Mass spectrometry-based serum lipidomics strategy to explore the mechanism of Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. leaves in the treatment of ischemic stroke.

Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. leaves (ESL) were reported to have neuroprotective function and are also used to treat cranial and cerebral traumas as a traditional Chinese medicine and food herbage plant. However, there has been no previous study on ESL treatment for stroke at the level of lipid disorders. To clarify the mechanism of ESL in treating ischemic stroke, this study was carried out from 3 aspects, namely, the regulation of lipid disorders, protection of the nervous system, as well as anti-inflammatory and antioxidant actions. This study established a lipidomics research strategy that was developed by UPLC-Q-TOF/MS analysis. The quantification of neurotransmitters in the serum and brain tissue of rats was performed using UPLC-TQ/MS. Also, we quantified the oxidative stress and inflammatory reaction by measuring the contents of SOD, MDA, TNF-α, IL-6, and IL-10 via the ELISA kits for serum and brain tissue. According to UPLC-Q-TOF/MS-based lipidomics analysis, 27 lipidomics biomarkers were identified in this study, including PC, PE, SM, and TG, which were distributed in various lipid metabolic pathways, including glycerophospholipid, linoleic acid, alpha-linolenic acid, glycerolipid, sphingolipid, and arachidonic acid metabolism pathways. By reversing the changes in the lipid content caused by the disease, ESL has a therapeutic effect on ischemic stroke. Furthermore, quantitative results of neurotransmitters indicated that they can be regulated by ESL. Finally, the results of ELISA showed that ESL can treat ischemic stroke to a certain extent by reducing the oxidative and inflammatory damage. Therefore, ESL may play a therapeutic role in the treatment of ischemic stroke in different ways. This research preliminarily revealed the mechanism of ESL in the treatment of ischemic stroke and provided support for the further application of ESL.

Ferumoxytol Attenuates the Function of MDSCs to Ameliorate LPS-Induced Immunosuppression in Sepsis.

Sepsis-induced immunosuppression is recognized as one of the main features responsible for therapeutic failures. Myeloid-derived suppressor cells (MDSCs), which are mainly characterized by their suppressive properties, have been reported to be expanded in sepsis. Ferumoxytol (FMT), an FDA-approved iron supplement, has been shown to possess immune-modulatory properties in tumors. However, it is unclear whether FMT alters the functions of MDSCs to reduce late-sepsis immunosuppression. Here, we showed an immunomodulatory effect of FMT on MDSCs to ameliorate lipopolysaccharide (LPS)-induced immunosuppression in the late stage of sepsis. Separation of cells with internalized FMT and detection of the intracellular iron content showed that MDSCs could uptake FMT. Low doses of FMT had no effects on the cell viability of MDSCs, but FMT inhibited the expansion of MDSCs in vitro. Moreover, FMT significantly downregulated the expression levels of Arg-1, S100A8, S100A9, and p47phox as well as ROS production in MDSCs. FMT decreased the percentage of granulocytic MDSCs (G-MDSCs) and promoted the differentiation of MDSCs into macrophages. Furthermore, FMT reduced white blood cell recruitment and alveolar wall thickening in the lungs and areas of necrosis in the liver as well as some biochemical markers of liver dysfunction. FMT decreased the percentage of G-MDSCs and monocytic MDSCs (M-MDSCs) in the spleens of LPS-induced septic mice. Of note, FMT reduced the T cell immunosuppressive functions of both G-MDSCs and M-MDSCs. Expectedly, FMT also significantly reduced Arg-1 and p47phox gene expression in splenic CD11b+Gr-1+ cells isolated from LPS-challenged mice. These data indicate that FMT decreased the immunosuppressive functions of MDSCs by decreasing Arg-1 and ROS production, suggesting that FMT may reduce long-term immunosuppression in the late stage of sepsis.

Mass spectrometry-based urinary metabolomics for the investigation on the mechanism of action of Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. leaves against ischemic stroke in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: As a traditional Chinese medicine, Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. leaves (ESL) can treat ischemic, neurasthenia, and hypertension diseases. However, only few studies have been conducted on the mechanism of action of ESL for ischemic disease treatment. AIM OF THE STUDY: This study aimed to discover the potential biomarkers in the rats caused by ischemic stroke and build a gene-enzyme-biomarker network to explore the mechanism of ESL treatment on ischemic stroke further. MATERIALS AND METHODS: The urinary metabolomics strategy was developed by combining UPLC-Q-TOF/MS with multivariate data analysis. The gene-enzyme-biomarker network was built by Cytoscape 3.6.0 on the basis of the potential biomarkers filtered out via urinary metabolomic analysis. Then, the potential target enzymes of ESL in the treatment of ischemic stroke were selected for further validation analysis via the ELISA kits. RESULTS: A total of 42 biomarkers associated with ischemic stroke have been identified, among which 38 species can be adjusted by ESL, including 5'-methylthioadenosine, prostaglandin A2, l-methionine, aldosterone, 11b-hydroxyprogesterone, prostaglandin E3, dehydroepiandrosterone, taurine, 5-methoxyindoleacetate, and p-cresol glucuronide. These biomarkers were involved in several metabolic pathways, including taurine and hypotaurine, arachidonic acid, cysteine and methionine, steroid hormone biosynthesis, tryptophan, and tyrosine metabolism pathways. The gene-enzyme-biomarker network was built, and three predicted target proteins, including cyclooxygenase-2 (COX-2), monoamine oxidase (MAO), and nitric oxide synthase (NOS), were selected as the potential target enzymes for ESL in ischemic stroke treatment. CONCLUSIONS: All results showed that ESL can play a therapeutic role in treating ischemic stroke through different pathways. This study will provide an overall view of the mechanism underlying the action of ESL against ischemic stroke.