Search

Background: To investigate the long term effects of ionizing radiation (IR) on hematopoietic stem/progenitor cells (HSPCs), immune tissues and cells, and the effects of Siwu decoction (SWD) on immune senescence mice. Methods: C57BL/6 J mice were exposed to 6.0 Gy 60Co γ irradiation. After 8-weeks of IR, SWD (5, 10, 20 g/kg/d) was administered for 30 days. The changes of HSPCs in bone marrow (BM) and T, B type lymphocyte and natural killer (NK) cells in spleen were detected by flow cytometry. The changes of peripheral blood cells were also examined. Hematoxylin–eosin staining were used to detect the pathological lesions of hippocampus, spleen and thymus tissues. Absolute mouse telomere length quantification qPCR assay kit was used to measure the telomere length of BM cells. The expression of factors associated with inflammation and aging such as p16, β-galactosidase in spleen, thymus and BM was determined. Results: Administration of SWD could increase the proportion of LSK (Lin−, Sca-1 + , c-Kit−), multipotent progenitor cells and multipotent progenitor cells and decrease the proportion of common myeloid progenitors and granulocyte–macrophage progenitors in BM. The proportion of B cells and NK cells in spleen and the content of white blood cells, red blood cells, hemoglobin, lymphocytes and eosinophils in peripheral blood were increased, at the same time, the proportion of neutrophils and monocytes was reduced by SWD. The pathological lesions of hippocampus, spleen and thymus were improved. The expression of p16 and β-galactosidase in spleen, thymus and BM was reduced and shortening of the telomere of BM cells was inhibited after administration. In addition, SWD could reduce the content of Janus activated kinase (JAK) 1, JAK2 and signal transducer and activator of transcription 3 (STAT3) in BM and spleen. Conclusions: SWD could slow down IR-induced immune senescence by improving hematopoietic and immunologic injury. SWD might reduce the inflammation level of BM hematopoietic microenvironment by acting on JAK/STAT signaling pathway, while the immune damage of mice was improved by affecting the differentiation of HSPCs. The remission of hematopoietic and immunologic senescence was further demonstrated at the overall level. Highlights: Siwu decoction (SWD) could relieve IR-induced senescence in mice. SWD could improve the learning and memory ability and the pathological damage of hippocampus. SWD could ameliorate the lymphatic/myeloid differentiation bias of bone marrow (BM) hematopoietic stem/progenitor cells (HSPCs) and immune imbalance in peripheral blood and spleen. SWD could inhibit the shortening of telomere of BM cells. SWD could alleviate the inflammation level of hematopoietic microenvironment and spleen, and reduce the expression of senescence related molecules (p16, β-galactosidase, etc.) in BM, spleen and thymus. [ABSTRACT FROM AUTHOR]

Tanshinone IIA (Tan IIA) is one of the main natural active ingredients purified from Salvia miltiorrhiza radix, which has long been used in clinical practice in China to treat diseases including liver fibrosis, Alzheimer׳s disease, and cardiovascular diseases. Tan IIA has hepatoprotective properties, and is an efficacious PXR agonist. Our study was designed to observe the function and mechanism of the hepatoprotective properties of Tan IIA. HepG2 cells were used to investigate the vitrol effects of Tan IIA on PXR and CYP 3 A 4. Gut-formed LCA is hepatotoxic, and has been implicated in the pathogenesis of cholestatic diseases. To further investigate the hepatoprotective mechanisms of Tan IIA against LCA-induced cholestasis in vivo, we choose the normal mice and siRNA-treated mice. The in vitro study demonstrated that the effect of Tan IIA on CYP 3 A 4 was mediated by transactivation of PXR in a dose- and time-dependent manner. The in vivo experiments using PXR siRNA revealed that Tan IIA could protect against LCA-induced hepatotoxicity and cholestasis in a dose-dependent manner. These effects were partially caused by the upregulation of PXR , as well as Cyp 3 a 11, Cyp 3 a 13, and Mdr 1, which are the enzymes responsible for LCA metabolism. This is the first report showing that the hepatoprotective effects of Tan IIA are partly mediated by PXR . [ABSTRACT FROM AUTHOR]

Garlic (Allium sativum L.) is a widely consumed spice and condiment around the world, applied both as a food and as a traditional medicine, and is a natural strengthening agent for the body's circulatory and nervous systems. Diallyl trisulfide (DATS) is the major volatile organosulfur phytochemical found in garlic, with antithrombotic, anticoagulant, and antiplatelet activities as well as antioxidant, anti-infective, and other pharmacological effects. However, the safe dose and the underlying mechanisms of its toxic effects remain elusive. DATS, an important pharmacologically active compound found in garlic, has garnered attention for its ability to fight cancer, antioxidant, anti-infective, and cardioprotective. The aim of this study was to evaluate the safety of DATS and to elucidate the potential mechanisms of its toxicity. In this study, ICR mice were selected for acute and subacute toxicity experiments according to OECD guidelines. The toxicity profile of DATS was analyzed by computer prediction software. Also, key differential proteins in spleen and serum were analyzed by proteomics. The binding stability of DAST to differential proteins was analyzed by molecular docking. Additionally, the regulatory relationship between DATS and differential proteins was verified by Western blot and ELISA experiments. The results showed that the LD 50 value of DATS in acute toxicity was 188.67 mg/kg. In subacute toxicity, water consumption and food intake were reduced in both male and female mice. In addition, the spleen and small intestinal organ coefficients were significantly elevated in male mice at the high dose of DATS; the blood biochemical indices ALB and TP were also significantly elevated. HE staining results showed significant damage to the spleen, liver, small intestine, and kidney of mice at high doses of DATS. Spleen and serum proteomics analyses showed that DATS significantly inhibited ZBP1 expression and upregulated TEC. ADMETlab 2.0 software predictions identified DATS as having potential genotoxicity, dermal sensitization, carcinogenicity, and respiratory and ocular toxicity. Docking results showed that the binding energies between DATS and TEC protein (PDB: 6F3F) and ZBP1 protein (PDB: 4KA4) were −3.7 kcal/mol, −2.4 kcal/mol, respectively. Western blot results showed that DATS-H significantly inhibited the expression of ZBP1 (only in male mice) and Bcl-2 proteins. ELISA results showed that DATS-H significantly increased the level of TEC protein both in male and female mice. Long-term administration of high-dose DATS may carry some risk of toxicity. Based on the amount of DATS in garlic, it is recommended that adults should not take more than 359 mg of DATS and 84.5 g of garlic per day. The mechanism of toxicity may be related to the fact that DATS significantly inhibits ZBP1 expression, upregulates TEC, and promotes apoptosis. This study provides valuable toxicological data for the effective evaluation of the long-term toxicity of DATS and offers an additional experimental basis for developing DATS as a healthy food or drug. [Display omitted] • Spleen, small intestinal and liver damage only occurs with overdose and prolonged use of DATS. It is recommended that adults should not take more than 359 mg of DATS per day. • DATS taken in low doses is a significant benefit for immune modulation. • The mechanism of DATS toxicity may be related to significant inhibition of ZBP1, upregulation of TEC, and promotion of apoptosis. [ABSTRACT FROM AUTHOR]

Cistanche deserticola is a kind of parasitic plant living in the roots of desert trees. It is a rare Chinese medicine, which has the effect of tonifying kidney Yang, benefiting essence and blood and moistening the intestinal tract. Cistache deserticola phenylethanoid glycoside (PGS), an active component found in Cistanche deserticola Ma, have potential kidney tonifying, intellectual enhancing, and neuroprotective effects. Cistanche total glycoside capsule has been marketed to treat vascular dementia disease. To identify the potential renal, intellectual enhancing and neuroprotective effects of PGS and explore the exact targets and mechanisms of PGS. This study systematically investigated the four types of pathways leading to ferroptosis through transcriptome, metabolome, ultrastructure and molecular biology techniques and explored the molecular mechanism by which multiple PGS targets and pathways synergistically exert neuroprotective effects on hypoxia. PGS alleviated learning and memory dysfunction and pathological injury in mice exposed to hypobaric hypoxia by attenuating hypobaric hypoxia-induced hippocampal histopathological damage, impairing blood‒brain barrier integrity, increasing oxidative stress levels, and increasing the expression of cognitive proteins. PGS reduced the formation of lipid peroxides and improved ferroptosis by upregulating the GPX-4/SCL7A311 axis and downregulating the ACSL4/LPCAT3/LOX axis. PGS also reduced ferroptosis by facilitating cellular Fe2+ efflux and regulating mitochondrial Fe2+ transport and effectively antagonized cell ferroptosis induced by erastin (a ferroptosis inducer). This study demonstrated the mechanism by which PGS prevents hypobaric hypoxic nerve injury through four types of ferroptosis pathways, achieved neuroprotective effects and alleviated learning and memory dysfunction in hypobaric hypoxia mice. This study provides a theoretical basis for the development and application of PGS. [Display omitted] [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Inflammatory bowel disease (IBD) is associated with chronic inflammation of the intestinal tract. Piperine (1-peperoylpiperidine), the primary lipophilic component in black pepper ( Piper nigrum ) and long pepper ( Piper longum ), has been reported to be effective for anti-inflammatory. Rencently, several ethnopharmacological purity compounds, such as baicalin and artemisinin, are reported to have potentially therapeutic role in treating IBD. In the present study, the effects of piperine on pregnane X receptor (PXR)-mediated CYP3A expression and its therapeutic role in IBD were investigated. Materials and methods LS174T cells and C57BL/6J mice were treated by the piperine. Gene expressions were analyzed by real-time PCR, Western blot analysis, transient transfections assay and histological analysis. Results Data indicated that treatment of LS174T cells with piperine markedly increased both CYP3A4 and PXR mRNA and protein. Transient transfection experiments indicated that transcriptional activation of the CYP3A4 gene via piperine was PXR-dependent. Data show that pre-administration of piperine decreased clinical hallmarks of colitis in DSS-treated PXR mice as measured by body weight loss and assessment of diarrhea, rectal bleeding, colon length, and histology. Inflammatory mediators (CCR2, ICAM-1, IL-1β, IL-6, IL-10, iNOS, MCP-1, and TNFα) after DSS treatment were significantly decreased in mice pretreated with piperine but corresponding conditions did not occur in mice with down-regulation of PXR by small interfering RNA (siRNA). Conclusion Piperine is a potential agonist of PXR and an inducer of PXR, which may induce CYP3A4 gene expression at the mRNA and protein levels. These results establish that piperine may contribute to prevention or reduction of colonic inflammation. [ABSTRACT FROM AUTHOR]