Search

Background: Although stem cell transplantation is a promising approach for the treatment of myocardial infarction (MI), there are still some problems faced such as the low survival rate of stem cells. Here, we investigated the role of Notoginsenoside R1 (NGR1) pretreatment in improving the effects of neonatal rat bone marrow mesenchymal stem cell (MSC) transplantation for treatment of MI. Methods: Cardiac functions were detected by echocardiography and the myocardial infarct size was determined by Masson's trichrome staining in a rat model of MI. The cardioprotective effects of NGR1/LY294002 co-pretreated MSCs was evaluated to explore the underlying mechanism. The angiogenesis was determined by vWF and α-SMA immunofluorescence staining and cell apoptosis was detected by TUNEL. In vitro, the effects of NGR1 on stem cell proliferation was examined by CCK-8 and levels of P-Akt, P-CREB, P-FoxO1 were detected by western blot. Apoptosis, ROS content, and cytokine levels were examined by DAPI and TUNEL staining, a ROS assay kit, and ELISA, respectively. Results: NGR1 elevated the therapeutic effect of MSC transplantation on infarction by preserving cardiac function, increasing angiogenesis and expressions of IGF-1, VEGF, and SDF-1, and reducing cell apoptosis, whereas the addition of LY294002 prior to NGR1 treatment significantly counteracted the foregoing effects of NGR1. NGR1 pretreatment and SC79 pretreatment were similar in that both significantly increased P-Akt and P-FoxO1 levels in MSC and did not affect P-CREB levels. Besides, both NGR1 and SC79 promoted VEGF, SCF and bFGF levels in MSC cultures, and significantly reduced ROS accumulation and the attenuated cell apoptosis in MSC triggered by H2O2. Similarly, addition of LY294002 before NGR1 treatment significantly counteracted the aforementioned effects of NGR1 in vitro. Conclusions: NGR1 pretreatment enhances the effect of MSC transplantation for treatment of MI through paracrine signaling, and the mechanism underlying this effect may be associated with PI3K/Akt/FoxO1 signaling pathways. [ABSTRACT FROM AUTHOR]

Abstract Background Although stem cell transplantation is a promising approach for the treatment of myocardial infarction (MI), there are still some problems faced such as the low survival rate of stem cells. Here, we investigated the role of Notoginsenoside R1 (NGR1) pretreatment in improving the effects of neonatal rat bone marrow mesenchymal stem cell (MSC) transplantation for treatment of MI. Methods Cardiac functions were detected by echocardiography and the myocardial infarct size was determined by Masson’s trichrome staining in a rat model of MI. The cardioprotective effects of NGR1/LY294002 co-pretreated MSCs was evaluated to explore the underlying mechanism. The angiogenesis was determined by vWF and α-SMA immunofluorescence staining and cell apoptosis was detected by TUNEL. In vitro, the effects of NGR1 on stem cell proliferation was examined by CCK-8 and levels of P-Akt, P-CREB, P-FoxO1 were detected by western blot. Apoptosis, ROS content, and cytokine levels were examined by DAPI and TUNEL staining, a ROS assay kit, and ELISA, respectively. Results NGR1 elevated the therapeutic effect of MSC transplantation on infarction by preserving cardiac function, increasing angiogenesis and expressions of IGF-1, VEGF, and SDF-1, and reducing cell apoptosis, whereas the addition of LY294002 prior to NGR1 treatment significantly counteracted the foregoing effects of NGR1. NGR1 pretreatment and SC79 pretreatment were similar in that both significantly increased P-Akt and P-FoxO1 levels in MSC and did not affect P-CREB levels. Besides, both NGR1 and SC79 promoted VEGF, SCF and bFGF levels in MSC cultures, and significantly reduced ROS accumulation and the attenuated cell apoptosis in MSC triggered by H2O2. Similarly, addition of LY294002 before NGR1 treatment significantly counteracted the aforementioned effects of NGR1 in vitro. Conclusions NGR1 pretreatment enhances the effect of MSC transplantation for treatment of MI through paracrine signaling, and the mechanism underlying this effect may be associated with PI3K/Akt/FoxO1 signaling pathways.

Atherosclerosis represents the major cause of mortality worldwide and triggers higher risk of acute cardiovascular events. Pericytes‐endothelial cells (ECs) communication is orchestrated by ligand‐receptor interaction generating a microenvironment which results in intraplaque neovascularization, that is closely associated with atherosclerotic plaque instability. Notoginsenoside R1 (R1) exhibits anti‐atherosclerotic bioactivity, but its effect on angiogenesis in atherosclerotic plaque remains elusive. The aim of our study is to explore the therapeutic effect of R1 on vulnerable plaque and investigate its potential mechanism against intraplaque neovascularization. The impacts of R1 on plaque stability and intraplaque neovascularization were assessed in ApoE−/− mice induced by high‐fat diet. Pericytes‐ECs direct or non‐direct contact co‐cultured with VEGF‐A stimulation were used as the in vitro angiogenesis models. Overexpressing Ang1 in pericytes was performed to investigate the underlying mechanism. In vivo experiments, R1 treatment reversed atherosclerotic plaque vulnerability and decreased the presence of neovessels in ApoE−/− mice. Additionally, R1 reduced the expression of Ang1 in pericytes. In vitro experiments demonstrated that R1 suppressed pro‐angiogenic behavior of ECs induced by pericytes cultured with VEGF‐A. Mechanistic studies revealed that the anti‐angiogenic effect of R1 was dependent on the inhibition of Ang1 and Tie2 expression, as the effects were partially reversed after Ang1 overexpressing in pericytes. Our study demonstrated that R1 treatment inhibited intraplaque neovascularization by governing pericyte‐EC association via suppressing Ang1‐Tie2/PI3K‐AKT paracrine signaling pathway. R1 represents a novel therapeutic strategy for atherosclerotic vulnerable plaques in clinical application. [ABSTRACT FROM AUTHOR]

This study examines the impact of Notoginsenoside R1 (NGR1), a compound from Panax notoginseng, on the maturation of porcine oocytes and their embryonic development, focusing on its effects on antioxidant levels and mitochondrial function. This study demonstrates that supplementing in vitro maturation (IVM) medium with NGR1 significantly enhances several biochemical parameters. These include elevated levels of glutathione (GSH), nuclear factor erythrocyte 2‐related factor 2 (NRF2) and mRNA expression of catalase (CAT) and GPX. Concurrently, we observed a decrease in reactive oxygen species (ROS) levels and an increase in JC‐1 immunofluorescence, mitochondrial distribution, peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC1α) and nuclear NRF2 mRNA levels. Additionally, there was an increase in ATP production and lipid droplets (LDs) immunofluorescence. These biochemical improvements correlate with enhanced embryonic outcomes, including a higher blastocyst rate, increased total cell count, enhanced proliferative capacity and elevated octamer‐binding transcription factor 4 (Oct4) and superoxide dismutase 2 (Sod2) gene expression. Furthermore, NGR1 supplementation resulted in decreased apoptosis, reduced caspase 3 (Cas3) and BCL2‐Associated X (Bax) mRNA levels and decreased glucose‐regulated protein 78 kD (GRP78) immunofluorescence in porcine oocytes undergoing in vitro maturation. These findings suggest that NGR1 plays a crucial role in promoting porcine oocyte maturation and subsequent embryonic development by providing antioxidant levels and mitochondrial protection. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a cardiovascular disease, accounting for the most common mortality cause worldwide. Notoginsenoside R1 (NGR1) is a characteristic saponin of Radix notoginseng that exhibits anti-inflammatory and antioxidant effects while modulating lipid metabolism. Evidence suggests that NGR1 exerts cardioprotective, neuroprotective, and anti-atherosclerosis effects. However, underlying NGR1 mechanisms alleviating atherosclerosis (AS) have not been examined. This study used a network pharmacology approach to construct the drug-target-disease correlation and protein–protein interaction (PPI) network of NGR1 and AS. Moreover, functional annotation and pathway enrichment analyses deciphered the critical biological processes and signaling pathways potentially regulated by NGR1. The protective effect of NGR1 against AS and the underlying mechanism(s) was assessed in an atherogenic apolipoprotein E-deficient (ApoE−/−) mice in vivo and an oxidized low-density lipoprotein (ox-LDL)-induced macrophage model in vitro. The network pharmacology and molecular docking analyses revealed that NGR1 protects against AS by targeting the NLRP3/caspase-1/IL-1β pathway. NGR1 reduced foam cell formation in ox-LDL-induced macrophages and decreased atherosclerotic lesion formation, serum lipid metabolism, and inflammatory cytokines in AS mice in vivo. Therefore, NGR1 downregulates the NLRP3 inflammasome complex gene expression of NLRP3, caspase-1, ASC, IL-1β, and IL-18, in vivo and in vitro. [ABSTRACT FROM AUTHOR]

High-altitude pulmonary edema (HAPE) is a potentially fatal condition that occurs when exposed to high-altitude hypoxia environments. Currently, there is no effective treatment for HAPE, and available interventions focus on providing relief. Notoginsenoside R1 (NGR1), a major active constituent of Panax notoginseng (Burkill) F.H.Chen (sānqī), has demonstrated heart and lung-protective effects under hypobaric hypoxia. However, there is a lack of clarity regarding the precise mechanisms that underlie the protective effects of NGR1 against inflammation. In this study, a rat model of HAPE was developed to assess the effect of NGR1 on this pathology. High-altitude hypoxia corresponding to 6000 m altitude was simulated with a hypobaric chamber. We found that NGR1 dose-dependently alleviated pulmonary oxidative stress damage and inflammatory response, and prevented acid-base balance disruption. In addition, NGR1 restored the expression levels of hypoxia-inducible factor-1 alpha, vascular endothelial growth factor, and aquaporin protein-5, correlated with the development of pulmonary edema induced by hypobaric hypoxia. Furthermore, NGR1 pre-treatment remarkably mitigated NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-induced pyroptosis, and this effect was partially counteracted by the use of an NLRP3 agonist. Thus, NGR1 may exert a lung-protective effect against HAPE by ameliorating hypoxia-induced lung edema, oxidative damage, and inflammation through inhibition of the NLRP3/Caspase-1/ GSDMD signaling pathway.

Liying Ma,1,2 Yansong Gao,1 Ge Yang,1 Lei Zhao,2 Zijian Zhao,1 Yujuan Zhao,1 Yuhang Zhang,2 Shenhui Li,2 Shengyu Li1 1Institute of Agricultural Products Processing Technology, Jilin Academy of Agricultural Sciences (Northeast Agricultural Research Center of China), Changchun, 130033, People’s Republic of China; 2School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun, 130117, People’s Republic of ChinaCorrespondence: Shengyu Li, Institute of Agro-Food Technology, Jilin Academy of Agricultural Sciences (Northeast Agricultural Research Center of China), No. 1363 Sheng-Tai Street, Changchun, Jilin Province, 130033, People’s Republic of China, Tel +86 431 87063289, Fax +86 431 87063075, Email lisy720@126.comAim: The inflammatory response plays a pivotal role in the occurrence, progression, and plaque formation of atherosclerosis. The study was performed to investigate the impacts of notoginsenoside R1 on the development of atherosclerosis (AS) and the potential mechanisms.Methods: Rats induced with AS by a high-fat-diet and vitamin D3 were treated with notoginsenoside R1 for six weeks. The ameliorative effect of NR1 on AS rats was assessed by detecting pathological changes in the abdominal aorta, biochemical indices in serum and protein expression in the abdominal aorta, as well as by analysing the gut microbiota.Results: The NR1 group exhibited a noticeable reduction in plaque pathology. Notoginsenoside R1 can significantly improve serum lipid profiles, encompassing TG, TC, LDL, ox-LDL, and HDL. Simultaneously, IL-6, IL-33, TNF-α, and IL-1β levels are decreased by notoginsenoside R1 in lowering inflammatory elements. Notoginsenoside R1 can suppress the secretion of VCAM-1 and ICAM-1, as well as enhance the levels of plasma NO and eNOS. Furthermore, notoginsenoside R1 inhibits the NLRP3/Cleaved Caspase-1/IL-1β inflammatory pathway and reduces the expression of the JNK2/P38 MAPK/VEGF endothelial damage pathway. Fecal analysis showed that notoginsenoside R1 remodeled the gut microbiota of AS rats by decreasing the count of pathogenic bacteria (such as Firmicutes and Proteobacteria) and increasing the quantity of probiotic bacteria (such as Bacteroidetes).Conclusion: Notoginsenoside R1, due to its unique anti-inflammatory properties, may potentially prevent the progression of atherosclerosis. This mechanism helps protect the vascular endothelium from damage, while also regulating the imbalance of intestinal microbiota, thereby maintaining the overall health of the body. Keywords: notoginsenoside R1, inflammation, endothelial damage, gut microbiota

Chronic obstructive pulmonary disease (COPD) is a common disorder that is characterized by systemic and lung inflammation. Notoginsenoside R1 (NGR1) displays anti-inflammatory properties in numerous diseases. We aimed to explore the function and mechanism of NGR1 in COPD. COPD rats were established through cigarette smoke exposure, lipopolysaccharide injection, and cold stimulation. Rat airway smooth muscle cells (ASMCs) were separated and identified. Then, ASMCs were treated with NGR1 (25 or 50 μM) and cigarette smoke extract (CSE). Thereafter, the vitality, proliferation, and migration of ASMCs were measured. Additionally, cell cycle, inflammation-related factors, α-SMA, and PI3K/AKT pathway-related marker expressions of the ASMCs were also detected. Molecular docking experiments were conducted to explore the interaction of NGR1 to PI3K, TGF-β, p65, and AKT. Moreover, 740 Y-P (a PI3K/Akt pathway agonist) were used to validate the mechanism of NGR1 on COPD. NGR1 inhibited the proliferation and migration, but caused cell cycle arrest for CSE-triggered ASMCs. Furthermore, NGR1 not only decreased IL-1β, IL-6, IL-8, and TNF-α contents, but also reduced α-SMA expression in CSE-stimulated ASMCs. Moreover, NGR1restrainedTGF-β1 expression, PI3K, p65, and AKT phosphorylation in CSE-stimulated ASMCs. Molecular docking experiments showed NGR1 exhibited a strong binding ability to PI3K, TGF-β1, p65, and AKT. Notably, the effects of NGR1 on the proliferation and migration of CSE-induced ASMCs were reversed by 740 Y-P. NGR1 can restrain the proliferation and migration of CSE-induced ASMCs, indicating that NGR1 may be a therapeutic candidate for treating COPD. [ABSTRACT FROM AUTHOR]

β2 adrenergic receptor (β2AR) is a G-protein-coupled receptor involved in cardiac protection. In chronic heart failure (CHF), persistent sympathetic nervous system activation occurs, resulting in prolonged β2AR activation and subsequent receptor desensitization and downregulation. Notoginsenoside R1 (NGR1) has the functions of enhancing myocardial energy metabolism and mitigating myocardial fibrosis. The mechanisms of NGR1 against ischemic heart failure are unclear. A left anterior descending (LAD) artery ligation procedure was performed on C57BL/6 J mice for four weeks. From the 4th week onwards, they were treated with various doses (3, 10, 30 mg/kg/day) of NGR1. Subsequently, the impacts of NGR1 on ischemic heart failure were evaluated by assessing cardiac function, morphological changes in cardiac tissue, and the expression of atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC). H9c2 cells were protected by NGR1 when exposed to OGD/R conditions. H9c2 cells were likewise protected from OGD/R damage by NGR1. Furthermore, NGR1 increased β2AR levels and decreased β2AR ubiquitination. Mechanistic studies revealed that NGR1 enhanced MDM2 protein stability and increased the expression of MDM2 and β-arrestin2 while inhibiting their interaction. Additionally, under conditions produced by OGD/R, the protective benefits of NGR1 on H9c2 cells were attenuated upon administration of the MDM2 inhibitor SP141. According to these findings, NGR1 impedes the interplay between β-arrestin2 and MDM2, thereby preventing the ubiquitination and degradation of β2AR to improve CHF.

High-altitude myocardial injury (HAMI) represents a critical form of altitude illness for which effective drug therapies are generally lacking. Notoginsenoside R1, a prominent constituent derived from Panax notoginseng, has demonstrated various cardioprotective properties in models of myocardial ischemia/reperfusion injury, sepsis-induced cardiomyopathy, cardiac fibrosis, and myocardial injury. The potential utility of notoginsenoside R1 in the management of HAMI warrants prompt investigation. Following the successful construction of a HAMI model, a series of experimental analyses were conducted to assess the effects of notoginsenoside R1 at dosages of 50 mg/Kg and 100 mg/Kg. The results indicated that notoginsenoside R1 exhibited protective effects against hypoxic injury by reducing levels of CK, CK-MB, LDH, and BNP, leading to improved cardiac function and decreased incidence of arrhythmias. Furthermore, notoginsenoside R1 was found to enhance Nrf2 nuclear translocation, subsequently regulating the SLC7A11/GPX4/HO-1 pathway and iron metabolism to mitigate ferroptosis, thereby mitigating cardiac inflammation and oxidative stress induced by high-altitude conditions. In addition, the application of ML385 has confirmed the involvement of Nrf2 nuclear translocation in the therapeutic approach to HAMI. Collectively, the advantageous impacts of notoginsenoside R1 on HAMI have been linked to the suppression of ferroptosis via Nrf2 nuclear translocation signaling.

[Objectives] To establish the quality standard of hospital preparation Jiedu Shengxue granules. [Methods] Scleromitrion diffusum and Prunella vulgaris in Jiedu Shengxue granules were qualitatively identified by thin layer chromatography (TLC). A high performance liquid chromatography (HPLC) was established to determine the content of notoginsenoside R1 in the granule. [Results] The traditional Chinese medicinal materials in Jiedu Shengxue granules could be identified by TLC, and the characteristic spots were stable and clear. Notoginsenoside R1 had a good linear relationship in the range of 10.45-104.5 μg/mL, with an average recovery of 98.52% and RSD=2.36%. [Conclusions] TLC and HPLC, as the quality control methods of Jiedu Shengxue granules, have high accuracy and good repeatability, which lays a foundation for the quality control of this mixture. [ABSTRACT FROM AUTHOR]

Human bone marrow mesenchymal stem cells (hBMSCs) are attractive therapeutic agents for bone tissue regeneration owing to their osteogenic differentiation potential. Notoginsenoside R1 (NGR1) is a novel phytoestrogen with diverse pharmacological activities. Here, we probed whether NGR1 has an effect on the osteogenic differentiation of hBMSCs. EdU, CCK‐8 and Transwell assays were used to measure proliferation and migration of hBMSCs after treatment with different doses of NGR1. hBMSCs were treated with osteogenic differentiation induction medium for osteogenesis. Alizarin red S (ARS) and alkaline phosphatase (ALP) staining were used to measure mineralized nodule formation and ALP activity in hBMSCs, respectively. ICI 182780, an antagonist of oestrogen receptor alpha (ERα) was used to inhibit ERα expression. The results showed that NGR1 enhanced hBMSC proliferation and migration. NGR1 increased ALP activity and mineralized nodule formation as well as promoting ALP, RUNX2 and OCN expression in hBMSCs. NGR1 enhanced ERα expression and promoted GSK‐3β/β‐catenin signal transduction in hBMSCs. ICI 182780 reversed NGR1‐mediated activation of the GSK‐3β/β‐catenin signalling and promoted an effect on hBMSC behaviour. Thus NGR1 promotes proliferation, migration and osteogenic differentiation of hBMSCs via the ERα/GSK‐3β/β‐catenin signalling pathway. [ABSTRACT FROM AUTHOR]

Objective To determine the effects of main components (Rg1, Re and R1) of Panax notoginseng saponins on platelet activation and aggregation induced by shear stress. Methods A narrow microfluidic chip model was established, and used to evaluate the effects of Rg1, Re and R1 at different concentrations (0.05, 0.1, 0.25 and 0.5 mg/mL) on shear-induced platelet aggregation under different shear rates (1 500, 4 500 and 9 000 s-1). Flow cytometry was used to quantitatively detect the shear-induced platelet activation (P-selectin and PAC-1) after the treatment of Rg1, Re and R1. PL-12 analyzer was performed to measure the effects of Rg1, Re and R1 on platelet aggregation induced by arachidonic acid (AA) and adenosine diphosphate (ADP). Results Rg1, Re and R1 inhibited platelet aggregation induced by high shear stress in a concentration-dependent manner (P < 0.01), but had no such inhibitory effect under lower shear stress. Among the 3 components, Re had the strongest inhibitory effect, and their IC50 value was 0.1, 0.07, and 0.2 mg/mL, respectively. No synergistic effect was observed when the 3 components were used together at the same dose. Rg1, Re and R1 inhibited the expression of P-selectin and PAC-1 (P < 0.01), which was consistent with the results of the aggregation experiment. In addition, the 3 components also could inhibit platelet aggregation induced by AA and ADP. Conclusion The main components of Panax notoginseng saponins exert their antiplatelet activity by inhibiting shear-induced platelet aggregation.

Abstract Background Diabetic nephropathy (DN) is a chronic condition resulting from microangiopathy in a high-glucose environment. The evaluation of vascular injury in DN has primarily focused on active molecules of VEGF, namely VEGFA and VEGF2(F2R). Notoginsenoside R1 (NGR1), a traditional anti-inflammatory medication, exhibits vascular activity. Therefore, identifying classical drugs with vascular inflammatory protection for the treatment of DN is a valuable pursuit. Methods The “Limma” method was employed to analyze the glomerular transcriptome data, while the Spearman algorithm for Swiss target prediction was utilized to analyze the drug targets of NGR1. The molecular docking technique was employed to investigate the relationship between vascular active drug targets, and the COIP experiment was conducted to verify the interaction between fibroblast growth factor 1 (FGF1) and VEGFA in relation to NGR1 and drug targets. Results According to the Swiss target prediction, the LEU32(b) site of the Vascular Endothelial Growth Factor A (VEGFA) protein, as well as the Lys112(a), SER116(a), and HIS102(b) sites of the Fibroblast Growth Factor 1 (FGF1) protein, are potential binding sites for NGR1 through hydrogen bonding. Additionally, the Co-immunoprecipitation (COIP) results suggest that VEGFA and FGF1 proteins can interact with each other, and NGR1 can impede this interaction. Furthermore, NGR1 can suppress the expression of VEGFA and FGF1 in a high-glucose environment, thereby decelerating podocyte apoptosis. Conclusion The inhibition of the interaction between FGF1 and VEGFA by NGR1 has been observed to decelerate podocyte apoptosis.

Notoginsenoside R1 (NGR1), derived from the Panax notoginseng root and rhizome, exhibits diverse pharmacological influences on the brain, neurons, and osteoblasts, such as antioxidant effects, mitochondrial function protection, energy metabolism regulation, and inhibition of oxygen radicals, apoptosis, and cellular autophagy. However, its effect on early porcine embryonic development remains unclear. Therefore, we investigated NGR1's effects on blastocyst quality, reactive oxygen species (ROS) levels, glutathione (GSH) levels, mitochondrial function, and embryonic development‐related gene expression in porcine embryos by introducing NGR1 during the in vitro culture (IVC) of early porcine embryos. Our results indicate that an addition of 1 μM NGR1 significantly increased glutathione (GSH) levels, blastocyst formation rate, and total cell number and proliferation capacity; decreased ROS levels and apoptosis rates in orphan‐activated porcine embryos; and improved intracellular mitochondrial distribution, enhanced membrane potential, and reduced autophagy. In addition, pluripotency‐related factor levels were elevated (NANOG and octamer‐binding transcription factor 4 [OCT4]), antioxidant‐related genes were upregulated (nuclear factor‐erythroid 2‐related factor 2 [NRF2]), and apoptosis‐ (caspase 3 [CAS3]) and autophagy‐related genes (light chain 3 [LC3B]) were downregulated. These results indicate that NGR1 can enhance early porcine embryonic development by protecting mitochondrial function. [ABSTRACT FROM AUTHOR]

Notoginsenoside R1 is known as the main bioactive compound of the traditional Chinese medicine and functional food, Panax notoginseng. Network pharmacology prediction indicated that notoginsenoside R1 might be effective in the treatment of pulmonary fibrosis. This study investigated the effectiveness and pharmacological mechanism of notoginsenoside R1 on attenuating pulmonary fibrosis in mice. The results showed that notoginsenoside R1 alleviated the inflammatory response in the lung by down-regulating the polarization of M1 macrophages via the SOCS3/STAT3 pathway. Meanwhile, notoginsenoside R1 promoted the transcription of SH2 domain containing inositol 5′-phosphatase (SHIP) by down-regulating methyl-CpG binding domain 2 (MBD2) expression, thus attenuated PI3K/AKT-mediated polarization of M2 macrophages, and finally regulated the TGF-β1/Smad3 signaling pathway in order to attenuate pulmonary fibrosis. This study presented some possible mechanism of notoginsenoside R1 in the treatment of pulmonary fibrosis, suggesting that P. notoginseng may be served as potential medicined diet in preventing and treating such diseases.

Notoginsenoside R1 (R1), which originated from the rhizomes and roots of Panax notoginseng, is classified as a Biopharmaceutical Classification System class III drug with good solubility but poor oral absorption. Although R1 can alleviate the inflammation of dextran sulfate sodium (DSS)-induced colitis in mice, the problem of acid degradation and low bioavailability limit its application. The purpose of this study was aimed to design one kind of pH-dependent solid dispersion for oral colon-targeted delivery of R1. Using Eudragit S100 (ES 100) and PEG 4000 as the pH-dependent carriers, R1 solid dispersion (R1-SD) was fabricated by solvent evaporation method. Scanning electron microscopy, differential scanning calorimetry, and powder X-ray diffraction analysis indicated that R1-SD was completely formed, the surface was smooth surface and the strip crystal structure of R1 disappeared. The in vitro release profile of R1-SD (R1-ES 100-PEG 4000, 1:7:1, weight ratio) exhibited that R1-SD was not released in media simulating the gastric condition (pH 1.2), but better release characteristics of the drug could be obtained in media simulating the intestinal condition (less than 30% in pH 6.8 phosphate-buffered saline and more than 90% in pH 7.6 condition). The in vitro colon absorption test showed that the absorption rate and cumulative release of R1-SD were higher than those of R1. R1-SD and R1 had apparent protective effect on colon shortening, inflammatory infiltrating tissue injury, weight loss, diarrhea, blood stool in mice with ulcerative colitis induced by DSS, and the protective effect of R1-SD was better than that of R1, which indicated R1-SD has good practical application prospects.

Background: Diabetic nephropathy (DN) is a chronic condition resulting from microangiopathy in a high-glucose environment. The evaluation of vascular injury in DN has primarily focused on active molecules of VEGF, namely VEGFA and VEGF2(F2R). Notoginsenoside R1 (NGR1), a traditional anti-inflammatory medication, exhibits vascular activity. Therefore, identifying classical drugs with vascular inflammatory protection for the treatment of DN is a valuable pursuit. Methods: The "Limma" method was employed to analyze the glomerular transcriptome data, while the Spearman algorithm for Swiss target prediction was utilized to analyze the drug targets of NGR1. The molecular docking technique was employed to investigate the relationship between vascular active drug targets, and the COIP experiment was conducted to verify the interaction between fibroblast growth factor 1 (FGF1) and VEGFA in relation to NGR1 and drug targets. Results: According to the Swiss target prediction, the LEU32(b) site of the Vascular Endothelial Growth Factor A (VEGFA) protein, as well as the Lys112(a), SER116(a), and HIS102(b) sites of the Fibroblast Growth Factor 1 (FGF1) protein, are potential binding sites for NGR1 through hydrogen bonding. Additionally, the Co-immunoprecipitation (COIP) results suggest that VEGFA and FGF1 proteins can interact with each other, and NGR1 can impede this interaction. Furthermore, NGR1 can suppress the expression of VEGFA and FGF1 in a high-glucose environment, thereby decelerating podocyte apoptosis. Conclusion: The inhibition of the interaction between FGF1 and VEGFA by NGR1 has been observed to decelerate podocyte apoptosis. [ABSTRACT FROM AUTHOR]

Copyright of China Tropical Medicine is the property of China Tropical Medicine Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Panax notoginseng is an ancient Chinese medicinal plant that has great clinical value in regulating cardiovascular disease in China. As a single component of panax notoginosides, notoginsenoside R1 (NGR1) belongs to the panaxatriol group. Many reports have demonstrated that NGR1 exerts multiple pharmacological effects in ischemic stroke, myocardial infarction, acute renal injury, and intestinal injury. Here, we outline the available reports on the pharmacological effects of NGR1 in ischemia-reperfusion (I/R) injury. We also discuss the chemistry, composition and molecular mechanism underlying the anti-I/R injury effects of NGR1. NGR1 had significant effects on reducing cerebral infarct size and neurological deficits in cerebral I/R injury, ameliorating the impaired mitochondrial morphology in myocardial I/R injury, decreasing kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in renal I/R injury and attenuating jejunal mucosal epithelium injury in intestinal I/R injury. The various organ anti-I/R injury effects of NGR1 are mainly through the suppression of oxidative stress, apoptosis, inflammation, endoplasmic reticulum stress and promotion of angiogenesis and neurogenesis. These findings provide a reference basis for future research of NGR1 on I/R injury.

Ruiqi Han,1 Wenjuan Zhang,2 Lina Zhang,3 Jinghua Zou,1 Yanran Yang,1 Hongkun Li,1 Jun Zhang1 1Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2Department of Orthodontics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China; 3Department of Orthodontics, Faculty of Stomatology, Liaocheng People’s Hospital, Liaocheng, People’s Republic of ChinaCorrespondence: Jun Zhang, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, No. 44-1 Wenhua Road West, Jinan, 250012, Tel +86 13953109816, Email zhangj@sdu.edu.cnPurpose: To investigate the roles of Notoginsenoside R1 (NG-R1) on the proliferation and osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) and explore its possible mechanism.Methods: hPDLSCs were isolated and, then characterized by flow cytometry. Cell-counting kit-8 (CCK-8) and colony assays were used to validate the effect of different NG-R1 concentrations on hPDLSCs proliferation and the optimal concentration was determined. Quantitative detection of alkaline phosphatase (ALP) activity at optimal concentration and the mineralization of the cells was investigated by Alizarin Red S staining. qRT-PCR and Western blot were utilized to examine the factors expression levels of ALP, Runx Family Transcription Factor 2 (RUNX2), Collagen I (Col-1) and catenin beta 1 (CTNNB1; β-catenin). In addition, the tankyrase inhibitor XAV-939 was used to explore NG-R1’s role in canonical Wnt signaling.Results: hPDLSCs were positive for surface antigens CD90 while negative for CD34 and CD45, which indicated that we have successfully isolated the hPDLSCs. Furthermore, a concentration of 20μmol NG-R1 dramatically enhanced hPDLSCs proliferation, ALP activity, and mineral deposition. ALP, RUNX2, COL-1, and β-catenin expression were all rised in comparison to control group. After XAV-939 was added to disrupt the canonical Wnt signaling, the impact of NG-R1 appeared to be reversed.Conclusion: These findings suggest that NG-R1 can stimulate osteogenic differentiation of hPDLSCs, which is probably attributable to canonical Wnt signaling activation.Keywords: notoginsenoside R1, NG-R1, human periodontal ligament stem cells, hPDLSCs, osteogenesis, β-catenin

Sepsis-induced cardiomyopathy (SIC) is an important manifestation of sepsis, and abnormal cardiac function affects the development of sepsis. Notoginsenoside R1 (NG-R1) is a unique bioactive component of Panax notoginseng with antiinflammatory and antioxidant effects. However, the effects and possible mechanisms of NG-R1 on SIC are not clear. The purpose of this study was to identify the potential targets and regulatory mechanisms of the action of NG-R1 on SIC. To investigate the potential mechanism, we used network pharmacology, molecular docking, qRT-PCR, and immunofluorescence. The results showed that NG-R1 ameliorated myocardial fibrosis in septic mice. Validation of network pharmacology and molecular docking results revealed that NG-R1 reduced tumor necrosis factor-Alpha (TNF-a) expression in myocardial tissues and AC16 cardiomyocytes in mice, as well as inflammatory factor release in AC16 cells, so TNF-a may be a potential target of NG-R1 against SIC. The present study demonstrated that NG-R1 could protect against SIC and by regulating the expression of TNF-a inflammatory factors, providing a new idea for sepsis drug development. [ABSTRACT FROM AUTHOR]

Panax notoginseng is an ancient Chinese medicinal plant that has great clinical value in regulating cardiovascular disease in China. As a single component of panax notoginosides, notoginsenoside R1 (NGR1) belongs to the panaxatriol group. Many reports have demonstrated that NGR1 exerts multiple pharmacological effects in ischemic stroke, myocardial infarction, acute renal injury, and intestinal injury. Here, we outline the available reports on the pharmacological effects of NGR1 in ischemia-reperfusion (I/R) injury. We also discuss the chemistry, composition and molecular mechanism underlying the anti-I/R injury effects of NGR1. NGR1 had significant effects on reducing cerebral infarct size and neurological deficits in cerebral I/R injury, ameliorating the impaired mitochondrial morphology in myocardial I/R injury, decreasing kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in renal I/R injury and attenuating jejunal mucosal epithelium injury in intestinal I/R injury. The various organ anti-I/R injury effects of NGR1 are mainly through the suppression of oxidative stress, apoptosis, inflammation, endoplasmic reticulum stress and promotion of angiogenesis and neurogenesis. These findings provide a reference basis for future research of NGR1 on I/R injury. [ABSTRACT FROM AUTHOR]

Introduction and Objective. Notoginsenoside R1 (NG-R1) is isolated from Panax notoginseng, a medicinal herb well-known for its long use in traditional Chinese medicine. NG-R1 is relatively under-studied in research on bacteria. The aim of the study was to investigate antioxidant properties of NG-R1 saponin of selected bacterial strains of intestinal microbiota that may be involved in the pathogenesis of thromboembolic diseases. Enterococcus faecalis and Escherichia coli were used in the study. Materials and method. The study determined the concentration of hydroperoxides, the level of lipid peroxidation, as well as carbonyl groups and free thiol groups. The research carried out in this way will allow determination of the influence of the above factors on bacteria living in intestinal microbiota. Results. An evaluation of selected parameters of oxidative stress allowed to check whether the tested compound could reduce the pro-thrombotic activity of bacteria that were stimulated with H2O2. It was found that NG-R1 reduced hydroperoxide levels in both types of bacteria. In turn, lipid peroxidation initiated by H2O2 was suppressed by NG-R1. Hydrogen peroxide led to a strong increase in the level of carbonyl groups in Enterococcus faecalis and, to a lesser extent, in Escherichia coli. The addition of NG-R1 to the medium significantly reduced the level of carbonyls. Additionally, NG-R1 also induced a significant increase in the level of free thiol groups. Conclusions. Obtained results indicate that NG-R1 may have a protective effect on the intestinal microbiom through mechanisms involving changes in the redox state. [ABSTRACT FROM AUTHOR]

The hepatitis B virus (HBV) infection remains highly prevalent globally. The present study aimed to explore the possible therapeutic effect of notoginsenoside R1, which has attracted considerable attention due to its diverse pharmacological effects, on HBV infection. The HBV-containing hepatocellular carcinoma cell lines, HepG2 and MHCC97H, were used in this study. We first treated the two cell lines with different concentrations of notoginsenoside R1 and subsequently measured the relative levels of HBV DNA, HBV surface antigen, HBV core antigen, and sirtuin 1 (SIRT1) using reverse transcription-quantitative polymerase chain reaction and western blotting. Finally, an HBV hemodynamic replication model was created to test the effect of notoginsenoside R1 on HBV replication. Notoginsenoside R1 inhibited the replication of HBV. This inhibitory effect was mediated through the downregulation of SIRT1 activity. Additionally, the inhibition of SIRT1 activity by silencing its expression or treatment with the SIRT1 inhibitor, selisistat, suppressed HBV replication. Furthermore, our animal experiments demonstrated that notoginsenoside R1 was effective at suppressing HBV replication in vivo. Thus, notoginsenoside R1 suppresses HBV replication by downregulating SIRT1 activity in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a devastating incident that induces neuronal loss and dysfunction. Notoginsenoside R1 (NGR1) has been reported to exhibit a neuroprotective role after SCI. In this study, the effect and molecular mechanisms of NGR1 in models of SCI were further investigated. Rat adrenal pheochromocytoma cell line (PC-12) were stimulated with lipopolysaccharide (LPS) to establish a cell model of SCI-like condition. The changes of proinflammatory cytokines and associated proteins were analyzed using enzyme linked immunosorbent assay (ELISA) and western blotting. A rat model of SCI was established. Nissl staining were used to observe the morphological characteristics of spinal cord tissues. reverse transcription-quantitative PCR (RT-qPCR) was used to measure the expression of miR-301a andKrüppel-like factor 7 (KLF7). Our results showed that NGR1 alleviated LPS-triggered apoptosis and inflammation in PC-12 cells. MiR-301a was upregulated in LPS-stimulated PC-12 cells and was downregulated by NGR1 treatment. MiR-301a overexpression reversed the effect of NGR1 in LPS-treated PC-12 cells. KLF7 was verified to be targeted by miR-301a. NGR1 activated Wnt/β-catenin signaling in LPS-treated PC-12 cells by inhibiting miR-301a and upregulating KLF7. Moreover, blocking wingless/integrated (Wnt)/β-catenin signaling eliminated the protective effect of NGR1 against SCI in vitro and in vivo. Overall, NGR1 could reduce inflammation and apoptosis and promote functional recovery of SCI rats by activating Wnt/β-catenin pathway.

A wirelessly powered near-infrared light drug-loaded microneedle device designed for skin wound healing can achieve synergistic photo-drug therapy. The device adheres to the skin, capable of penetrating the stratum corneum to achieve precise targeted drug delivery, while effectively delivering near-infrared light from the skin surface to deeper tissues. [Display omitted] • A new structure of a phototherapy-drug combined microneedle system has been proposed. • The application of programmable wireless power supply light sources makes treatment more convenient. • A new scheme for treating skin wounds has been proposed. The healing of linear skin wounds is a complex biological process, and traditional treatment methods have certain limitations. This study proposes a wireless power supply near-infrared light drug-loaded microneedle system (NIR-LED-NG-R1-MN), which utilizes microneedles (MNs) to achieve targeted delivery of the active component of traditional Chinese medicine, Notoginsenoside R1 (NG-R1), and combines the biological regulatory effect of near-infrared light (NIR) to achieve efficient synergistic treatment for linear skin wounds. Experimental results show that the device can significantly promote the wound closure rate and reduce the levels of inflammatory factors and the risk of scar formation. By comparing the wound repair conditions of different treatment groups, it was found that the group treated with the NIR-LED-NG-R1-MN patch for NG-R1 and NIR synergistic treatment (MN@NG-R1@LED group) showed superior wound repair effects compared to other groups, thus confirming the synergistic therapeutic advantages of NG-R1 and NIR in skin wound healing. In addition, the application of wireless power supply technology used in this system eliminates the dependence on external power sources, enhancing the convenience of treatment. This study clearly demonstrates that the NIR-LED-NG-R1-MN has the potential to become a new clinical method for the treatment of linear skin wound healing. [ABSTRACT FROM AUTHOR]

High-altitude pulmonary edema (HAPE) is a potentially fatal condition that occurs when exposed to high-altitude hypoxia environments. Currently, there is no effective treatment for HAPE, and available interventions focus on providing relief. Notoginsenoside R1 (NGR1), a major active constituent of Panax notoginseng (Burkill) F.H.Chen (sānqī), has demonstrated heart and lung-protective effects under hypobaric hypoxia. However, there is a lack of clarity regarding the precise mechanisms that underlie the protective effects of NGR1 against inflammation. In this study, a rat model of HAPE was developed to assess the effect of NGR1 on this pathology. High-altitude hypoxia corresponding to 6000 m altitude was simulated with a hypobaric chamber. We found that NGR1 dose-dependently alleviated pulmonary oxidative stress damage and inflammatory response, and prevented acid-base balance disruption. In addition, NGR1 restored the expression levels of hypoxia-inducible factor-1 alpha, vascular endothelial growth factor, and aquaporin protein-5, correlated with the development of pulmonary edema induced by hypobaric hypoxia. Furthermore, NGR1 pre-treatment remarkably mitigated NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-induced pyroptosis, and this effect was partially counteracted by the use of an NLRP3 agonist. Thus, NGR1 may exert a lung-protective effect against HAPE by ameliorating hypoxia-induced lung edema, oxidative damage, and inflammation through inhibition of the NLRP3/Caspase-1/ GSDMD signaling pathway. [Display omitted] • Pyroptosis may be a concomitant feature of HAPE in animals at 6000 m. • Notoginsenoside R1 from Panax notoginseng exhibits efficacy in protecting against pulmonary edema induced by hypobaric hypoxia. • Notoginsenoside R1 against HAPE through inhibition of the NLRP3/Caspase-1/ GSDMD signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract Endothelial dysfunction in atherosclerotic cardiovascular diseases has become one of the main characteristics in patients with diabetes mellitus, which is usually caused by abnormal inflammation and oxidative stress response. Presently, we focused on the role of Notoginsenoside R1 (NR1), a major component isolated from Panax notoginseng, in endothelial dysfunction caused by high glucose (HG). Human umbilical vein endothelial cells (HUVECs) were treated with HG and then dealt with NR1. Cell counting kit‐8 assay and 5‐bromo‐2′‐dexoyuridine assay were conducted to examine cell proliferation and viability. Flow cytometry was used to measure apoptosis. The angiogenesis of HUVECs was determined by tube formation assay. Moreover, the expressions of miR‐147a, inflammatory cytokines (TNF‐α, IL‐6, and IL‐10) and oxidative stress markers malondialdehyde, superoxide dismutase, and glutathione peroxidase were measured. The protein levels of MyD88/TRAF6/NF‐κB axis, Bax, Bcl2, and Caspase3 were detected by Western blot. Furthermore, gain and loss of functional assays of miR‐147a were performed to verify the role of miR‐147a in NR1‐mediated effects. Our data confirmed that NR1 (at 10–40 μM) reduces HG‐induced HUVECs proliferation and viability inhibition, mitigates apoptosis, and enhances tube formation ability. Meanwhile, NR1 inhibited oxidative stress and inflammatory response and blocked the activation of the MyD88/TRAF6/NF‐κB pathway induced by HG. In addition, NR1 promoted the expression of miR‐147a, which targeted MyD88. Overexpression of miR‐147a markedly inactivated MyD88/TRAF6/NF‐κB pathway, while the miR‐147a inhibitors reversed NR1‐mediated protective effect in HG‐induced HUVECs through activating MyD88/TRAF6/NF‐κB pathway. In conclusion, NR1 relieves HG‐induced endothelial cell injury by downregulating the MyD88/TRAF6/NF‐κB pathway via upregulating miR‐147a.

Vascular calcification is a significant factor contributing to the rupture of vulnerable atherosclerotic plaques, ultimately leading to cardiovascular disease. However, no effective treatments are currently available to slow the progression of vascular calcification. Notoginsenoside R1 (R1) and protocatechuic aldehyde (PCAD), primary active components extracted from Panax notoginseng and Salvia miltiorrhiza Burge, have shown potential in mitigating endothelial injury and atherosclerosis. This study investigated the effects of R1-PCAD on nitric oxide (NO) production in endothelial cells (ECs) and its role in counteracting vascular calcification and inflammation. Additionally, it explored the mechanisms underlying these effects. To simulate atherosclerotic calcification, apolipoprotein E-deficient (ApoE -/- ) mice were fed a high-fat diet and given intraperitoneal injections of vitamin D3. Treatment with the R1-PCAD combination improved endothelial function, reduced inflammation in the aorta, and lowered calcium deposition. Mechanistically, R1-PCAD enhanced eNOS-Ser1177 phosphorylation by activating the AMPKα/Akt pathway, which stimulated NO production and eNOS activation in ECs. In an in vitro co-culture model involving vascular smooth muscle cells (VSMCs) and ECs, R1-PCAD similarly reduced inflammation and calcification in VSMCs triggered by β-glycerophosphate, with these effects partially dependent on NO levels and EC functionality. Further investigation revealed that R1-PCAD facilitated NO release from ECs, which subsequently inhibited TGFβR1 activation in VSMCs. This inhibition reduced Smad2/3 activation and nuclear translocation of YAP/TAZ, thereby diminishing inflammation and calcification in VSMCs. These findings suggest that R1-PCAD alleviates vascular inflammation and calcification primarily via the NO-TGFβR1-YAP/TAZ signaling pathway. This study presents a promising new approach for treating vascular calcification by targeting intercellular signaling pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Suitable bone grafts are commonly required to achieve successful bone regeneration, wherein much effort has been spent to optimize their osteogenesis. Increasing evidence has demonstrated that reducing the levels of TNF-α can enhance bone regeneration at the injury site. Notoginsenoside R1 (NGR1) has been extensively studied in the field of anti-inflammation and regenerative medicine. Nanosized hydroxyapatite (nHAp) possesses excellent biocompatibility and osteoconductivity. In this study, we fabricated a thermoresponsive, injectable hyaluronic acid/nHAp (HA/nHAp) composite hydrogel incorporated with NGR1 to promote bone regeneration. Furthermore, NGR1-HA/nHAp hydrogel could enhance bone regeneration than those of HA and HA/nHAp hydrogels, profited by the underlying osteoblastic mechanism that NGR1 could facilitate activation of the MAPK/ERK signaling pathway and down-regulate the expression of TNF-α, ultimately upregulated expression of osteogenic genes. In summary, the NGR1-HA/nHAp composite hydrogel with controlled inflammation, and excellent osteogenic effect, will have great potential for use in bone regeneration applications.

Background: Keloid is a fibrotic disease characterized by hyperproliferative fibroblasts. Notoginsenoside R1 (NGR1) possesses inhibitory roles on cell proliferation. Thus, the research sought to assess the mechanism of action of NGR1 against keloid. Materials and Methods: Cell viability of normal and keloid fibroblasts pretreated with different NGR1 concentrations was determined by Cell Counting Kit-8 assay. Cell cycle, apoptosis rate, and tube length were detected using flow cytometry and tube formation assay. Vascular endothelial growth factor (VEGF) expression was measured by quantitative real-time polymerase chain reaction and western blot. To verify the reversal effect of VEGF on NGR1, KEL FIB cells were transfected with pcDNA3-VEGF plasmids following treatment with 40 μM NGR1; subsequently, the above indicators were determined again. Results: NGR1 decreased cell viability, and 20, 30, and 40 μM NGR1 concentrations were selected for the next investigation. After KEL FIB was treated with NGR1, the apoptosis rate was increased, cell cycle was arrested, and tube formation was suppressed in a dose-dependent manner. The expression of VEGF was also suppressed. In further experiments, cell cycle and tube formation were promoted and apoptosis rate was decreased in NGR1-treated cells when VEGF was overexpressed. Conclusion: NGR1 may play as an inhibitor of endogenous VEGF, and NGR1 exerts its inhibitory effects on keloid fibroblasts by downregulating VEGF. [ABSTRACT FROM AUTHOR]

Ischemic heart diseases are responsible for more than one-third of all deaths worldwide. Radix notoginseng is widely used to treat ischemic heart disease in China and other Asian countries, and notoginsenoside R1 (NGR1) is its characteristic and large-amount ingredient. However, the potential molecular mechanisms of NGR1 in improving ischemic heart diseases are unclear. In this study, we combined pharmacological evaluation with network pharmacology, myocardial proteomics, and conventional molecular dynamics (MD) simulation to explore the cardio-protection mechanisms of NGR1. Our results revealed that NGR1 improved the echocardiographic, tissue pathological, and serum biochemical perturbations in myocardial ischemic rats. The network pharmacology studies indicated that NGR1 mainly regulated smooth muscle cell proliferation, vasculature development, and lipid metabolism signaling, especially in the PI3K/AKT pathway. Myocardial proteomics revealed that the function of NGR1 was focused on regulating metabolic and energy supply processes. The research combined reverse-docked targets with differential proteins and demonstrated that NGR1 modulated lipid metabolism in ischemic myocardia by interacting with mTOR and AKT. Conventional MD simulation was applied to investigate the influence of NGR1 on the structural stabilization of the mTOR and AKT complex. The results suggested that NGR1 can strengthen the affinity stabilization of mTOR and AKT. Our study first revealed that NGR1 enhanced the affinity stabilization of mTOR and AKT, thus promoting the activation of the AKT/mTOR pathway and improving lipid metabolic abnormity in myocardial ischemic rats. [ABSTRACT FROM AUTHOR]

Cellular activities, such as attachment, spreading, proliferation, migration, and differentiation are indispensable for the success of bone tissue engineering. Mesenchymal stromal cells (MSCs) are the key precursor cells to regenerate bone. Bioactive compounds from natural products had shown bone regenerative potential. Notoginsenoside R1 (NGR1) is a primary bioactive natural compound that regulates various biological activities, including cardiovascular protection, neuro-protection, and anti-cancer effects. However, the effect of NGR1 on migration, adhesion, spreading, and osteogenic differentiation of MSCs required for bone tissue engineering application has not been tested properly. In this study, we aimed to analyze the effect of NGR1 on the cellular activities of MSCs. Since human adipose-derived stromal cells (hASCs) are commonly used MSCs for bone tissue engineering, we used hASCs as a model of MSCs. The optimal concentration of 0.05 μg/mL NGR1 was biocompatible and promoted migration and osteogenic differentiation of hASCs. Pro-angiogenic factor VEGF expression was upregulated in NGR1-treated hASCs. NGR1 enhanced the adhesion and spreading of hASCs on the bio-inert glass surface. NGR1 robustly promoted hASCs adhesion and survival in 3D-printed TCP scaffold both in vitro and in vivo. NGR1 mitigated LPS-induced expression of inflammatory markers IL-1β, IL-6, and TNF-α in hASCs as well as inhibited the RANKL/OPG expression ratio. In conclusion, the biocompatible NGR1 promoted the migration, adhesion, spreading, osteogenic differentiation, and anti-inflammatory properties of hASCs. [ABSTRACT FROM AUTHOR]

Notoginsenoside R1 (NGR1) is the main monomeric component extracted from the dried roots and rhizomes of Panax notoginseng, and exerts pharmacological action against myocardial infarction (MI). Owing to the differences in compound distribution, absorption, and metabolism in vivo, exploring a more effective drug delivery system with a high therapeutic targeting effect is crucial. In the early stages of MI, CD11b-expressing monocytes and neutrophils accumulate at infarct sites. Thus, we designed a mesoporous silica nanoparticle-conjugated CD11b antibody with loaded NGR1 (MSN-NGR1-CD11b antibody), which allowed NGR1 precise targeted delivery to the heart in a noninvasively manner. By increasing targeting to the injured myocardium, intravenous injection of MSN-NGR1-CD11b antibody nanoparticle in MI mice improved cardiac function and angiogenesis, reduced cell apoptosis, and regulate macrophage phenotype and inflammatory factors and chemokines. In order to further explore the mechanism of NGR1 protecting myocardium, cell oxidative stress model and oxygen-glucose deprivation (OGD) model were established. NGR1 protected H9C2 cells and primary cardiomyocytes against oxidative injury induced by H2O2 and OGD treatment. Further network pharmacology and molecular docking analyses suggested that the AKT, MAPK and Hippo signaling pathways were involved in the regulation of NGR1 in myocardial protection. Indeed, NGR1 could elevate the levels of p-Akt and p-ERK, and promote the nuclear translocation of YAP. Furthermore, LY294002 (AKT inhibitor), U0126 (ERK1/2 inhibitor) and Verteporfin (YAP inhibitor) administration in H9C2 cells indicated the involvement of AKT, MAPK and Hippo signaling pathways in NGR1 effects. Meanwhile, MSN-NGR1-CD11b antibody nanoparticles enhanced the activation of AKT and MAPK signaling pathways and the nuclear translocation of YAP at the infarcted site. Our research demonstrated that MSN-NGR1-CD11b antibody nanoparticle injection after MI enhanced the targeting of NGR1 to the infarcted myocardium and improved cardiac function. More importantly, our pioneering research provides a new strategy for targeting drug delivery systems to the ischemic niche.

Ischemic heart diseases are responsible for more than one-third of all deaths worldwide. Radix notoginseng is widely used to treat ischemic heart disease in China and other Asian countries, and notoginsenoside R1 (NGR1) is its characteristic and large-amount ingredient. However, the potential molecular mechanisms of NGR1 in improving ischemic heart diseases are unclear. In this study, we combined pharmacological evaluation with network pharmacology, myocardial proteomics, and conventional molecular dynamics (MD) simulation to explore the cardio-protection mechanisms of NGR1. Our results revealed that NGR1 improved the echocardiographic, tissue pathological, and serum biochemical perturbations in myocardial ischemic rats. The network pharmacology studies indicated that NGR1 mainly regulated smooth muscle cell proliferation, vasculature development, and lipid metabolism signaling, especially in the PI3K/AKT pathway. Myocardial proteomics revealed that the function of NGR1 was focused on regulating metabolic and energy supply processes. The research combined reverse-docked targets with differential proteins and demonstrated that NGR1 modulated lipid metabolism in ischemic myocardia by interacting with mTOR and AKT. Conventional MD simulation was applied to investigate the influence of NGR1 on the structural stabilization of the mTOR and AKT complex. The results suggested that NGR1 can strengthen the affinity stabilization of mTOR and AKT. Our study first revealed that NGR1 enhanced the affinity stabilization of mTOR and AKT, thus promoting the activation of the AKT/mTOR pathway and improving lipid metabolic abnormity in myocardial ischemic rats.

β2 adrenergic receptor (β2AR) is a G-protein-coupled receptor involved in cardiac protection. In chronic heart failure (CHF), persistent sympathetic nervous system activation occurs, resulting in prolonged β2AR activation and subsequent receptor desensitization and downregulation. Notoginsenoside R1 (NGR1) has the functions of enhancing myocardial energy metabolism and mitigating myocardial fibrosis. The mechanisms of NGR1 against ischemic heart failure are unclear. A left anterior descending (LAD) artery ligation procedure was performed on C57BL/6 J mice for four weeks. From the 4th week onwards, they were treated with various doses (3, 10, 30 mg/kg/day) of NGR1. Subsequently, the impacts of NGR1 on ischemic heart failure were evaluated by assessing cardiac function, morphological changes in cardiac tissue, and the expression of atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC). H9c2 cells were protected by NGR1 when exposed to OGD/R conditions. H9c2 cells were likewise protected from OGD/R damage by NGR1. Furthermore, NGR1 increased β2AR levels and decreased β2AR ubiquitination. Mechanistic studies revealed that NGR1 enhanced MDM2 protein stability and increased the expression of MDM2 and β-arrestin2 while inhibiting their interaction. Additionally, under conditions produced by OGD/R, the protective benefits of NGR1 on H9c2 cells were attenuated upon administration of the MDM2 inhibitor SP141. According to these findings, NGR1 impedes the interplay between β-arrestin2 and MDM2, thereby preventing the ubiquitination and degradation of β2AR to improve CHF. • Notoginsenoside R1 improved cardiac function and remodeling in chronic heart failure mice. • Notoginsenoside R1 increased β2AR levels and decreased β2AR ubiquitination. • β2AR ubiquitanation was inhibited by Notoginsenoside R1 via regulation of the MDM2/β-arrestin2. [ABSTRACT FROM AUTHOR]

High-altitude myocardial injury (HAMI) represents a critical form of altitude illness for which effective drug therapies are generally lacking. Notoginsenoside R1, a prominent constituent derived from Panax notoginseng, has demonstrated various cardioprotective properties in models of myocardial ischemia/reperfusion injury, sepsis-induced cardiomyopathy, cardiac fibrosis, and myocardial injury. The potential utility of notoginsenoside R1 in the management of HAMI warrants prompt investigation. Following the successful construction of a HAMI model, a series of experimental analyses were conducted to assess the effects of notoginsenoside R1 at dosages of 50 mg/Kg and 100 mg/Kg. The results indicated that notoginsenoside R1 exhibited protective effects against hypoxic injury by reducing levels of CK, CK-MB, LDH, and BNP, leading to improved cardiac function and decreased incidence of arrhythmias. Furthermore, notoginsenoside R1 was found to enhance Nrf2 nuclear translocation, subsequently regulating the SLC7A11/GPX4/HO-1 pathway and iron metabolism to mitigate ferroptosis, thereby mitigating cardiac inflammation and oxidative stress induced by high-altitude conditions. In addition, the application of ML385 has confirmed the involvement of Nrf2 nuclear translocation in the therapeutic approach to HAMI. Collectively, the advantageous impacts of notoginsenoside R1 on HAMI have been linked to the suppression of ferroptosis via Nrf2 nuclear translocation signaling. [Display omitted] • High-altitude exposure can cause myocardial injury, signs of tissue hypoxia, and ECG abnormalities. • Notoginsenoside R1 ameliorated myocardial injury caused by high-altitude stimulation. • Notoginsenoside R1 decreased ferroptosis in myocardial cells. • The effects of notoginsenoside R1 were mediated through the Keap1/Nrf2 signaling pathway to facilitated Nrf2 nuclear translocation. [ABSTRACT FROM AUTHOR]

Ischemic stroke (IS) ranks as the second common cause of death worldwide. However, a narrow thrombolysis timeframe and ischemia-reperfusion (I/R) injury limits patient recovery. Moreover, anticoagulation and antithrombotic drugs do not meet the clinical requirements. Studies have demonstrated close communication between the brain and gut microbiota in IS. Notoginsenoside R1 (NG-R1), a significant component of the total saponins from Panax notoginseng , has been demonstrated to be effective against cerebral I/R injury. Total saponins have been used to treat IS in Chinese pharmacopoeia. Furthermore, previous research has indicated that the absorption of NG-R1 was controlled by gut microbiota. This study aimed to access the impact of NG-R1 treatment on neuroinflammation and investigate the microbiota-related mechanisms. NG-R1 significantly reduced neuronal death and neuroinflammation in middle cerebral artery occlusion/reperfusion (MCAO/R) models. 16S rRNA sequencing revealed that NG-R1 treatment displayed the reversal of microbiota related with MCAO/R models. Additionally, NG-R1 administration attenuated intestinal inflammation, gut barrier destruction, and systemic inflammation. Furthermore, microbiota transplantation from NG-R1 exhibited a similar effect in the MCAO/R models. In summary, NG-R1 treatment resulted in the restoration of the structure of the blood-brain barrier (BBB) and reduction in neuroinflammation via suppressing the stimulation of astrocytes and microglia in the cerebral ischemic area. Mechanistic research demonstrated that NG-R1 treatment suppressed the toll-like receptor 4/myeloid differentiation primary response 88/nuclear factor kappa B (TLR4/MyD88/NF-κB) signaling pathway in both the ischemic brain and colon. NG-R1 treatment enhanced microbiota dysbiosis by inhibiting the TLR4 signaling pathway to protect MCAO/R models. These findings elucidate the mechanisms by which NG-R1 improve stroke outcomes and provide some basis for Panax notoginseng saponins in clinical treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Due to sudden loss of cerebral blood circulation, acute ischemic stroke (IS) causes neuronal energy attenuation or even exhaustion by mitochondrial dysfunction resulting in aggravation of neurological injury. In this study, we investigated if Notoginsenoside R1 ameliorated cerebral energy metabolism by limiting neuronal mitochondrial dysfunction in acute IS. Male Sprague–Dawley rats (260–280 g) were selected and performed by permanent middle cerebral artery occlusion model. In vitro, the oxygen glucose deprivation (OGD) model of Neuro2a (N2a) cells was established. We found Notoginsenoside R1 treatment reduced rats' cerebral infarct volume and neurological deficits, with increased Adenosine triphosphate (ATP) level together with upregulated expression of glucose transporter 1/3, monocarboxylate transporter 1 and citrate synthase in brain peri‐ischemic tissue. In vitro, OGD‐induced N2a cell death was inhibited, cell mitochondrial morphology was improved. Mitochondrial amount, mitochondrial membrane potential, and mitochondrial DNA copy number were increased by Notoginsenoside R1 administration. Furthermore, mitochondrial energy metabolism‐related mRNA array found Atp12a and Atp6v1g3 gene expression were upregulated more than twofold, which were also verified in rat ischemic tissue by quantitative polymerase chain reaction (qPCR) assay. Therefore, Notoginsenoside R1 administration increases cerebral glucose and lactate transportation and ATP levels, ameliorates neuronal mitochondrial function after IS. Notoginsenoside R1 may be a novel protective agent for neuronal mitochondria poststroke. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is primarily characterized by synovial inflammation. Our previous studies demonstrated that the lymphatic system is critical for the development and maintenance of RA disease, and sufficient lymph drainage helps to improve joint inflammation. In this study, we found that NG-R1, the main active component in the traditional Chinese medicinal herb Sanchi, activating lymphatic function can attenuate synovial inflammation. According to histopathological staining of ankle sections, NG-R1 significantly decreased the area of inflammation and reduced bone destruction of ankle joints in TNF-Tg mice. Near infrared-indocyanine green (NIR-ICG) lymphatic imaging system has shown that NG-R1 significantly improved the lymphatic drainage function. However, the molecular mechanism of its activity is not properly understood. Our in-depth study demonstrates that NG-R1 reduced the inflammatory cytokine production of lymphatic endothelial cells (LECs) stimulated by TNF-α, and the mechanism ameliorated the phosphorylation of IKKα/β and p65, and the translocation of p65 into the nucleus. In summary, this study proved that NG-R1 promoted lymphatic drainage function to ameliorating rheumatoid arthritis in TNF-Tg mice by suppressing NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Activation of the hepatic stellate cell is implicated in pathological vascularization during development of liver fibrosis. MAPK signaling is involved in the activation of hepatic stellate cell. Oxidative stress and inflammation are also involved in the pathogenesis of liver fibrosis. Notoginsenoside R1 is an effective saponin isolated from the roots of Panax notoginseng (Burk) F. H. Chen and exerts anti-oxidant, anti-inflammatory and anti-fibrotic roles in various diseases. However, the role of Notoginsenoside R1 in liver fibrosis has not been investigated yet. First, a rat model with liver fibrosis was established through oral gavage administration with carbon tetrachloride. Data from hematoxylin and eosin (H&E) and Masson's trichrome stainings showed that carbon tetrachloride induced severe hepatic damages, including inflammatory cell infiltration, lipid droplets deposition in hepatocytes and liver centrilobular necrosis. Meanwhile, the rats were also intraperitoneal injected with different concentrations of Notoginsenoside R1. Results demonstrated that Notoginsenoside R1 treatment suppressed the pathological changes in the livers with enhanced levels of ALB and TP, and reduced levels of ALP, AST and ALT. Second, Notoginsenoside R1 also significantly attenuated carbon tetrachloride-induced decrease in PPAR- γ and increase in Coll-a1, α -SMA and TIMP1 in liver tissues (p < 0.001). Third, the decrease in GSH, SOD and GST and increase in MDA, IL-1 β , IL-6 and TNF- α induced by carbon tetrachloride were markedly restored by Notoginsenoside R1 (p < 0.001). Lastly, Notoginsenoside R1 counteracted with the promotive effects of carbon tetrachloride on levels of proteins involved in MAPK signaling, including phosphorylated p65 (p-p65), p-ERK, p-JNK and p-p38. In conclusion, Notoginsenoside R1 suppressed the activation of hepatic stellate cells and exerted anti- oxidant and anti-inflammatory to attenuate carbon tetrachloride-induced liver fibrosis through inactivation of NF- κ B and MAPK signaling. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a devastating incident that induces neuronal loss and dysfunction. Notoginsenoside R1 (NGR1) has been reported to exhibit a neuro-protective role after SCI. In this study, the effect and molecular mechanisms of NGR1 in models of SCI were further investigated. Rat adrenal pheochromocytoma cell line (PC-12) were stimulated with lipopolysaccharide (LPS) to establish a cell model of SCI-like condition. The changes of proinflammatory cytokines and associated proteins were analyzed using enzyme linked immunosorbent assay (ELISA) and western blotting. A rat model of SCI was established. Nissl staining were used to observe the morphological characteristics of spinal cord tissues. reverse transcription-quantitative PCR (RT-qPCR) was used to measure the expression of miR-301a and Krüppel-like factor 7 (KLF7). Our results showed that NGR1 alleviated LPS-triggered apoptosis and inflammation in PC-12 cells. MiR-301a was upregulated in LPS-stimulated PC-12 cells and was downregulated by NGR1 treatment. MiR-301a overexpression reversed the effect of NGR1 in LPS-treated PC-12 cells. KLF7 was verified to be targeted by miR-301a. NGR1 activated Wnt/β-catenin signaling in LPS-treated PC-12 cells by inhibiting miR-301a and upregulating KLF7. Moreover, blocking wingless/integrated (Wnt)/β-catenin signaling eliminated the protective effect of NGR1 against SCI in vitro and in vivo. Overall, NGR1 could reduce inflammation and apoptosis and promote functional recovery of SCI rats by activating Wnt/β-catenin pathway. [ABSTRACT FROM AUTHOR]

Notoginsenoside R1 (NG-R1), the extract and the main ingredient of Panax notoginseng, has anti-inflammatory effects and can be used in treating acute lung injury (ALI). In this study, we explored the pulmonary protective effect and the underlying mechanism of the NG-R1 on rats with ALI induced by severe acute pancreatitis (SAP). MiR-128-2-5p, ERK1, Tollip, HMGB1, TLR4, IκB, and NF-κB mRNA expression levels were measured using real-time qPCR, and TLR4, Tollip, HMGB1, IRAK1, MyD88, ERK1, NF-κB65, and P-IκB-α protein expression levels using Western blot. The NF-κB and the TLR4 activities were determined using immunohistochemistry, and TNF-α, IL-6, IL-1β, and ICAM-1 levels in the bronchoalveolar lavage fluid (BALF) using ELISA. Lung histopathological changes were observed in each group. NG-R1 treatment reduced miR-128-2-5p expression in the lung tissue, increased Tollip expression, inhibited HMGB1, TLR4, TRAF6, IRAK1, MyD88, NF-κB65, and p-IκB-α expression levels, suppressed NF-κB65 and the TLR4 expression levels, reduced MPO activity, reduced TNF-α, IL-1β, IL-6, and ICAM-1 levels in BALF, and alleviated SAP-induced ALI. NG-R1 can attenuate SAP-induced ALI. The mechanism of action may be due to a decreased expression of miR-128-2-5p, increased activity of the Tollip signaling pathway, decreased activity of HMGB1/TLR4 and ERK1 signaling pathways, and decreased inflammatory response to SAP-induced ALI. Tollip was the regulatory target of miR-128-2-5p. [ABSTRACT FROM AUTHOR]

Introduction: Isoflurane inhalation leads to apoptotic neurodegeneration and further results in learning and cognitive dysfunction. Notoginsenoside R1 (NGR1), a major ingredient from Radix notoginseng, has been reported to exert neuroprotective effect during brain or neuron injury. This study aimed to investigate the effect of NGR1 on neurological impairment. Methods: Sixty-four male Sprague Dawley rat pups (15–20 g) of postnatal day 7 were recruited. Spatial learning and memory were assessed by the Morris water maze test, and the neurological severity score was determined. Real-time quantitative PCR was used to detect the expression levels of microRNA (miR)-29a. Enzyme-linked immunosorbent assay was applied to estimate the levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the hippocampal tissues. Results: NGR1 attenuated neurological impairment induced by isoflurane, shown by the decrease in neurological function score and escape latency and the increase in staying time in the original quadrant in rats. NGR1 reversed the downregulation of miR-29a expression induced by isoflurane treatment. After the treatment of NGR1, the elevated levels of IL-6, TNF-α, and IL-1β induced by isoflurane were all decreased significantly in the hippocampal tissues of rats. Additionally, the repressive action of NGR1 in neurological impairment and neuroinflammation was eliminated by downregulating miR-29a in rats. Conclusion: NGR1 protects against isoflurane-induced neurological impairment. The protective effect of NGR1 might be achieved by promoting the expression of miR-29a and preventing inflammatory response. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction in atherosclerotic cardiovascular diseases has become one of the main characteristics in patients with diabetes mellitus, which is usually caused by abnormal inflammation and oxidative stress response. Presently, we focused on the role of Notoginsenoside R1 (NR1), a major component isolated from Panax notoginseng, in endothelial dysfunction caused by high glucose (HG). Human umbilical vein endothelial cells (HUVECs) were treated with HG and then dealt with NR1. Cell counting kit‐8 assay and 5‐bromo‐2′‐dexoyuridine assay were conducted to examine cell proliferation and viability. Flow cytometry was used to measure apoptosis. The angiogenesis of HUVECs was determined by tube formation assay. Moreover, the expressions of miR‐147a, inflammatory cytokines (TNF‐α, IL‐6, and IL‐10) and oxidative stress markers malondialdehyde, superoxide dismutase, and glutathione peroxidase were measured. The protein levels of MyD88/TRAF6/NF‐κB axis, Bax, Bcl2, and Caspase3 were detected by Western blot. Furthermore, gain and loss of functional assays of miR‐147a were performed to verify the role of miR‐147a in NR1‐mediated effects. Our data confirmed that NR1 (at 10–40 μM) reduces HG‐induced HUVECs proliferation and viability inhibition, mitigates apoptosis, and enhances tube formation ability. Meanwhile, NR1 inhibited oxidative stress and inflammatory response and blocked the activation of the MyD88/TRAF6/NF‐κB pathway induced by HG. In addition, NR1 promoted the expression of miR‐147a, which targeted MyD88. Overexpression of miR‐147a markedly inactivated MyD88/TRAF6/NF‐κB pathway, while the miR‐147a inhibitors reversed NR1‐mediated protective effect in HG‐induced HUVECs through activating MyD88/TRAF6/NF‐κB pathway. In conclusion, NR1 relieves HG‐induced endothelial cell injury by downregulating the MyD88/TRAF6/NF‐κB pathway via upregulating miR‐147a. [ABSTRACT FROM AUTHOR]