Molecular engineering to elevate reactive oxygen species generation for synergetic damage on lipid droplets and mitochondria.

Photodynamic therapy (PDT), characterized by high treatment efficiency, absence of drug resistance, minimal trauma, and few side effects, has gradually emerged as a novel and alternative clinical approach compared to traditional surgical resection, chemotherapy and radiation. Whereas, considering the limited diffusion distance and short lifespan of reactive oxygen species (ROS), as well as the hypoxic tumor microenvironment, it is crucial to design photosensitizers (PSs) with suborganelle specific targeting ability and low-oxygen dependence for accurate and highly efficient photodynamic therapy. In this study, we have meticulously designed three PSs, namely CIH, CIBr, and CIPh, based on molecular engineering. Theoretical calculation demonstrate that the three compounds possess good molecular planarity with calculated S1-T1 energy gaps (ΔES1-T1) of 1.04 eV for CIH, 0.92 eV for CIBr, and 0.84 eV for CIPh respectively. Notably, CIPh showcases remarkable dual subcellular targeting capability towards lipid droplets (LDs) and mitochondria owing to the synergistic effect of lipophilicity derived from coumarin's inherent properties combined with electropositivity conferred by indole salt cations. Furthermore, CIPh demonstrates exclusive release of singlet oxygen (1O2)and highly efficient superoxide anion free radicals(O2⦁-) upon light irradiation supported by its smallest S1-T1 energy gap (ΔES1-T1 = 0.84 eV). This leads to compromised integrity of LDs along with mitochondrial membrane potential, resulting in profound apoptosis induction in HepG2 cells. This successful example of molecular engineering guided by density functional theory (DFT) provides valuable experience for the development of more effective PSs with superior dual targeting specificity. It also provides a new idea for the development of advanced PSs with efficient and accurate ROS generation ability towards fluorescence imaging-guided hypoxic tumor therapy.

Exposure to OPFRs Is Associated with Obesity and Dysregulated Serum Lipid Profiles: Data from 2017-2018 NHANES.

Widespread exposure to organophosphorus flame retardants (OPFRs) has been observed in the general population. Emerging studies have revealed OPFRs possess endocrine-disturbing properties. The present study aims to assess the association between urinary metabolites of OPFRs, BMI, and serum lipid profiles. Data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 were obtained, with 1334 adults enrolled in the current study. Urinary concentrations of bis (1-chloro-2-propyl) phosphate (BCIPP), bis(2-chloroethyl) phosphate (BCEP), bis(1,3-dichloro-2-propyl) phosphate (BDCPP), dibutyl phosphate (DBUP), and diphenyl phosphate (DPHP) were quantified to assess OPFR exposure. Covariate-adjusted linear and logistic regression models were conducted to explore the associations between log2-transformed concentrations of OPFR metabolites, BMI, obesity, and serum lipid profiles. Stratified analyses were performed to assess the heterogeneity of associations by age, gender, race, etc. Positive associations were found between OPFR exposure and the risk of obesity. The multivariate linear analysis indicated that a one-unit increase in log2-transformed urinary concentrations of BCEP and BDCPP was associated with 0.27 (95% CI: 0.02-0.52, p = 0.0338) and 0.56 (95% CI: 0.25-0.87, p = 0.0004) higher BMI value, respectively. One log2-unit increase in urinary BCEP and BDCPP concentrations was associated with 1.1-fold (95% CI: 1.02-1.18, p = 0.0096) and 1.19-fold (95% CI: 1.09-1.30, p = 0.0001) risk for developing obesity. Furthermore, the non-linear relationship between exposure to OPFRs and obesity was identified. Additionally, multivariable linear regression showed that urinary DPHP concentrations were inversely correlated with serum triglyceride (TG) levels (ß = -7.41, 95% CI: -12.13 to -2.68, p = 0.0022). However, no other OPFR metabolites were found to be significantly statistically associated with serum lipid levels after adjusting for potential confounders. In conclusion, environmental exposure to OPFRs might contribute to obesity and dysregulated TG concentrations in adults. Future prospective research is warranted to confirm the causal relationship between metabolites of OPFRs and obesity.

Depleting ANTXR1 suppresses glioma growth via deactivating PI3K/AKT pathway.

Gliomas are commonly known as primary brain tumors and associated with frequent recurrence and an unsatisfactory prognosis despite extensive research in the underlying molecular mechanisms. We aimed to examine the role of ANTXR1 in glioma tumorigenesis and explore its downstream regulatory mechanism. ANTXR1 expression in clinical specimens and its relationship with some pathological characteristics were detected using immunohistochemical staining. After silencing/upregulating ANTXR1 through lentiviral transfection in glioma cell lines, qRT-PCR and western blotting were used to examine mRNA and protein levels, and cell phenotype was also detected. ANTXR1-knockdown and -overexpression cells were then processed by AKT activator and PI3K inhibitor, respectively, to verify downstream PI3K/AKT pathway regulated by ANTXR1. Xenograft nude mice models were constructed to verify the role of ANTXR1 in vivo. We found overexpression of ANTXR1 in both cell lines in comparison with those in normal brain tissues. Glioma cell growth and migratory ability were dramatically impaired as a result of silencing ANTXR1 by shANTXR1 lentiviruses. ANTXR1 blockade also accelerated cell apoptosis and held back cell cycle via targeting G2 phrase during cell mitosis. In vivo xenograft models verified in vitro findings above. Further exploration disclosed that AKT activator promoted anti-tumor effects mediated by ANTXR1 knockdown, while PI3K inhibitor limited pro-tumor effects mediated by ANTXR1 overexpression, indicating that ANTXR1 functioned in glioma cells through regulating PI3K/AKT pathway. ANTXR1 could play an indispensable role in glioma tumorigenesis via activating PI3K/AKT-mediated cell growth. Our study provides a theoretical basis for targeting ANTXR1 as a molecular target in glioma clinical therapeutics.

Occurrence and accumulation characteristics of legacy and novel brominated flame retardants in surface soil and river sediments from the downstream of Chuhe River basin, East China.

Surface soil and river sediment samples were collected from the downstream of Chuhe River basin, East China, to investigate the occurrence and accumulation characteristics of legacy and novel brominated flame retardants (NBFRs). The respective concentrations of BDE-209 and nine NBFRs ranged from n.d. to 41.4 ng/g dry weight (dw) and from 0.35 to 362.78 ng/g dw in the collected surface soil samples and ranged from 0.29 to 19.73 ng/g dw and from 0.70 to 66.83 ng/g dw in the collected river sediment samples. Soil samples exhibited a higher potential to accumulate BTBPE while the relative abundance of PBT in the collected sediment samples was significantly higher than that in soils. Even so, BTBPE was the predominant NBFR in both soil and sediment samples. The concentrations and relative abundances of legacy and NBFRs exhibited large spatial variation. The calculated concentration ratios of the total of the nine NBFRs (∑9NBFRs) to BDE-209 (∑9NBFRs/BDE-209) in most of the analyzed samples far exceeded 1, implying a clear shift from legacy brominated flame retardants to NBFRs in the downstream of Chuhe River basin.

LncRNA FEZF1-AS1 aggravates cell proliferation and migration in glioblastoma.

OBJECTIVES: Glioblastoma (GBM) represents the commonest malignant glioma. Long non-coding RNA (lncRNA) FEZ family zinc finger 1 antisense RNA 1 (FEZF1-AS1) has been validated to play an oncogenic role in multiple human malignancies, while its function in GBM has not been largely reported. We aim to identify the regulatory mechanism of FEZF1-AS1 in GBM. MATERIALS & METHODS: The expression pattern of FEZF1-AS1 was firstly figured out in GBM cells using RT-qPCR. Then, functional assays were conducted to examine the influence FEZF1-AS1 had on the biological properties of GBM cells. The downstream targets of FEZF1-AS1 were predicted and the underlying regulatory mechanism was determined by mechanism assays. RESULTS: FEZF1-AS1 possessed high expression in GBM cells. Down-regulation of FEZF1-AS1 suppressed GBM cell proliferation, migration and invasion while inducing cell apoptosis. With the help of bioinformatics prediction and mechanism assays, FEZF1-AS1 was found to bind to miR-363-3p and NOB1 was determined to be the downstream gene. Finally, results of rescue assays verified that the suppressive function of FEZF1-AS1 inhibition on GBM development were restored by miR-363-3p depletion or overexpression of NOB1. CONCLUSION: FEZF1-AS1 had oncogenic function in the advancement of GBM by targeting miR-363-3p/NOB1, which made FEZF1-AS1 a potential biomarker for GBM treatment.

High expression of PYCARD is an independent predictor of unfavorable prognosis and chemotherapy resistance in glioma.

BACKGROUND: PYD and CARD domain-containing (PYCARD) was upregulated in TMZ-resistant cell lines and glioma tissue and was correlated with poor prognosis, its role in glioma is unclear known. The aim of this study was to elucidate the relationship between PYCARD and glioma based on Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and Chinese Glioma Genome Atlas (CGGA) databases. METHODS: Glioma-resistant cells were compared with parental cells based on the GSE53014 and GSE113510 data sets. The relationship between PYCARD, tumor microenvironment, and long noncoding RNAs (lncRNAs) was assessed using logistic regression. Moreover, Kaplan-Meier and Cox regression were used to analyze the relationship between PYCARD expression and survival rate. Gene set enrichment analysis (GSEA) was also used to determine the biological function of PYCARD and lncRNAs. Cell viability and cell migration assays were used to evaluate the ability of cells to migrate and proliferate. Finally, we analyzed the expression patterns of PYCARD genes in a wide range of cancers. RESULTS: Elevated expression of PYCARD promoted glioma cell proliferation and migration. PYCARD expression was significantly positively associated with gamma delta T cells but negatively correlated with M2 macrophages in glioblastoma multiforme (GBM). Likewise, PYCARD expression was significantly positively associated with monocytes but negatively associated with activated mast cells in low grade glioma (LGG). We also found that 3 PYCARD-related lncRNAs in GBM and 4 PYCARD-related lncRNAs in LGG had a predictive value for glioma patients. The pan-cancer analysis showed that PYCARD expression was higher in most cancer groups. CONCLUSIONS: High expression of PYCARD is an independent predictor of unfavorable prognosis and chemotherapy resistance in glioma.

COX10-AS1 Facilitates Cell Proliferation and Inhibits Cell Apoptosis in Glioblastoma Cells at Post-Transcription Level.

Glioblastoma (GBM) is an invasive cancer with poor prognosis in patients. Researching on molecular functions in GBM has attracted more and more attention. Actin gamma 1 (ACTG1) was reported as a pathogenic gene in skin cancer and colorectal cancer. Present study was designed to explore the biological role and underlying mechanism of ACTG1 in GBM cells. It was uncovered that ACTG1 presented high expression trends in GBM cells. Moreover, ACTG1 suppression hindered cell proliferation and boosted cell apoptosis in GBM. Then, according to the results of bioinformatics analysis and mechanism assays including RIP, RNA pull down and luciferase reporter assay, ACTG1 was verified to be targeted by miR-361-5p in GBM. Next, COX10-AS1 (COX10 antisense RNA 1) was identified as an endogenous sponge for miR-361-5p in GBM. Moreover, COX10-AS1 acted as a competing endogenous RNA (ceRNA) to positively regulate ACTG1 expression via sponging miR-361-5p. The following rescue assays demonstrated that COX10-AS1 promoted GBM cell proliferation and inhibited GBM cell apoptosis through ACTG1 up-regulation at a miR-361-5p dependent way. On the whole, present study uncovered a novel ceRNA pattern in which COX10-AS1 sponged miR-361-5p to elevate ACTG1 expression, therefore accelerating tumorigenesis in GBM. The findings suggested new promising targets for GBM treatment.

Circular RNA SMO sponges miR-338-3p to promote the growth of glioma by enhancing the expression of SMO.

Glioma is one of the most common tumors in the brain and complete cure still a challenge. The present research aimed to investigate the molecular mechanism of circular RNA SMO (circSMO742) in glioma, via targeting miR-338-3p and regulating SMO expression. QRT-PCR was utilized to examine the expression profiles of circSMO742 and microRNA-338-3p (miR-338-3p) in glioma. SMO protein in glioma was tested via western blot. RNA pulldown assay and dual luciferase reporter assays were used to explore the targeting correlation between RNAs. MTT assay, transwell assays and flow cytometry were used to investigate cell proliferation, migration and invasion, and apoptosis, respectively. Tumor xenograft was done to ascertain the effect of circSMO742 knocking down on tumor growth. CircSMO742 and SMO were highly expressed in glioma tissues, while miR-338-3p expression was reduced. CircSMO742 together with SMO could promote cells proliferation, migration and invasion while inhibit cells apoptosis, whereas miR-338-3p showed negative impacts on the cell activity. Knocking down of circSMO742 suppressed glioma growing in vivo. CircSMO742 promoted glioma growth by sponging miR-338-3p to regulate SMO expression. Our research revealed a new molecular mechanism of glioma growth and provide a fresh perspective on circRNAs in glioma progression.

Differential miRNA expression profiles in human keratinocytes in response to protein kinase C inhibitor.

Aberrant expression of microRNAs (miRNAs) is widely accepted to be involved in keratinocyte differentiation and to be dependent on activation of the protein kinase C (PKC) pathway. However, the miRNA profiles and biological characteristics of keratinocytes induced by specific inhibitors of PKC have yet to be elucidated. The present study aimed to explore the differential miRNA expression profiles in keratinocytes treated with the PKC inhibitor GF109203X, by conducting a bioinformatics analysis. Parts of the GF109203X­induced keratinocytes formed distinct clones after 2 days of culture, and the expression of intergrin ß1, cytokeratin (CK)19 and CK14 were positive, whereas CK10 expression was negative. A total of 79 miRNAs were differentially expressed in keratinocytes treated with GF109203X, among which 45 miRNAs were upregulated and 34 were downregulated. The significantly upregulated microRNAs includedhsa­miR­1­3p and miR­181c­5p, whereas hsa­miR­31­5p and hsa­let­7c­3p were significantly downregulated. In addition, the results of reverse transcription­quantitative polymerase chain reaction exhibited consistency with the microarray results. An enrichment analysis demonstrated that certain target genes of the differentially expressed miRNAs serve an important role in cell proliferation and differentiation, cell cycle progression and apoptosis, etc. These results revealed that GF109203X induced the differential expression of certain miRNAs when keratinocytes began showing the characteristics of epidermal­like stem cells, which may provide a novel approach for wound healing and regeneration of skin tissues.