Adipose-derived stem cells ameliorate radiation-induced lung injury by activating the DDAH1/ADMA/eNOS signaling pathway.

Background: Ionizing radiation-induced lung injury is caused by the initial inflammatory reaction and leads to advanced fibrosis of lung tissue. Adipose-derived stem cells (ASCs) are a type of mesenchymal stem cell that can differentiate into various functional cell types with broad application prospects in the treatment of tissue damage. The purpose of this study was to explore the protective effect of ASCs against radiation-induced lung injury and to provide a novel basis for prevention and treatment of radiation-induced lung injury. Materials and methods: Fifty mice were randomly divided into a control group (Ctrl), radiation exposure group (IR), radiation exposure plus ASC treatment group (IR + ASC), radiation exposure plus L-257 group (IR + L-257), and radiation exposure plus ASC treatment and L-257 group (IR + ASC + L-257). Mice in IR, IR + ASC, and IR + ASC + L-257 groups were exposed to a single whole-body dose of 5 Gy X-rays (160 kV/25 mA, 1.25 Gy/min). Within 2 h after irradiation, mice in IR + ASC and IR + ASC + L-257 groups were injected with 5 × 106 ASCs via the tail vein. Mice in IR + L-257 and IR + ASC + L-257 groups were intraperitoneally injected with 30 mg/kg L-257 in 0.5 mL saline. Results: The mice in the IR group exhibited lung hemorrhage, edema, pulmonary fibrosis, and inflammatory cell infiltration, increased release of proinflammatory cytokines, elevation of oxidative stress and apoptosis, and inhibition of the dimethylarginine dimethylamino hydratase 1 (DDAH1)/ADMA/eNOS signaling pathway. ASC treatment alleviated radiation-induced oxidative stress, apoptosis, and inflammation, and restored the DDAH1/ADMA/eNOS signaling pathway. However, L-257 pretreatment offset the protective effect of ASCs against lung inflammation, oxidative stress, and apoptosis. Conclusions: These data suggest that ASCs ameliorate radiation-induced lung injury, and the mechanism may be mediated through the DDAH1/ADMA/eNOS signaling pathway.

Competitive Risk Model Nomogram to Predict Prognosis in Patients Aged Over 65 Years with nonmetastatic Cervical Cancer: A SEER Population-Based Study.

Objective: The prognostic factors for elderly patients with cervical cancer differ from those of younger patients. Competitive risk events could cause biases in the Cox proportional hazards (PH) model. This study aimed to construct a competitive risk model (CRM) nomogram for patients aged > 65 years with nonmetastatic cervical cancer. Methods: We retrospectively analyzed data extracted from the Surveillance, Epidemiology, and End Results (SEER) database and a total of 1856 patients from 18 cancer registries across the United States diagnosed between 2010 and 2015 were included. Kaplan-Meier analysis and log-rank tests were used to compare intergroup survival. Univariate and multivariate Cox proportional regression analyses were performed to identify independent prognostic factors. The cumulative incidence function (CIF) and Fine and Gray's test were used to determine the impact of competitive risk events on prognosis. The CRM nomogram was internally and externally validated using time-dependent receiver operator characteristic (ROC) curve (time-AUC), Brier scores, Harrell's concordance index (C-index), calibration curve, and decision curve analysis (DCA). Results: Analyses revealed that histology, age, the International Federation of Gynaecologists and Obstetricians (FIGO) stage, number of in situ malignancies, chemotherapy, radiotherapy (RT), and surgery were independent prognostic factors. The CRM nomogram accurately predicted 1-year, 3-year, and 5-year disease-specific survival (DSS). The C-indexes and Brier scores of the CRM nomogram were 0.641 and 0.094, respectively, at the 1-year cut-off in the training set. The time-AUC of the CRM nomogram at the 1-year, 3-year, and 5-year intervals in the training set were 77.6%, 77.3%, and 74.5%, respectively. The calibration curve demonstrated a favorable concordance. DCA suggested that the nomogram had a good net benefit. Therefore, the Cox model underestimated the weight of risk factors compared to CRM. Conclusions: This study presents the CRM nomogram to predict DSS in patients aged > 65 years with nonmetastatic cervical cancer. It can help clinicians implement more accurate personalized diagnostic and treatment modalities for elderly patients with cervical cancer.

Irradiation-Induced Intestinal Injury is Associated With Disorders of Bile Acids Metabolism.

PURPOSE: Intestinal injury commonly occurs in radiation therapy, but its pathogenesis is not well understood. The relationship between irradiation-induced intestinal injury and bile acids (BAs) metabolism remains elusive. This study intends to clarify the role of BAs metabolism in irradiation-induced intestinal injury and the potential for supplementation with BAs to alleviate this injury. MATERIALS AND METHODS: BAs metabolomic analysis of fecal pellets from normal and 12 Gy γ-ray total abdominal irradiation (TAI) treated mice was performed. The effects of a crude bile extract (BAmix) or lithocholic acid (LCA) on mice exposed to 12 Gy γ-ray TAI were determined by analyzing weight loss, colon length, villus length, crypt number, and the expression of leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) and yes-associated protein 1 (YAP1). The effects of BAmix or LCA on intestinal organoids after 4 Gy irradiation were analyzed. ELISA assay was applied to test IL-1ß, IL-6 and TNF-α levels in mouse intestine. The expression changes of G protein-coupled receptor 1 (TGR5) and YAP1 in the colonic mucosa of patients with radiation-induced intestinal injury were determined by IHC. RESULTS: The relative abundance of secondary BAs was decreased while the relative abundance of primary BAs was increased in irradiated mice, and LCA was the most obvious change. BAmix and LCA alleviated irradiation-induced intestinal injury in a mouse model, as reflected by reduced body weight loss, longer colon, higher villus, more crypts, and increased Lgr5 expression. In intestinal organoids, BAmix and LCA enhanced newborn crypts formation after irradiation. LCA treatment improved the expression of TGR5 and YAP1 in mouse intestinal crypts. LCA has potential to reduce the inflammation levels in irradiated mice. Additionally, the expression levels of TGR5 and YAP1 in the colonic mucosa of patients with radiation enteritis were also significantly decreased. CONCLUSIONS: Radiation-induced intestinal injury is associated with disorders of BAs metabolism, and treatment with LCA had a protective effect against radiation-induced intestinal injury in mice by modulating TGR5 and YAP1.

Modified birnessite MnO2 as efficient Fenton-like catalysts through electron transfer process between the simultaneously surface-activated peroxymonosulfate and pollutants.

The development of efficient and eco-friendly Mn-based hybrids for the degradation of biorefractory organic pollutants via peroxymonosulfate (PMS) activation is highly desired. In this study, a novel graphite nanosheet (GNs)-based Fe-Mn bimetallic oxide (Fe doped birnessite MnO2, FeMn/GNs) was synthesized under mild conditions. Compared with monometallic Fe or Mn oxide on GNs, FeMn/GNs exhibited a higher surface area, decreased Mn oxidation states, stronger interaction with GNs, and more active sites for PMS adsorption. Among different Fe/Mn ratios, Fe2Mn1/GNs showed the optimum performance for bisphenol A (BPA) degradation with the first-order rate constant of 0.22 min-1, which was about 8.5 and 12.9 times higher than that of Mn/GNs and Fe/GNs, respectively. Different from the pollutant-catalyst-PMS electron transfer mechanism for Mn/GNs, the direct two-electron transfer in FeMn/GNs+PMS system, was mainly processed between the simultaneously activated BPA and PMS. This was probably based on the double adsorption sites of Fe and Mn species on the same catalyst: PMS was adsorbed by Fe species through hydroxyl groups, while BPA was mainly coordinated with Mn species due to the layered structure and hydrophobicity of the Mn oxide. This study is expected to provide the rational design of efficient Mn-based hybrids for PMS activation.

HIF-3α-Induced miR-630 Expression Promotes Cancer Hallmarks in Cervical Cancer Cells by Forming a Positive Feedback Loop.

Purpose: Hypoxia has crucial functions in the development and metastasis of cervical cancer by inducing the expression of numerous genes, including microRNA genes. But we know little about how the hypoxia factors and microRNAs orchestrate to regulate hallmarks of cervical cancer cells. Methods: We conducted RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) experiments to investigate the targets of HIF-3α or miR-630. ChIP-qPCR and RT-qPCR were carried out to validate the results of ChIP-seq and RNA-seq. Cellular, molecular, and radiation experiments were conducted to explore the functions of miR-630. Results: In this study, we showed that hypoxia-induced overexpression of HIF-3α increased the expression of dozens of miRNAs, including miR-630. Hypoxia could also directly induce miR-630 expression. ChIP-seq data showed that HIF-3α activates miR-630 expression by directly binding to the promoter of its host gene. Meanwhile, stable overexpression of miR-630 increased the expression of HIF-3α, but repressed the expression of HIF-1α, indicating a positive feedback loop between HIF-3α and miR-630. Consequently, stable overexpression of miR-630 in HeLa cells promotes cancer hallmarks, including radioresistance, inhibition of apoptosis, increased migration and invasion, and EMT-mediated metastasis. Meanwhile, inhibition of miR-630 showed opposite features. Conclusion: Taken together, our findings indicate a novel hypoxia-induced HIF-3α and miR-630 regulatory feedback loop contributing to metastasis and progression of cervical cancer cells and suggest that HIF-3α and miR-630 might act as potential biomarkers and therapeutic targets for cervical cancer in the future.

Pretreatment with metformin protects mice from whole-body irradiation.

Metformin, a first-line oral drug for type II diabetes mellitus, not only reduces blood glucose levels, but also has many other biological effects. Recent studies have been conducted to determine the protective effect of metformin in irradiation injuries. However, the results are controversial and mainly focus on the time of metformin administration. In this study, we aimed to investigate the protective effect of metformin in BALB/c mice exposed to 6 Gy or 8 Gy of a 60Co source of γ-rays for total body irradiation (TBI). Survival outcomes were assessed following exposure to 8 Gy or 6 Gy TBI, and hematopoietic damage and intestinal injury were assessed after exposure to 6 Gy TBI. Metformin prolonged the survival of mice exposed to 8 Gy TBI and improved the survival rate of mice exposed to 6 Gy TBI only when administered before exposure to irradiation. Moreover, pretreatment with metformin reduced the frequency of micronuclei (MN) in the bone marrow of mice exposed to 6 Gy TBI. Pretreatment of metformin also protected the intestinal morphology of mice, reduced inflammatory response and decreased the number of apoptotic cells in intestine. In conclusion, we demonstrated that pretreatment with metformin could alleviate irradiation injury.

Characterization of the antioxidative polysaccharides from Ziziphus jujube cv. Goutouzao and its tumor-inhibitory effects on human colorectal carcinoma LoVo cells via immunocyte activation.

Colorectal cancer, the most common malignancy in Asian and west world, is listed as the fourth lethal neoplastic disease with increasing incidence worldwide. Recently, Ziziphus jujube were reported with hepatoprotective, antihypertensive, and hypoglycemic functions. The polysaccharides from Ziziphus jujube was considered as the main component for these bioactivities. In this study, polysaccharides from Ziziphus jujube cv. Goutouzao (GZSP) was comprehensively investigated, and characterized as a heteropolysaccharide with antioxidant activity. Besides, it can stimulate the viability of immune cells RAW 264.7, which in turn inhibited the proliferation of colorectal carcinoma cells (LoVo) by inducing apoptosis, arresting cell cycle in G0/G1, and increasing intracellular ROS, as demonstrated by Flow Cytometric analyses. The results suggest that, different from chemotherapeutic modalities, GZSP can exert antitumor effects by activating immune reaction, providing more evidence for the development of GZSP-based functional foods and anticancer drugs serving as human colon cancer prevention. PRACTICAL APPLICATIONS: Natural products from medicinal and edible plant are great sources of phytochemicals beneficial to human health, such as tea polyphenols, carotenoids, and phytosterols, etc. In this study, GZSP, the polysaccharides from a well-received fruit, Ziziphus jujube cv. Goutouzao, has been comprehensively investigated. The results show that GZSP fights against free radicals commonly found in human circulation, a property that enables it to be used as an antioxidant food additive with jujube flavor. More importantly, GZSP impedes neoplastic progression by activating immune response, as evidenced by the inhibition of colorectal carcinoma (LoVo) cells. Comparing with chemotherapies usually imposing cytotoxicity on normal tissues, natural product GZSP is able to exert the antiproliferative effects on carcinoma cells with minimal side-effects. Therefore, GZSP-based functional foods and anticancer drugs with the purpose of preventing human colon cancer formation are promising to be developed.