Temporal analysis of lung injury induced by real-ambient PM2 .5 exposure in mice.

Fine particulate matter (PM2.5 ) has been shown to induce lung injury. However, the pathophysiological mechanisms of PM2.5 -induced pulmonary injury after different exposure times are poorly understood. In this study, we exposed male ICR mice to a whole-body PM2.5 inhalation system at daily mean concentration range from 92.00 to 862.00 µg/m3 for 30, 60, and 90 days. We found that following prolonged exposure to PM2.5 , pulmonary injury was increasingly evident with significant histopathological alterations. Notably, the pulmonary inflammatory response and fibrosis caused by PM2.5 after different exposure times were closely associated with histopathological changes. In addition, PM2.5 exposure caused oxidative stress, DNA damage and impairment of DNA repair in a time-dependent manner in the lung. Importantly, exposure to PM2.5 eventually caused apoptosis in the lung through upregulation of cleaved-caspase-3 and downregulation of Bcl-2. Overall, our data demonstrated that PM2.5 led to pulmonary injury in a time-dependent manner via upregulation of proinflammatory and fibrosis-related genes, and activation of the DNA damage response. Our findings provided a novel perspective on the pathophysiology of respiratory diseases caused by airborne pollution.

Association of DLT versus SLT with postoperative pneumonia during esophagectomy in China: a retrospective comparison study.

BACKGROUND: Double lumen tube (DLT) and single lumen tube (SLT) are two common endotracheal tube (ETT) types in esophageal cancer surgery. Evidence of the relationship between two ETT types and postoperative pneumonia (PP) remains unclear. We aimed to determine the association between two types of ETT (DLT and SLT) and PP and assess the perioperative risk-related parameters that affect PP. METHODS: This study included 680 patients who underwent esophageal cancer surgery from January 01, 2010 through December 31, 2020. The primary outcome was PP, and the secondary outcome was perioperative risk-related parameters that affect PP. The independent variable was the type of ETT: DLT or SLT. The dependent variable was PP. To determine the relationship between variables and PP, univariate and multivariate analyses were performed. The covariables included baseline demographic characteristics, comorbidity disease, neoadjuvant chemotherapy, tumor location, laboratory parameters, intraoperative related variables. RESULTS: In all patients, the incidence of postoperative pneumonia in esophagectomy was 32.77% (36.90% in DLT group and 26.38% in SLT group). After adjusting for potential risk factors, we found that using an SLT in esophagectomy was associated with lower risk of postoperative pneumonia compared to using a DLT (Odd ratio = 0.41, 95% confidence interval (CI): 0.22, 0.77, p = 0.0057). Besides DLT, smoking history, combined intravenous and inhalation anesthesia (CIIA) and vasoactive drug use were all significant and independent risk factors for postoperative pneumonia in esophagectomy. These results remained stable and reliable after subgroup analysis. CONCLUSIONS: During esophagectomy, there is significant association between the type of ETT (DLT or SLT) and PP. Patients who were intubated with a single lumen tube may have a lower rate of postoperative pneumonia than those who were intubated with a double lumen tube. This finding requires verification in follow-up studies.

Long non-coding RNAs mediate the association between short-term PM2.5 exposure and circulating biomarkers of systemic inflammation.

Although short-term fine particulate matter (PM2.5) exposure is associated with systemic inflammation, the effect of lncRNA on these association remains unknown. This study aims to investigate whether the plasma lncRNA mediate the effect of short-term PM2.5 exposure on systemic inflammation. In this cross-sectional study, plasma Clara cell protein 16 (CC16), interleukin 6 (IL-6), IL-8, tumor necrosis factor-α (TNF-α) and lncRNA expression levels were measured in 161 adults between March and April in 2018 in Shijiazhuang, China. PM2.5 concentrations were estimated 0-3 days prior to the examination date and the moving averages were calculated. Multiple linear regressions were used to evaluate the associations between PM2.5, the four biomarkers and lncRNA expression levels. Mediation analyses were performed to explore the potential roles of lncRNA expression in these associations. The median concentration of PM2.5 ranged from 39.65 to 60.91 mg/m3 across different lag days. The most significant effects on IL-6 and TNF-α per interquartile range increase in PM2.5 were observed at lag 0-3 days, with increases of 0.70 pg/mL (95% CI: 0.33, 1.07) and 0.21 pg/mL (95% CI: 0.06, 0.36), respectively. While the associations between PM2.5 and IL-8 (0.68 pg/mL, 95% CI: 0.34, 1.02) and CC16 (3.86 ng/mL, 95% CI: 1.60, 6.13) were stronger at lag 0 day. Interestingly, a negative association between PM2.5 and the expression of four novel lncRNAs (lnc-ACAD11-1:1, lnc-PRICKLE1-4:1, lnc-GPR39-7:2, and lnc-MTRNR2L12-3:6) were observed at each lag days. Furthermore, these lncRNAs mediated the effects of PM2.5 on the four biomarkers, with proportions of mediation ranged from 2.27% (95% CI: 1.19%, 9.82%) for CC16 to 35.60% (95% CI: 17.16%, 175.45%) for IL-6. Our findings suggested that plasma lncRNA expression mediat the acute effects of PM2.5 exposure on systematic inflammation. These highlight a need to consider circulating lncRNA expression as biomarkers to reduce health risks associated with PM2.5.

circCIMT Silencing Promotes Cadmium-Induced Malignant Transformation of Lung Epithelial Cells Through the DNA Base Excision Repair Pathway.

Changes in gene expression in lung epithelial cells are detected in cancer tissues during exposure to pollutants, highlighting the importance of gene-environmental interactions in disease. Here, a Cd-induced malignant transformation model in mouse lungs and bronchial epithelial cell lines is constructed, and differences in the expression of non-coding circRNAs are analyzed. The migratory and invasive abilities of Cd-transformed cells are suppressed by circCIMT. A significant DNA damage response is observed after exposure to Cd, which increased further following circCIMT-interference. It is found that APEX1 is significantly down-regulated following Cd exposure. Furthermore, it is demonstrated that circCIMT bound to APEX1 during Cd exposure to mediate the DNA base excision repair (BER) pathway, thereby reducing DNA damage. In addition, simultaneous knockdown of both circCIMT and APEX1 promotes the expression of cancer-related genes and malignant transformation after long-term Cd exposure. Overall, these findings emphasis the importance of genetic-epigenetic interactions in chemical-induced cancer transformation.

Active meiosis during dinoflagellate blooms: A 'sex for proliferation' hypothesis.

In dinoflagellates, sexual reproduction is best known to be induced by adverse environmental conditions and culminate in encystment for survival ('sex for encystment'). Although increasing laboratory observations indicate that sex can lead to production of vegetative cells bypassing encystment, the occurrence of this alternative pathway in natural populations and its ecological roles remain poorly understood. Here we report evidence that sex in dinoflagellates can potentially be an instrument for bloom proliferation or extension. By bloom metatranscriptome profiling, we documented elevated expression of meiosis genes in two evolutionarily distinct species (Prorocentrum shikokuense and Karenia mikimotoi) during bloom, a timing unexpected of the 'sex for encystment' scenario. To link these genes to meiosis, we induced encystment and cyst germination in the cyst-forming species Scrippsiella acuminata, and found that five of these genes were upregulated during cyst germination, when meiosis occurs. Integrating data from all three species revealed that SPO11, MND1, and DMC1 were likely common between cyst-forming and non-encysting sex in dinoflagellates. Furthermore, flow cytometric analyses revealed consecutive rounds of DNA halving during blooms of P. shikokuense and K. mikimotoi, evidencing meiosis. These data provided novel evidence that sexual reproduction in dinoflagellates might serve to promote cell proliferation, and along with the consequent enhancement of genetic diversity facilitating resistance against pathogens and environmental stress, to boost or extend a bloom ('sex for proliferation'). The putative meiosis-specific genes and insights reported here will prove to be helpful for rigorously testing the hypothesis and addressing whether the two modes of sex are genetically predisposed (i.e. species-specific) or environmentally induced (switchable within species), and if the latter what triggers the switch.

Neutrophil-to-lymphocyte ratio trend: A novel prognostic predictor in patients with nasopharyngeal carcinoma receiving radiotherapy.

BACKGROUND: Peripheral neutrophil-lymphocyte ratio (NLR), reflecting immune-inflammation status, shows great potential for tumor progression and outcome. Pre-treatment NLR does not fully reflect the immune-inflammatory response to treatment. This study aimed to introduce the NLR trend as a new indicator and to investigate its prognostic value in patients with nasopharyngeal carcinoma receiving radiotherapy. METHODS: This retrospective study evaluated patients with nasopharyngeal carcinoma treated with radiotherapy. The NLR trend value was calculated from the fitted line gradient via the NLRs before, during (at least once), and after each patient's first radiotherapy. The Kaplan-Meier curve and log-rank test were used to calculate and compare survival outcomes of different pretreatment NLRs and NLR trends for progression-free survival, locoregional recurrence-free survival (LRFS), and overall survival at 3 and 5 years. Multivariate Cox regression analyses were performed to assess the association between the NLR trend plus 3- and 5-year overall survival. RESULTS: The study included 528 patients. A lower NLR trend predicted worse progression-free survival, LRFS, plus 3- and 5-year overall survival. Multivariate Cox regression analysis showed that the NLR trend independently predicted 3- and 5-year overall survival. Sub-group analysis showed that the prognosis of patients with a low pretreatment NLR and a high NLR trend were superior to those of other groups. CONCLUSION: The NLR trend independently predicted the prognosis of patients with nasopharyngeal carcinoma receiving radiotherapy. The NLR trend and the pretreatment NLR combination is more precise than pretreatment NLR in predicting prognosis. A high NLR trend may be evidence of a positive immune response to radiotherapy in patients with nasopharyngeal carcinoma.

Upregulation of Circ_0035266 Contributes to the Malignant Progression of Inflammation-Associated Malignant Transformed Cells Induced by Tobacco-Specific Carcinogen NNK.

Cigarette smoking-induced chronic inflammation has been considered a vital driver of lung tumorigenesis. The compounds 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific carcinogen, and lipopolysaccharide (LPS), an inflammatory inducer, are important components of tobacco smoke which have been implicated in inflammation-driven carcinogenesis. However, the biological effects and underlying mechanisms of LPS-mediated inflammation on NNK-induced tumorigenesis are still unclear. In this study, BEAS-2B human bronchial epithelial cells were exposed to NNK, LPS or both, for short- or long-term periods. We found that acute LPS exposure promoted the secretion of granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin (IL)-6 in NNK-treated BEAS-2B cells. In addition, chronic LPS exposure facilitated the NNK-induced malignant transformation process by promoting cell proliferation, cell cycle alteration, migration, and clonal formation. Previously, we determined that circular RNA circ_0035266 enhanced cellular inflammation in response to NNK + LPS by sponging miR-181d-5p and regulating expression of its downstream target DEAD-Box Helicase 3 X-Linked (DDX3X). Here, we found that knockdown of circ_0035266 or DDX3X led to a remarkable inhibition of the proliferation, cell cycle progression, and migration of NNK + LPS-transformed BEAS-2B cells, whereas overexpression of these genes produced the opposite effects, indicating the oncogenic roles of circ_0035266 and DDX3X in the malignant progression of chronic inflammation-driven malignant transformed cells. Moreover, the regulatory relationships among circ_0035266, miR-181d-5p, and DDX3X were further confirmed using a group of lung cancer tissues. Conclusively, our findings provide novel insights into our understanding of inflammation-driven tumorigenesis using a cellular malignant transformation model, and indicate a novel tumor-promoting role for circ_0035266 in chemical carcinogenesis.

The involvement of copper, circular RNAs, and inflammatory cytokines in chronic respiratory disease.

Exposure to high concentrations of copper is associated with pulmonary inflammation and chronic respiratory disease (CRD). Epigenetic modulation of noncoding RNAs contributes to the development of several CRDs. It is unknown whether epigenetic modulation is involved in copper mediated pulmonary inflammation and CRD. We conducted a case-control study of 101 CRD cases and 161 control subjects in Shijiazhuang, China, and evaluated circRNAs and cytokine levels (IL-6 and IL-8) by qPCR and ELISA. Urinary copper concentration was determined by inductively coupled plasma mass spectrometry. Linear mixed models and generalized linear mixed models were used to assess the associations of circRNAs with CRD, urinary copper, and cytokines. We exposed the human bronchial epithelial cell line, 16HBE, to copper and assessed the functional role of a circRNA, circ_0008882, by RNA overexpression. Cellular location of circ_0008882 was assessed by separation of nuclear and cytoplasmic RNAs. Nine circRNAs were associated with an increased risk for CRDs, while the relative expression of circ_0008882 was decreased after copper exposure in vitro and in vivo. Copper exposure stimulated 16HBE cells to release proinflammatory IL-6 and IL-8. The release of the cytokines was inhibited by overexpression of circ_0008882. These results suggest a role for circ_0008882 in the regulation of CRD associated inflammation following copper exposure.

Circular RNA circNIPBL promotes NNK-induced DNA damage in bronchial epithelial cells via the base excision repair pathway.

Environmental chemical exposure often causes DNA damage, which leads to cellular dysfunction and the development of diseases. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific carcinogen that is known to cause DNA damage, while remains unknown about the underlying mechanism. In this study, simulated doses of NNK exposure in smokers, ranging from 50 to 300 µM, were used to detect the DNA damage effects of NNK in two human bronchial epithelial cells, 16HBE and BEAS-2B. The comet assay revealed increased DNA damage in response to NNK treatment, as measured by increased Olive tail moment (OTM). NNK treatment also led to elevated foci formation and protein expression of γ-H2AX, a DNA damage sensor. Dysregulation of proliferation, cell cycle arrest and apoptosis, was also observed in NNK-treated cells. Furthermore, the most effective dose of NNK (300 µM) was used in subsequent mechanistic studies. A circular RNA circNIPBL was identified to be significantly up-regulated in NNK-treated cells, circNIPBL knockdown successfully alleviated NNK-induced DNA damage and reversed the cellular dysregulation, while circNIPBL overexpression had the opposite effect. Mechanistically, we identified an interaction between circNIPBL and PARP1, a critical enzyme of the base excision repair (BER) pathway. CircNIPBL silencing successfully alleviated the NNK-induced inhibition of BER pathway proteins, including PARP1, XRCC1, PCNA and FEN1, while overexpression of circNIPBL had the opposite effect. In summary, our study shows for the first time that circNIPBL promotes NNK-induced DNA damage and cellular dysfunction through the BER pathway. In addition, our findings reveal the crucial role of epigenetic regulation in carcinogen-induced genetic lesions and further our understanding of environmental carcinogenesis.

Effect of intravenous lidocaine on propofol consumption in elderly patients undergoing colonoscopy: a double-blinded, randomized, controlled trial.

BACKGROUND: Elderly patients undergoing colonoscopy with propofol as sedation are prone to respiratory or cardiovascular complications. Intravenous lidocaine has analgesic efficacy and reduces propofol consumption during surgery. Here, the effect of intravenous lidocaine on propofol consumption was evaluated in elderly patients undergoing colonoscopy. METHODS: Patients were randomly allocated to receive intravenous lidocaine (1.5 mg/kg bolus dose, followed by a 2 mg/kg/h continuous infusion during the procedure; Group L) or a placebo (saline; Group N). During the procedure, sedation was achieved by propofol. The following outcomes were recorded: total propofol consumption; time to loss of consciousness; number of airway modifications; time to the first airway intervention; incidence of sedation-related events; pain score after awakening; endoscopists' and patients' satisfaction scores; memory level of the procedure; and adverse events within 24 h postoperatively. RESULTS: Compared with Group N, propofol consumption was reduced by 13.2% in Group L (100.30 ± 25.29 mg vs. 115.58 ± 27.52 mg, respectively, p = 0.008). Kaplan-Meier curves showed that the median time to the loss of consciousness episode was shorter in Group L than in Group N (40 s vs. 55 s, respectively, log rank p < 0.0001). The number of airway modifications, time to the first airway intervention, incidence of sedation-related events, time to awakening, pain score after awakening, endoscopists' and patients' satisfaction scores, memory level of the procedure and adverse events within 24 h postoperatively did not differ between the two groups (p > 0.05). CONCLUSIONS: Intravenous lidocaine can reduce propofol consumption in elderly patients undergoing colonoscopy, with quicker time to loss of consciousness. TRIAL REGISTRATION: The clinical trial was registered at (12/01/2021, ChiCTR2100042001 ).

The fowl adenovirus serotype 4 (FAdV-4) induce cellular pathway in chickens to produce interferon and antigen-presented molecules (MHCI/II).

FAdV-4 is the major strain of adenovirus that responsible for hydro-pericardial syndrome (HPS) in poultry. In this study, the virus's specific gene fragments were isolated from clinically suspected cases and amplified by PCR. Finally, after a viral infection to investigate the immune response of the host, the gene expression of MHC (major histo-compatible) molecules (MHCIα, MHCIIß), Ii (Invariant Chain) gene, inflammatory cytokines (IFN-ß, IFN-γ, and IL-1ß), and transcription factors (MDA5, STING, IRF7, and NF-kB) were detected by real-time PCR (fluorescence technology). The results of sequence comparison showed that the clinically isolated virus was 100% homologous to a virulent strain of avian adenovirus group C serotype 4 (FAdV-4), which were named AH-FAdV-4. The TCID50 and pathogenicity of the virus were determined that was 106.52/0.1 mL with a mortality rate of 100% in chickens and 0% in ducks. Furthermore, results showed that the expression level of MHCIα, MHCIIß, and Ii genes in chicken embryo kidney cells significantly (P < 0.01) upregulated (increased) after infection, which was 43, 5.2, and 2.5 times higher than the control group. With the addition of PDTC, an inhibitor of NF-kB, then the expression level of MHCIα, MHCIIß, and Ii was decreased significantly (P < 0.01) than the control group. The transcription levels of these genes were decreased 0.64, 0.27, and 0.26 respectively. Simultaneously, the expression levels of IFN-ß, IFN-γ, and IL-1ß were also significantly (P < 0.01) up-regulated (increased) 7.8, 22.7, and 5 times higher than the control group. It was found that up-regulation of STING and NF-κB pathways are directly involved in the regulation of inflammatory cytokines (IFN-ß, IFN-γ, and IL-1ß), MHC molecules (MHCIα, MHCIIß), and Ii gene. The results also showed that the gene regulation pathways consecutively increased the expression levels of MDA5, STING, IRF7, and NF-kB. It is conducted that the expression levels of cytokines, MHC molecules, and li gene were increased by STING and NF-kB pathways.

The Circ_CARM1 controls cell migration by regulating CTNNBIP1 in anti-benzo[a]pyrene-trans-7,8-dihydrodiol-9,10-epoxide-transformed 16HBE cells.

BACKGROUND: Circular RNAs (circRNAs) have an important role in the development and progression of human tumors, including lung cancer. Yet, their role in lung cancer induced by benzo(a)pyrene (B[a]P) remains unclear. In this study, circRNA chips and qRT-PCR were used to examine downregulated circRNAs in malignantly transformed 16HBE cells (16HBE-T) induced by B[a]P. Five down-regulated circRNAs were found, among which hsa_circ_0004552 (circ_CARM1) had the most significant downregulation. Consequently, the role of circ_CARM1 on 16HBE-T cells biological behavior was further examined using several in vitro experiments. MATERIALS AND METHODS: Detecting RNA expression via qRT-PCR. Fluorescence in situ hybridization (FISH) was used to identify the localization of circ_CARM1 in 16HBE-T. The effect of circ_CARM1 on cell behavior (cell migration, proliferation, and apoptosis) was explored by transfecting cells with a vector carrying an overexpression and then using wound healing, transwell migration assay, and flow cytometry. Also, the regulation mechanism for circ_CARM1, miR-1288-3p, and CTNNBIP1 was studied by Dual-Luciferase® Reporter (DLR™) Assay System and western blotting. RESULTS: Reduced expression of circ_CARM1 is observed in 16HBE-T. The overexpression of circ_CARM1 further inhibited the migration of 16HBE-T cells but did not affect cell proliferation and apoptosis. Furthermore, bioinformatic analysis and Dual-Luciferase® Reporter (DLR™) Assay System showed that the competitive binding of circ_CARM1 and miR-1288-3p enhanced the expression of CTNNBIP1, thereby inhibiting the migration of 16HBE-T cells. CONCLUSION: Downregulation of circ_CARM1 can stimulate the expression of miR-1288-3p, thereby reducing the expression of CTNNBIP1, spurring cell migration.

Tobacco-Related Exposure Upregulates Circ_0035266 to Exacerbate Inflammatory Responses in Human Bronchial Epithelial Cells.

One of the most carcinogenic chemicals found in cigarette tobacco smoke is 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which has been confirmed to be associated with the etiology of diverse cancers. Lipopolysaccharide (LPS), another biologically active component of cigarette smoke, is a risk factor which enhances NNK-induced lung tumorigenesis due to chronic lung inflammation. Although inflammatory responses play critical roles in the initiation of many tumors, our knowledge about the mechanisms of NNK+LPS on inflammation is currently limited. Here, we investigated the inflammatory effects of NNK+LPS in human bronchial epithelial cells (BEAS-2B) and explored the underlying mechanisms mediated by circular RNAs (circRNAs). We identified a novel circRNA, circ_0035266, which was strongly upregulated in NNK+LPS-induced BEAS-2B cells and enhanced the inflammatory responses to NNK+LPS by regulating the secretion of pro-inflammatory cytokines interleukin (IL)-6 and IL-8. Specifically, circ_0035266 knockdown alleviated NNK+LPS-induced inflammatory responses, whereas overexpression of circ_0035266 had the opposite effect. Moreover, dual-luciferase reporter and fluorescence in situ hybridization (FISH) assays verified that circ_0035266 bound to miR-181d-5p directly in the cytoplasm. qRT-PCR, dual-luciferase reporter assays, and Western blot analyses showed that DDX3X (DDX3) was the downstream target of miR-181d-5p and that DDX3X expression levels were modulated by circ_0035266. These results suggested that circ_0035266 served as a competitive endogenous RNA for miR-181d-5p to regulate DDX3X expression, which is involved in the modulation of NNK+LPS-induced inflammatory responses in BEAS-2B cells.

The Roles of DNA Methyltransferases 1 (DNMT1) in Regulating Sexual Dimorphism in the Cotton Mealybug, Phenacoccus solenopsis.

The cotton mealybug, Phenacoccus solenopsis, is an invasive pest that can cause massive damage to many host plants of agricultural importance. P. solenopsis is highly polyphagous, and shows extreme sexual dimorphism between males and females. The functions of DNA methyltransferase (DNMT) enzymes in the cotton mealybug have not been well studied. Here, we carried out an investigation of DNMTs in cotton mealybug to study their roles in sexual dimorphism. We found that the cotton mealybug has two copies of PsDnmt1, but Dnmt3 is absent. We then amplified the full-length cDNAs of PsDnmt1A (2,225 bp) and PsDnmt1B (2,862 bp) using rapid amplification cDNA ends (RACE). Quantitative reverse transcriptase PCR shows that both PsDnmt1A and PsDnmt1B are highly expressed in adult males, while the expression of PsDnmt1B is 30-fold higher in gravid females than in virgin females. We knocked down PsDnmt1A and PsDnmt1B with small interfering RNAs (siRNAs), and both genes were successfully down-regulated after 24 h or 72 h in adult females and pupa (t-test, p < 0.05). Down-regulating the expression of these two DNMT genes led to offspring lethality and abnormal body color in adult females. Furthermore, the silencing of PsDnmt1B induced abnormal wing development in emerged adult males. Our results provide evidence that PsDnmt1 plays a crucial role in regulating sexual dimorphism in the cotton mealybug.

Circular RNA 0039411 Is Involved in Neodymium Oxide-induced Inflammation and Antiproliferation in a Human Bronchial Epithelial Cell Line via Sponging miR-93-5p.

Adverse health effects induced by neodymium oxide (Nd2O3) particles have raised concern as a result of their increasing applications in various arenas. However, information on their potential cytotoxicity is currently limited. In the present study, we investigated the underlying cytotoxicity of Nd2O3 in human bronchial epithelial cells (16HBE) and the potential mechanisms mediated by circular RNAs (circRNAs). Nd2O3 exposure initiated an inflammatory response in 16HBE cells via the release of the proinflammatory cytokines interleukin (IL)-6 and IL-8. The 5-ethynyl-2'-deoxyuridine assays showed that Nd2O3 treatment inhibited 16HBE cell proliferation and caused cell cycle arrest at G0/G1 phase and cell apoptosis. Microarray analyses demonstrated that Nd2O3 treatment altered circRNA expression profiles and significantly upregulated circRNA 0039411 (circ_0039411) in 16HBE cells. Further functional studies showed that silencing circ_0039411 prevented Nd2O3-induced inflammation and reversed its antiproliferative effect by moderating the G0/G1 phase cell cycle arrest, whereas overexpression of circ_0039411 had the opposite effects. Luciferase reporter assays showed that circ_0039411 bound to miR-93-5p, whereas fluorescence in situ hybridization showed that circ_0039411 and miR-93-5p colocalized in the cytoplasm. Moreover, transfection of 16HBE cells with a miR-93-5p mimic decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3). The levels of phospho-STAT3 were decreased by circ_0039411 silencing and elevated after circ_0039411 overexpression. These results suggested that upregulation of circ_0039411 mediated Nd2O3-induced inflammation and dysfunction by sponging miR-93-5p.

A novel model for the pharmacokinetic studies of bevacizumab and etanercept in healthy volunteers and patients.

Therapeutic monoclonal antibodies (mAbs) have been successfully applied to treat various diseases and shown a promising prospect in medical treatment. MAbs have some unique characteristics when compared with small chemical drugs, and their pharmacokinetic (PK) properties are much more complex than those of small chemical drugs, whose eliminations are usually linear. In this study, a new model was established through taking into account the mechanisms of the elimination of mAbs. The proposed model was applied to the modeling and simulation of two kinds of mAbs, including bevacizumab and etanercept, in PK studies of healthy volunteers and eligible patients, and the classical linear compartment model was set as control. The goodness-of-fit of the fitting concentration-time curve of mAbs was calculated to verify the accuracy of both models during the modeling and simulation. The accuracy of the proposed model was better than that of classical linear compartment model in healthy volunteers and even much better in patients. The proposed model demonstrates a stronger ability in the modeling and simulation of mAbs, and may provide a new option for the PK studies of those reagents.

A novel pharmacokinetic model based on the complex elimination of monoclonal antibodies for bevacizumab pharmacokinetic study in rabbits.

Monoclonal antibodies (mAbs) complex pharmacokinetic (PK) properties including a nonlinear pharmacokinetics and a significant variation in individual PK process cannot be appropriately described by classic PK models, probably derived form a poor understanding of the complex elimination of mAbs. In this study, a novel PK model based on mAbs' complex drug elimination was established. Subsequently, this new model was used to fit bevacizumab plasma concentration data from PK rabbits, and the outcomes of model fitting were compared with those came from a fit with classic models. In addition, the variations existing in the parameters set in the new model were analyzed. As a result, this novel model reasonably described the single-dose PK profiles of bevacizumab in rabbits, and its fitting efficiency was greatly improved compared with those fitted with classic PK models in terms of the weighted residual sum of squares. Moreover, the variations existing in the new model's parameters CA(antibody) and K0 could reasonably explain the individual variations of bevacizumab's PK profiles. In conclusion, the novel model reasonably explained the elimination of bevacizumab, and exhibited a potential as a useful tool for the PK studies of bevacizumab and other mAbs in practice.

Rhodopsin gene expression regulated by the light dark cycle, light spectrum and light intensity in the dinoflagellate Prorocentrum.

The proton pump rhodopsin is widely found in marine bacteria and archaea, where it functions to capture light energy and convert it to ATP. While found in several lineages of dinoflagellates, this gene has not been studied in Prorocentrales species and whether it functionally tunes to light spectra and intensities as in bacteria remains unclear. Here we identified and characterized this gene in the bloom-forming Prorocentrum donghaiense. It is a 7-helix transmembrane polypeptide containing conserved domains and critical amino acid residues of PPR. This gene is phylogenetically affiliated to the xanthorhodopsin clade, but seems to have a distinct evolutionary origin. Quantitative reverse transcription PCR showed that in regular cultures, the transcript abundance of the gene exhibited a clear diel pattern, high abundance in the light period and low in the dark. The same diel pattern was observed for protein abundance with a Western blot using specific antiserum. The rhythm was dampened when the cultures were shifted to continuous dark or light condition, suggesting that this gene is not under circadian clock control. Rhodopsin transcript and protein abundances varied with light intensity, both being highest at a moderate illumination level. Furthermore, the expression of this gene responded to different light spectra, with slightly higher transcript abundance under green than blue light, and lowest abundance under red light. Transformed Escherichia coli over-expressing this rhodopsin gene also exhibited an absorption maximum in the blue-green region with slightly higher absorption in the green. These rhodopsin-promoting light conditions are similar to the relatively turbid marine habitat where the species forms blooms, suggesting that this gene may function to compensate for the light-limited photosynthesis in the dim environment.

Chemerin and apelin are positively correlated with inflammation in obese type 2 diabetic patients.

BACKGROUND: As two novel adipocytokines, chemerin and apelin play a key role in the pathological process of insulin resistance (IR), glucose metabolism and obesity, researchers have found that the levels of chemerin and apelin changed significantly in type 2 diabetic patients with obesity, however, the underlying mechanism involved remains unclear. The aim of this study was to investigate whether chemerin and apelin play an important role in the pathophysiologic proceeding of diabetes. METHODS: This study enrolled 81 newly diagnosed obese type 2 diabetes mellitus (T2DM) patients (T2DM group, n = 81). All the patients were randomly assigned to DM1 group treated with metformin (n = 41) and DM2 group treated with pioglitazone (n = 40). After hypoglycemic agents treatment, patients under better blood glucose control were chosen to be given antioxidant treatment. Another 79 subjects without T2DM were recruited as normal control group (NC group), including 40 subjects (NC1 group) with normal body mass index (BMI) and 39 obese subjects (NC2 group). Levels of chemerin, apelin, BMI, tumor necrosis factor-α (TNF-α), homeostasis model assessment of IR (HOMA-IR) and 8-isoprotaglandim F2α (8-iso-PGF2α) were examined at baseline and post-treatment. The relationship between chemerin, apelin and BMI, TNF-α, HOMA-IR, 8-iso-PGF2α was analyzed. RESULTS: The baseline levels of chemerin, apelin, TNF-α, HOMA-IR and 8-iso-PGF2α in T2DM group were significantly higher than normal control group (P < 0.001). All indices mentioned above were significantly decreased after treatment (P < 0.05). In T2DM patients treated with pioglitazone, indices mentioned above except for HOMA-IR, were decreased significantly compared with patients treated with metformin (P < 0.05). After antioxidant treatment using lipoic acid, levels of chemerin, apelin, TNF-α and 8-iso-PGF2α were further significantly decreased (P < 0.05). Correlation analysis showed that the levels of chemerin and apelin correlated positively with BMI, TNF-α, HOMA-IR and 8-iso-PGF2α before and after treatment with hypoglycemic agents (P < 0.01). The levels of chemerin and apelin also had positive correlation with TNF-α and 8-iso-PGF2α after antioxidant treatment (P < 0.05). CONCLUSIONS: The levels of chemerin and apelin in obese T2DM patients are closely related to IR. The increased levels may be a result of compensatory response to IR, and also may be the causative factor of IR. The levels of chemerin and apelin correlate closely with oxidative stress and inflammation. The two adipokines may be inflammatory factors playing important roles in the initiation and development of obese T2DM. Chemerin and apelin are related to the pathophysiology of IR, oxidative stress and inflammation.