Phthalate esters are a group of synthetic industrial chemicals that are widely used in plastics. Urinary phthalate metabolites are short-term exposure markers frequently used to represent exposure ...levels in environmental epidemiology studies. Human hair is an alternative matrix for recording long-term exposure, but there are still analytical challenges that need to be addressed. In this study, an analytical method was established for simultaneously measuring nine major phthalate metabolites in human hair and successfully applied to measure phthalate metabolites in 30 hair samples collected from 30 individual human volunteers without known occupational exposure to phthalates. Two portions of 25 mg of hair samples were extracted by acidified methanol and water in 240 min of ultrasonication and then analyzed using a liquid chromatography-tandem mass spectrometry system. The limit of quantification ranged from 0.72 to 10.7 ng/g hair for nine phthalate metabolites. All nine phthalate metabolites were detected in more than 70% of the 30 individual human hair samples. The measured levels of hair phthalate metabolites were (in descending order): MEHP > MMP ≫ MEP > MBP (MnBP + MiBP) > MiNP > MEHHP ≈ MEOHP ≈ MECPP. The primary metabolite, MEHP (692 ± 582 ng/g), is the major DEHP metabolite in hair. This result is consistent with the findings in blood but not in urine, in which the secondary metabolites are the major DEHP metabolites. This method is easy to foresee with a clinical application and applies to human biomonitoring studies to assess long-term environmental phthalate exposure.
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•Hair is a promising matrix for biomonitoring long-term phthalate exposure.•A method was established for measuring nine phthalate metabolites in human hair.•Hair levels in 30 volunteers: MEHP > MMP ≫ MEP > MBP > MiNP > MEHHP ≈ MEOHP ≈ MECPP.•Mono-phthalate esters are the major metabolites in hair and blood but not in urine.•Hair shafts seldom contain glucuronide-conjugated phthalate metabolites.
Capsule: Established long-term exposure markers for phthalate esters in human hair using LC-MS/MS.
G protein‐coupled estrogen receptor‐1 (GPER), a member of the G protein‐coupled receptor (GPCR) superfamily, mediates estrogen‐induced proliferation of normal and malignant breast epithelial cells. ...However, its role in breast cancer stem cells (BCSCs) remains unclear. Here we showed greater expression of GPER in BCSCs than non‐BCSCs of three patient‐derived xenografts of ER−/PR+ breast cancers. GPER silencing reduced stemness features of BCSCs as reflected by reduced mammosphere forming capacity in vitro, and tumor growth in vivo with decreased BCSC populations. Comparative phosphoproteomics revealed greater GPER‐mediated PKA/BAD signaling in BCSCs. Activation of GPER by its ligands, including tamoxifen (TMX), induced phosphorylation of PKA and BAD‐Ser118 to sustain BCSC characteristics. Transfection with a dominant‐negative mutant BAD (Ser118Ala) led to reduced cell survival. Taken together, GPER and its downstream signaling play a key role in maintaining the stemness of BCSCs, suggesting that GPER is a potential therapeutic target for eradicating BCSCs.
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G protein‐coupled estrogen receptor‐1 (GPER) mediates estrogen‐induced proliferation of normal and malignant breast epithelial cells. However, the role of GPER in breast cancer stem cells (BCSC) biology remains unclear. Here, using patient‐derived xenografts of ER–/PR+ breast cancer, the authors found higher expression of GPER in BCSCs than non‐BCSCs. Moreover, the results indicated that stemness features were sustained via GPER‐mediated PKA/BAD phosphorylation. Stimulation by the GPER ligand tamoxifen enhanced BCSC cell viability and population and BAD phosphorylation. The findings revealed a vital role of GPER‐mediated signaling pathways in BCSC survival, suggesting GPER as a potential therapeutic target for eradicating BCSCs.
Taiwan has significantly fewer senior nursing personnel than many other countries, which can be attributed in part to the prevalence of interpersonal stress and same-sex conflicts that often arise in ...female-dominated workplaces such as nursing. This study explored how team reflexivity and gender-role attitudes influence the stay intent of female nursing personnel using a cross-sectional design. Results showed group-level team reflexivity has more positive impact on nurses’ stay intent via team-based self-esteem than individual perceived team reflexivity, but traditional gender-role attitudes weaken this impact. Our findings indicate mutual understanding and trust is crucial for nursing teams to function effectively.
Anxiety and depression are great public health concerns among college students. The purpose of this study was to explore whether sleep quality and quality of life (QoL) play mediating roles in ...anxiety and depression among Chinese college students.
A total of 2757 college students (mean age = 19.07; SD = 1.14) completed the questionnaires, including a brief demographic survey. The 2-item General Anxiety Disorder (GAD-2) and the 2-item Patient Health Questionnaire (PHQ-2) were used to assess the symptoms of anxiety and depression, respectively. And the Pittsburgh Sleep Quality Index (PSQI) and the Short-Form 36 Health Survey (SF-36) were used to evaluate college students' sleep quality and QoL, respectively. Mediation analyses were conducted by using PROCESS macro in the SPSS software.
Anxiety had both direct and indirect effects on depression. Sleep quality and QoL were not only independent mediators in the relationship between anxiety and depression but also chain mediators.
The results of the current study highlight the crucial role of early intervention for depression with a focus on college students with anxiety, more especially, on those with poorer sleep quality and lower QoL.
The large amounts of engineered titanium dioxide nanoparticles (TiO2NPs) that have been manufactured have inevitably been released into the ecosystem. Reports have suggested that TiO2 is a relatively ...inert material that has low toxicity to animals. However, as various types of NPs increasingly accumulate in the ocean, their effects on aquatic life-forms remain unclear. In this study, a zebrafish model was used to investigate TiO2NP-induced injury and mortality. We found that the treatment dosages of TiO2NP are positively associated with increased motility of zebrafish and the bacterial counts in the water. Notably, gill but not dorsal fin and caudal fin of the zebrafish displayed considerably increased bacterial load. Metagenomic analysis further revealed that gut microflora, such as phyla Proteobacteria, Bacteroidetes, and Actinobacteria, involving more than 95% of total bacteria counts in the NP-injured zebrafish gill samples. These results collectively suggest that opportunistic bacterial infections are associated with TiO2NP-induced mortality in zebrafish. Infections secondary to TiO2NP-induced injury could be a neglected factor determining the detrimental effects of TiO2NPs on wild fish.
Blood–brain barrier (BBB) characteristics are induced and maintained by crosstalk between brain microvascular endothelial cells and neighboring cells. Using in vitro cell models, we previously found ...that a bystander effect was a cause for Japanese encephalitis‐associated endothelial barrier disruption. Brain astrocytes, which neighbor BBB endothelial cells, play roles in the maintenance of BBB integrity. By extending the scope of relevant studies, a potential mechanism has been shown that the activation of neighboring astrocytes could be a cause of disruption of endothelial barrier integrity during the course of Japanese encephalitis viral (JEV) infection. JEV‐infected astrocytes were found to release biologically active molecules that activated ubiquitin proteasome, degraded zonula occludens‐1 (ZO‐1) and claudin‐5, and disrupted endothelial barrier integrity in cultured brain microvascular endothelial cells. JEV infection caused astrocytes to release vascular endothelial growth factor (VEGF), interleukin‐6 (IL‐6), and matrix metalloproteinases (MMP‐2/MMP‐9). Our data demonstrated that VEGF and IL‐6 released by JEV‐infected astrocytes were critical for the proteasomal degradation of ZO‐1 and the accompanying disruption of endothelial barrier integrity through the activation of Janus kinase‐2 (Jak2)/signal transducer and activator of transcription‐3 (STAT3) signaling as well as the induction of ubiquitin–protein ligase E3 component, n‐recognin‐1 (Ubr 1) in endothelial cells. MMP‐induced endothelial barrier disruption was accompanied by MMP‐mediated proteolytic degradation of claudin‐5 and ubiquitin proteasome‐mediated degradation of ZO‐1 via extracellular VEGF release. Collectively, these data suggest that JEV infection could activate astrocytes and cause release of VEGF, IL‐6, and MMP‐2/MMP‐9, thereby contributing, in a concerted action, to the induction of Japanese encephalitis‐associated BBB breakdown. GLIA 2015;63:1915–1932
Main Points
JEV‐infected astrocytes disrupted endothelial barrier integrity.
JEV infection caused astrocytes to release MMP‐2/MMP‐9, IL‐6, and VEGF.
IL‐6 and VEGF activated Jak2/STAT3/Ubr 1 leading to ZO‐1 degradation and endothelial barrier disruption.
Lung cancer is one of the most common cancers and the leading cause of death in humans worldwide. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases and is often ...diagnosed at a late stage. Among patients with NSCLC, 50% die within 1 year after diagnosis. Even with clinical intervention, the 5-year survival rate is only approximately 20%. Therefore, the development of an advanced therapeutic strategy or novel agent is urgently required for treating NSCLC. Berberine exerts therapeutic activity toward NSCLC; therefore, its activity as an antitumor agent needs to be explored further. In this study, three terpenylated-bromide derivatives of berberrubine were synthesized and their anti-NSCLC activities were evaluated. Each derivative had higher anti-NSCLCs activity than berberrubine and berberine. Among them, 9-O-gernylberberrubine bromide (B4) and 9-O-farnesylberberrubine bromide (B5) showed greater growth inhibition, cell-cycle regulation, in vitro tumorigenesis suppression, and tumor migration reduction. In addition, some degree of apoptosis and autophagic flux blocking was noted in the cells under B4 and B5 treatments. Our study demonstrates that the berberrubine derivatives, B4 and B5, exhibit impressive anti-NSCLC activities and have potential for use as chemotherapeutic agents against NSCLC.
The epidermal growth factor (EGF) receptor (EGFR) overexpressed in many cancers, including lung and head and neck cancers, and is involved in cancer cell progression and survival. PD‐L1, increases in ...tumor cells to evade and inhibit CD8+ T cells, is a clinical immunotherapeutic target. This study investigated the molecular mechanism of EGF on regulating PD‐L1 in EGFR‐positive cancers and determined potential agents to reduce PD‐L1 expression. RNA sequencing (RNAseq) and bioinformatics analysis were performed to determine potential driver genes that regulate PD‐L1 in tumor cells‐derived tumorspheres which mimicking cancer stem cells. Then, the specific inhibitors targeting EGFR were applied to reduce the expression of PD‐L1 in vitro and in vivo. We validated that EGF could induce PD‐L1 expression in the selected EGFR‐positive cancers. RNAseq results revealed that STAT1 increased as a driver gene in KOSC‐3‐derived tumorspheres; these data were analyzed using PANTHER followed by NetworkAnalyst. The blockade of EGFR by afatinib resulted in decreased STAT1 and IRF‐1 levels, both are transcriptional factors of PD‐L1, and disabled the IFNr‐STAT1‐mediated PD‐L1 axis in vitro and in vivo. Moreover, STAT1 knockdown significantly reduced EGF‐mediated PD‐L1 expression, and ruxolitinib, a JAK1/JAK2 inhibitor, significantly inhibited STAT1 phosphorylation to reduce the IFNr‐mediated PD‐L1 axis. These results indicate that EGF exacerbates PD‐L1 by increasing the protein levels of STAT1 to enforce the IFNr‐JAK1/2‐mediated signaling axis in selected EGFR‐positive cancers. The inhibition of EGFR by afatinib significantly reduced PD‐L1 and may be a potential strategy for enhancing immunotherapeutic efficacy.
Adequate stress on the Endoplasmic Reticulum (ER) with the Unfolded Protein Response (UPR) could maintain glioma malignancy. Uncontrolled ER stress, on the other hand, predisposes an ...apoptosis-dominant UPR program. We studied here the proapoptotic actions of the Epidermal Growth Factor Receptor (EGFR) inhibitor gefitinib, with the focus on ER stress. The study models were human H4 and U87 glioma cell lines. We found that the glioma cell-killing effects of gefitinib involved caspase 3 apoptotic cascades. Three branches of ER stress, namely Activating Transcription Factor-6 (ATF6), Protein Kinase R (PKR)-Like ER Kinase (PERK), and Inositol-Requiring Enzyme 1 (IRE1), were activated by gefitinib, along with the elevation of intracellular free Ca
, Reactive Oxygen Species (ROS), and NADPH Oxidase2/4 (NOX2/4). Specifically, elevated IRE1 phosphorylation, Tumor Necrosis Factor (TNF) Receptor-Associated Factor-2 (TRAF2) expression, Apoptosis Signal-Regulating Kinase-1 (Ask1) phosphorylation, c-Jun N-Terminal Kinase (JNK) phosphorylation, and Noxa expression appeared in gefitinib-treated glioma cells. Genetic, pharmacological, and biochemical studies further indicated an active ROS/ER stress/Ask1/JNK/Noxa axis causing the glioma apoptosis induced by gefitinib. The findings suggest that ER-stress-based therapeutic targeting could be a promising option in EGFR inhibitor glioma therapy, and may ultimately achieve a better patient response.
Lung cancer is the leading cause of death in the world, and the most common type of lung cancer is non-small-cell lung cancer (NSCLC), accounting for 85% of lung cancer. Patients with NSCLC, when ...detected, are mostly in a metastatic stage, and over half of patients diagnosed with NSCLC die within one year after diagnosis; the 5-year survival rate is 24%. However, in patients with metastatic NSCLC, the 5-year survival rate is 6%. Therefore, development of a new therapeutic agent or strategy is urgent for NSCLCs. Berberine has been illustrated to be a therapeutic agent of NSCLC. In the present study, we synthesized six derivatives of berberine, and the anti-NSCLC activity of these agents was examined. Some of them exert increasing proliferation inhibition comparing with berberine. Further studies demonstrated that two of the most effective agents, 9-
-decylberberrubine bromide (B6) and 9-
-dodecylberberrubine bromide (B7), performed cell cycle regulation, in-vitro tumorigenesis inhibition and autophagic flux blocking, but not induction of cellular apoptosis in NSCLC cells. Moreover, B6 and B7 were determined to be green fluorescent and could be penetrated and localized in cellular mitochondria. Herein, B6 and B7, the berberine derivatives we synthesized, revealed better anti-NSCLC activity with berberine and may be used as therapeutic candidates for the treatment of NSCLCs.
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