Echinacoside ameliorates post-stroke depression by activating BDNF signaling through modulation of Nrf2 acetylation.

BACKGROUND: Post-stroke depression (PSD) affects approximately one-third of stroke survivors, leading to adverse outcomes in rehabilitation, reduced quality of life, and increased mortality rates. Despite these implications, the underlying causes of PSD remain unclear, posing challenges for prevention and treatment. Echinacoside (ECH), a natural compound with known neuroprotective and antidepressant properties, holds significant therapeutic potential for PSD. However, the precise mechanism of its action remains unknown. PURPOSE: To unravel the specific mechanism through which ECH alleviates PSD by exploring the intricate interplay between ECH and Nrf2, as well as its impact on the BDNF/TrkB signaling axis. STUDY DESIGN AND METHODS: A rat PSD model was established though middle cerebral artery occlusion coupled with chronic unpredictable mild stress, followed by ECH treatment. The rats' depressive state was evaluated using the sucrose preference test and force swimming test. Brain damage was assessed through TTC staining, Nissl staining, and TUNEL assay. The multifaceted mechanism of ECH in PSD was investigated using immunofluorescence, immunohistochemistry, RT-qPCR, dual-luciferase assay, and western blotting. Additionally, the interaction between ECH and Nrf2 was explored through molecular docking and microscale thermophoresis. RESULTS: Our findings unveiled a novel facet of ECH action, demonstrating its unique ability to upregulate Nrf2 through acetylation within the hippocampus of PSD-affected rats (p < 0.05). Moreover, ECH showcased its distinctive potential by enhancing BDNF transcriptional activity, activating the BDNF/TrkB signaling axis, and orchestrating a comprehensive response against oxidative stress and apoptosis, thereby alleviating PSD symptoms in rats (p < 0.05). CONCLUSIONS: This study not only provides insights into the pivotal role of Nrf2 in mediating the BDNF/TrkB axis activation by ECH but also highlights the novelty of ECH's mechanism in addressing PSD. The elucidation of these unique aspects positions ECH as a groundbreaking candidate for further exploration and development in the realm of PSD intervention.

Echinacoside exerts neuroprotection via suppressing microglial α-synuclein/TLR2/NF-κB/NLRP3 axis in parkinsonian models.

BACKGROUND: Echinacoside (ECH), a natural active compound, was found to exert neuroprotection in Parkinson's disease (PD). However, the underlying molecular mechanisms remain controversial. PURPOSE: This study aimed to explore the roles of ECH in PD and its engaged mechanisms. CONCLUSION: In vivo, MPTP was adapted to construct subacute PD mouse model to explore the regulation of ECH on NLRP3 inflammasome. In vitro, α-synuclein (α-syn)/MPP+ was used to mediate the activation of NLRP3 inflammasome in BV2 cells, and the mechanism of ECH regulation of it was explored with molecular docking, immunofluorescence, Western blotting, and small molecule inhibitors. CONCLUSION: The activation of microglial NLRP3 inflammasome could be evoked by MPTP in vitro, but its toxic metabolite MPP+ alone cannot trigger the activation of NLRP3 inflammasome in vitro, which requires α-synuclein (α-syn) priming. Exogenous α-syn could evoke microglial TLR2/NF-κB/NLRP3 axis, playing the priming role in MPP+ -mediated NLRP3 inflammasome activation. ECH can suppress the upregulation of α-syn in MPTP-treated mice and BV2 microglia. It can also suppress the activation of the TLR2/NF-κB/NLRP3 axis induced by α-syn. CONCLUSION: ECH exerts neuroprotective effects by downregulating the TLR2/NF-κB/NLRP3 axis via reducing the expression of α-syn in the PD models.

Echinacoside Prevents Sepsis-Induced Myocardial Damage via Targeting SOD2.

Echinacoside (ECH) is a prominent naturally occurring bioactive compound with effects of alleviating myocardial damage. We aimed to explore the beneficial effects of ECH against sepsis-induced myocardial damage and elucidate the potential mechanism. Echocardiography and Masson staining demonstrated that ECH alleviates cardiac function and fibrosis in the cecal ligation and puncture (CLP) model. Transcriptome profiling and network pharmacology analysis showed that there are 51 overlapping targets between sepsis-induced myocardial damage and ECH. Subsequently, chemical carcinogenesis-reactive oxygen species (ROS) were enriched in multiple targets. Wherein, SOD2 may be the potential target of ECH on sepsis-induced myocardial damage. Polymerase chain reaction results showed that ECH administration could markedly increase the expression of SOD2 and reduce the release of ROS. Combined with injecting the inhibitor of SOD2, the beneficial effect of ECH on mortality, cardiac function, and fibrosis was eliminated, and release of ROS was increased after inhibiting SOD2. ECH significantly alleviated myocardial damage in septic mice, and the therapeutic mechanism of ECH is achieved by upregulating SOD2 which decreased the release of ROS.

Sirtuin1 Mediates the Protective Effects of Echinacoside against Sepsis-Induced Acute Lung Injury via Regulating the NOX4-Nrf2 Axis.

Currently, the treatment for sepsis-induced acute lung injury mainly involves mechanical ventilation with limited use of drugs, highlighting the urgent need for new therapeutic options. As a pivotal aspect of acute lung injury, the pathologic activation and apoptosis of endothelial cells related to oxidative stress play a crucial role in disease progression, with NOX4 and Nrf2 being important targets in regulating ROS production and clearance. Echinacoside, extracted from the traditional Chinese herbal plant Cistanche deserticola, possesses diverse biological activities. However, its role in sepsis-induced acute lung injury remains unexplored. Moreover, although some studies have demonstrated the regulation of NOX4 expression by SIRT1, the specific mechanisms are yet to be elucidated. Therefore, this study aimed to investigate the effects of echinacoside on sepsis-induced acute lung injury and oxidative stress in mice and to explore the intricate regulatory mechanism of SIRT1 on NOX4. We found that echinacoside inhibited sepsis-induced acute lung injury and oxidative stress while preserving endothelial function. In vitro experiments demonstrated that echinacoside activated SIRT1 and promoted its expression. The activated SIRT1 was competitively bound to p22 phox, inhibiting the activation of NOX4 and facilitating the ubiquitination and degradation of NOX4. Additionally, SIRT1 deacetylated Nrf2, promoting the downstream expression of antioxidant enzymes, thus enhancing the NOX4-Nrf2 axis and mitigating oxidative stress-induced endothelial cell pathologic activation and mitochondrial pathway apoptosis. The SIRT1-mediated anti-inflammatory and antioxidant effects of echinacoside were validated in vivo. Consequently, the SIRT1-regulated NOX4-Nrf2 axis may represent a crucial target for echinacoside in the treatment of sepsis-induced acute lung injury.

[Echinacoside hampers malignant progression of breast cancer MCF-7 cells by modulating AKR1B10/ERK signal transduction].

This study analyzes the impact of echinacoside(ECH) in the proliferation, metastasis and adriamycin(ADR) resistance of breast cancer(BC) MCF-7 cells via the modulation of aldo-keto reductase family 1 member 10(AKR1B10)/extracellular signal-regulated kinase(ERK) pathway. The chemical structure of ECH was firstly confirmed. MCF-7 cells were treated with different concentration(0, 10, 20, 40 µg·mL~(-1)) of ECH for 48 h. Western blot was used to analyze expression of AKR1B10/ERK pathway-associated proteins and cell counting kit-8(CCK-8) assay to determine cell viability. MCF-7 cells were collected and classified into control group, ECH group, ECH + Ov-NC group, and ECH + Ov-AKR1B10 group. Then Western blot was employed to analyze the expression of AKR1B10/ERK pathway-associated proteins. CCK-8 and 5-ethynyl-2'-deoxyuridine(EdU) assay were used to examine cell proliferation. Cell migration was appraised with scratch assay, Transwell assay, and Western blot. Eventually, MCF-7 cells were treated with ADR for 48 h to induce ADR resistance. Cell viability was tested by CCK-8 assay and cell apoptosis was estimated based on terminal-deoxynucleoitidyl transferase mediated nick end labeling(TUNEL) assay and Western blot. Based on Protein Data Bank(PDB) and molecular docking, the binding affinity of ECH to AKR1B10 was assessed. Various doses of ECH decreased the expression of AKR1B10/ERK pathway-associated proteins in a dose-dependent manner and declined cell viability compared with the control group. Compared with the control group, 40 µg·mL~(-1) ECH blocked the AKR1B10/ERK pathway in MCF-7 cells and inhibited the proliferation, metastasis and ADR resistance of the cells. Compared with the ECH + Ov-NC group, ECH + Ov-AKR1B10 group showed the recovery of some biological behaviors of MCF-7 cells. ECH also targeted AKR1B10. ECH can inhibit the proliferation, metastasis, and ADR resistance of BC cells by blocking AKR1B10/ERK pathway.

Effects of a natural nutritional supplement on immune cell infiltration and immune gene expression in exercise-induced injury.

Inflammatory immune response plays a key role in exercise-induced injury and healing; however, the relevant regulatory mechanisms of immune infiltration in exercise-induced injuries remain less studied. In the present study, a highly efficient system for screening immunity-related biomarkers and immunomodulatory ability of natural nutritional supplements was developed by integrating intelligent data acquisition, data mining, network pharmacology, and computer-assisted target fishing. The findings demonstrated that resting natural killer cells showed a higher rate of infiltration after exercise, whereas naive B cells and activated dendritic cells showed higher rate of infiltration before exercise. Four key genes, namely PRF1, GZMB, CCL4, and FASLG, were associated with exercise-induced injuries and inflammatory immune response. In total, 26 natural compounds including echinacoside, eugenol, tocopherol, and casuariin were predicted by using the HERB databases. Molecular docking analysis showed that GZMB, FASLG, and CCL4 bound to echinacoside. In vivo experiments in mice showed that after 30 min swimming, natural killer (NK) cells showed high infiltration rates, and the key genes (GZMB, PRF1, FASLG, and CCL4) were highly expressed; however, echinocandin significantly reduced the level of NK cells and decreased the expression of the four key genes post exercise. This natural nutritional supplement may act to protect against inflammatory injury after exercise by suppressing specific immune infiltration.

Echinacoside inhibited cardiomyocyte pyroptosis and improved heart function of HF rats induced by isoproterenol via suppressing NADPH/ROS/ER stress.

Prevalence of heart failure (HF) continues to rise over time and is a global difficult problem; new drug targets are urgently needed. In recent years, pyroptosis is confirmed to promote cardiac remodelling and HF. Echinacoside (ECH) is a natural phenylethanoid glycoside and is the major active component of traditional Chinese medicine Cistanches Herba, which is reported to possess powerful anti-oxidation and anti-inflammatory effects. In addition, we previously reported that ECH reversed cardiac remodelling and improved heart function, but the effect of ECH on pyroptosis has not been studied. So, we investigated the effects of ECH on cardiomyocyte pyroptosis and the underlying mechanisms. In vivo, we established HF rat models induced by isoproterenol (ISO) and pre-treated with ECH. Indexes of heart function, pyroptotic marker proteins, ROS levels, and the expressions of NOX2, NOX4 and ER stress were measured. In vitro, primary cardiomyocytes of neonatal rats were treated with ISO and ECH; ASC speckles and caspase-1 mediated pyroptosis in cardiomyocytes were detected. Hoechst/PI staining was also used to evaluate pyroptosis. ROS levels, pyroptotic marker proteins, NOX2, NOX4 and ER stress levels were all tested. In vivo, we found that ECH effectively inhibited pyroptosis, down-regulated NOX2 and NOX4, decreased ROS levels, suppressed ER stress and improved heart function. In vitro, ECH reduced cardiomyocyte pyroptosis and suppressed NADPH/ROS/ER stress. We concluded that ECH inhibited cardiomyocyte pyroptosis and improved heart function via suppressing NADPH/ROS/ER stress.

Targeting UBR5 in hepatocellular carcinoma cells and precise treatment via echinacoside nanodelivery.

BACKGROUND: Hepatocellular carcinoma (HCC) is among the most common and malignant cancers with no effective therapeutic approaches. Echinacoside (ECH), a phenylethanoid glycoside isolated from Chinese herbal medicine, Cistanche salsa, can inhibit HCC progression; however, poor absorption and low bioavailability limit its biological applications. METHODS: To improve ECH sensitivity to HepG2 cells, we developed a mesoporous silica nanoparticle (MSN)-based drug delivery system to deliver ECH to HepG2 cells via galactose (GAL) and poly(ethylene glycol) diglycidyl ether (PEGDE) conjugation (ECH@Au@MSN-PEGDE-GAL, or ECH@AMPG). Gain- and loss-of-function assays were conducted to assess the effects of UBR5 on HCC cell apoptosis and glycolysis. Moreover, the interactions among intermediate products were also investigated to elucidate the mechanisms by which UBR5 functions. RESULTS: The present study showed that ubiquitin protein ligase E3 component N-recognin 5 (UBR5) acted as an oncogene in HCC tissues and that its expression was inhibited by ECH. AMPG showed a high drug loading property and a slow and sustained release pattern over time. Moreover, owing to the valid drug accumulation, ECH@AMPG promoted apoptosis and inhibited glycolysis of HepG2 cells in vitro. In vivo experiments demonstrated that AMPG also enhanced the antitumor effects of ECH in HepG2 cell-bearing mice. CONCLUSIONS: Our results indicated the clinical significance of UBR5 as a therapeutic target. On the basis of the nontoxic and high drug-loading capabilities of AMPG, ECH@AMPG presented better effects on HCC cells compared with free ECH, indicating its potential for the chemotherapy of HCC.

Echinacoside Alleviates Cognitive Impairment in Cerebral Ischemia Rats through α 7nAChR-Induced Autophagy.

OBJECTIVES: To evaluate the effect of echinacoside (ECH) on cognitive dysfunction in post cerebral stroke model rats. METHODS: The post stroke cognitive impairment rat model was created by occlusion of the transient middle cerebral artery (MCAO). The rats were randomly divided into 3 groups by a random number table: the sham group (sham operation), the MCAO group (received operation for focal cerebral ischemia), and the ECH group (received operation for focal cerebral ischemia and ECH 50 mg/kg per day), with 6 rats in each group. The infarct volume and spatial learning were evaluated by triphenyl tetrazolium chloride staining and Morris water maze. The expression of α7nAChR in the hippocampus was detected by immunohistochemistry. The contents of acetylcholine (ACh), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), activities of choline acetyltransferase (ChAT), acetylcholinesterase (AChE), and catalase (CAT) were evaluated by enzyme linked immunosorbent assay. The neural apoptosis and autophagy were determined by TUNEL staining and LC3 staining, respectively. RESULTS: ECH significantly lessened the brain infarct volume and ameliorated neurological deficit in infarct volume and water content (both P<0.01). Compared with MCAO rats, administration of ECH revealed shorter escape latency and long retention time at 7, 14 and 28 days (all P<0.01), increased the α7nAChR protein expression, ACh content, and ChAT activity, and decreased AChE activity in MCAO rats (all P<0.01). ECH significantly decreased MDA content and increased the GSH content, SOD, and CAT activities compared with MCAO rats (all P<0.05). ECH suppressed neuronal apoptosis by reducing TUNEL-positive cells and also enhanced autophagy in MCAO rats (all P<0.01). CONCLUSION: ECH treatment helped improve cognitive impairment by attenuating neurological damage and enhancing autophagy in MCAO rats.

Echinacoside Ameliorates Cyclophosphamide-Induced Bladder Damage in Mice.

Interstitial cystitis (IC) is featured by apoptosis and chronic inflammation in bladder tissue. We aimed to evaluate the effect of echinacoside (ECH), which is known to modulate inflammation and apoptosis on IC using relevant models. We established a mouse model of cystitis using cyclophosphamide (CYP) and treated human urothelium cells (SV-HUC-1) with lipopolysaccharide (LPS) + ATP as in vitro model. The bladder function was tested by urodynamics. Apoptosis of bladder cells was assessed by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Expressions of apoptosis-associated and inflammation-related proteins were assessed using western blotting. Treatment with ECH significantly improved bladder function, reduced inflammatory damage, and decreased apoptosis in the models. Furthermore, ECH decreased the phosphorylation levels of IκB and NF-κB(p65), and upregulated the expression of peroxisome proliferator-activated receptor gamma (PPARγ), which are related to apoptosis and inflammation in CYP-induced mouse cystitis. Moreover, ECH did not reduce apoptosis of urothelial cells after treatment with PPARγ antagonist GW9662. Our findings suggest that ECH might have protective effect against IC in bladder and be mediated through modulation of the PPARγ/NF-κB pathway.

Exploration of the Effect and Potential Mechanism of Echinacoside Against Endometrial Cancer Based on Network Pharmacology and in vitro Experimental Verification.

Background: Endometrial cancer (EC) is one of the most common gynecological malignancies, especially in postmenopausal women. Echinacoside (ECH) is a major natural bioactive ingredient derived from Cistanches Herba and Echinacea that has a variety of pharmacological effects. However, the efficacy and the mechanism of ECH against EC have not been elucidated yet. Purpose: A compound-target-disease network was constructed to explore the potential targets and mechanism of ECH against EC. Molecular docking and in vitro experiments further verified the effect of ECH against EC. Methods: The potential targets of ECH against EC were retrieved from multiple public databases. Then, the protein-protein interaction (PPI) network was constructed to screen hub targets. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed to discover the potential mechanism. Molecular docking was utilized to verify the binding affinity between hub targets and ECH. Finally, in vitro experiments were conducted to demonstrate the anti-EC effect of ECH. Results: A total of 110 genes were identified as potential targets of ECH against EC. The GO enrichment analysis found that targets were primarily related to oxygen species, apoptosis, and other physiological processes. KEGG pathway analysis showed that PI3K/Akt signaling pathways might play an important role in ECH against EC. Molecular docking indicated that ECH had a significant binding ability with the EGFR, AKT1, ESR1, CASP3, HSP90AA1and MMP9 targets. Results from in vitro experiments revealed that ECH induced apoptosis of Ishikawa and HEC-1-B cells by promoting the arrest of the G2M phase, increasing ROS levels, and decreasing mitochondrial membrane potential (MMP) levels. Furthermore, treatment of ECH significantly reduced the expression levels of PI3K and p-AKT, and the combination of the PI3K inhibitor (LY294002) further enhanced the effects of ECH against EC. The findings suggested that ECH exerted an inhibitory effect on EC cells by inhibiting the PI3K/AKT pathway. Conclusion: Based on network pharmacology, molecular docking technology and in vitro experiments, we comprehensively clarified the anti-EC efficacy of ECH through multiple targets and signal pathways. Furthermore, we provided a novel idea of Traditional Chinese medicine (TCM) against EC.

Echinacoside inhibits the proliferation, migration, invasion and angiogenesis of ovarian cancer cells through PI3K/AKT pathway.

Echinacoside is a group of natural compounds extracted from medicinal plants Cistanche and Echinacea, which has neuroprotective, antiaging, immunomodulatory and anticancer effects, but its specific role and mechanism in tumor remains partially unclear. To our knowledge, it was the first time to reported the effect of Echinacoside in ovarian cancer. Colony formation, TUNEL staining, Transwell and tube formation assays were conducted to analyze the proliferation, apoptosis, invasion and tube formation abilities of serous ovarian carcinoma cells (SKOV3 and OVCAR-3), respectively. The expressions of apoptosis-, invasion- and PI3K/AKT pathway-related proteins were measured by western blotting. In addition, PI3K agonist (740Y-P) was used to assess the regulatory effect of Echinacoside on PI3K/AKT signaling in ovarian cancer. Finally, the anti-tumor effect of Echinacoside on SKOV3-xenografted mice was evaluated by xenograft tumor mouse model. Our results demonstrated Echinacoside concentration-dependently reduced the proliferation, migration and angiogenesis of ovarian cancer cells, whereas promoted apoptosis. Moreover, western blotting revealed that Echinacoside suppressed the growth of ovarian cancer cells by downregulating the phosphorylation levels of PI3K, AKT and mTOR, which could be partially reversed by 740Y-P. Further, in vivo results showed that Echinacoside could effectively alleviate the tumor growth of xenograft mice, accompanied by the decrease of PI3K/AKT signaling. In general, our results demonstrate that Echinacoside could reduce the ovarian cancer progression through inhibition of PI3K/AKT pathway, suggesting that Echinacoside may be a new treatment option for ovarian cancer.

Echinacoside Suppresses the Progression of Breast Cancer by Downregulating the Expression of miR-4306 and miR-4508.

The main treatment of breast cancer includes surgical resection, radiotherapy, chemotherapy, endocrine therapy, and molecular targeted therapy, but the outcomes remain unsatisfactory. Previous studies demonstrated that echinacoside, microRNA (miRNA/miR)-4306 and miR-4508 were associated with lymph node metastasis, chemoresistance and self-renewal capability in breast cancer, but in-depth studies on the underlying mechanism of their anticancer effects have not been performed to date. In order to identify the role of miR-4306 and miR-4508, and the mechanism of the antitumor effect of echinacoside in breast cancer, the present study first examined the expression of miR-4306 and miR-4508 in breast cancer tissues to examine their possible role in the development of breast cancer, then evaluated the effect of echinacoside on the expression of miR-4306 and miR-4508 on the viability, apoptosis, cell cycle, migration, and invasion abilities of breast cancer cells to explore the anti-cancer effect of echinacoside and the involvement of miR-4306 and miR-4508. Finally, the breast cancer cells and mice bearing breast cancer xenografts were treated with echinacoside and inhibitors of miR-4508 or miR-4306 to confirm their role on the anticancer effect of echinacoside. The results showed that miR-4306 and miR-4508 were decreased in breast cancer tissues and cells. Echinacoside inhibited cell proliferation, invasion and migration, and promoted the apoptosis of breast cancer cells by downregulating the expression of miR-4306 and miR-4508. In conclusion, this is the first study to show the association between echinacoside and miRNAs in cancer. The present study elucidates an underlying molecular mechanism of the antitumor effect of echinacoside on breast cancer, and thus may contribute to preventive and therapeutic strategies for breast cancer.

Cistanches Herba, from an endangered species to a big brand of Chinese medicine.

Cistanches Herba (CH, Chinese name: Roucongrong), is a very precious, tonic Chinese medicine. Cistanche deserticola and Cistanche tubulosa are the two commonly used species and authenticated in Chinese Pharmacopoeia. Due to the parasitic nature of Cistanche plants, the wild source was once endangered and listed in the Appendix II of Convention on International Trade in Endangered Species of Wild Fauna and Flora. However, after continuously struggling in the past decades, CH has grown up to a big brand of Chinese medicine featured with the cultivation area as 1.26 million mu, the annual output as 6000 tons, and the related industrial output value as more than 20 billion China Yuan, attributing to large-scale cultivation and in-depth phytochemical and pharmacological investigations. Noteworthily, great achievements have reached concerning the research and development of relevant products, such as modern drugs, traditional Chinese medicine prescriptions, and dietary supplements. The current review summarizes the research progresses concerning the distribution and cultivation, phytochemistry, pharmacology, metabolism and product development of CH in the past decades, and the emerging challenges and developing prospects are discussed as well.

Echinacoside reverses myocardial remodeling and improves heart function via regulating SIRT1/FOXO3a/MnSOD axis in HF rats induced by isoproterenol.

Myocardial remodelling is important pathological basis of HF, mitochondrial oxidative stress is a promoter to myocardial hypertrophy, fibrosis and apoptosis. ECH is the major active component of a traditional Chinese medicine Cistanches Herba, plenty of studies indicate it possesses a strong antioxidant capacity in nerve cells and tumour, it inhibits mitochondrial oxidative stress, protects mitochondrial function, but the specific mechanism is unclear. SIRT1/FOXO3a/MnSOD is an important antioxidant axis, study finds that ECH binds covalently to SIRT1 as a ligand and up-regulates the expression of SIRT1 in brain cells. We hypothesizes that ECH may reverse myocardial remodelling and improve heart function of HF via regulating SIRT1/FOXO3a/MnSOD signalling axis and inhibit mitochondrial oxidative stress in cardiomyocytes. Here, we firstly induce cellular model of oxidative stress by ISO with AC-16 cells and pre-treat with ECH, the level of mitochondrial ROS, mtDNA oxidative injury, MMP, carbonylated protein, lipid peroxidation, intracellular ROS and apoptosis are detected, confirm the effect of ECH in mitochondrial oxidative stress and function in vitro. Then, we establish a HF rat model induced by ISO and pre-treat with ECH. Indexes of heart function, myocardial remodelling, mitochondrial oxidative stress and function, expression of SIRT1/FOXO3a/MnSOD signalling axis are measured, the data indicate that ECH improves heart function, inhibits myocardial hypertrophy, fibrosis and apoptosis, increases the expression of SIRT1/FOXO3a/MnSOD signalling axis, reduces the mitochondrial oxidative damages, protects mitochondrial function. We conclude that ECH reverses myocardial remodelling and improves cardiac function via up-regulating SIRT1/FOXO3a/MnSOD axis and inhibiting mitochondrial oxidative stress in HF rats.

Astragaloside IV and echinacoside benefit neuronal properties via direct effects and through upregulation of SOD1 astrocyte function in vitro.

Amyotrophic lateral sclerosis (ALS), also known as a major type of motor neuron disease, is a disease characterized by the degeneration of both upper and lower motor neurons. Astragaloside IV (AST) is one of the most effective compounds isolated from Astragalus membranaceus. Echinacoside (ECH) is also an active constituent in Cistanche tubulosa. These two herbs had been used in treating disease described like ALS in ancient China under the guidance of traditional Chinese medicine theory and now they are still being used extensively for ALS in current Chinese medicine practice, but whether AST or ECH has effect on ALS disease condition is still unclear. Survivals of primary cultured neuron and astrocyte were determined by the MTS assay. Proteins including GLT1 and GFAP, from SOD1 G93A Tg (transgenic) astrocyte lysate were determined by Western blot. Synaptic markers, PSD95 and VGLUT1, were stained by immunofluorescence and observed by a confocal microscope. Proper dilution of AST and ECH was confirmed to be not harmful to both astrocytes and neurons. AST and ECH enhanced neuronal synaptic markers density or intensity/area in different aspects. Both AST and ECH could significantly rescue SOD1 astrocyte conditional medium-treated neuronal survival and synapse loss. Ten micromolars ECH could significantly rescue the suppressed GLT1 level expressed by SOD1 Tg astrocyte. This present research proved that AST and ECH could benefit neuronal properties and rescue certain dysfunction, such as GLT1 low expression, loss of neuron-supporting function, of astrocytes under SOD1 condition.

Echinacoside prevents hypoxic pulmonary hypertension by regulating the pulmonary artery function.

Hypoxic pulmonary hypertension (HPH) is a progressive and irreversible disease that reduces survival. Echinacoside is a phenylethanoid glycoside from Tibetan herbs known for its vasorelaxant effect and for inhibiting the proliferation of rat pulmonary arterial smooth muscle cells. This study aimed to investigate the effect of echinacoside on HPH. Sprague Dawley rats were housed in a hypobaric hypoxia chamber (4500 m) for 28 days to obtain the HPH model. Echinacoside (3.75, 7.5, 15, 30 and 40 mg/kg) was administered by intraperitoneal injection from the 1st to the 28th day. The mean pulmonary artery pressure (mPAP), right ventricular hypertrophy index, hemoglobin, hematocrit, red blood cell concentration and morphological change of pulmonary arteries were evaluated. Vascular perfusion assay was used to assess the pulmonary artery function. Echinacoside reduced mPAP, hemoglobin, hematocrit, right ventricular hypertrophy index and mean wall thickness% of pulmonary arteries in HPH rats. It significantly increased maximum vasoconstriction percentage of pulmonary arteries induced by noradrenaline in a dose-dependent manner. In addition, it improved the responsiveness of pulmonary arteries to acetylcholine and sodium nitroprusside. Therefore, Echinacoside might be an effective treatment against HPH, since it regulated pulmonary artery endothelium and smooth muscle layer function and improved the remodeling of pulmonary artery.

Therapeutic potential of phenylethanoid glycosides: A systematic review.

Phenylethanoid glycosides (PhGs) are generally water-soluble phenolic compounds that occur in many medicinal plants. Until June 2020, more than 572 PhGs have been isolated and identified. PhGs possess antibacterial, anticancer, antidiabetic, anti-inflammatory, antiobesity, antioxidant, antiviral, and neuroprotective properties. Despite these promising benefits, PhGs have failed to fulfill their therapeutic applications due to their poor bioavailability. The attempts to understand their metabolic pathways to improve their bioavailability are investigated. In this review article, we will first summarize the number of PhGs compounds which is not accurate in the literature. The latest information on the biological activities, structure-activity relationships, mechanisms, and especially the clinical applications of PhGs will be reviewed. The bioavailability of PhGs will be summarized and factors leading to the low bioavailability will be analyzed. Recent advances in methods such as bioenhancers and nanotechnology to improve the bioavailability of PhGs are also summarized. The existing scientific gaps of PhGs in knowledge are also discussed, highlighting research directions in the future.

Establishment of the concurrent experimental model of osteoporosis combined with Alzheimer's disease in rat and the dual-effects of echinacoside and acteoside from Cistanche tubulosa.

ETHNOPHARMACOLOGICAL RELEVANCE: Cistanche tubulosa is a precious traditional Chinese medicine that has been widely used in the treatment of osteoporosis and Alzheimer's disease. Echinacoside and acteoside are the main active constituents in Cistanche tubulosa that have the pharmacological activities with research value. It has been reported that echinacoside and acteoside could improve the learning and memory ability, promote the proliferation and differentiation of osteoblast. AIM OF STUDY: Echinacoside and acteoside from Cistanche tubulosa have shown significant activities of anti-osteoporosis and anti-Alzheimer's disease, while these effects have not been studied concurrently in a rat model. The aim of this study was to establish and verify the model of osteoporosis combined with Alzheimer's disease in rat, and to investigate the double effects of echinacoside and acteoside on this concurrent model. MATERIALS AND METHODS: Three model groups of ovariectomy (OVX), sham surgery with D-galactose and AlCl3 (D), ovariectomy with D-galactose and AlCl3 (OVX + D) were set at the same time. The rats in drug treatment groups were ovariectomized. While conducting the intraperitoneal injection of D-galactose and intragastric administration of AlCl3 in the rats of drug treatment groups, the rats were orally administered echinacoside (90 mg/kg/d), acteoside (90 mg/kg/d) and the positive control drugs of estradiol valerate (0.6 mg/kg/d), donepezil HCl (0.8 mg/kg/d), respectively. After the drug treatment of 8 weeks, Morris Water Maze (MWM) test for 6 days was firstly performed. The rats were then sacrificed to harvest the blood, uteri, femora, tibiae and brain tissues. The serum was used for biochemical tests. The uteri were used for histomorphometry. The right femora were used for Micro-CT and histomorphometry, respectively. The right tibiae were used for biomechanical test. The hippocampus collected on ice box was used for biochemical tests. The brain collected by perfusion was used for histomorphometry. RESULTS: Compared with Sham group, OVX + D group could significantly reduce the learning and memory ability by causing oxidative damage, impairing neurons in hippocampus and affecting the hydrolysis and synthesis of acetylcholine. Meanwhile, the activities of BALP and TRAP in OVX + D group increased significantly (P < 0.001) as compared to Sham group. In addition, compared with Sham group, the mean bone mineral density obviously decreased (P < 0.05), the trabecular bone mass and microarchitecture were also destroyed significantly in OVX + D group. Furthermore, the maximum load and maximum stress significantly reduced (P < 0.01) and the energy absorption also decreased greatly as compared to Sham group. After administrated with echinacoside and acteoside, the typical pathological features of osteoporosis and Alzheimer's disease were ameliorated. CONCLUSIONS: The model of osteoporosis combined with Alzheimer's disease in rat was feasible and successfully established. Echinacoside and acteoside also showed some significant effects on this concurrent model, and they could be potential candidates from Cistanche tubulosa with double effects for further study.

Cistanche polysaccharides enhance echinacoside absorption in vivo and affect the gut microbiota.

The polysaccharides and phenylethanoid glycosides from Cistanche deserticola have been demonstrated with various health benefits, however the interactive effect between these two kinds of compounds in vivo are not in detail known. The objective of this study was to investigate the synergistic actions of cistanche polysaccharides with phenylethanoid glycoside and the effects of polysaccharides on gut microbiota. Sprague-Dawley rats were fed with different kinds of cistanche polysaccharides for 20 days, on the last day, all rats were administered the echinacoside at 100 mg/kg. The results were compared mainly on the difference of pharmacokinetic parameters, gut microbiota composition, and short chain fatty acids contents. The results indicated that all the cistanche polysaccharides, including crude polysaccharide, high molecular weight polysaccharide and low molecular weight polysaccharide, could regulate the gut microbiota diversity, increase beneficial bacteria and particularly enhance the growth of Prevotella spp. as well as improve the production of short chain fatty acids and the absorption of echinacoside. By exploring the synergistic actions of polysaccharides with small molecules, these findings suggest that cistanche polysaccharides, particularly low molecular weight polysaccharides, could be used as a gut microbiota manipulator for health promotion.