Panax Notoginsenoside Research Articles

Taohong Siwu Decoction Promotes Osteo-Angiogenesis in Fractures by Regulating the HIF-1α Signaling Pathway.

Background Vascular damage is a major consequence of bone fracture. Taohong Siwu decoction (TSD) can raise the expression of vascular endothelial growth factor (VEGF) in fracture healing. However, its molecular mechanism in promoting angiogenesis is still unknown. The aim of this study was to investigate the potential mechanisms of TSD in the regulation of osteo-angiogenesis in fracture healing. Methods A rat tibial fracture model was established. After low- (4.5 g·kg−1), medium- (9 g·kg−1), and high-dose TSD (18 g·kg−1) and panax notoginsenoside (25 mg kg−1) treatment, hematoxylin-eosin staining was employed to visualize pathological changes in bone tissues. The levels of cytokines (interleukin (IL)-2, tumor necrosis factor-α (TNF-α), IL-6, and IL-1β), thromboxane B2 (TXB2), and 6 ketone prostaglandin F1α (6-Keto-PGF1α) were quantified by enzyme-linked immunosorbent assay (ELISA). Immunofluorescence was used to identify the rat aortic endothelial cells (RAECs). Control serum, 10% TSD-containing serum, and 10% TSD-containing serum combined with hypoxia-inducible factor-1α (HIF-1α) inhibitor were used to treat the RAECs and rat osteoblasts. Transwell migration assay was utilized to examine the migration of the RAECs. The Matrigel tubulogenesis assay was used for the assessment of angiogenesis. The expression of angiogenesis- (von Hippel-Lindau tumor suppressor (VHL), HIF-1α, VEGF, angiopoietin-2 (Ang-2), and pVHL) and osteogenesis-related (alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), and osteopontin-1 (OPN-1)) protein and gene was detected by western blot and quantitative real-time PCR (qRT-PCR). Results Compared with the model group, TSD increased the trabecular bone areas, numbers, and thicknesses in fractured rats. In the plasma, the levels of cytokines and TXB2 in the middle- and high-dose TSD group were significantly lower than those in the model group (P < 0.01). The 6-keto-PGF1α content was increased by middle- and high-dose TSD intervention (P < 0.01). Compared to the control serum group, the angiogenesis and migration of the RAECs were enhanced in the TSD group (P < 0.001). The expression of HIF-1α, VEGF, and Ang-2 in the TSD group upregulated significantly (P < 0.001). VHL and pVHL were inhibited under TSD-containing serum treatment (P < 0.001). ALP, Runx2, and OPN-1 were increased obviously in the TSD group (P < 0.001). Nevertheless, the HIF-1α inhibitor reversed these changes (P < 0.001). Conclusion TSD promotes angiogenesis and osteogenesis by regulating the HIF-1α signaling pathway. Meanwhile, it can effectively reduce the risk of inflammation and improve blood circulation.

Global analysis of qualitative and quantitative metabolism of Notoginsenoside R1 in rat liver-brain-gut axis based on LC-IT-TOF/MS combing mMDF strategy

The metabolism study of active components for traditional Chinese medicine (TCM) in target organs is conducive to clarify the authentic active ingredients. Notoginsenoside R1 (NG-R1), one of the bioactive components of Panax notoginsenoside (PNS), is commonly acknowledged as the characteristic marker of PNS. However, the metabolism of NG-R1 in target organs has not been clarified yet due to the lack of robust technique and approach. The present study aimed to develop a reliable and efficient strategy and technology for revealing the qualitative and quantitative metabolism of active components of TCMs in target organs, and to clarify the biotransformation of NG-R1 in liver-brain-intestinal axis. The metabolic transformation of NG-R1 in the brain gut axis was investigated in the in vitro incubation system of fresh rat brain, liver homogenate, and intestinal flora. To quickly lock the target metabolites, we set the mass defect filter (MDF) in different ranges to screen metabolites with different molecular weight (MW). This strategy was defined as multi-stage MDF (mMDF). In addition, we performed relative quantitative analysis on all metabolites according to the peak area acquired by LC-IT-TOF/MS to overcome the challenge that metabolites are difficult to be quantified due to the lack of standards. When MDF was set at 0.50 to 0.65 to screen metabolites with MW of 900 to 1200 Da, 6 novel metabolites were quickly found, and then identified as glucuronic acid binding, oxidation, dehydrogenation, methylation and hydrogenation products according to their LC and MS characteristics. When setting MDF at 0.42 - 0.52, 6 metabolites with MW of 600 to 900 Da were effectively screened and identified as Rg1, NG-R2, Rh1, Rg1+CH2+2H and Rg1+CH2. To screen the metabolites with MW of 300 to 600 Da, MDF was set at 0.25 - 0.42, and 4 novel metabolites were screened rapidly. The results of quantitative metabolism suggested that intestinal flora was the main metabolic site of NG-R1 in rat, and more than 60% of NG-R1 was converted to Rg1 by deglycosylation in the intestinal flora. The mMDF strategy can significantly improve the research efficiency of qualitative metabolism of saponins. Although NG-R1 could be transformed into a variety of metabolites in rat liver and brain homogenate, it still existed mainly in prototype form. In the rat flora, NG-R1 mainly existed in the form of deglycosylated metabolite Rg1.

Panax Notoginseng Saponin Rg1 Can Effectively Improve the Cognitive Function of 5 × FAD Mice.

In order to investigate the effect of notoginsenoside Rg1 on cognitive function in 5∗FAD mice and the mechanism of Cx43 in improving cognitive function in mice, the methods 5∗FAD mice are selected as experimental animals and normal mice as healthy control. They were divided into three groups: healthy control group (n = 10), disease group (n = 10), and treatment group (n = 10, Panax notoginsenoside Rg 1150 mg/kg/d) for 2 months. Two months later, three groups of mice were subjected to classical water maze and Y-maze to test the cognitive ability of mice, and the correct response times and total response time were recorded. At the end of the cognitive function test, the mice were executed, and the brain tissues were taken. The expression of Cx43 protein and the changes of glial cells and neurons in the brain of the mice were analyzed at the cellular level. After treatment with Panax notoginseng saponin Rg 1150 mg/kg/d, it was found that the escape latency of mice in the treatment group was significantly lower than that in the disease group from the third day of training (P < 0.05); the time spent on the platform quadrant and the number of times crossing the platform in the treated mice were significantly increased, and the difference was statistically significant (P < 0.05); the expression of Cx43 protein in the brain of mice after treatment was significantly higher than that of mice in the disease group (P < 0.05). Conclusion. Panax notoginseng saponin Rg1 can effectively improve the cognitive function of 5∗FAD mice by increasing the secretion of Cx43 protein, thus increasing the reactivity of glial cells and neurons.

Panax notoginseng glycosides with astragaloside IV improve cerebral ischemic injury through autophagy-NLRP3 inflammasome pathway

Autophagy-NLRP3 pathway participates in cerebral ischemia injury. However, whether Panax notoginsenoside (PN) combined with astragaloside IV (A-IV) plays an anti-inflammatory role in cerebral ischemia injury remains unclear. SD rats were in this study divided into sham operation group, model group, combination drug low-dose group (PN 40 mg/kg+ A-IV 14 mg/kg), medium dose group (80 mg/kg+ 28 mg/kg), high dose group (160 mg/kg+ 56 mg/kg), control group (propofol 4–6 mg/kg) followed by analysis of cerebral ischemia injury and PINK1/Parkin signaling. The model group presented increased infarct volume and NLRP3 level compared to drug and sham operation group. However, the higher the dose, the smaller was the infarct volume and lower NLRP3 expression (P &lt; 0.05). LC3-II/LC3-I ratio increased with ischemia injury, while the ratios of P62, COX4 II and TomM20 were contrary. P62 presented declined level in treatment group compared to model group (P &lt; 0.05). P62, COX4 II and TOMM20 levels were lower in the high-dose group and higher in the P62 group (P &lt; 0.01). After 3-MA and mdivi-1 intervention, NLRP3-related pathway, LC3-II/LC3-I and P62 abundance in mitochondria were highest in the model group with downregulated COX4 II and TOMM20. The neurological deficit score and infarct volume were highest in the model group and improved in medium dose group. The cerebral infarction volume and neurological deficit score were elevated in the drug group combined with 3-MA and MIDIV-1 (P &lt; 0.05). The higher the dose was, the lower were the expressions of PINK and Parkin (P &lt; 0.01). In conclusion, Panax notoginsenoside combined with astragaloside IV effectively alleviated cerebral ischemia injury in rats and improved mitochondrial autophagy by inhibiting inflammasome activation.

Restoring perturbed oxylipins with Danqi Tongmai Tablet attenuates acute myocardial infarction

Salvianolic acids have a special synergic effect on panax notoginsenosides in acute myocardial infarction (AMI) and have been developed into a new drug as Danqi Tongmai Tablet (DQTT). To explore candidate targets and mechanisms of DQTT on AMI, a network pharmacology-based analysis was performed on absorbed prototype compounds of DQTT in rat plasma. Target prediction from network analysis indicated that the arachidonic acid pathway might contribute to the therapeutic effects of DQTT on AMI, and the regulatory effects on cyclooxygenase (COX) and lipoxygenase (LOX) were validated using an oxygen-glucose deprivation/reoxygenation model established on H9c2 cardiomyocytes. To further explore the action mechanisms of DQTT, 38 oxylipins were quantitatively analyzed among high, medium, and low doses of DQTT using a rat AMI model with an ultra high performance liquid chromatograph coupled with a triple quadrupole mass spectrometry (UHPLC-QqQ/MS) detection system. As attenuation was observed in AMI with DQTT treatment, the perturbed arachidonic acid metabolome was partly restored in a dose-dependent fashion with a significant elevation of anti-inflammatory metabolites, while pro-inflammatory lipids were decreased. Cytokine array analysis also supported the anti-inflammatory effects of DQTT, as significant down-regulation of pro-inflammatory cytokines was observed. The analysis of ischemic heart tissues demonstrated that COX and LOX, the inflammation-induced catalytic enzymes of arachidonic acid metabolism, were inhibited on both gene expression and protein level. These results confirmed that DQTT could restore the arachidonic acid metabolome to maintain an anti-inflammatory profile against the ischemic tissue injury and support that DQTT can be a promising medicinal therapy against AMI.

NotoginsenosideR1 induces DNA damage via PHF6protein to inhibit cervical carcinoma cell proliferation.

Notoginsenoside R1 (NGR1), a monomer of Traditional Chinese medicine, is from the Panax notoginsenoside complex, and has been reported to inhibit the proliferation of various types of cancer. However the mechanism underlying NGR1-mediated inhibition of cervical carcinoma cell proliferation remains unclear. Therefore, the current study aimed to investigate the antitumor effects of NGR1 on cervical carcinoma cell lines (CaSki and HeLa cells) in vitro. The Cell Counting Kit-8 and soft agar cell colony formation assay results revealed that NGR1 suppressed the viability and the number colonies of CaSki and HeLa cells, respectively. Furthermore, the DAPI staining, flow cytometry and western blotting results revealed that NGR1 induced cervical carcinoma cell apoptosis, cell cycle arrest in the S phase, upregulation of cyclin A2 and CDK2 expression levels, and downregulation of cyclin D1 expression levels. To further investigate the mechanisms of NGR1, DNA-damage-related proteins, including H2A.X variant histone (H2AX), ATR serine/threonine kinase (ATR) and p53, and the nucleolus protein, plant homeodomain finger protein 6 (PHF6) were analyzed. The results indicated that NGR1 triggered the phosphorylation of H2AX and ATR in a dose- and time-dependent manner, and downregulated the expression level of PHF6 and upregulated the expression level of p53 in a dose- and time-dependent manner. In conclusion, the findings of the present indicated that NGR1 may inhibit the viability of cervical carcinoma cells and induce cell apoptosis via DNA damage, which may be activated by the downregulation of PHF6 expression levels, and the subsequent triggering of the phosphorylation of H2AX and ATR. In addition, NGR1 may exert an ability to arrest cervical carcinoma cells in the S phase and upregulate the expression levels of cyclin A2 and CDK2. Therefore, NGR1 may serve as a novel chemotherapeutic agent for cervical carcinoma.

Panax notoginsenoside Rb1 Restores the Neurotrophic Imbalance Following Photothrombotic Stroke in Rats.

Mature brain-derived neurotrophic factor (mBDNF) has neuroprotection in cerebral ischemia. Conversely, the precursor of brain-derived neurotrophic factor (proBDNF) has the opposite function to its mature form, inducing apoptosis. However, whether the neuroprotection of Panax notoginsenoside Rb1 (PNS-Rb1) on ischemic stroke is due to, at least partially, its modulation of suppressing proBDNF/P75NTR/sortilin or upregulation of mBDNF is not clear. To test this hypothesis, rats induced by photothrombotic stroke were treated with PNS-Rb1 100mg/kg or nimodipine 1mg/kg twice a day until 3, 7, and 14days. Our data indicate that PNS-Rb1 significantly reduced cerebral infarction rate, proBDNF/P75NTR/sortilin, and plasminogen activator inhibitor-1 (PAI-1) protein levels, and improved sensorimotor dysfunctions induced by ischemic stroke, upregulation of BDNF/TrkB levels, and its processing enzymes (tissue plasminogen activator, tPA) in a time-dependent manner. Taken together, our findings indicate that the improvement of sensorimotor dysfunctions by PNS-Rb1 following ischemic stroke is made, at least partially, by activating the BDNF/TrkB and inhibiting proBDNF/sortilin/P75NTR.

Exploring the protective effects of Danqi Tongmai tablet on acute myocardial ischemia rats by comprehensive metabolomics profiling

BackgroundDanqi Tongmai tablet (DQTM), a combination of salvianolic acids (SA) and panax notoginsenosides (PNS), is now in phase II clinical trial developed for the treatment of cardiovascular diseases. However, the mechanisms of its protective effects through regulating endogenous metabolites remain unclear. PurposeThe purpose of this study was to explore the protective effects of DQTM on acute myocardial ischemia rats by comprehensive metabolomics profiling. Study designThe rats were divided into three groups: sham-operating, acute myocardial ischemia (AMI) and DQTM groups. The plasma and heart were collected and profiled by LC-MS based metabolomics and lipidomics. Based on the identified differential metabolites, the pathway analysis results were obtained and further validated using the network pharmacology approach. MethodsThe AMI model was induced by ligating the left anterior descending coronary artery. The metabolomics and lipidomics profiling were based on two established LC–QTOF/MS analysis methods. The raw data were processed using XCMS Online, then the differential metabolites with nonparametric t-test p value less than 0.05 were selected and identified using HMDB and METLIN. The pathway analysis was conducted using MetaboAnalyst and validated with the predicted network results obtained by BATMAN-TCM. ResultsThe metabolomics and lipidomics profiles of plasma and heart in response to AMI and DQTM were significantly different. The AMI operation had a serious influence on metabolites in heart ischemia region, while DQTM had a greater impact on lipids in heart non-ischemia region. A total of 151 differential metabolites were identified, including mainly amino acids and fatty acids. Multiple metabolic pathways were disturbed after AMI and could be restored by DQTM, of which arachidonic acid metabolism was further validated with the predicted results of network pharmacology. ConclusionThe protective effects of DQTM on acute myocardial ischemia rats could be achieved through the regulation of multiple metabolic pathways.

Study on the herb-herb interaction of Danqi Tongmai Tablet based on the pharmacokinetics of twelve notoginsenoides in acute myocardial ischemia and sham rats

Danqi Tongmai tablet (DQTT), an innovative TCM formula under clinical trials, is composed of salvianolic acids (SA) and panax notoginsenosides (PNE) for the treatment of coronary heart disease and angina pectoris. However, the in vivo herb-herb interaction of DQTT remains unclear. In the present research, a rapid, reliable and sensitive method for quantitative analysis of multi-notoginsenoside in rat plasma based on ultra high performance liquid chromatography coupled with triple quadrupole mass spectrometry (UHPLC-TQ/MS) was established and then applied to explore the herb-herb interaction mechanism of DQTT based on the pharmacokinetics in acute myocardial ischemia (AMI) and sham rats after oral administration of DQTT and PNE. Compared with sham rats after oral administration of PNE, the values of AUC0-t for Rf and Rb2 were significantly higher in DQTT group. Compared with AMI rats after oral PNE, AUC0-t for NR1, Rg1, Re, Rb1, Rd, Rg2, Rb2, NR2, Rh1, F1 and F2 were significantly increased after oral administration of DQTT. These results hinted that SA could improve the bioavailability of notoginsenosides in AMI rats, which provides scientific information for better understanding the herb-herb interaction mechanism and offers a reference for clinical administration of DQTT. Additionally, the presently developed methodology was simple, robust, accurate, precise, and would be useful for the pharmacokinetic studies for all kinds of notoginsenosides and other herbal saponins.

Panax notoginsenoside saponins Rb1 regulates the expressions of Akt/ mTOR/PTEN signals in the hippocampus after focal cerebral ischemia in rats

Panax notoginsenoside saponins Rb1 (PNS-Rb1) is an important active ingredient of panax notoginseng for effective treatment of cerebrovascular diseases. However, the mechanism underlying its actions in the state of cerebral ischemia is still unclear. We asked whether the potential neuroprotection of PNS-Rb1 on the brain is due to, at least partially, its modulation of AkT/mTOR/PTEN signalling pathway along with down-regulation of caspase-3 in rats subjected to phototrombic stroke. To test this hypothesis, rats with induced photothrombotic stroke were treated with PNS-Rb1 (applied in three different doses, 25 mg/kg, 50 mg/kg,100 mg/kg, respectively) or saline, while sham operated rats injected with saline were used as the control. Our results indicate that PNS-Rb1 significantly alleviated the morphological lesion concomitant with improvement of cognitive and sensorimotor deficits induced by ischemic stroke. Moreover, immunohistochemistry and Western blot analyses showed that PNS Rb1 in a dose dependent manner increased the expressions of P-Akt, P-mTOR and reduced P-PTEN and caspase-3. The present study suggests that the improvement of cognitive and sensorimotor deficits by PNS-Rb1 is made, at least partially, by the modulation of the Akt/mTOR/PTEN signalling pathway.

Notoginsenoside R1 prevents H9c2 cardiomyocytes apoptosis against hypoxia/reoxygenation via the ERs/PI3K/Akt pathway

Notoginsenoside R1 (NGR1) is separate from Panax notoginsenosides (PNS), and plays a role similar to phytoestrogen in preventing and treating cardiovascular diseases. However, the protective mechanism of NGR1 in the myocardial ischemia/reperfusion injury via the estrogen receptor (ER) pathway remains unclear, which hinder its application. This study aimed to study the preventive mechanisms of NGR1 in the apoptosis of H9c2 cardiomyocytes after hypoxia/reoxygenation (H/R). NGR1 did not affect the expression of ERα and ERβ proteins in normal H9c2 cardiomyocytes. However, NGR1 could upregulate the ERα and G protein-coupled receptor 30 (GPR30) proteins in H9c2 cardiomyocytes after H/R without affecting ERβ levels. Moreover, it significantly affected the expression levels of PI3K and its downstream apoptosis proteins such as Bcl-2 Associated X Protein (Bax), B cell lymphoma/lewkmia-2 (Bcl-2), caspase-3, and so forth. Whereas, after adding the PI3K protein antagonist, the modulatory expression levels of PI3K and its downstream apoptosis proteins were remarkably abolished. After adding ERα and GPR30 antagonists, NGR1 had no significant effect on the expression of PI3K and its downstream Akt protein in the model group. The data of flow cytometry showed that after adding the ERα, GPR30 and PI3K antagonists, the apoptotic rate of cardiomyocytes had no significant changes compared with the model group. This study demonstrated that NGR1 protected H9c2 cardiomyocytes from the injury after H/R by affecting ERα and GPR30 to regulate the expression levels of PI3K and its downstream apoptosis proteins.

αvβ3 integrin receptor specific peptide modified, salvianolic acid B and panax notoginsenoside loaded nanomedicine for the combination therapy of acute myocardial ischemia

PurposeTo achieve the combination therapy of acute myocardial ischemia, arginyl-glycyl-aspartic acid (RGD) conjugated lipid was synthesized and RGD modified, salvianolic acid B (Sal B) and panax notoginsenoside (PNS) co-loaded lipid-polymer hybrid nanoparticles (RGD-S/P-LPNs) was fabricated an evaluated. MethodsRGD was conjugated to distearoyl phosphatidylethanolamine-polyethylene glycol (DSPE-PEG-NH2) through amide linkage. Lipid-polymer hybrid nanoparticles (LPNs) were fabricated by nanoprecipitation method. RGD-S/P-LPNs was characterized in terms of morphology, size, charge, drug loading, entrapment, stability, drug release and cytotoxicity in vitro. Cardiac distribution, pharmacokinetics study and infarct therapy effect were evaluated in vivo. ResultsThe LPNs are generally spherical in shape with uniform size distribution, have sizes of 100–200nm and zeta potentials range from −30.7∼ −39.8. In vitro release behaviors of drugs loaded LPNs are in a sustained release manner, which does not exhibit obviously cytotoxicity against H9c2 cardiomyocytes. RGD-S/P-LPNs group shows the most significant cardiac distribution and infarct therapy effect in vivo. ConclusionThe results illustrated that RGD modified dual drugs co-loaded LPNs are stable, sustained release carriers. Cardiac distribution, pharmacokinetics, and infarct therapy effect results suggested that the RGD-S/P-LPNs could improve the in vivo therapeutic efficacy of the double drugs.

Low Cerebral Exposure Cannot Hinder the Neuroprotective Effects of Panax Notoginsenosides.

A bidirectional route of communication between the gastrointestinal tract and the central nervous system, termed the "gut-brain axis," is becoming increasingly relevant to treatment of cerebral damage. Panax Notoginsenoside extract (PNE) is popular for prevention and treatment of cardio-cerebrovascular ischemic diseases although plasma and cerebral exposure levels are extremely low. To date, the mechanisms underlying the neuroprotective effects of PNE remain largely unknown. In the present study, the neuroprotective effects of PNE were systematically studied via investigation of the regulation by PNE of the gastrointestinal microbial community and γ aminobutyric acid (GABA) receptors. The results demonstrated that pretreatment with PNE exerted a remarkable neuroprotective effect on focal cerebral ischemia/reperfusion (I/R) injury in rats, and the efficiency was attenuated in germ-free rats. Pretreatment with PNE could significantly prevent downregulation of Bifidobacterium longum (B.L) caused by I/R surgery, and colonization by B.L could also exert neuroprotective effects. More importantly, both PNE and B.L could upregulate the expression of GABA receptors in the hippocampus of I/R rats, and coadministration of a GABA-B receptor antagonist could significantly attenuate the neuroprotective effects of PNE and B.L. The study above suggests that the neuroprotective effects of PNE may be largely attributable to its regulation of intestinal flora, and oral treatment with B.L was also useful in therapy of ischemia/reperfusion injury (I/R) by upregulating GABA-B receptors.

Combination of ginsenoside Rb1 and Rd protects the retina against bright light-induced degeneration

Photoreceptor degeneration is a central pathology of various retinal degenerative diseases which currently lack effective therapies. Antioxidant and anti-inflammatory activities are noted for Panax notoginsenoside saponins (PNS) and related saponin compound(s). However, the photoreceptor protective potentials of PNS or related saponin compound(s) remain unknown. The current study revealed that PNS protected against photoreceptor loss in bright light-exposed BALB/c mice. Combination of ginsenoside Rb1 and Rd, two major saponin compounds of PNS, recapitulated the retinal protection of PNS and attenuated retinal oxidative stress and inflammatory changes. Rb1 or Rd partially alleviated all-trans-Retinal-induced oxidative stress in ARPE19 cells. Rb1 or Rd suppressed lipopolysaccharides (LPS)-induced proinflammatory gene expression in ARPE19 and RAW264.7 cells. Rb1 or Rd also modulated the expression of proinflammatory microRNA, miR-155 and its direct target, anti-inflammatory SHIP1, in LPS-stimulated RAW264.7 cells. The retinal expression of miR-155 and SHIP1 was altered preceding extensive retinal damage, which was maintained at normal level by Rb1 and Rd combination. This work shows for the first time that altered expression of miR-155 and SHIP1 are involved in photoreceptor degeneration. Most importantly, novel retinal protective activities of combination of Rb1 and Rd justify further evaluation for the treatment of related retinal degenerative disorders.

Stability of Xuesaitong capsules in gastrointestinal lavage fluid

ObjectiveTo obtain a formulation with high bioavailability through evaluation of the stability of three types of Xuesaitong capsules in the stomachs and intestines of rats. We compared the stability of the Panax notoginsenoside R1 as well as the ginsenosides Rg1, Rb1, Re, and Rd in different formulations. MethodsArtificial stomach fluid (ASF) and artificial intestinal fluid (AIF) were prepared. Stability of three types of Xuesaitong capsules was examined for 4 h in stomachs and 24 h in intestines. Samples were analyzed at different times by high-performance liquid chromatography. Percent content of NGR1, GRg1, GRb1, GRe, and GRd at different times was calculated. ResultsHard capsules incubated in ASF disintegrated within 2–3 min, whereas soft capsules disintegrated within 7–8 min. Components in hard capsules were dissolved rapidly in water, with content of each compound reaching 90% in 5 min, and degradation of each compound reaching 30–50% after incubation for 240 min. Dissolution and degradation of each component in soft capsules with a water-soluble base tended to balance at 30–90 min. Contents in soft capsules with a lipid-soluble base showed slow dissolution after ASF incubation for 120 min. Five saponins in identical types of capsules incubated in ASF had similar stability curves. Contents of hard capsules and soft capsules with a water-soluble base degraded rapidly within 30 min and reached a plateau when Xuesaitong capsules were incubated in AIF. ConclusionsContents of capsules with a lipid-soluble base degraded slower than the other two types of capsules incubated in ASF and AIF, suggesting that they may have better bioavailability.

Possible mechanism of PNS protection against cisplatin-induced nephrotoxicity in rat models

This study investigates the mechanism of the protective effect of Panax notoginsenosides (PNS) against cisplatin-induced nephrotoxicity via the hypoxia inducible factor 1 (HIF-1)/Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) pathway of autophagy. The rats underwent intraperitoneal injection with a single dose of cisplatin and a subset of rats were also intraperitoneally injected with 31.35 mg/kg PNS once a day. After 24 h exposure to cisplatin, the concentrations of urinary N-acetyl-β-d-glucosaminidase (NAG), blood urea nitrogen (BUN) and serum creatinine (Scr) were determined. The rat renal tissue was examined using H&E-staining, and the mitochondria of renal tubular epithelial cells were observed using transmission electron microscopy. The expressions of microtubule-associated protein-1 light chain (LC)3, autophagy-related gene (Atg)5, Beclin-1 and BNIP3 in rat renal tissue were detected using western blotting. The expression of HIF-1 was detected by immunohistochemistry. The results showed that PNS significantly protected against cisplatin-induced nephrotoxicity, as evidenced by decreasing the concentration of blood BUN and Scr, the attenuation of renal histopathological changes and the mitochondrial damages of renal cells, and the increase of mitochondria autophagosome in renal tubular epithelial cells. Additionally, PNS significantly increased the expression of LC3 and the ratio of LC3II/LC3I in rat renal tissue. Moreover, PNS significantly increased the expression of HIF-1α, BNIP3, Atg5 and Beclin-1 in rat renal tissue. In conclusion, the protective effect of PNS on cisplatin-induced nephrotoxicity was mainly due to its ability to enhancing the mitochondrial autophagy of renal tissue via the HIF-1α/BNIP3 pathway, and here is the first demonstration about it.

Panax notoginseng and Ginsenoside‐Rg1 contribute to down‐regulation of P‐glycoprotein level after the cerebral ischemia/reperfusion in rats

The blood‐brain barrier possesses active transporters carrying brain‐permeable xenobiotics, including many kinds of medicine, back into the blood against injuries. P‐glycoprotein(P‐gp), one kind of important multidrug resistance transporter, is upregulated on capillary endothelium after cerebral ischemia, which may refer as to protect the brain from the poison but may result in the treatment failure of the stroke. Panax notoginseng, a traditional Chinese medicine, has been used for thousands of years to treat ischemic patients. Panax notoginsenoside (PNS) is primarily composed of ginsenosides. Ginsenoside ‐Rg1 is an important part of saponin components in PNS. As such, here we aimed to study the role of PNS and ginsenosides Rg1 against overexpression of P‐glycoprotein in experiment induced cerebral ischemia–reperfusion (I/R) adult in rats. Male SD rats were randomly divided into sham‐injured, vehicle, PNS or Rg1 groups. The expression of P‐gp in cortex, hippocampus, striatum were detected by Imunohisochemistry, Western blot and RT‐PCR. The results show that PNS or Rg1 significantly reduced P‐gp in cortex and striatum infarction area caused by cerebral I/R. The increased expressions of P‐gp caused by cerebral I/R were restored with PNS treatment groups, as well as in Rg1 treatment groups. These results suggest that PNS and Rg1 have similar roles in adjusting overexpression of P‐gp from ischemic/reperfusion damage. PNS could be considered as an inhibitor of P‐gp in brain injuries therapy strategy for use in the case of cerebral ischemic stroke.

Preparation, Characterization, and Dissolution Rate In Vitro Evaluation of Total Panax Notoginsenoside Nanoparticles, Typical Multicomponent Extracts from Traditional Chinese Medicine, Using Supercritical Antisolvent Process

Total Panax notoginsenosides nanoparticles, typical multicomponent extracts from traditional Chinese medicine, were prepared with a supercritical antisolvent (SAS) process using ethanol as solvent and carbon dioxide as antisolvent. The optimum conditions were determined to be as follows: TPNS solution concentration of 2.5 mg/mL, TPNS solution flow rate of 6.6 mL/min, precipitation temperature of 40°C, and precipitation pressure of 20 MPa. Under the optimum conditions, TPNS nanoparticles with a MPS of 141.5 ± 18.2 nm and total saponins amounts (TSA) of 78.9% were obtained. The TPNS nanoparticles obtained were characterized by scanning electron microscopy (SEM), dynamic light scattering (DLS), Fourier‐transform infrared spectroscopy (FTIR), differential scanning calorimeters (DSC), and high performance liquid chromatography (HPLC). The results showed that the chemical and crystal structure of the obtained TPNS nanoparticles has not changed. Dissolution in vitro studies showed that the solubility and dissolution rate of notoginsenosides R1 and ginsenoside Rb1 in TPNS nanoparticles are higher than these in raw TPNS, with no obvious difference in Rg1. These results suggest that TPNS nanoparticles can be helpful to the improvement of its bioavailability for the treatment of cardiovascular diseases.

Enhanced local bioavailability of single or compound drugs delivery to the inner ear through application of PLGA nanoparticles via round window administration.

In this paper, the potential of poly(d,l-lactide-co-glycolide acid) (PLGA) nanoparticles (NPs) for carrying single or compound drugs traversing the round window membrane (RWM) was examined after the round window (RW) administration of different NPs to guinea pigs. First, coumarin-6 was incorporated into PLGA NPs as a fluorescent probe to investigate its ability to cross the RWM. Then, PLGA NPs with salvianolic acid B (Sal B), tanshinone IIA (TS IIA), and total panax notoginsenoside (PNS) including notoginsenoside R1 (R1), ginsenoside Rg1 (Rg1), and ginsenoside Rb1 (Rb1) were developed to evaluate whether NPs loaded with compound drugs would pass through the RWM and improve the local bioavailability of these agents. PLGA NPs loaded with single or compound drugs were prepared by the emulsification solvent evaporation method, and their particle size distribution, particle morphology, and encapsulation efficiency were characterized. In vitro release study showed sustained-release profiles of Sal B, TS IIA, and PNS from the NPs. The pharmacokinetic results showed that NPs applied to the RWM significantly improved drug distribution within the inner ear. The AUC0–t of coumarin-6 in the perilymph (PL) following RW administration of NPs was 4.7-fold higher than that of coumarin-6 solution, and the Cmax was 10.9-fold higher. Furthermore, the AUC0–t of R1, Rg1, and Rb1 were 4.0-, 3.1-, and 7.1-fold greater, respectively, after the application of NPs compared to the compound solution, and the Cmax were, respectively, 14.4-, 10.0-, and 16.7-fold higher. These findings suggest that PLGA NPs with unique properties at the nanoscale dimensions have a powerful ability to transport single or compound drugs into the PL through the RWM and remarkably enhance the local bioavailability of the encapsulated drugs in the inner ear. The use of PLGA NPs as nanoscale delivery vehicles to carry drugs across the RWM may be a promising strategy for the treatment of inner ear diseases.

Advance in studies of Panax notoginseng saponins on pharmacological mechanism of nervous system disease

The pharmacological mechaisms of Panax notoginseng saponins on nervous system diseases (Alzheimer's disease, Parkinson's disease, ischermic cerebral apoplexy and depressive disorder) , including panax notoginseng saponins, protoparaxotriol saponins, panasadiol saponins, ginsenoside Rg1, ginsenoside Rb1, ginsenoside Re and notoginsenoside R1 were summarized to analyze the study hotspots and potential advantages (such as estrogen-like effect) of notoginsenoside's pharmacological actions, provide reference for further pharmacological studies and new ideas for clinical treatment of nervous system diseases and drug studies and development.