As the important active ingredients of Astragali Radix (AR), Astragalus polysaccharides (APs) have therapeutic potential for multiple diseases including nervous system diseases, cardiovascular ...diseases, diabetes mellitus, and cancer. A large number of cell experiments combined with animal experiments have shed light on the therapeutic mechanisms and therapeutic effects of APs on a variety of diseases. However, the clinical application of APs is not widespread, except for the use of injected APs in the clinical adjuvant therapy of cancer. Due to the excessive molecular weight, bulky, low solubility and negatively charged characteristics, APs have low bioavailability which limits their clinical application. With the deepening of researches on the pharmaceutics of APs, the nanocrystals and moderate structural modification enormously boost the bioavailability, which may expand the application of APs. This review summarizes the studies in pharmacodynamic properties and pharmaceutics of APs, with the purpose of providing experimental researches and clinical application data for expanding the clinical development through expounding the therapeutic mechanisms and pharmaceutical researches of APs.
•The therapeutic mechanisms of Astragalus polysaccharides (APs) were reviewed.•The researches of APs nanoparticles and structural modifications were reviewed.•The effects of molecular weights and structure on pharmacodynamics were discussed.•The relationship of gut microbiome on APs was discussed.•The objective limitations of APs researches were discussed.
Formononetin is a type of phytoestrogen obtained from the Chinese medical herb Red Clover. It exhibits anti-neoplastic hepatoprotective, and neuroprotective properties. However, the anti-inflammatory ...effect of formononetin in cerebral ischemia-reperfusion injury has not been reported.
To explore the potential mechanism of action of formononetin in cerebral ischemia-reperfusion injury with regard to the JAK2/STAT3 signaling pathway.
Male SD rats were used to establish a middle cerebral artery occlusion (MCAO) model and randomly divided into 5 groups: Sham, MCAO, JAK2 Inhibitor (Ag490), Formononetin, Inhibitor + Formononetin. The protective effect of formononetin in MCAO rats was detected by performing neurological deficit testing, TTC staining, H&E staining, Nissl staining, ELISA, RT-PCR, western blotting and immunofluorescence.
Formononetin significantly alleviated the neurological deficit and the pathological state of brain tissues, and reduced the volume of cerebral infarction, levels of IL-18 and TNF-α inflammatory factors in plasma, mRNA levels of IL-6 and IL-1β in rat brain tissue, and the protein levels of p-JAK2, p-STAT3, NLRP3, ASC, cl-Caspase-1, and cl-IL-1β in the MCAO rat brain tissue.
Formononetin has anti-inflammatory effects. It may inhibit the relevant targets in the JAK2/STAT3 signaling pathway, thereby having a certain protective effect against cerebral ischemia-reperfusion injury.
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•Formononetin can improve the neurological function in MCAO rats.•Formononetin and Ag490 can reduce the levels of inflammation-related mRNA and proteins.•Formononetin can protect against inflammation by inhibiting the JAK2/STAT3 signaling pathway.
Ischemic stroke is a worldwide complex brain disease that results in numerous disabilities and deaths. It leads to the deprivation of oxygen and glucose, which causes energy failure and neuronal ...death. The activation of astrocytes contributes to neuronal damage or repair after brain ischemia/reperfusion, although astrocytes get little attention as potential drug targets. This study investigated the protective effects of Astragaloside IV (AS-IV) on oxygen glucose deprivation/reoxygenation (OGD/R)-induced damage in rat primary cultured astrocytes and the underlying molecular mechanism. The results showed that compared with the control group, astrocytes under OGD/R exposure significantly decreased cell viability and increased the number of apoptotic cells, whereas AS-IV evidently protected the astrocytes against OGD/R-induced cell damage. In addition, low and medium concentrations of AS-IV can promote the increase of intracellular superoxide dismutase (SOD) level, as well as restored the morphological changes caused by OGD/R exposure. Supplementation with AS-IV after OGD/R exposure promoted the expression of oxidation and apoptosis indexes and further study demonstrated that AS-IV inhibited CXCR4 receptor and downregulated the activation of p-JNK/JNK pathway, which suppressed the expression of Bax/Bcl-2, and finally uprising Nrf2/Keap1 signaling. In conclusion, these findings revealed that AS-IV protected against OGD/R-induced astrocytes through inhibiting oxidative stress and apoptotic pathways.
Natural deep eutectic solvents (NaDESs) are recently developed green solvent alternatives to conventional fossil solvents. The present work systematically screened 22 different NaDESs for the ...ultrasonic-assisted extraction of bioactive components from
(SM), a widely used traditional Chinese medical plant. The suitable solvent and extraction condition were optimized in a two-round screening. In comparison with fossil solvents, NaDESs, especially L-proline-lactic acid (L-Pro-Lac) showed significant advantages in the extraction of salvianolic acid B (SAB), tanshinone IIA (TIIA) and cryptotanshinone (CYT). The optimized yields of the three targeting compounds were 42.05, 1.485 and 0.839 mg/g, respectively. The present method was also applied to the pretreatment of SM samples from different geographic origins. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activities of NaDES extracts were determined in the study to prove the feasibility of NaDES in bioactive component extraction. The application of NaDESs in the extraction of both hydrophilic and hydrophobic small molecules from SM is proved to be a green and efficient method for pretreatment of herbal materials.
Natural deep eutectic solvent (NaDES) is generally considered as a greener alternative to fossil solvent, with great potential in various areas. In the present work, 25 different NaDESs were screened ...for the extraction of puerarin (PUE) and its two natural derivatives from
(RP). As the main isoflavone in RP, PUE has a wide range of biological activities. However, its application is restricted due to its poor solubility in water and low oral bioavailability. In this study, the extraction of PUE with NaDESs showed significant advantages compared with traditional solvents. While using L-Pro-Maa (L-proline-malic acid) under optimal conditions, the optimized yields of PUE, 3-MPR and PRX were 98.7 mg/g, 16.3 mg/g and 9.9 mg/g, respectively, which were 2.2-, 2.9- and 3.4-fold higher than that of water. Furthermore, the oral bioavailability of PUE in NaDES extracts was comparatively investigated in rats with HPLC-MS technique. Pharmacokinetic analysis revealed that the relative bioavailability of PUE in L-Pro-Maa extract is 323%. The result indicated that NaDES is not only a sustainable ionic liquid with higher extraction efficiency, but also an enhancer of oral bioavailability of specific natural products.
Danhong injection (DHI) is a compound Chinese medicine widely used in China for treatment of ischemic cardio-cerebrovascular diseases. However, limited data are available regarding the protective ...effect of DHI on the ischemic penumbra in ischemic stroke. This study aimed to investigate the effect of intravenous DHI on neuronal injure in the ischemic penumbra after cerebral ischemia/reperfusion (CI/R), focusing especially on the involvement of intracellular energy metabolism coupling. Male Sprague-Dawley rats were subjected to right middle cerebral artery occlusion for 60 min followed by reperfusion with or without intravenous DHI (0.5, 1.0, or 2.0 mL/kg) once daily for 7 days. Post-treatment with DHI ameliorated neurological defects, diminished cerebral infarction, alleviated cerebral edema, improved microcirculatory perfusion after 7days of reperfusion, and inhibited apoptosis and enhanced neuronal survival in the ischemic penumbra. In addition, DHI significantly ameliorated oxidative stress, reduced DNA damage, and inhibited the activation of PARP1/AIF pathway, thereby restoring cytoplasmic glycolytic activity. Furthermore, this drug increased PDH activity by inhibiting the HIF1α/PDK1 signaling pathway, thus eliminating the inhibitory effect of CI/R on mitochondrial metabolism. The results of this study suggest that DHI can alleviate cerebral edema after CI/R and rescue the ischemic penumbra, and these protective effects are due to the regulation of intracellular energy metabolic coupling.
A diagrammatic sketch showing the protective effect of DHI on CI/R-elicited ischemic penumbra injury. CI/R inhibits cytoplasmic glycolysis and triggers parthanatos by activating the PARP1/ AIF signaling pathway, and downregulates PDH activity by activating the HIF1α/PDK1 signaling pathway, thereby reducing intracellular ATP production and resulting in neuronal death in the ischemic penumbra. Brain edema induced by ATP deficiency aggravates microvascular hypoperfusion and further promotes the destruction of ischemic penumbra. DHI reverses these changes and mitigates injure to the ischemic penumbra. Display omitted
Salvianolic acid C (SAC) is a major bioactive component of
(Danshen), a Chinese herb for treating ischemic stroke (IS). However, the mechanism by which SAC affects the IS has not yet been evaluated, ...thus a network pharmacology integrated molecular docking strategy was performed to systematically evaluate its pharmacological mechanisms, which were further validated in rats with cerebral ischemia. A total of 361 potential SAC-related targets were predicted by SwissTargetPrediction and PharmMapper, and a total of 443 IS-related targets were obtained from DisGeNET, DrugBank, OMIM, and Therapeutic Target database (TTD) databases. SAC-related targets were hit by the 60 targets associated with IS. By Gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment combined with the protein-protein interaction (PPI) network and cytoHubba plug-ins, nine related signaling pathways (proteoglycans in cancer, pathways in cancer, PI3K-Akt signaling pathway, Focal adhesion, etc.), and 20 hub genes were identified. Consequently, molecular docking indicated that SAC may interact with the nine targets (F2, MMP7, KDR, IGF1, REN, PPARG, PLG, ACE and MMP1). Four of the target proteins (VEGFR2, MMP1, PPARγ and IGF1) were verified using western blot. This study comprehensively analyzed pathways and targets related to the treatment of IS by SAC. The results of western blot also confirmed that the SAC against IS is mainly related to anti-inflammatory and angiogenesis, which provides a reference for us to find and explore the effective anti-IS drugs.
Hydroxysafflor yellow A (HSYA) is derived from
L. (Honghua in Chinese) and is used to treat cardiovascular and cerebrovascular disease. However, the mechanism by which HSYA treats ischemic stroke ...following atherosclerosis (ISFA) remains unclear. The targets and pathways of HSYA against ISFA were obtained using network analysis. A total of 3335 potential IFSA-related targets were predicted using the GenCards and Drugbank databases, and a total of 88 potential HSYA-related targets were predicted using the Swiss Target Prediction database. A total of 62 HSYA-related targets against IFSA were obtained. The network was composed of HSYA, 62 targets, and 20 pathways. The top 20 targets were constructed via the protein-protein interaction (PPI) network. Gene Ontology analysis revealed that the targets were involved in signal transduction, protein phosphorylation, the cytoplasm, the plasma membrane, the cytosol, zinc ion binding, ATP binding, protein kinase binding/activity, and enzyme binding. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that the pathways were associated with cancer, inflammatory mediator regulation of the transient receptor potential channels, and microRNA in cancer. Additionally, molecular docking indicated that HSYA mainly interacts with five targets, namely interleukin 1 beta (IL-1β), signal transducer and activator of transcription 3 (STAT3), E1A-binding protein p300 (EP300), protein kinase C alpha (PRKCA), and inhibitor of nuclear factor kappa B kinase subunit beta (IKBKB). In animal experiments, HSYA administration ameliorated the infarct size, neurological deficit score, histopathological changes, carotid intima-media thickness (IMT), and blood lipid level (total cholesterol and triglycerides). Immunochemistry and quantitative PCR showed that HSYA intervention downregulated the expression of STAT3, EP300, PRKCA, and IKBKB, and the enzyme-linked immunoassay showed reduced IL-1β levels. The findings of this study provide a reference for the development of anti-ISFA drugs.
Astragalus and Safflower are commonly used in the treatment of stroke. Studies have shown that their two active components, hydroxysafflor yellow A (HSYA) and calycosin (CA), have protective effects ...on cerebral ischemia-reperfusion injury (I/R). However, the pharmacokinetic-pharmacodynamic (PK-PD) modeling study of the combination of the two components has not been reported in rats. The study aimed to perform combined PK-PD modeling of HSYA and CA in normal and cerebral ischemia model rats to explain quantitatively their time-concentration-effect relationship.
To make the middle cerebral artery occlusion (MCAO) model. SD rats were randomly divided into normal treated group (NTG) (n = 6), model group (MDG) (n = 6) and model treated group (MTG) (n = 6). Plasma was collected from the mandibular vein after 0, 2, 5, 10, 15, 20, 30, 45, 60, 75, 90, 120, 180, and 240 min after intravenous administration. Rats in NTG and MTG were administered the same dose of HSYA (5 mg/kg) and CA (8 mg/kg) by tail vein injection. HPLC-VWD method was used for detection and analysis. Simultaneously, ELISA was performed to detect the levels of IL-1β and caspase-9 in rat plasma at different time points. The improvement in the above indicators was compared after administration. Lastly, after combining the pharmacokinetic parameters and pharmacodynamic indicators in vivo, DAS 3.2.6 software was used to fit the PK-PD model.
The MCAO model was successfully established. Compared to NTG, there was a significant difference (P < 0.05) in t1/2α, t1/2β, V1, V2, CL1, CL2, AUC(0−t), AUC (0-∞), and K12 of MTG for HSYA, and there was a significant difference (P < 0.05) in t1/2α, V1, CL1, AUC(0−t), AUC (0-∞), and K10 of MTG for CA. Compared to NTG, the PK parameters of t1/2α, V1, V2, CL1, and K10 were higher for HSYA in MTG, while AUC(0−t), AUC (0-∞), K12, and K21 were lower; the PK parameters of t1/2α, V1, V2, AUC(0−t), and AUC(0-∞) were higher for CA in MTG, while CL1, CL2, K10, K12, and K21 were lower. Also, the results of PD showed extremely significant differences in the levels of caspase-9 and IL-1β at the different time points in MTG (P < 0.01) compared with 0 min. The levels of caspase-9 and IL-1β in NTG rats showed little fluctuation and were relatively stable; however, their levels in MTG showed a downward trend with time. There were highly significant differences in the levels of each of the pharmacodynamic indicators at every time point between NTG and MTG (P < 0.01).
The PK-PD model of the combined administration of HSYA and CA was successfully established in rats, and the differences in pharmacodynamic and pharmacokinetic properties between the normal and cerebral ischemic rats were evaluated. Based on comprehensive data analysis, we found that the combination of HSYA and CA may exert protective effects against I/R injury in rats via anti-apoptotic and anti-inflammatory pathways. The study provided additional insights into the development of drugs for ischemic stroke as well as the design of appropriate dosing regimens.
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•An HPLC-VWD method for the determination of HSYA and CA in different samples.•The bioavailability of CA increased in cerebral ischemic rats.•The first study for PK-PD model of HSYA and CA in normal and cerebral ischemic rats.•A sigmoid Emax function was utilized to establish the PK-PD model.
Cerebral ischemia threatens human health and life. Hyperlipidemia is a risk of cerebral ischemia. Danhong injection (DHI) is a traditional Chinese medical preparation for the treatment of ...cerebrovascular diseases. However, the effects of DHI on mitochondria-dependent apoptosis and mitochondrial function following cerebral ischemia in hyperlipidemia rats are not clear. In this study, SD rats were fed by high-fat diet for six weeks to establish the hyperlipidemia model, except for the sham and ischemia-reperfusion (I/R) groups. Hyperlipidemia rats were assigned into I/R + high-fat diet (HFD) group, DHI 1 mL/kg group, and DHI 2 mL/kg group. DHI was administrated to the drug group via caudal vein for seven consecutive days (once per day). Subsequently, rats underwent middle cerebral artery occlusion (MCAO) for 1 h and reperfusion for 24 h. The results showed that DHI significantly reduced cerebral infarction volume, ameliorated neurological function, improved pathological changes, and inhibited apoptosis. DHI could significantly restore the levels of mitochondrial respiratory chain complexes I-IV, increase the ATP content and COX activity, and decrease the level of OFR in the ischemic brain mitochondria of hyperlipidemia rats after I/R. DHI significantly regulated the levels of cytochrome c (Cyt c), Apaf1, Bax, Bcl-2, Caspase-3, and Caspase-9 in brain tissue, and improved mitochondrial dynamics (Mfn1, Mfn2, OPA1, Drp1, and Fis1). The results indicate that DHI could alleviate ischemic brain injury in hyperlipidemia rats, and the mechanism may be to improve mitochondrial function by restoring the mitochondrial respiratory chain and changing the protein balance of mitochondrial fusion and fission, and inhibiting mitochondria-dependent apoptosis.
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•Danhong injection (DHI) protects against cerebral ischemia-reperfusion injury (CIRI) in hyperlipidemia rats.•DHI may exert its protection via restoring the mitochondrial respiratory chain and changing the protein balance of mitochondrial fusion and fission, and inhibiting mitochondria-dependent apoptosis.
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