MYEOV with High Frequencies of Mutations in Head and Neck Cancers Facilitates Cancer Cell Malignant Behaviors.

Cancer driver genes (CDGs) and the driver mutations disrupt the homeostasis of numerous critical cell activities, thereby playing a critical role in tumor initiation and progression. In this study, integrative bioinformatics analyses were performed based on a series of online databases, aiming to identify driver genes with high frequencies of mutations in head and neck cancers. Higher myeloma overexpressed (MYEOV) genetic variation frequency and expression level were connected to a poorer prognosis in head and neck cancer patients. MYEOV was dramatically upregulated within head and neck tumor samples and cells. Consistently, MYEOV overexpression remarkably enhanced the aggressiveness of head and neck cancer cells by promoting colony formation, cell invasion, and cell migration. Conversely, MYEOV knockdown attenuated cancer cell aggressiveness and inhibited tumor growth and metastasis in the oral orthotopic tumor model. In conclusion, MYEOV is overexpressed in head and neck cancer, with greater mutation frequencies correlating to a poorer prognosis in head and neck cancer patients. MYEOV serves as an oncogene in head and neck cancer through the promotion of tumor cell colony formation, invasion, and migration, as well as promoting tumor growth and metastasis in the oral orthotopic tumor model.

Evaluation of safety and efficacy of the bone marrow mesenchymal stem cell and gelatin-nano-hydroxyapatite combination in canine femoral defect repair.

Femoral shaft fracture is a common bone trauma in dogs. The limitation of mesenchymal stem cells in bone defect applications is that the cell suspension cannot be fixed to the bone defect site. In the study, our objective was to substantiate the combined application of canine bone marrow mesenchymal stem cells (cBMSCs) and gelatin-nano-hydroxyapatite (Gel-nHAP) and evaluate its therapeutic effect on bone defect diseases in dogs. Experiments were performed to evaluate the following: (1) the porosity of Gel-nHAP; (2) the adhesion of cBMSCs to Gel-nHAP; and (3) the effect of Gel-nHAP on cBMSC proliferation. The efficacy and safety of the combination of cBMSC and Gel-nHAP in the repair of femoral shaft defects were evaluated in animal experiments. The results showed that Gel-nHAP supported the attachment of cBMSCs and exhibited good biocompatibility. In the animal bone defect repair experiment, significant cortical bone growth was observed in the Gel-nHAP group at week 8 (p < 0.05) and in the cBMSCs-Gel-nHAP group at week 4 (p < 0.01). We demonstrated that Gel-nHAP could promote the repair of bone defects, and the effect of cBMSC-Gel-nHAP on the repair of bone defects was profound.

The mechanism of monobutyl phthalate -induced ferroptosis via TNF/IL6/STAT3 signal pathway in TM-3 cells.

As a common environmental endocrine disruptor, monobutyl phthalate (MBP) has been connected to reports of ROS accumulation, sperm destruction and reproductive damage. However, the specific mechanism of reproductive injury caused by MBP remains uncertain. Ferroptosis is a non-apoptotic, controlled oxidative damage-related cell death that is usually connected with reactive oxygen species and lipid peroxidation. In this work, to evaluate the mechanism of MBP-induced ferroptosis in reproductive damage, bioinformation analysis and experimental validation were used. Based on bioinformatics analysis, the interleukin-6 (IL-6) and signal transducer and activator of transcription 3 (STAT3) genes may be involved in the tumor necrosis factor (TNF) signaling pathway, which controls inflammation. Experimental study validated the significance of IL6 and STAT3 in MBP-induced ferroptosis. Western blotting and quantitative real-time PCR revealed that Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4), Tumor necrosis factor-α (TNF-α), IL6, and STAT3 were all elevated with treatment of MBP, but Glutathione peroxidase 4 was significantly decreased. To determine the participation of IL6/STAT3, we added the ferroptosis inhibitor Ferrastain-1 (Fer-1) and the IL6/STAT3 pathway inhibitor Angoline. In conclusion, we found that MBP induced ferroptosis in TM3 cells to damage male reproductive system through the TNF/IL6/STAT signal pathway, resulting in lipid peroxidation and iron metabolite degradation.

Gastric cancer-associated long non-coding RNA profiling and noninvasive biomarker screening based on a high-risk population cohort.

BACKGROUND: Effective noninvasive biomarkers of gastric cancer (GC) are critical for early detection and improvement of prognosis. We performed genome-wide long non-coding RNA (lncRNA) microarray analysis to identify and validate novel GC biomarkers depending on a high-risk population cohort. METHODS: LncRNA profiles were described using the Human LncRNA Microarray between GC and control plasma samples. The differential candidate lncRNAs were validated in two stages by quantitative reverse transcription polymerase chain reaction (qRT-PCR). We further evaluated the joint effect between the GC-associated lncRNA and Helicobacter pylori (H. pylori) infection on the risk of cardia and non-cardia GC, respectively. RESULTS: Different lncRNA expression profiles were identified between GC and control plasma with a total of 1206 differential lncRNAs including 470 upregulated and 736 downregulated in GC compared with the control group. The eight significantly upregulated lncRNAs (RP11-521D12.1, AC011995.3, RP11-5P4.3, RP11-244 K5.6, RP11-422 J15.1, CTD-2306 M5.1, CTC-428G20.2, and AC009133.20) in GC cases both in the present study and a similar microarray screening study by our collaborative team were selected for a two-stage validation. After the large sample size validation, the subjects with higher expression of RP11-244 K5.6 showed a significantly increased risk of GC with an adjusted odds ratio (OR) as 2.68 and 95% confidence interval (CI) as 1.15-6.24. Joint effects between RP11-244 K5.6 expression and H. pylori infection on the risk of GC were evaluated with no statistical significance. CONCLUSIONS: Our study found different lncRNA expression profiles between GC and control plasma and preliminarily identified RP11-244 K5.6 as a potential noninvasive biomarker for GC screening.

Trace elements in red swamp crayfish (Procambarus clarkii) in China: Spatiotemporal variation and human health implications.

The enrichment and health risk assessment of trace elements in crayfish on a national scale are significant for food safety due to the rapidly expanding crayfish consumption in China. In the present study, 4709 samples were extracted from databases to explore the spatiotemporal variation characteristics of trace elements in crayfish. Due to the variance in the background value of trace elements, the level of trace elements varies by region. Additionally, levels of As and Cr in crayfish increased with the promotion of intensive rice-crayfish coculture in China. Health risk assessment results revealed that trace elements may cause non-carcinogenic risk for crayfish consumption for adults and children from the mid-lower reaches of the Yangtze River, and the main risk was from As and Hg. The cancer risk values of As for children and adults in Zhejiang, Anhui, Heilongjiang, Hubei, Hunan, Jiangsu, Jiangxi and Shandong provinces were above the allowable value. There is concern about the non-carcinogenic and carcinogenic risk of consuming crayfish containing trace elements in some areas in China. Therefore, the results can serve as a critical reference for policy purposes in China. In addition, it is recommended that further research and assessment on crayfish consumption are required.

Microcystin-LR-induced nuclear translocation of cGAS promotes mutagenesis in human hepatocytes by impeding homologous recombination repair.

Microcystin-LR (MC-LR) has been recognized as a typical hepatotoxic cyclic peptides produced by cyanobacteria. Nowadays, due to the frequent occurrence of cyanobacterial blooms, the underlying hepatotoxic mechanism of MC-LR has become the focus of attention. In our present work, the mutagenic effect of MC-LR on human normal hepatic (HL-7702) cells regulated by cGAS was mainly studied. Here, we showed that exposure to MC-LR for 1-4 days could activate the cGAS-STING signaling pathway and then trigger immune response in HL-7702 cells. Notably, relative to the treatment with 1 µM MC-LR for 1-3 days, it was observed that when HL-7702 cells were exposed to 1 µM MC-LR for 4 days, the mutation frequency at the Hprt locus was remarkably increased. In addition, cGAS in HL-7702 cells was also found to complete the nuclear translocation after 4-day exposure. Moreover, co-immunoprecipitation and homologous recombination (HR)-directed DSB repair assay were applied to show that homologous recombination repair was inhibited after 4-day exposure. However, the intervention of the nuclear translocation of cGAS by transfecting BLK overexpression plasmid restored homologous recombination repair and reduced the mutation frequency at the Hprt locus in HL-7702 cells exposed to MC-LR. Our study unveiled the distinct roles of cGAS in the cytoplasm and nucleus of human hepatocytes as well as potential mutagenic mechanism under the early and late stage of exposure to MC-LR, and provided a novel insight into the prevention and control measures about the hazards of cGAS-targeted MC-LR.

Selenomethionine mitigate PM2.5-induced cellular senescence in the lung via attenuating inflammatory response mediated by cGAS/STING/NF-κB pathway.

Particulate matter 2.5 (PM2.5) is a widely known atmospheric pollutant which can induce the aging-related pulmonary diseases such as acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD) and interstitial pulmonary fibrosis (IPF). In recent years, with the increasing atmospheric pollution, airborne fine PM2.5, which is an integral part of air pollutants, has become a thorny problem. Hence, this study focused on the effect of PM2.5 on cellular senescence in the lung, identifying which inflammatory pathway mediated PM2.5-induced cellular senescence and how to play a protective role against this issue. Our data suggested that PM2.5 induced time- and concentration-dependent increasement in the senescence of A549 cells. Using an inhibitor of cGAS (PF-06928215) and an inhibitor of NF-κB (BAY 11-7082), it was revealed that PM2.5-induced senescence was regulated by inflammatory response, which was closely related to the cGAS/STING/NF-κB pathway activated by DNA damage. Moreover, our study also showed that the pretreatment with selenomethionine (Se-Met) could inhibit inflammatory response and prevent cellular senescence by hindering cGAS/STING/NF-κB pathway in A549 cells exposed to PM2.5. Furthermore, in vivo C57BL/6J mice model demonstrated that aging of mouse lung tissue caused by PM2.5 was attenuated by decreasing cGAS expression after Se-Met treatment. Our findings indicated that selenium made a defense capability for PM2.5-induced cellular senescence in the lung, which provided a novel insight for resisting the harm of PM2.5 to human health.

Role of Wnt/ß-catenin signaling pathway in ameloblast differentiation in relevance to dental fluorosis.

Excess consumption of fluoride during the development of tooth enamel will cause dental fluorosis, but the exact molecular mechanisms remain to be elucidated. Circadian rhythm is implicated in many physiological processes and various diseases. There is increasing evidence indicates that ameloblast differentiation is under the control of clock genes. However, it has not been reported whether fluoride regulates ameloblast differentiation through clock genes and the downstream PPARγ. To explore the effect of fluoride on ameloblast differentiation and the underlying regulatory mechanism, we used both rat dental fluorosis model and an ameloblast cell line LS8 to conduct a series of experiments. Our results showed that fluoride significantly reduced the expression of PCNA, RUNX2 and MMP9 in rat ameloblasts and LS8 cells (P < 0.05). Fluoride increased nuclear translocation of ß-catenin in vivo and in vitro, and 0.1 µg/ml Dkk1 pretreatment ameliorated the decreased expression of CXXC5, RUNX2 and MMP9 induced by fluoride. Furthermore, we found fluoride significantly inhibited the expression of Clock, Bmal1, Per2 and PPARγ in rat mandibular ameloblasts and LS8 cells by immunostaining, qPCR and Western blot (P < 0.05). Flow cytometry analysis showed that fluoride promoted ROS generation. Remarkably, 50 µM resveratrol significantly ameliorated the inhibitory effect of fluoride on ameloblast differentiation markers, clock genes and PPARγ, and inhibited the Wnt/ß-catenin signaling (P < 0.05). Taken together, these findings suggested that excessive fluoride promoted ROS generation, leading to the inhibition of clock genes, which resulted in reduced PPARγ and activated Wnt/ß-catenin signaling pathway, thus inhibiting ameloblast differentiation and matrix degradation. This study provides a better understanding of the molecular mechanism of enamel defects in dental fluorosis.

miR-340-5p affects oral squamous cell carcinoma (OSCC) cells proliferation and invasion by targeting endoplasmic reticulum stress proteins.

Lip and oral cancer is the 12th most common malignancy and oral squamous cell carcinoma (OSCC) represents about 90% of all oral malignant tumors, with an annual mortality rate exceeding 50%. Recent studies have concluded that endoplasmic reticulum stress may have a close link to tumor genesis, progression, and prognosis. As an epigenetic regulatory factor, miRNA exerts a substantial effect on tumor development. This study found that transcription factor 6 (ATF6) and Protein kinase R-like endoplasmic reticulum kinase (PERK) were abnormally increased within OSCC tissue samples and oral cancer cell lines. The biological functions of ATF6 and PERK within CAL-27 and SCC-9 oral cancer cell lines were investigated. In vitro experiments revealed that silencing ATF6 and PERK suppressed the ability of cells to proliferate and to invade and mitigated cell endoplasmic reticulum (ER) stress. As predicted by bioinformatics analyses and experiments, miR-340-5p could simultaneously bind to ATF6 and PERK 3' untranslated region (UTR) and inhibit ATF6 and PERK expression. miR-340-3p overexpression inhibited while down-regulation of miR-340-5p boosted the invading and proliferating ability of oral cancer cells, and miR-340-3p also affects ER stress. When co-transfected in oral cancer cells, dynamic effects of miR-340-5p and its targets PERK and ATF6 on cell phenotypes in vitro and in vivo were investigated. PERK or ATF6 overexpression dramatically attenuated phenotypes of miR-340-5p up-regulation. Altogether, miR-340-5p targets the endoplasmic reticulum stress proteins PERK and ATF6 to affect OSCC cell proliferation and invasion.

Network Pharmacology-Based Identification of Potential Targets of Lonicerae japonicae Flos Acting on Anti-Inflammatory Effects.

Lonicerae japonicae flos (LJF) is widely used for the treatment of inflammation-related diseases in traditional Chinese medicine (TCM). To clarify the anti-inflammatory mechanism of LJF, 29 compounds with high content in LJF were selected for network pharmacology. Then, a comprehensive network pharmacology strategy was implemented, which involved compound-inflammation-target construction, protein-protein interaction (PPI) network analysis, and enrichment analysis. Finally, molecular docking and in vitro experiments were performed to verify the anti-inflammatory activity and targets of the key compound. As a result, 279 inflammation-associated proteins were identified, which are mainly involved in the AGE/RAGE signaling pathway in diabetic complications, the HIF-1 signaling pathway, the PI3K-AKT signaling pathway, and EGFR tyrosine kinase inhibitor resistance. A total of 12 compounds were linked to more than 35 targets, including apigenin, kaempferol, quercetin, luteolin, and ferulic acid. The results of molecular docking showed that AKT has the most binding activity, exhibiting certain binding activity with 10 compounds, including vanillic acid, protocatechuic acid, secologanic acid, quercetin, and luteolin; the results of qRT-PCR and WB confirmed that two key compounds, secologanic acid and luteolin, could significantly decrease the secretion of TNF-α and the AKT expression of RAW264.7 murine macrophages stimulated by LPS (lipopolysaccharide). These results demonstrate that the comprehensive strategy can serve as a universal method to illustrate the anti-inflammatory mechanisms of traditional Chinese medicine by identifying the pathways or targets.

Fluoride regulates chondrocyte proliferation and autophagy via PI3K/AKT/mTOR signaling pathway.

Fluorine is an essential trace element for human health. However, excessive fluoride intake causes skeletal fluorosis which affects cartilage development. Fluoride inhibited chondrocyte proliferation which is the initial and critical step of endochondral ossification, but the underlying mechanism has not been clearly illustrated. Mammalian target of rapamycin (mTOR) is an important protein kinase which modulates various cellular processes and is believed to be a central regulator of chondrocyte proliferation and autophagy. In this study, we explored the effect of fluoride on the proliferation and autophagy of chondrocytes and the regulatory role of mTOR signaling pathway. Our results suggested that NaF inhibited the protein expressions of proliferating cell nuclear antigen (PCNA) and pS6 in cultured fetal rat tibias. Furthermore, NaF significantly downregulated the expressions of mTOR signaling pathway-related genes, including PI3K, AKT, mTOR, 4EBP1 and S6K1 in mouse ATDC5 chondrogenic cell line. We also found that NaF increased autophagy in ATDC5 cells. The mRNA and protein levels of autophagy-related genes LC3, Beclin1 and p62 were significantly changed after NaF treatment. Further studies demonstrated that MHY1485, a small-molecular mTOR activator, totally reversed fluoride-induced promotion of autophagy. MHY1485 also recovered the downregulation of proliferative chondrocytes markers Sox9 and Type Ⅱ Collagen (Col2a1) induced by fluoride in ATDC5 cells. Taken together, our result demonstrate that fluoride suppressed proliferation and facilitated autophagy via PI3K/AKT/mTOR signaling pathway in chondrogenesis.

Tribocatalytic degradation of dyes by tungsten bronze ferroelectric Ba2.5Sr2.5Nb8Ta2O30 submicron particles.

Searching for a new approach in environmental remediation in terms of dye degradation is important in industrialized society. In this work, ferroelectric Ba2.5Sr2.5Nb8Ta2O30 (BSNT) submicron powders prepared by the high-temperature solid-phase method are used for dye degradation under magnetic stirring. The dye in solution can be quickly degraded by magnetically stirring BSNT submicron particles in the dark in ambient temperature conditions. More importantly, the degradation efficiency can be greatly improved through simple modification of the stirring materials from glass to polypropylene, with a degradation efficiency of rhodamine B as high as 99% in 1.5 h at a gentle stirring speed of 300 rpm. Control experiments reveal that the degradation of the dye is mainly contributed by the friction between BSNT submicron particles and PTFE stirring rods. It is proposed that the friction between ferroelectric polar BSNT particles and PTFE causes charge transfer and induces a non-zero internal electric field to drive the separation of electron-hole pairs in BSNT particles, resulting in a novel tribocatalytic degradation of the dye, which is proven by the detection of ˙OH and ˙O2 - intermediate products during stirring. This work demonstrates that the friction energy of ferroelectric materials with strong polarization is an alternative approach for highly efficient dye degradation.

Suppression of Helicobacter pylori infection by daily cranberry intake: A double-blind, randomized, placebo-controlled trial.

BACKGROUND AND AIM: Dietary strategies that contribute to reducing incidence of Helicobacter pylori infection without negative side effects are highly desirable owing to worldwide bacterial prevalence and carcinogenesis potential. The aim of this study was to determine dosage effect of daily cranberry consumption on H. pylori suppression over time in infected adults to assess the potential of this complementary management strategy in a region with high gastric cancer risk and high prevalence of H. pylori infection. METHODS: This double-blind, randomized, placebo-controlled trial on 522 H. pylori-positive adults evaluated dose-response effects of proanthocyanidin-standardized cranberry juice, cranberry powder, or their placebos on suppression of H. pylori at 2 and 8 weeks by 13 C-urea breath testing and eradication at 45 days post-intervention. RESULTS: H. pylori-negative rates in placebo, low-proanthocyanidin, medium-proanthocyanidin, and high-proanthocyanidin cranberry juice groups at week 2 were 13.24%, 7.58%, 1.49%, and 13.85% and at week 8 were 7.35%, 7.58%, 4.48%, and 20.00%, respectively. Consumption of high-proanthocyanidin juice twice daily (44 mg proanthocyanidin/240-mL serving) for 8 weeks resulted in decreased H. pylori infection rate by 20% as compared with other dosages and placebo (P < 0.05). Percentage of H. pylori-negative participants increased from 2 to 8 weeks in subjects who consumed 44 mg proanthocyanidin/day juice once or twice daily, showing a statistically significant positive trend over time. Encapsulated cranberry powder doses were not significantly effective at either time point. Overall trial compliance was 94.25%. Cranberry juice and powder were well-tolerated. CONCLUSIONS: Twice-daily consumption of proanthocyanidin-standardized cranberry juice may help potentiate suppression of H. pylori infection. TRIAL REGISTRATION: ChiCTR1800017522, per WHO ICTRP.

Fluoride regulates the expression of extracellular matrix HSPG and related signaling pathways FGFR3 and Ihh/PTHrP feedback loop during endochondral ossification.

Skeletal fluorosis causes growth plate impairment and growth retardation during bone development. Longitudinal bone development is accomplished by endochondral ossification in growth plate. However, the mechanism of fluoride impairs growth plate is unclear. To explore the effect of fluoride on various glycosaminoglycans (GAGs) and related signaling pathways in growth plate during endochondral ossification, SD rats and ATDC5 cells were treated with fluoride and carried out a series of experiments. We found that the expression of heparan sulfate (HS), a kind of GAGs in extracellular matrix, was significantly increased in the growth plate of fluoride-treated rats compared with control rats. Furthermore, the expression of HS synthetic enzyme exostosin 1 (EXT1) and glypican 6 (GPC6), a core protein of HS proteoglycan (HSPG), were significantly increased in fluoride-treated ATDC5 cells compared with control cells (P < 0.05). The expression of related molecules including fibroblast growth factor receptor-3 (FGFR3), signal transducer and activator of transcription 1 (STAT1) and parathyroid hormone-related protein (PTHrP) were significantly increased in the fluoride-treated groups compared with control groups (P < 0.05), and there was significantly decreased in the expression of Indian hedgehog (Ihh) in fluoride-treated groups compared with control groups (P < 0.05). Our data suggested that fluoride increased the content of HSPG in extracellular matrix by promoting the expression of EXT1 and GPC6. Fluoride also activated FGFR3 signaling pathway, inhibited Ihh/PTHrP feedback loop and inhibited endochondral ossification. Nevertheless, the regulation of fluoride on HSPG and related pathways FGFR3 and Ihh/PTHrP feedback loop during endochondral ossification needs to be further studied.

An overview on the organic pollution around the Qinghai-Tibet plateau: The thought-provoking situation.

The Qinghai-Tibet Plateau plays an important role in the ecological safety and human health of the surroundings due to its unique geographical position and function. Therefore, it is necessary to study the pollution status and potential risk in this area. This study summarizes the distribution of different organic pollutants in biota and environmental media of the Qinghai-Tibet Plateau. Moreover, it also pays attention to the potential health risks of these organic pollutants. Organochlorine pesticides (OCPs), polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs) were the most frequently detected in different matrices. In general, the carcinogenic risks of organic pollutants were ranked in the very-low to moderate range for both children and adults. The carcinogenic risks of organic pollutants in fish, food, and water for children were 1-2 times higher than those for adults, while risks of organic pollutants in soil/sediment and in air for children were generally 10.6-16.5 and 2.6-2.8 times higher than those for adults, respectively. The maximal hazard quotient for non-carcinogenic risk was 0.95 (potential risk for children posed by organic pollutants in yak milk of Ruoergai), almost reaching an unacceptable level. Therefore, the potential health risks could not be neglected, especially for children who were more likely to be affected by the pollutants.

Synergistic effects induced by a low dose of diesel particulate extract and ultraviolet-A in Caenorhabditis elegans: DNA damage-triggered germ cell apoptosis.

Diesel exhaust has been classified as a potential carcinogen and is associated with various health effects. A previous study showed that the doses for manifesting the mutagenetic effects of diesel exhaust could be reduced when coexposed with ultraviolet-A (UVA) in a cellular system. However, the mechanisms underlying synergistic effects remain to be clarified, especially in an in vivo system. In the present study, using Caenorhabditis elegans (C. elegans) as an in vivo system we studied the synergistic effects of diesel particulate extract (DPE) plus UVA, and the underlying mechanisms were dissected genetically using related mutants. Our results demonstrated that though coexposure of wild type worms at young adult stage to low doses of DPE (20 µg/mL) plus UVA (0.2, 0.5, and 1.0 J/cm2) did not affect worm development (mitotic germ cells and brood size), it resulted in a significant induction of germ cell death. Using the strain of hus-1::gfp, distinct foci of HUS-1::GFP was observed in proliferating germ cells, indicating the DNA damage after worms were treated with DPE plus UVA. Moreover, the induction of germ cell death by DPE plus UVA was alleviated in single-gene loss-of-function mutations of core apoptotic, checkpoint HUS-1, CEP-1/p53, and MAPK dependent signaling pathways. Using a reactive oxygen species (ROS) probe, it was found that the production of ROS in worms coexposed to DPE plus UVA increased in a time-dependent manner. In addition, employing a singlet oxygen (1O2) trapping probe, 2,2,6,6-tetramethyl-4-piperidone, coupled with electron spin resonance analysis, we demonstrated the increased 1O2 production in worms coexposed to DPE plus UVA. These results indicated that UVA could enhance the apoptotic induction of DPE at low doses through a DNA damage-triggered pathway and that the production of ROS, especially (1)O2, played a pivotal role in initiating the synergistic process.

Fluoride promotes osteoblastic differentiation through canonical Wnt/ß-catenin signaling pathway.

Although fluoride is known to stimulate bone formation, the underlying mechanisms are not fully understood. Recent studies have implicated the Wnt/ß-catenin pathway as a major signaling cascade in bone biology. Our earlier studies highlighted a probable role of canonical Wnt pathway in bone formation of chronic fluoride-exposed rats, but the mechanism remains unclear. The current study determined the involvement of Wnt/ß-catenin signaling in fluoride-induced osteoblastic differentiation. Using primary rat osteoblasts, we demonstrated that fluoride significantly promoted osteoblasts proliferation and alkaline phosphate (ALP) expression as well as the mRNA expression levels of bone differentiation markers, including type I collagen (COL1A1), ALP and osteonectin. We further found fluoride induced phosphorylations at serine 473 of Akt and serine 9 of glycogen synthase kinase-3ß (GSK3ß), which resulted in GSK-3ß inhibition and subsequently the nuclear accumulation of the ß-catenin, as shown by Western blot and immunofluorescence analysis. Moreover, fluoride also induced the expression of Wnt-targeted gene runt-related transcription factor 2 (Runx2). Importantly, the positive effect of fluoride on ALP activity and mRNA expressions of COL1A1, ALP, osteonection and Runx2 was abolished by DKK-1, a blocker of the Wnt/ß-catenin receptor. Taken together, these findings suggest that fluoride promotes osteoblastic differentiation through Akt- and GSK-3ß-dependent activation of Wnt/ß-catenin signaling pathway in primary rat osteoblasts. Our findings provide novel insights into the mechanisms of action of fluoride in osteoblastogenesis.

Radiation-induced bystander signaling from somatic cells to germ cells in Caenorhabditis elegans.

Recently, radiation-induced bystander effects (RIBE) have been studied in mouse models in vivo, which clearly demonstrated bystander effects among somatic cells. However, there is currently no evidence for RIBE between somatic cells and germ cells in animal models in vivo. In the current study, the model animal Caenorhabditis elegans was used to investigate the bystander signaling from somatic cells to germ cells, as well as underlying mechanisms. C. elegans body size allows for precise microbeam irradiation and the abundant mutant strains for genetic dissection relative to currently adopted mouse models make it ideal for such analysis. Our results showed that irradiation of posterior pharynx bulbs and tails of C. elegans enhanced the level of germ cell apoptosis in bystander gonads. The irradiation of posterior pharynx bulbs also increased the level of DNA damage in bystander germ cells and genomic instability in the F1 progeny of irradiated worms, suggesting a potential carcinogenic risk in progeny even only somatic cells of parents are exposed to ionizing radiation (IR). It was also shown that DNA damage-induced germ cell death machinery and MAPK signaling pathways were both involved in the induction of germ cell apoptosis by microbeam induced bystander signaling, indicating a complex cooperation among multiple signaling pathways for bystander effects from somatic cells to germ cells.

[Effects of the ultra-filtration extract mixture from Hedysarum Polybotrys on human liver cells HepG2 radiosensitivity].

OBJECTIVE: To investigate the effects of the ultra-filtration extract mixture from Hedysarum Polybotrys (UEMHP) on the radiosensitivity of HepG2 cells, and to explore its possible mechanisms. METHODS: The proliferation inhibition effects of UEMHP on HepG2 cells was detected by CCK-8 assay. The colony formation assay was used for the survival fraction (SF) analysis. The distribution of the cell cycle and the apoptosis rate were detected using flow cytometry (FCM). The survivin mRNA expression level was detected using reverse transcription-PCR assay. RESULTS: The inhibition of UEMHP on HepG2 cells was time-and dose-dependent at the concentration ranging between 5 -50 mg/L (P < 0.05). The parameters of the two curve for SF (P < 0.05) showed statistical difference between the irradiation group and the UEMHP irradiation group. UEMHP could inhibit the clone formation of HepG2 cells and enhance the radiosensitivity of HepG2 cells. The results of FCM showed that UEMHP could induce G2/M phase arrest. The apoptosis rate in the UEMHP irradiation group (21.42% +/- 3.74%) was higher than that in the control group (5.35% +/- 0.41%), the only UEMHP group (10.36% +/- 1.75%), or the irradiation group (10.58% +/- 2.01%) (P < 0.01). RT-PCR showed that the survivin mRNA expression level was lower in the UEMHP irradiation group (0.31 +/- 0.02) than in the control group (0.82 +/- 0.06) and the irradiation group (0.58 +/- 0.04) respectively, showing statistical difference (P < 0.01). CONCLUSION: UEMHP can enhance the radiosensitivity of HepG2 cells, and its possible mechanisms might be correlated to down-regulating the survivin mRNA expression and promoting the apoptosis.

Sorption of four hydrophobic organic compounds by three chemically distinct polymers: role of chemical and physical composition.

The sorption behavior of four hydrophobic organic contaminants (HOCs) (i.e., phenanthrene, naphthalene, lindane, and 1-naphthol) by three types of polymers namely polyethylene (PE), polystyrene (PS), and polyphenyleneoxide (PPO) was examined in this work. The organic carbon content-normalized sorption coefficients (K(oc)) of phenanthrene, lindane, and naphthalene by PEs of same composition but distinct physical makeup of domains increased with their crystallinity reduction (from 58.7 to 25.5%), suggesting that mobility and abundance of rubbery domains in polymers regulated HOC sorption. Cross-linking in styrene-divinylbenzene copolymer (PS2) created substantial surface area and porosity, thus, K(oc) values of phenanthrene, lindane, naphthalene, and 1-naphthol by PS2 were as high as 274.8, 212.3, 27.4, and 1.5 times of those by the linear polystyrene (PS1). The K(oc) values of lindane, naphthalene, and 1-naphthol by polar PPO were approximately 1-3 orders of magnitude higher than those by PS1, and PPO had comparable sorption for phenanthrene but higher sorption for naphthalene and 1-naphthol than PS2. This can be a result that a portion of O-containing moieties in PPO were masked in the interior part, while leaving the hydrophobic domains exposed outside, therefore demonstrating the great influence of the spatial arrangement of domains in polymers on HOC sorption.