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.
Display omitted
•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.
Differential evolution of apoptosis, programmed necrosis, and autophagy, parthanatos is a form of cell death mediated by poly(ADP-ribose) polymerase 1 (PARP1), which is caused by DNA damage. PARP1 ...hyper-activation stimulates apoptosis-inducing factor (AIF) nucleus translocation, and accelerates nicotinamide adenine dinucleotide (NAD+) and adenosine triphosphate (ATP) depletion, leading to DNA fragmentation. The mechanisms of parthanatos mainly include DNA damage, PARP1 hyper-activation, PAR accumulation, NAD+ and ATP depletion, and AIF nucleus translocation. Now, it is reported that parthanatos widely exists in different diseases (tumors, retinal diseases, neurological diseases, diabetes, renal diseases, cardiovascular diseases, ischemia-reperfusion injury...). Excessive or defective parthanatos contributes to pathological cell damage; therefore, parthanatos is critical in the therapy and prevention of many diseases. In this work, the hallmarks and molecular mechanisms of parthanatos and its related disorders are summarized. The questions raised by the recent findings are also presented. Further understanding of parthanatos will provide a new treatment option for associated conditions.
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.
A significant amount of evidence from the past few years has shown that Sirtuin 1 (SIRT1), a histone deacetylase dinucleotide of nicotinamide adenine dinucleotide (NAD
+
) is closely related to the ...cerebral ischemia. Several potential neuroprotective strategies like resveratrol, ischemia preconditioning, and caloric restriction exert their neuroprotection effects through SIRT1-related signaling pathway. However, the potential mechanisms and neuroprotection of SIRT1 in the process of cerebral ischemia injury development and recovery have not been systematically elaborated. This review summarized the the deacetylase activity and distribution of SIRT1 as well as analyzed the roles of SIRT1 in astrocytes, microglia, neurons, and brain microvascular endothelial cells (BMECs), and the molecular mechanisms of SIRT1 in cerebral ischemia, providing a theoretical basis for exploration of new therapeutic target in future.
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.
Many traditional Chinese medicines, including Danhong injection (DHI), can be used to treat cerebral ischemia-reperfusion injury and have neuroprotective effects on the brain; however, few studies ...have explored the mechanism by which this effect is generated. In this study, we investigated the neuroprotective effect of DHI against cerebral ischemia-reperfusion injury mediated via the PI3K-Akt signaling pathway. After establishing the model of middle cerebral artery occlusion (MCAO), 60 male Sprague-Dawley rats were allocated to six groups as follows: sham, MCAO, DHI (MCAO + DHI), LY294002 (MCAO + LY294002 PI3K-Akt pathway specific inhibitor), DHI + LY294002 (MCAO + DHI + LY294002), and NMDP + LY294002 (MCAO + NMDP nimodipine + LY294002). Hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining were used to evaluate the pathological changes of brain tissue and the degree of neuronal apoptosis. Real-time quantitative polymerase chain reaction (qRT-PCR), western blot analysis and enzyme-linked immunosorbent assays were used to measure the expression of Bad, Bax, Bcl-2, Bim, P53, MDM2, Akt, PI3K, p-Akt, p-PI3K, and Cyt-C. Compared with the MCAO group, brain tissue cell apoptosis was significantly reduced in the DHI group, and the brain function score was significantly improved. In addition, the expression of pro-apoptotic factors (Bad, Bax, and Bim) was significantly downregulated in the DHI group, while expression of the anti-apoptotic factor Bcl-2 was significantly upregulated, and expression of the apoptotic gene p53 was also significantly attenuated. Moreover, this neuroprotective effect was attenuated by the PI3K-Akt signaling pathway inhibitor (LY294002). Thus, our results confirmed the neuroprotective effects of DHI in rats with ischemia-reperfusion injury and indicate that these effects on the brain are partly generated by activation of the PI3K-Akt signaling pathway.
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.
Traumatic brain injury (TBI) leads to structural damage in the brain, and is one of the major causes of disability and death in the world. Herein, we developed a composite injectable hydrogel ...(HA/Gel) composed of hyaluronic acid (HA) and gelatin (Gel), loaded with vascular endothelial growth factor (VEGF) and salvianolic acid B (SAB) for treatment of TBI. The HA/Gel hydrogels were formed by the coupling of phenol-rich tyramine-modified HA (HA-TA) and tyramine-modified Gel (Gel-TA) catalyzed by horseradish peroxidase (HRP) in the presence of hydrogen peroxide (H
O
). SEM results showed that HA/Gel hydrogel had a porous structure. Rheological test results showed that the hydrogel possessed appropriate rheological properties, and UV spectrophotometry results showed that the hydrogel exhibited excellent SAB release performance. The results of LIVE/DEAD staining, CCK-8 and Phalloidin/DAPI fluorescence staining showed that the HA/Gel hydrogel possessed good cell biocompatibility. Moreover, the hydrogels loaded with SAB and VEGF (HA/Gel/SAB/VEGF) could effectively promote the proliferation of bone marrow mesenchymal stem cells (BMSCs). In addition, the results of H&E staining, CD31 and α-SMA immunofluorescence staining showed that the HA/Gel/SAB/VEGF hydrogel possessed good in vivo biocompatibility and pro-angiogenic ability. Furthermore, immunohistochemical results showed that the injection of HA/Gel/SAB/VEGF hydrogel to the injury site could effectively reduce the volume of defective tissues in traumatic brain injured mice. Our results suggest that the injection of HA/Gel hydrogel loaded with SAB and VEGF might provide a new approach for therapeutic brain tissue repair after traumatic brain injury.
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
PDF
