Probiotic Consortia Protect the Intestine Against Radiation Injury by Improving Intestinal Epithelial Homeostasis.

PURPOSE: Radiation-induced intestinal injury (RIII) commonly occur during abdominal-pelvic cancer radiation therapy; however, no effective prophylactic or therapeutic agents are available to manage RIII currently. This study aimed to clarify the potential of probiotic consortium supplementation in alleviating RIII. METHODS AND MATERIALS: Male C57BL/6J mice were orally administered a probiotic mixture comprising Bifidobacterium longum BL21, Lactobacillus paracasei LC86, and Lactobacillus plantarum Lp90 for 30 days before exposure to 13 Gy of whole abdominal irradiation. The survival rates, clinical scores, and histologic changes in the intestines of mice were assessed. The impacts of probiotic consortium treatment on intestinal stem cell proliferation, differentiation, and epithelial barrier function; oxidative stress; and inflammatory cytokines were evaluated. A comprehensive examination of the gut microbiota composition was conducted through 16S rRNA sequencing, while changes in metabolites were identified using liquid chromatography-mass spectrometry. RESULTS: The probiotic consortium alleviated RIII, as reflected by increased survival rates, improved clinical scores, and mitigated mucosal injury. The probiotic consortium treatment exhibited enhanced therapeutic effects at the histologic level compared with individual probiotic strains, although there was no corresponding improvement in survival rates and colon length. Moreover, the probiotic consortium stimulated intestinal stem cell proliferation and differentiation, enhanced the integrity of the intestinal epithelial barrier, and regulated redox imbalance and inflammatory responses in irradiated mice. Notably, the treatment induced a restructuring of the gut microbiota composition, particularly enriching short-chain fatty acid-producing bacteria. Metabolomic analysis revealed distinctive metabolic changes associated with the probiotic consortium, including elevated levels of anti-inflammatory and antiradiation metabolites. CONCLUSIONS: The probiotic consortium attenuated RIII by modulating the gut microbiota and metabolites, improving inflammatory symptoms, and regulating oxidative stress. These findings provide new insights into the maintenance of intestinal health with probiotic consortium supplementation and will facilitate the development of probiotic-based therapeutic strategies for RIII in clinical practice.

Fraxin (7-hydroxy-6-methoxycoumarin 8-glucoside) confers protection against ionizing radiation-induced intestinal epithelial injury in vitro and in vivo.

The small intestine exhibits remarkable sensitivity to ionizing radiation (IR), which significantly hampers the effectiveness of radiotherapy in the treatment of abdominal and pelvic tumors. Unfortunately, no effective medications are available to treat radiation-induced intestinal damage (RIID). Fraxin (7-hydroxy-6-methoxycoumarin 8-glucoside), is a coumarin derivative extracted from the Chinese herb Cortex Fraxini. Several studies have underscored the anti-inflammatory, antibacterial, antioxidant, and immunomodulatory properties of fraxin. However, the efficacy of fraxin at preventing or mitigating RIID remains unclear. Thus, the present study aimed to investigate the protective effects of fraxin against RIID in vitro and in vivo and to elucidate the underlying mechanisms. The study findings revealed that fraxin markedly ameliorated intestinal injuries induced by 13 Gy whole abdominal irradiation (WAI), which was accompanied by a significant increase in the population of Lgr5+ intestinal stem cells (ISCs) and Ki67+ progeny. Furthermore, fraxin mitigated WAI-induced intestinal barrier damage, and reduced oxidative stress and intestinal inflammation in mice. Transcriptome sequencing of fraxin-treated mice revealed upregulation of IL-22, a pleiotropic cytokine involved in regulating the function of intestinal epithelial cells. Moreover, in both human intestinal epithelial cells and ex vivo cultured mouse intestinal organoids, fraxin effectively ameliorated IR-induced damage by promoting the expression of IL-22. The radioprotective effects of fraxin were partially negated in the presence of an IL-22-neutralizing antibody. In summary, fraxin is demonstrated to possess the ability to alleviate RIID and maintain intestinal homeostasis, suggesting that fraxin might serve as a strategy for mitigating accidental radiation exposure- or radiotherapy-induced RIID.

Effectiveness of Internet-delivered self-help acceptance and commitment therapy (iACT) on nurses' obsessive-compulsive symptoms and sleep quality: A randomized controlled trial with 3-month follow-up.

BACKGROUND: Frontline nurses suffered unprecedented mental distress during the COVID-19 pandemic. It's essential to explore new and more accessible alternatives to improve the availability of psychological treatments. This study aimed to investigate the influence of online self-help iACT linear intervention and iACT loop intervention on sleep quality (SQ), obsessive-compulsive symptoms (OCS), and psychological flexibility (PF) in nurses. METHODS: A randomized controlled trial was conducted at a hospital in China. 602 participants were randomly assigned to the iACT linear intervention, iACT loop intervention, or wait list control group, and required to complete the questionnaires of OCS, PF and SQ. The linear mixed effects analysis (LMM) was used to analyze the impact of the intervention on outcome variables. RESULTS: LMM analyses demonstrated that both two intervention had significant improvement on OCS (t = -38.235, p < 0.001), PF (t = 28.156, p < 0.001), as well as SQ (t = -16.336, p < 0.001). There were significant differences between the linear group and loop group on the PF in T2 (t = -8.271, p < 0.001), T3 (t = -8.366, p < 0.001), T4 (t = -8.302, p < 0.001), with the iACT loop model (Cohen's d = 1.652) showing a slight advantage over the iACT linear model (Cohen's d = 1.134). CONCLUSIONS: The findings indicate that two interventions positively impact OCS, PF, and SQ. Compared to the iACT linear psychotherapy model, the iACT loop model shows greater effectiveness in enhancing PF, making it helpful to promote significant improvements in psychotherapy planning.

Mediating role of psychological flexibility in the effect of obsessive-compulsive symptoms on sleep quality among nurses during the COVID-19 pandemic.

Front-line nurses suffered unprecedented mental distress and severe insomnia during the COVID-19 pandemic. Present study aimed to explore the relationship between obsessive-compulsive symptoms and sleep quality and examine the potential mediating role of psychological flexibility between obsessive-compulsive symptoms and sleep quality. A total of 496 nurses from a Chinese large-scale Class 3 A Comprehensive Hospital were included in an online cross-sectional survey and completed the revised obsessive-compulsive inventory (OCI-R), Multidimensional Psychological Flexibility Inventory (MPFI) and Pittsburgh Sleep Quality Index (PSQI). As predicted, obsessive-compulsive symptoms were negatively associated with psychological flexibility and sleep quality, and psychological flexibility was positively associated with sleep quality. In addition, the relationship between obsessive-compulsive symptoms and sleep quality was partially mediated by psychological flexibility, which can provide some reference for the treatment of the obsessive-compulsive disorder (OCD) and insomnia, and lead to improvements in clinical and psychotherapy planning.

ZIM3 activation of CCL25 expression in pulmonary metastatic nodules of osteosarcoma recruits M2 macrophages to promote metastatic growth.

Tumor-associated macrophages (TAMs) play an important role in tumor growth and metastasis. However, the involvement of TAMs infiltration in pulmonary osteosarcoma (OS) metastasis remains poorly understood. Therefore, the effect of OS cells on macrophages migration was investigated by in vivo and in vitro experiments to evaluate the infiltration and mechanism of TAMs in pulmonary OS metastases. The results showed that the zinc finger protein ZIM3 was upregulated in OS cells than in osteoblasts and activated the expression of CCL25, which subsequently promoted the migration of M2 macrophages. CCL25 or ZIM3 silencing in OS cells inhibited the infiltration of M2 macrophages and the formation of pulmonary metastatic nodules in a mouse model of pulmonary OS metastasis and prolonged the survival of the mice. Furthermore, bioinformatics analyses revealed that CCL25 and ZIM3 expressions are negatively correlated with the prognosis of OS patients. In conclusion, this study found that a large number of M2 TAMs were recruited into pulmonary metastatic nodules of OS through the activation of the ZIM3-CCL25 axis in OS cells, thereby facilitating OS metastasis. Therefore, the suppression of ZIM3-CCL25-induced recruitment of M2 TAMs to the metastatic sites might be considered as a therapeutic approach to inhibit the growth of pulmonary OS metastases.

Mental fatigue and negative emotion among nurses during the COVID-19 pandemic.

COVID-19 is a major public health event affecting the people worldwide. Nurses are still under immense psychological pressure. This study aimed to explore the relationship between mental fatigue and negative emotions among frontline medical staff during the COVID-19 pandemic. The study was conducted in August 2020, which included 419 medical staff between 17 to 28 years. The Fatigue Scale, Multidimensional Mental Flexibility Questionnaire, Cognitive Fusion Scale, and Depression-Anxiety-Stress Brief Version Scale were used. During the data collection period, the pandemic was under control in China and continued worldwide. The results indicated that 27.7% of the medical staff experienced depression, and 32.3% of them feel stressed. Specifically, first, correlation analyses showed significant positive pairwise correlations between mental fatigue, psychological inflexibility, cognitive fusion, and negative emotions among nurses. Second, mediation model tests showed statistically significant mediating effects of psychological inflexibility and cognitive fusion between mental fatigue on nurses' negative emotions, and statistically, significant chain mediating effects of psychological inflexibility and cognitive fusion. Mental fatigue indirectly affects nurses' negative effects through the mediating effects of psychological inflexibility, cognitive fusion, and the chain mediating effects of psychological inflexibility and cognitive fusion, respectively. the negative effects of mental fatigue come from impairment of cognitive functioning, and interventions using acceptance and commitment therapy for mental fatigue and negative emotions are more effective since both psychological inflexibility and cognitive fusion are important components of the therapy.

Osteosarcoma exocytosis of soluble LGALS3BP mediates macrophages toward a tumoricidal phenotype.

This study aimed to elucidate the interactions between osteosarcoma (OS) and M1 macrophages infiltrated into the tumor microenvironment and to explore the underlying mechanisms whereby M1 macrophages influence the growth of OS, so that novel treatments of OS can be developed. A transwell co-culture system, an indirect conditioned medium culture system and two orthotopic bearing OS models were established to assess for the interplay between M1 macrophages and OS. We found that the co-culture of M1 macrophages with OS cells significantly inhibited the growth of the tumor cells by inducing apoptosis. Furthermore, HSPA1L secreted by M1 macrophages exerted this anti-tumor effect through the IRAK1 and IRAK4 pathways. LGALS3BP secreted by OS cells bound to the ligand LGALS3 on M1 macrophages and thereby induced the secretion of Hspa11 via Akt phosphorylation. In vivo experiments demonstrated that the culture supernatant of OS-stimulated M1 macrophages significantly inhibited the growth of OS, whereas silencing Lgals3bp promoted the progression of OS. In conclusion, OS modifies the phenotype of tumor-associated macrophages (TAMs) and thereby influences the apoptosis of OS cells through soluble factors. The modulation of TAMs may be a promising and effective therapeutic approach in OS.

Confocal Raman microspectroscopic analysis on the time-dependent impact of DAPT, a γ-secretase inhibitor, to osteosarcoma cells.

Confocal Raman microspectroscopy (CRM) analysis provides subcellular compositional and morphology related information. In this study, we used CRM in conjunction with multivariate statistical analysis to elucidate the time-dependent impact of the γ-secretase inhibitor, DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester) of osteosarcoma (OS) cells. The interactions of DAPT (20 µM) with a murine OS cell line K7M2 at 24 and 48 h were monitored. The spectral characteristics of drug action were identified to illustrate the cellular compositional alterations, showing that DAPT induced apoptosis by reducing the protein, lipid and nucleic acid content and structural changes. Multivariate algorithms, principal component analysis (PCA) and linear discriminant analysis (LDA) revealed a clear separation among cells in the untreated control (UT), 24H (DAPT-treated for 24 h), and 48H (DAPT-treated for 48 h) groups, achieving sensitivities of 100%, 96%, 100% and specificities of 98%, 100%, 100%, respectively. After point-scanned spectral imaging, K-means clustering analysis (KCA) was further used to visualize sub-cellular morphological changes and the underlying spectral characteristics in a temporal sequence. Compared with the UT group, Raman imaging results exhibited gradually increased nuclear division of OS cells with DAPT treatment duration extension, along with changes in the physiology of other organelles within the cell. By providing a unique perspective for understanding the temporary cellular responses to DAPT at molecular level, the achieved results form the foundation of strategies for the application of CRM and other Raman-based techniques for studying the therapeutic responses of other anticancer agents in cancer model systems.

Confocal Raman Spectral Imaging Study of DAPT, a γ-secretase Inhibitor, Induced Physiological and Biochemical Reponses in Osteosarcoma Cells.

Confocal Raman microspectral imaging was adopted to elucidate the cellular drug responses of osteosarcoma cells (OC) to N-[N-(3, 5-difluorophenyl acetyl)-L-alanyl]-sphenylglycine butyl ester (DAPT), a γ-secretase inhibitor, by identifying the drug induced subcellular compositional and structural changes. Methods: Spectral information were acquired from cultured osteosarcoma cells treated with 0 (Untreated Group, UT), 10 (10 µM DAPT treated, 10T), 20 µM (20 µM DAPT treated, 20T) DAPT for 24 hours. A one-way ANOVA and Tukey's honest significant difference (HSD) post hoc multiple test were sequentially applied to address spectral features among three groups. Multivariate algorithms such as K-means clustering analysis (KCA) and Principal component analysis (PCA) were used to highlight the structural and compositional differences, while, univariate imaging was applied to illustrate the distribution pattern of certain cellular components after drug treatment. Results: Major biochemical changes in DAPT-induced apoptosis came from changes in the content and structure of proteins, lipids, and nucleic acids. By adopted multivariate algorithms, the drug induced cellular changes was identified by the morphology and spectral characteristics between untreated cells and treated cells, testified that DAPT mainly acted in the nuclear region. With the increase of the drug concentration, the content of main subcellular compositions, such nucleic acid, protein, and lipid decreased. In an addition, DAPT-induced nuclear fragmentation and apoptosis was depicted by the univariate Raman image of major cellular components (nucleic acids, proteins and lipids). Conclusions: The achieved Raman spectral and imaging results illustrated detailed DAPT-induced subcellular compositional and structural variations as a function of drug dose. Such observations can not only explain drug therapeutic mechanisms of OC DAPT treatment, and also provide new insights for accessing the medicine curative efficacy and predicting prognosis.

Overexpression of FER1L4 promotes the apoptosis and suppresses epithelial-mesenchymal transition and stemness markers via activating PI3K/AKT signaling pathway in osteosarcoma cells.

Novel long non-coding RNA Fer-1-like protein 4 (FER1L4) has been identified as a tumor suppressor in endometrial carcinoma, ovarian cancer, hepatocellular carcinoma, esophageal squamous cell carcinoma. However, the function of FER1L4 in osteosarcoma has not been clear. The aim of the research was to explore the effects of FER1L4 in osteosarcoma. Results showed that FER1L4 was observed to be lowly expressed in osteosarcoma cell lines (US-O2, MG-63 and SaOS-2 cells), especially MG63 cells. Besides, overexpression of FER1L4 remarkably repressed the proliferation, migration and invasion of MG63 cells. FER1L4-induced apoptotic cell death leaded to the activation of caspase-3 and Bax/Bcl2. Moreover, epithelial-mesenchymal transition (EMT) was tremendously suppressed by increased FER1L4, evidences were the increased E-cadherin and reduced vimentin and fibronectin. Blocking FER1L4 expression by sh-FER1L4 treatment increased the expression of SOX9, CD44, ALDH1, Nanog and Oct4, indicating that FER1L4 could effectively decrease cell stemness in osteosarcoma. Furthermore, the protein levels of p-AKT and p-PI3K were remarkably suppressed when FER1L4 was knocked down. In conclusion, the study indicated that FER1L4 acted as a tumor suppressor in osteosarcoma via activating PI3K/AKT pathway may be a new prognostic biomarker and potential therapeutic target for osteosarcoma intervention.

Meta-analysis of clinical significance of p53 protein expression in patients with osteosarcoma.

AIM: The prognostic role of p53 protein expression in osteosarcoma has been reported, but the results remain conflicting. MATERIALS & METHODS: The relevant literature databases were searched to get eligible articles published in English. The overall ORs or HRs and their corresponding 95% CIs were calculated. RESULTS: The results indicated that p53 protein expression was not linked to age factor, gender, tumor grade, cancer metastasis and response to chemotherapy. p53 expression was significantly lower in osteogenic osteosarcoma than in nonosteogenic osteosarcoma (OR = 0.40; p = 0.006). p53 expression was associated with a poor prognosis of patients in overall survival (univariate analysis: HR: 2.49; p < 0.001 and multivariate analysis: HR: 2.92; p < 0.001). CONCLUSION: p53 expression was correlated with pathological type and may become a useful prognostic biomarker in overall survival in osteosarcoma.