Radiation protection of sodium alginate and its regulatory effect on intestinal microflora in mice.

Prolonged or high-dose exposure to ionizing radiation (IR) can cause damage to normal tissues of the body. Therefore, it is imperative to find effective radiation protective agents to mitigate IR-induced damage. This study evaluated the effects of sodium alginate (SA) on the radiation protection and modulatory effects of gut microorganisms using a 60Coγ-induced damage model in mice. Results showed that SA could reduce the damage of hematopoietic system; and alleviate the oxidative damage in irradiated mice by inhibiting the content of malondialdehyde (MDA) and increasing the activities of superoxide dismutase (SOD) and glutathione (GSH) in serum, spleen, jejunum and liver. Moreover, SA treatment ameliorated IR-induced small intestine lesions and alleviated liver injury. This was consistent with decreased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and tumor necrosis factor-α (TNF-α), and increased levels of interferon-γ (IFN-γ) and interleukin-2 (IL-2) after SA treatment. Furthermore, SA treatment reversed IR-induced gut dysbiosis, elevated the Firmicutes/Bacteroidetes ratio, increased the beneficial bacteria and reduced the pathogenic bacteria in the small intestine. In conclusion, the present study demonstrated that SA exerted good radioprotective effect by improving hematopoietic system, alleviating oxidative stress, attenuating liver injury and inflammatory response, and modulating the intestinal microbiota in irradiated mice.

Biyang floral mushroom-derived exosome-like nanovesicles: characterization, absorption stability and ionizing radiation protection.

Diet-derived exosome-like nanovesicles are a class of natural active substances that have similar structures and functions to mammalian exosomes. Biyang floral mushrooms and their active extracts have been found to possess radioprotective effects and to deeply explore their novel active substances, the radioprotective effects of Biyang floral mushroom-derived exosome-like nanovesicles (BFMELNs) were investigated in this study. Results showed that these surface-negatively charged vesicles possessed an ideal size and good stability against environmental changes such as temperature and gastrointestinal digestion. Furthermore, BFMELNs could effectively be taken up by HL-7702 cells and Caco-2 cells through cellular phagocytosis mediated by clathrin and dynein. Emphatically, BFMELNs with an exosome-like morphology contained RNA, proteins, lipids, polyphenols and flavonoids to exert good antioxidant and radioprotective effects in vitro. Meanwhile, BFMELNs also exhibited good radioprotective effects by restoring peripheral blood indexes, mitigating damage to organs, and regulating the redox state in mice. Collectively, BFMELNs showed promise as novel and natural radioprotective nano-agents for preventing IR-induced oxidative stress damage.

Investigating the effects of low-salt processing on the umami peptides of dry-cured ham using peptidomics techniques.

This study investigated the effect of low-salt processing on the umami peptide profile of dry-cured hams. Peptidomics data showed 633 umami peptides in the low- and full-salt groups. Among them, 36.2% and 26.5% of shared umami peptides in the low-salt group were significantly down- and up-regulated in relative abundance. Multivariate statistical analysis showed 1011 significantly different umami peptides (SDUPs) in the low- and full-salt groups. Creatine kinase M-type (CKM) and fast skeletal muscle troponin T (TnTf) were the main precursor proteins of these SDUPs. At the end of processing, the relative expression of CKM was lower in the low-salt group than in the full-salt group (P < 0.05), but there was no significant difference in TnTf. More dipeptidyl peptidase cleavage sites were observed in CKM and TnTf proteins in the low-salt group.

Exploring the novel antioxidant peptides in low-salt dry-cured ham: Preparation, purification, identification and molecular docking.

Dry-cured ham is important source of bioactive peptides. In this study, the antioxidant activities of peptides and components from low and fully salted dry-cured hams were compared by peptidomics. And novel antioxidant peptides were identified and characterized. The results showed that the peptides (<3 KDa) extracted from low-salt dry-cured ham had higher antioxidant activity. Therefore, the antioxidant peptides in low-salt dry-cured ham were further characterized and the mechanism of their antioxidant activity was investigated. From the five candidate peptides selected, we found DWPDARGIWHND (DD12) to be highly stable, non-sensitizing, and non-toxic with the highest free radical scavenging activity. Molecular docking predicted that DD12 interacted with Keap1 through hydrogen-bond formation and hydrophobic interactions, suggesting that DD12 had good cellular antioxidant activity. DD12 peptide can bind to DPPH• and ABTS•+, resulting in strong free radical scavenging activity. Our findings support the development and application of natural antioxidant peptides in dry-cured ham.

Correction to: Bioactive compounds and antioxidant activities of Quercus salicina Blume extract.

[This corrects the article DOI: 10.1007/s10068-020-00755-1.].

Activation of α7nAChR preserves intestinal barrier integrity by enhancing the HO-1 / STAT3 signaling to inhibit NF-κB activation in mice.

BACKGROUND: Activation of alpha-7 nicotinic acetylcholine receptor (α7nAChR) can inhibit a systemic inflammatory response and preserve intestinal barrier integrity. This study aimed at elucidating the molecular mechanisms by which α7nAChR activation could inhibit intestinal barrier injury and cholestatic liver fibrosis in mice following bile duct ligation (BDL). MATERIALS AND METHODS: The intestine-specific heme oxygenase-1 (HO-1) knockout VillinCreHmox1-/- and control Hmox1flox/flox C57BL/6 mice were subjected to the BDL procedure. The therapeutic effects of GST-21, a specific ligand for α7nAChR, on systemic and intestinal inflammation, intestinal barrier integrity, liver fibrosis and injury, HO-1 expression, STAT3, AKT and NF-κBp65 activation were examined in these mice and intestinal epithelial cells after being co-cultured with macrophages. RESULTS: Compared with the vehicle-injected BDL group, treatment with GST-21 to activate α7nAChR decreased intestinal and liver injury and fibrosis in BDL mice, accompanied by reducing serum cytokine levels. In addition, activation of α7nAChR preserved the levels of tight junction protein expression and intestinal epithelial barrier integrity in BDL mice and epithelial cells following co-cultured with macrophages. The therapeutic effects of α7nAChR activation were mediated by enhancing HO-1 expression and STAT3 phosphorylation, and reducing the NF-κBp65 activation in intestinal tissues and epithelial cells co-cultured with macrophages. Finally, activation of α7nAChR induced HO-1 expression and STAT3 phosphorylation in an interdependent manner, independent of the PI3K/AKT signaling. CONCLUSION: Activation of α7nAChR enhanced HO-1 expression and STAT3 signaling to inhibit NF-κB activation, preserving the intestinal barrier integrity, and reducing inflammation and liver fibrosis in cholestatic mice. Therefore, targeting α7nAChR may be a promising interventional strategy for primary biliary cholangitis.

Electroacupuncture Ameliorates Intestinal Barrier Destruction in Mice With Bile Duct Ligation-Induced Liver Injury by Activating the Cholinergic Anti-Inflammatory Pathway.

OBJECTIVES: Electroacupuncture (EA) at Zusanli (ST36) can attenuate inflammation in different rodent models. However, the therapeutic mechanisms underlying its action in inhibiting intestinal barrier destruction and liver injury in cholestasis mice have not been clarified. This study aimed at investigating whether EA at ST36 could activate the cholinergic anti-inflammatory pathway to inhibit intestinal barrier destruction and liver injury in cholestasis mice. MATERIALS AND METHODS: Male Hmox1floxp/floxp C57BL/6 mice were randomized and subjected to a sham or bile duct ligation (BDL) surgery. The BDL mice were randomized and treated with, or without (BDL group), sham EA at ST36 (BDL+sham-ST36) or EA at ST36 (BDL+ST36), or received α-bungarotoxin (α-BGT), a specific inhibitor of nicotinic acetylcholine receptor α7 subunit (α7nAChR), before stimulation (BDL+ST36+α-BGT). These mice, together with a group of intestine-specific heme oxygenase-1 (HO-1) knockout (KO) Villin-Cre-HO-1-/- mice, were monitored for their body weights before and 14 days after BDL. The levels of plasma cytokines and liver injury-related alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured by enzyme-linked immunoassay, and pathological changes in the intestinal mucosa and liver fibrosis as well as intestinal barrier permeability in individual mice were examined by histology and immunohistochemistry. The levels of α7nAChR, HO-1, ZO-1, Occludin, Claudin-1, and NF-κBp65 expression and NF-κBp65 phosphorylation in intestinal tissues were quantified. RESULTS: Compared with the sham group, BDL significantly increased the levels of plasma interleukin (IL)-1ß, IL-6, IL-10, tumor necrosis factor α, ALT, and AST and caused intestinal mucosal damages, high permeability, and liver fibrosis in mice, which were remarkably mitigated, except for further increased levels of plasma IL-10 in the BDL+ST36 group of mice. Similarly, EA at ST36 significantly up-regulated α7nAChR and HO-1 expression; mitigated the BDL-decreased ZO-1, Occludin, and Claudin-1 expression; and attenuated the BDL-increased NF-κBp65 phosphorylation in intestinal tissues of mice. The therapeutic effects of EA at ST36 were significantly abrogated by pretreatment with α-BGT or HO-1 KO. CONCLUSION: EA at ST36 inhibits the BDL-induced intestinal mucosal damage and liver fibrosis by activating the HO-1 cholinergic anti-inflammatory pathway in intestinal tissues of mice.

Protective effect of coix seed seedling extract on 60 Co-γ radiation-induced oxidative stress in mice.

Exposure to ionizing radiation (IR) can cause oxidative damage to human body, leading to various diseases and even death. In this study, the potential radioprotective effect of coix seed seedling extract (CSS-E) was studied through a model of 60 Co-γ radiation-induced oxidative stress in mice. Overall radioprotective effect of CSS-E against radiation-induced damage was evaluated by biochemical analysis and histopathological analysis. The results showed that CSS-E could significantly reduce the IR-induced damage to the hematopoietic system. CSS-E-M (200 mg/kg BW) pretreatment could increase the activities of superoxide dismutase in serum, liver, and spleen increased by 31.68%, 45.10%, and 56.67%, respectively, and the glutathione peroxidase levels in serum, liver, and spleen of mice were improved by 19.17%, 41.97%, and 130.56%, respectively. Meanwhile, the glutathione levels of serum, liver, and spleen in CSS-E-M group were increased by 17.10%, 35.06%, and 40.71%, respectively. The contents of MDA in different tissues and serum could be reduced by CSS-E-M treatment to the normal level. Moreover, CSS-E could markedly reduce the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in radiation mice, among which CSS-E-M group showed maximum restoration with decreased AST and ALT levels by 20.13% and 32.76% as compared against IR group. In conclusion, these results indicated that CSS-E could be used as a potential natural radioprotectant against IR-induced damage.

60Coγ induction improves the protective effect of Acetobacter pasteurianus against ionizing radiation in mice.

Exposure to ionizing radiation (IR) tends to cause serious health concerns. Thus, radioprotective agents are vital for the population exposed to radiation. As microorganisms have the advantages of fast reproduction and no geographical restrictions, direct microbe-based and environmental induction compounds are thriving radioprotectants resources. Oxidative system and oxidase in Acetobacter pasteurianus are unique and intriguing, the radioprotective effect of the cell-free extract from A. pasteurianus (APE) and 60Coγ-treated extract (IRE) were comparatively investigated in the present study. The survival rate of A. pasteurianus with IRE addition was 149.1% in H2O2 damage test, while that with APE was only 10.4%. The viability of 60Coγ-treated AML-12 cells was increased by 18.8% with IRE addition, yet APE showed no significant radioprotective effect. Moreover, in 60Coγ-treated mice, IRE could significantly protect the white blood cell, improve the liver index, and attenuate the injuries of immune organs in mice. Administration of IRE significantly raised the activities of superoxide dismutase (SOD) and reduced the products of lipid peroxidation. These results clarified that gavage with APE and IRE presented notable antioxidant and radioprotective efficacy. A. pasteurianus showed appealing potential to be novel radioprotective bioagents and 60Coγ treatment on microbe could be a new method for the development of better radioprotectant. KEY POINTS: • 60Coγ induction could improve the radioprotective effect of APE. • IRE protected white blood cell in mice under IR. • IRE products have broad application prospects in radioprotection based on microbes.

Potential of natural products as radioprotectors and radiosensitizers: opportunities and challenges.

Natural products can be used as natural radiosensitizers and radioprotectors, showing promising effects in cancer treatments in combination with radiotherapy, while reducing ionizing radiation (IR) damage to normal cells/tissues. The different effects of natural products on irradiated normal and tumor cells/tissues have attracted more and more researchers' interest. Nonetheless, the clinical applications of natural products in radiotherapy are few, which may be related to their low bioavailability in the human body. Here, we displayed the radiation protection and radiation sensitization of major natural products, highlighted the related molecular mechanisms of these bioactive substances combined with radiotherapy to treat cancer, and critically reviewed their deficiency and improved measures. Lastly, several clinical trials were presented to verify the clinical application of natural products as radiosensitizers and radioprotectors. Further clinical evaluation is still needed. This review provides a reference for the utilization of natural products as radiosensitizers and radioprotectors.

Bioactive compounds and antioxidant activities of Quercus salicina Blume extract.

Quercus salicina Blume (QS) is an oak species that is indigenous to Japan and Korea. Historically, extracts of leaves, stems, barks and buds from the QS tree had been extensively utilized as herbal medicines. As rich sources of natural antioxidants, QS extracts could prevent oxidative stress and the occurrence of related neurodegenerative diseases. In pharmaceutical applications, decoction or infusion of comminuted QS powder is prepared as an herbal tea for oral use. Various extraction methods and extracting mediums showed the potential antioxidant activities of QS extracts, as well as the different types and levels of bioactive compounds found in them. Due to their functional properties and possibly low-level of cytotoxicity, the potential application of QS extracts as a novel food ingredient could be considered. In this review paper, a brief overview about QS extracts and their bioactive components, antioxidant activities, toxicity and technological applications is described based on previous works.

Quantitative proteomic analysis reveals that Luks-PV exerts antitumor activity by regulating the key proteins and metabolic pathways in HepG2 cells.

Hepatocellular carcinoma (HCC) is a complicated and poor prognosis cancer, necessitating the development of a potential treatment strategy. In this study, we initially revealed that LukS-PV belonged to leukocidin family performs an anti-HCC action. Then, we used liquid chromatography-mass spectrometry (LC/MS) to compare protein expression profiles of the LukS-PV-treated human HCC cell lines HepG2 and the control cells. GO annotations and Kyoto Encyclopedia of Genes and Genomes pathway analysis were carried out of differential expression followed by protein-protein interactome, to explore the underlying cancer suppressor mechanisms of LukS-PV for human HCC. A total of 88 upregulated proteins and 46 downregulated proteins were identified. The top 10 proteins identified by the MCC method are FN1, APP, TIMP1, nucleobindin-1, GOLM1, APLP2, CYR61, CD63, ENG, and CD9. Our observation on protein expression indicated that LukS-PV produces a signature affecting central carbon metabolism in cancer, galactose metabolism, and fructose and mannose metabolism pathways. The results give a functional effects and molecular mechanism insight, following LukS-PV treatment.

LukS-PV induces apoptosis in acute myeloid leukemia cells mediated by C5a receptor.

LukS-PV is one of the two components of Panton-Valentine leucocidin (PVL). Our previous study showed that LukS-PV can induce apoptosis in human acute myeloid leukemia (AML) THP-1 and HL-60 cells. C5aR (C5a receptor) is the receptor for PVL, but whether C5aR plays a key role in LukS-PV induced apoptosis is unclear. The aim of this study was to establish whether C5aR plays a physiological role in apoptosis of leukemia cells induced by LukS-PV. We investigated the role of C5aR in leukemia cell apoptosis induced by LukS-PV by pretreatment of THP-1 and HL-60 cells with C5aR antagonist and transfection to knockdown C5aR in THP-1 cells or overexpress C5aR in Jurkat cells before treatment with LukS-PV. Cell apoptosis was analyzed by staining with Annexin V/propidium iodide or Annexin V-PE/7-AAD. Mitochondrial membrane potential (MMP) was determined using JC-1 dye. The expression of apoptosis-associated genes and proteins was identified by qRT-polymerase chain reaction and Western blotting analysis, respectively. As the C5aR antagonist concentration increased, the rate of apoptosis induced by LukS-PV decreased, the MMP increased, and expression of pro-apoptotic Bax and Bak genes and proteins was downregulated while that of anti-apoptotic Bcl-2 and Bcl-x genes and proteins was upregulated. Knockdown of C5aR also decreased LukS-PV-induced THP-1 cell apoptosis. LukS-PV did not induce apoptosis of Jurkat cells, which have no endogenous C5aR expression; however, LukS-PV did induce apoptosis in Jurkat cells after overexpression of C5aR. Correspondingly, the MMP decreased and Bax and Bak were upregulated while Bcl-2 and Bcl-x were downregulated. LukS-PV can induce apoptosis in AML cells by targeting C5aR. C5aR may be a potential therapeutic target for AML and LukS-PV is a candidate targeted drug for the treatment of AML.

Nuclear factor E2-related factor-2 (Nrf2) is required for NLRP3 and AIM2 inflammasome activation.

Despite the number of extensive studies on the immune function and signaling of inflammasomes in various diseases, the activating mechanism of inflammasome, especially the NLRP3 inflammasome, is not fully understood. Nuclear factor E2-related Factor-2 (Nrf2), a key transcription factor that regulates cellular redox homeostasis, has been reported to play both protective and pathogenic roles depending on the disease conditions through undefined mechanism. This study reveals an essential role of Nrf2 in inflammasome activation. LPS stimulation increased Nrf2 protein levels in a Myd88-dependent manner. When compared with wild-type controls, Nrf2-deficient (Nrf2(-/-)) macrophages showed decreased maturation and secretion of caspase-1 and IL-1ß and reduced apoptosis-associated speck-like protein containing CARD (ASC) speck formation in response to various NLRP3 and AIM2 inflammasome stimuli. In contrast, NLRC4 inflammasome activation was not controlled by Nrf2. Biochemical analysis revealed that Nrf2 appeared in the ASC-enriched cytosolic compartment after NLRP3 inflammasome activation. Furthermore, mitochondrial reactive oxygen species-induced NLRP3 activation also required Nrf2. Nrf2(-/-) mice showed a dramatic decrease in immune cell recruitment and IL-1ß generation in alum-induced peritonitis, which is a typical IL-1 signaling-dependent inflammation animal model. This work discovered a critical proinflammatory effect of Nrf2 by mediating inflammasome activation.

Interleukin-21 up-regulates interleukin-21R expression and interferon gamma production by CD8+ cells in SHIV-infected macaques.

Interleukin-21 (IL-21) is produced primarily by CD4+ T cells and regulates immunity against human/simian immunodeficiency virus (HIV/SIV) infection. Activated CD8+ cells and their secreted interferon-gamma (IFN-γ) are crucial for the control of acute HIV/SIV infection. However, whether IL-21 can regulate IFN-γ production by CD8+ cells remains controversial. Rhesus macaques (RMs, n = 8) were infected with SHIV and the levels of plasma IL-21, IFN-γ and the frequency of peripheral blood activated T cells were measured longitudinally. Following infection with SHIV, the levels of plasma IL-21 and IFN-γ increased, peaked at 17 days postinfection and declined later. Furthermore, IL-21 induced IL-21 receptor (IL-21R) and IFN-γ, perforin, but not granmyze B, expression in CD8+ cells from four selected SHIV-infected RMs. The regulatory effect of IL-21 on CD8+ cell function appeared to be associated with increased levels of STAT3, but not STAT5, phosphorylation in CD8+ cells from SHIV-infected RMs. In parallel, treatment with soluble IL-21R/Fc, an inhibitor of IL-21-induced activation of JAK1/3 and STAT3, abrogated IL-21-induced STAT3 activation and IFN-γ production in CD8+ cells from SHIV-infected RMs in vitro. Our data indicated that IL-21 was a positive regulator of IFN-γ-secreting CD8+ cells and increased the STAT3 phosphorylation, regulating T-cell immunity against acute SHIV infection in RMs. Our findings may provide a new basis for the development of immunotherapies for the control of SHIV/HIV infection.