induced cardiomyocyte apoptosis and the inflammatory response via the activation of ERα. Therefore, NG-R1 exerted direct anti-inflammatory and anti-apoptotic effects on the cardiomyocytes, representing a potent agent for the treatment of myocardial inflammation during septic shock.

The effects of notoginsenoside R1 on the intestinal absorption of geniposide by the everted rat gut sac model