Search

The beneficial effects of probiotics have been studied extensively in inflammatory bowel disease, nonalcoholic steatohepatitis (NASH), and alcoholic liver disease (ALD). Probiotic supplements are considered safer and more effective, but the potential mechanisms behind their benefits are unclear. An objective of the current study was to examine the effects of extracellular products of Lactobacillus plantarum on acute alcoholic liver injury. Mice on standard chow diet were supplemented with Lactobacillus plantarum ST-III culture supernatant (LP-cs) for 2 weeks and administered a dose of alcohol at 6 g/kg body weight by gavage. Alcohol-induced liver injury was assessed by measuring plasma alanine aminotransferase (ALT) activity levels, and liver steatosis was determined by triglyceride content. Intestine was measured by H&E staining and tight junction proteins were examined. LP-cs significantly inhibited the alcohol-induced fat accumulation, inflammatory reaction, and apoptosis by inhibiting oxidative stress and ER stress. In addition, LP-cs significantly inhibited the alcohol-induced intestinal injury and endotoxemia. According to these findings, LP-cs alleviates the acute alcohol-induced liver damage by inhibiting oxidative stress and ER stress in one way and suppressing alcohol-induced increased intestinal permeability and endotoxemia in another way. Our findings indicated that LP-cs supplements provided a novel strategy for ALD preventions and treatments.

BackgroundLong-term alcohol exposure is associated with oxidative stress, endoplasmic reticulum (ER) stress, and neuroinflammation, which may impair cognitive function. Probiotics supplements can significantly improve cognitive function in neurodegenerative diseases such as Alzheimer’s disease. Nevertheless, the effect of Lactobacillus plantarum ST-III culture supernatant (LP-cs) on alcohol-induced cognitive dysfunction remains unclear.MethodsA mouse model of cognitive dysfunction was established by intraperitoneal injection of alcohol (2 g/kg body weight) for 28 days. Mice were pre-treated with LP-cs, and cognitive function was evaluated using the Morris water maze test. Hippocampal tissues were collected for biochemical and molecular analysis.ResultsLP-cs significantly ameliorated alcohol-induced decline in learning and memory function and hippocampal morphology changes, neuronal apoptosis, and synaptic dysfunction. A mechanistic study showed that alcohol activated protein kinase R-like endoplasmic reticulum kinase (PERK) signaling and suppressed brain derived neurotrophic factor (BDNF) levels via ER stress in the hippocampus, which LP-cs reversed. Alcohol activated oxidative stress and inflammation responses in the hippocampus, which LP-cs reversed.ConclusionLP-cs significantly ameliorated alcohol-induced cognitive dysfunction and cellular stress. LP-cs might serve as an effective treatment for alcohol-induced cognitive dysfunction.

The study aimed to investigate the relationship between cerebrospinal fluid (CSF) metal ions and anxiety, depression, and insomnia among cigarette smokers.We measured CSF levels of various metal ions from 178 Chinese male subjects. Apart from sociodemographic and clinical characteristics data, the Fagerstrom Test for Nicotine Dependence (FTND), Beck Depression Inventory (BDI), Self-Rating Anxiety Scale (SAS), and Pittsburgh Sleep Quality Index (PSQI) were applied.BDI and PSQI scores (all p 0.001) were significantly higher in active smokers than nonsmokers. Active smokers have significantly higher CSF levels of magnesium, zinc, iron, lead, lithium, and aluminum (all p ≤ 0.002). Some metal ions, including zinc, iron, lead, and aluminum, were found to have a significant correlation with BDI scores, whereas metal ions, including zinc and lead, were found to have a significant correlation with PSQI scores in the general group. More interesting, mediation analysis showed that aluminum mediated the relationship between smoking and depression.Cigarette smoking was indeed associated with depression and insomnia. Active smokers had significantly higher CSF levels of magnesium, zinc, iron, lead, lithium, and aluminum. Furthermore, CSF aluminum played a mediating role in the relationship between smoking and depression, which further confirmed its neurotoxicity.

Objectives: Cigarette smoking is associated with postoperative pain perception, which might be mediated by beta-endorphin and substance P. These effects on postoperative pain perception have never been investigated in human cerebrospinal fluid (CSF), which reflects biochemical alterations in the brain. Therefore, we investigated the associations among cigarette smoking, postoperative pain, and levels of beta-endorphin and substance P in human CSF.Methods: We recruited 160 Chinese men (80 active smokers and 80 nonsmokers) who underwent lumbar puncture before anterior cruciate ligament reconstruction, and 5-ml CSF samples were collected. Pain visual analog scale (VAS) scores, post-anesthetic recovery duration (PARD), and smoking variables were obtained. CSF levels of beta-endorphin and substance P were measured.Results: Compared to non-smokers, active smokers had significantly higher pain VAS (2.40 ± 0.67 vs. 1.70 ± 0.86, p < 0.001) and PARD scores (9.13 ± 2.11 vs. 7.27 ± 1.35, p = 0.001), lower CSF beta-endorphin (33.76 ± 1.77 vs. 35.66 ± 2.20, p = 0.001) and higher CSF substance P (2,124.46 ± 217.34 vs. 1,817.65 ± 302.14, p < 0.001) levels. Pain VAS scores correlated with PARD in active smokers (r = 0.443, p = 0.001).Conclusions: Cigarette smoking is associated with increased postoperative pain intensity, shown by delayed pain perception, higher pain VAS scores, and lower beta-endorphin and higher substance P levels in the CSF of active smokers. The more extended postoperative pain perception is delayed, the more pain intensity increases.

Background: Acute liver injury (ALI) involves excessive oxidative stress(OS) and inflammatory responses, leading to a high mortality rate due to lack of effective therapy. Carbon tetrachloride (CCl4) is widely used to induce ALI by induction of reactive oxygen species. Probiotics, including Lactobacillus plantarum ST-III, have been shown to produce antibacterial and antioxidant substances such as organic acids or bacteriocins that reduce liver damage. Nevertheless, the effect of Lactobacillus plantarum ST-III culture supernatant (L-P-cs) on CCl4-induced liver injury remains unclear.Methods: Mice were pretreated with L-P-cs or medium for 14days before one dose of 0.2% CCl4 at 10ml/kg body weight delivered by intraperitoneal injection. CCl4-induced liver injury was examined by measuring serum levels of liver transaminases and high mobility-group box 1 protein (HMGB1) and liver histological staining. Inflammation and apoptosis in liver were evaluated by real-time PCR, enzyme-linked immunosorbent assay (ELISA), and TUNEL staining. Apoptosis in NCTC 1469 cells was detected using CCK8 and western blotting (WB). In liver, OS and endoplasmic reticulum stress(ERS)-related proteins were measured using kits and WB.Results: L-P-cs significantly ameliorated CCl4-induced liver injury and reduced CCl4- induced inflammatory response and apoptosis, consistent with NCTC 1469 cells' results. L-P-cs also restored CCl4-induced increases in cell OS and ERS to normalize liver function. Specifically, L-P-cs pretreatment decreased CCl4-induced increases in nuclear factor (erythroid-2 related) factor 2, HO-1, superoxide dismutase, glucose regulatory protein, and activating transcription factor 6.Conclusion: L-P-cs synergistically improves liver lobule necrosis, hepatocyte inflammation, and apoptosis by reducing liver OS and ERS.

Upon binding double-stranded DNA (dsDNA), cyclic GMP-AMP synthase (cGAS) is activated and initiates the cGAS-stimulator of IFN genes (STING)-type I interferon pathway. DEAD-box helicase 41 (DDX41) is a DEAD-box helicase, and mutations in DDX41 cause myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML). Here, we show that DDX41-knockout (KO) cells have reduced type I interferon production after DNA virus infection. Unexpectedly, activations of cGAS and STING are affected in DDX41 KO cells, suggesting that DDX41 functions upstream of cGAS. The recombinant DDX41 protein exhibits ATP-dependent DNA-unwinding activity and ATP-independent strand-annealing activity. The MDS/AML-derived mutant R525H has reduced unwinding activity but retains normal strand-annealing activity and stimulates greater cGAS dinucleotide-synthesis activity than wild-type DDX41. Overexpression of R525H in either DDX41-deficient or -proficient cells results in higher type I interferon production. Our results have led to the hypothesis that DDX41 utilizes its unwinding and annealing activities to regulate the homeostasis of dsDNA and single-stranded DNA (ssDNA), which, in turn, regulates cGAS-STING activation.

Upon binding double-stranded (ds)DNA, cGAS is activated and initiates the cGAS-STING-type I interferon pathway; thus, the availability of dsDNA ligand is critical for cGAS activation. DDX41 is a DEAD-box helicase and mutations in DDX41 cause myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Here, we found that DDX41-knockout (KO) human cells and mice primary cells had reduced type I interferon production after viral infection, which is consistent with previous reports. Unexpectedly, cGAS and STING activation were affected in DDX41 KO cells, suggesting that DDX41 functions upstream of cGAS. The recombinant DDX41 protein exhibited ATP-dependent DNA unwinding activity and ATP-independent strand annealing activity. The MDS/AML-derived mutant R525H had reduced unwinding activities but retained normal strand annealing activity and stimulated greater cGAS dinucleotide synthesis activity than WT-DDX41. Overexpression of R525H in either DDX41-deficient or -proficient cells resulted in higher type I interferon production, indicating that DDX41 inactivates cGAS-STING-type I interferon pathway by unwinding dsDNA to single-stranded (ss)DNA. Our results demonstrate that DDX41 utilizes its unwinding and annealing activities to regulate the homeostasis of dsDNA and ssDNA, which in turn modulates the cGAS-STING pathway; dysregulation of this pathway leads to MDS/AML. Funding Information: This work was supported by grants from the Natural Sciences and Engineering Research Council of Canada (NSERC, RGPIN 2019-04578) to YZ, the Canada Foundation for Innovation (CFI33364) and Cancer Research Society (CRS-22493) to FJV, the National Institutes of Health (R01-AI-085015) to SRR, and NSERC (RGPIN-2019-05487), the Canadian Breast Cancer Foundation (CBCF-R1636), and the Cancer Research Society (CRS-24139) to YW. Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: All studies were performed following the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The experiments performed with mice in this study were approved by the UIC ACC (protocol no. 15-222). Bone marrow aspirates were collected from 23 patients with AML or MDS who participated in the study according to the protocol approved by the ethics committee on human genome research at Hiroshima University.

The K-homology (KH) domain is a nucleic acid–binding domain present in many proteins. Recently, we found that the DEAD-box helicase DDX43 contains a KH domain in its N-terminus; however, its function remains unknown. Here, we purified recombinant DDX43 KH domain protein and found that it prefers binding ssDNA and ssRNA. Electrophoretic mobility shift assay and NMR revealed that the KH domain favors pyrimidines over purines. Mutational analysis showed that the GXXG loop in the KH domain is involved in pyrimidine binding. Moreover, we found that an alanine residue adjacent to the GXXG loop is critical for binding. Systematic evolution of ligands by exponential enrichment, chromatin immunoprecipitation–seq, and cross-linking immunoprecipitation–seq showed that the KH domain binds C-/T-rich DNA and U-rich RNA. Bioinformatics analysis suggested that the KH domain prefers to bind promoters. Using 15N-heteronuclear single quantum coherence NMR, the optimal binding sequence was identified as TTGT. Finally, we found that the full-length DDX43 helicase prefers DNA or RNA substrates with TTGT or UUGU single-stranded tails and that the KH domain is critically important for sequence specificity and unwinding processivity. Collectively, our results demonstrated that the KH domain facilitates the substrate specificity and processivity of the DDX43 helicase.

Leaf senescence is regulated by diverse developmental and environmental factors. Exogenous jasmonic acid (JA) can induce leaf senescence, whereas auxin suppresses this physiological process. Crosstalk between JA and auxin signaling has been well studied, but not during JA-induced leaf senescence. Here, we found that upon methyl jasmonate treatment, Arabidopsis thaliana wrky57 mutants produced typical leaf senescence symptoms, such as yellowing leaves, low chlorophyll content, and high cell death rates. Further investigation suggested that senescence-associated genes were upregulated in the wrky57 mutants. Chromatin immunoprecipitation experiments revealed that WRKY57 directly binds to the promoters of SENESCENCE4 and SENESCENCE-ASSOCIATED GENE12 and represses their transcription. In vivo and in vitro experiments suggested that WRKY57 interacts with JASMONATE ZIM-DOMAIN4/8 (JAZ4/8) and the AUX/IAA protein IAA29, repressors of the JA and auxin signaling pathways, respectively. Consistent with the opposing functions of JA and auxin in JA-induced leaf senescence, JAZ4/8 and IAA29 also displayed opposite functions in JA-induced leaf senescence and competitively interacted with WRKY57. Our results suggested that the JA-induced leaf senescence process can be antagonized by auxin via WRKY57. Moreover, WRKY57 protein levels were downregulated by JA but upregulated by auxin. Therefore, as a repressor in JA-induced leaf senescence, WRKY57 is a common component of the JA- and auxin-mediated signaling pathways.

Peter Newmark etait un celebre traducteur anglais et un theoricien de la traduction. Il etait aussi l’un des representants de la theorie de la traduction de l'ecole linguistique en Occident. Il est connu pour la praticabilite de sa theorie, resultat de sa pratique et son enseignement de traduction. Dans la seconde moitie du 20eme siecle, ses idees ont ete introduites en Chine, stimulant ainsi la recherche scientifique sur la traduction. Sa theorie de la traduction semantique et communicative a fait l'objet d'une etude poussee des theoriciens chinois. En 1994, Newmark a propose une approche correlative a la traduction, remplacant son ancienne theorie par dichotomie (la traduction semantique et communicative). Mais dans quel but Newmark a-t-il apporte ce changement a sa theorie? Quels rapports existent-ils entre ces methodes de traduction? Du point de vue chinoise, en examinant ses approches de traduction et leurs relations, nous en decouvrirons les principes ou theories d'application afin de guider les recherches et l’exercice de la traduction anglo-chinoise.