Tetrandrine alleviates pulmonary fibrosis by inhibiting alveolar epithelial cell senescence through PINK1/Parkin-mediated mitophagy.

Idiopathic pulmonary fibrosis (IPF) is a fatal and insidious interstitial lung disease. So far, there are no effective drugs for preventing the disease process. Cellular senescence plays a critical role in the development of IPF, with the senescence and insufficient mitophagy of alveolar epithelial cells being implicated in its pathogenesis. Tetrandrine is a natural alkaloid which is now produced synthetically. It was known that the tetrandrine has anti-fibrotic effects, but the efficacy and mechanisms are still not well evaluated. Here, we reveal the roles of tetrandrine on AECs senescence and the antifibrotic effects by using a bleomycin challenged mouse model of pulmonary fibrosis and a bleomycin-stimulated mouse alveolar epithelial cell line (MLE-12). We performed the ß-galactosidase staining, immunohistochemistry and fluorescence to assess senescence in MLE-12 cells. The mitophagy levels were detected by co-localization of LC3 and COVIX. Our findings indicate that tetrandrine suppressed bleomycin-induced fibroblast activation and ultimately blocked the increase of collagen deposition in mouse model lung tissue. It has significantly inhibited the bleomycin-induced senescence and senescence-associated secretory phenotype (SASP) in alveolar epithelial cells (AECs). Mechanistically, tetrandrine suppressed the decrease of mitochondrial autophagy-related protein expression to rescue the bleomycin-stimulated impaired mitophagy in MLE-12 cells. We revealed that knockdown the putative kinase 1 (PINK1) gene by a short interfering RNA (siRNA) could abolish the ability of tetrandrine and reverse the MLE-12 cells senescence, which indicated the mitophagy of MLE-12 cells is PINK1 dependent. Our data suggest the tetrandrine could be a novel and effective drug candidate for lung fibrosis and senescence-related fibrotic diseases.

Up-regulation of HSP90α in HDM-induced asthma causes pyroptosis of airway epithelial cells by activating the cGAS-STING-ER stress pathway.

Heat Shock protein 90 α (HSP90α), an main subtype of chaperone protein HSP90, involves important biological functions such as DNA damage repair, protein modification, innate immunity. However, the potential role of HSP90α in asthma occurrence and development is still unclear. This study aimed to elucidate the underlying mechanism of HSP90α in asthma by focusing on the cGAS-STING-Endoplasmic Reticulum stress pathway in inflammatory airway epithelial cell death (i.e., pyroptosis; inflammatory cell death). To accomplish that, we modeled allergen exposure in C57/6BL mice and bronchial epithelial cells with house dust mite. Protein technologies and immunofluorescence utilized to study the expression of HSP90α, activation of cGAS-STING pathway and pyroptosis. The effect of inhibitors on HDM-exposed mice detected by histological techniques and examination of bronchoalveolar lavage fluid. Results showed that HSP90α promotes asthma inflammation via pyroptosis and activation of the cGAS-STING-ER stress pathway. Treatment with the HSP90 inhibitor tanespimycin (17-AAG) significantly relieved airway inflammation and abrogated the effect of HSP90α on pyroptosis and cGAS-STING-ER stress in vitro and in vivo models of HDM. Further data indicated that up-regulation of HSP90α stabilized STING through interaction, which increased localization of STING on the ER. Activation of STING triggered ER stress and leaded to pyroptosis-related airway inflammation. The finding showed the potential role of pyroptosis caused by dysregulation of HSP90α on airway epithelial cells in allergic inflammation, suggested that targeting HSP90α in airway epithelial cells might prove to be a potential additional treatment strategy for asthma.

Association of blood metals with anxiety among adults: A nationally representative cross-sectional study.

BACKGROUND: Previous evidence demonstrated the inconsistent associations between metals and anxiety. The purpose of this study was to evaluate the individual and joint effects of blood lead (Pb), cadmium (Cd), mercury (Hg), selenium (Se) and manganese (Mn) on anxiety in the general population. METHODS: Data of 4000 participants (aged≥20 years) in the study were retrieved from the National Health and Nutrition Examination Survey (NHANES) 2011-2012. Multiple logistic regression, restricted cubic splines (RCS) logistic analysis, and weighted quantile sum (WQS) regression were fitted to explore the possible effects of single and mixed metal exposures on anxiety. Moreover, this association was assessed by smoking group. RESULTS: In the study, 24.60 % of participants were in an anxiety state. In logistic regression, blood Pb, Cd, Hg, Se and Mn were not significantly associated with anxiety in all participants. After stratified by smoking group, blood Cd was positively associated with anxiety in the current smoking group [P = 0.029, OR (95 %): 1.708(1.063, 3.040)], whereas not in other groups. In RCS regression, we observed a linear dose-response effect of blood Cd on anxiety stratified by smoking group. In WQS analysis, mixed metal exposures were positively associated with anxiety [P = 0.033, OR (95 %): 1.437(1.031, 2.003)], with Cd (33.69 %) contributing the largest weight to the index. CONCLUSIONS: Our study showed that excessive exposure to Cd is a significant risk factor for anxiety, and the co-exposures to Pb, Cd, Hg, Se and Mn were positively related with the risk of anxiety in current smokers.

Stanniocalcin 1 promotes lung metastasis of breast cancer by enhancing EGFR-ERK-S100A4 signaling.

Lung metastasis is the leading cause of breast cancer-related death. The tumor microenvironment contributes to the metastatic colonization of tumor cells in the lungs. Tumor secretory factors are important mediators for the adaptation of cancer cells to foreign microenvironments. Here, we report that tumor-secreted stanniocalcin 1 (STC1) promotes the pulmonary metastasis of breast cancer by enhancing the invasiveness of tumor cells and promoting angiogenesis and lung fibroblast activation in the metastatic microenvironment. The results show that STC1 modifies the metastatic microenvironment through its autocrine action on breast cancer cells. Specifically, STC1 upregulates the expression of S100 calcium-binding protein A4 (S100A4) by facilitating the phosphorylation of EGFR and ERK signaling in breast cancer cells. S100A4 mediates the effect of STC1 on angiogenesis and lung fibroblasts. Importantly, S100A4 knockdown diminishes STC1-induced lung metastasis of breast cancer. Moreover, activated JNK signaling upregulates STC1 expression in breast cancer cells with lung-tropism. Overall, our findings reveal that STC1 plays important role in breast cancer lung metastasis.

Soluble CD80 oral delivery by recombinant Lactococcus suppresses tumor growth by enhancing antitumor immunity.

CD80 is an important co-stimulatory molecule that participates in the immune response. Soluble CD80 can induce T cell activation and overcome PDL1-mediated immune suppression. In this study, we aimed to construct recombinant Lactococcus lactis for oral delivery of the soluble CD80 (hsCD80) protein or the fusion protein containing the cholera toxin B subunit (CTB) and hsCD80 (CTB-hsCD80) under the control of the nisin-inducible expression system. The recombinant L. lactis expressed and secreted hsCD80 or CTB-hsCD80 fusion proteins after induction by nisin in vitro and in the enteric cavity. Additionally, the CTB-hsCD80 fusion protein showed uptake by intestinal epithelial cells, was cleaved by the furin protease, and was released as free hsCD80 protein into the blood circulation. Orally administered hsCD80 and CTB-hsCD80 containing L. lactis increased the proportion of activated T cells in the spleen and intestinal epithelium, inhibited tumor growth, and prolonged the survival of tumor-bearing mice. The hsCD80-containing L. lactis showed greater therapeutic effects on primary colonic adenoma in APCmin/- mice and completely suppressed tumor growth. Further, recombinant CTB-hsCD80 in L. lactis was more efficient than hsCD80-containing bacteria in inhibiting the growth of xenografted colon cancer and melanoma cells. hsCD80 engineered probiotics may serve as a promising new approach for antitumor immunotherapy, especially for colorectal cancer.

Effects of Ecologically Relevant Concentrations of Cadmium on the Microbiota, Short-Chain Fatty Acids, and FFAR2 Expression in Zebrafish.

Exposure to cadmium (Cd) can affect neurodevelopment and results in increased potential of developing neurodegenerative diseases during the early developmental stage of organisms, but the mechanisms through which exposure to environmentally relevant concentrations of Cd lead to developmental neurotoxicity remain unclear. Although we know that microbial community fixations overlap with the neurodevelopmental window during early development and that Cd-induced neurodevelopmental toxicity may be related to the disruption of microorganisms during early development, information on the effects of exposure to environmentally relevant Cd concentrations on gut microbiota disruption and neurodevelopment is scarce. Therefore, we established a model of zebrafish exposed to Cd (5 µg/L) to observe the changes in the gut microbiota, SCFAs, and free fatty acid receptor 2 (FFAR2) in zebrafish larvae exposed to Cd for 7 days. Our results indicated that there were significant changes in the gut microbial composition due to the exposure to Cd in zebrafish larvae. At the genus level, there were decreases in the relative abundances of Phascolarctobacterium, Candidatus Saccharimonas, and Blautia in the Cd group. Our analysis revealed that the acetic acid concentration was decreased (p > 0.05) while the isobutyric acid concentration was increased (p < 0.05). Further correlation analysis indicated a positive correlation between the content of acetic acid and the relative abundances of Phascolarctobacterium and Candidatus Saccharimonas (R = 0.842, p < 0.01; R = 0.767, p < 0.01), and a negative correlation between that of isobutyric acid and the relative abundance of Blautia glucerasea (R = -0.673, p < 0.05). FFAR2 needs to be activated by SCFAs to exert physiological effects, and acetic acid is its main ligand. The FFAR2 expression and the acetic acid concentration were decreased in the Cd group. We speculate that FFAR2 may be implicated in the regulatory mechanism of the gut-brain axis in Cd-induced neurodevelopmental toxicity.

Disturbance of gut microbiota aggravates cadmium-induced neurotoxicity in zebrafish larvae through V-ATPase.

Cadmium (Cd) is a harmful environmental pollutant that causes damage to the nervous system, and exposure to Cd also disrupts the gut microbiota. However, it is still unclear whether Cd-induced neurotoxicity is related to alteration of the microbiota. In this study, we first established a germ-free (GF) zebrafish model to avoid the effects of gut microbiota disturbances caused by Cd exposure, and found that Cd-induced neurotoxic effects were weak in GF zebrafish. RNA sequencing showed that expression levels of V-ATPase family genes (atp6v1g1, atp6v1b2, and atp6v0cb) were significantly decreased in Cd-treated conventionally reared (CV) zebrafish, while this inhibition could be avoided in GF zebrafish. Overexpression of atp6v0cb in the V-ATPase family could partially rescue Cd-induced neurotoxicity. Our study shows that the disturbance of gut microbiota aggravates Cd-induced neurotoxicity, and that this may be associated with the expression of several genes in the V-ATPase family.

RNF130 protects against pulmonary fibrosis through suppressing aerobic glycolysis by mediating c-myc ubiquitination.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease,characterized by an excessive accumulation of extracellular matrix (ECM) proteins in response to chronic lung injury. Current evidence suggests that metabolic reprogramming is always accompanied by myofibroblast activation in IPFof whichthe underlying mechanisms remain unclear. Ring finger protein 130 (RNF130), was demonstrated involved in multiple diseases. However, whether RNF130 plays a critical role in the pathogenesis of IPF needs to be clarified. METHODS: We first investigated the expression of RNF130 in pulmonary fibrosis in vivo and in vitro. We then observed the effect and explored the molecular mechanism of RNF130 on the transition of fibroblast to myofibroblast and aerobic glycolysis. Further, we assessed the effects of adeno-associated virus (AAV)-induced RNF130 overexpression in the pulmonary fibrosis model, conducting pulmonary function, assessment of collagen depositionusing the hydroxyproline assay, and biochemical and histopathological analyses. RESULTS: We found that RNF130 was down-regulated in lung tissues of mice with bleomycin-induced pulmonary fibrosis and lung fibroblasts treated with transforming growth factor-ß1 (TGF-ß1). Then we demonstrated that RNF130 inhibitedthe transition of fibroblast to myofibroblast by suppressing aerobic glycolysis. Mechanistically, we revealed that RNF130 promotedc-myc ubiquitination and degradation, while c-myc overexpression reverses the inhibitory effects of RNF130. Importantly, pulmonary function, collagen deposition and fibroblast differentiation were significantly alleviated in adeno-associated virus serotype (AAV)6-RNF130 treated mice, which further validated the contribution of RNF130/c-myc signaling axis in pulmonary fibrosis pathological process. CONCLUSIONS: In summary, RNF130 participates in the pathogenesis of pulmonary fibrosis by inhibiting the transition of fibroblast to myofibroblast and aerobic glycolysis through promoting c-myc ubiquitination and degradation. Targeting RNF130-c-myc axismightrepresent a promising strategy to alleviate the progression of IPF.

TGF-ß1 promotes SCD1 expression via the PI3K-Akt-mTOR-SREBP1 signaling pathway in lung fibroblasts.

BACKGROUND: Lung fibroblast activation is associated with airway remodeling during asthma progression. Stearoyl-CoA desaturase 1 (SCD1) plays an important role in the response of fibroblasts to growth factors. This study aimed to explore the effects of SCD1 on fibroblast activation induced by transforming growth factor-ß1 (TGF-ß1) and the role of the phosphatidylinositol-3-kinase-AKT serine-threonine protein kinase-mechanistic target of rapamycin (PI3K-Akt-mTOR) pathway on the regulation of SCD1 expression in airway remodeling. METHODS: Female C57BL/6 mice were sensitized and challenged with house dust mites to generate a chronic asthma model. The inhibitor of SCD1 was injected i.g. before each challenge. The airway hyper-responsiveness to methacholine was evaluated, and airway remodeling and airway inflammation were assessed by histology. The effects of SCD1 on fibroblast activation were evaluated in vitro using an SCD1 inhibitor and oleic acid and via the knockdown of SCD1. The involvement of the PI3K-Akt-mTOR-sterol regulatory element-binding protein 1 (SREBP1) pathway in lung fibroblasts was investigated using relevant inhibitors. RESULTS: The expression of SCD1 was increased in fibroblasts exposed to TGF-ß1. The inhibition of SCD1 markedly ameliorated airway remodeling and lung fibroblast activation in peripheral airways. The knockdown or inhibition of SCD1 resulted in significantly reduced extracellular matrix production in TGF-ß1-treated fibroblasts, but this effect was reversed by the addition of exogenous oleic acid. The PI3K-Akt-mTOR-SREBP1 pathway was found to be involved in the regulation of SCD1 expression and lung fibroblast activation. CONCLUSIONS: The data obtained in this study indicate that SCD1 expression contributes to fibroblast activation and airway remodeling and that the inhibition of SCD1 may be a therapeutic strategy for airway remodeling in asthma.

Evaluation of the oxidative toxicity induced by lead, manganese, and cadmium using genetically modified nrf2a-mutant zebrafish.

Heavy metal pollution has become a serious environmental concern and a threat to public health. Three of the most common heavy metals are cadmium (Cd), lead (Pb), and manganese (Mn). Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor activated in the response to oxidative stress. In this study, mutant zebrafish with an nrf2a deletion of 7 bp were constructed by the CRISPR/Cas9 system to investigate the oxidative toxicity of these three heavy metals. The results of general toxicity tests showed that Pb exposure did not cause significant damage to mutant zebrafish compared with wild-type (WT) zebrafish. However, high Mn exposure increased mortality and malformation rates in mutant zebrafish. Of concern, Cd exposure caused significant toxic damage, including increased mortality and malformation rates, apoptosis of brain neurons, and severe locomotor behavior aberration in mutant zebrafish. The results of qRT-PCR indicated that Cd exposure could induce the activation of genes related to oxidative stress resistance in WT zebrafish, while the expression of these genes was inhibited in mutant zebrafish. This study showed that of the three heavy metals, Cd had the strongest oxidative toxicity, Mn had medium toxicity, and Pb had the weakest toxicity.

Multi-view spectral clustering with latent representation learning for applications on multi-omics cancer subtyping.

Driven by multi-omics data, some multi-view clustering algorithms have been successfully applied to cancer subtypes prediction, aiming to identify subtypes with biometric differences in the same cancer, thereby improving the clinical prognosis of patients and designing personalized treatment plan. Due to the fact that the number of patients in omics data is much smaller than the number of genes, multi-view spectral clustering based on similarity learning has been widely developed. However, these algorithms still suffer some problems, such as over-reliance on the quality of pre-defined similarity matrices for clustering results, inability to reasonably handle noise and redundant information in high-dimensional omics data, ignoring complementary information between omics data, etc. This paper proposes multi-view spectral clustering with latent representation learning (MSCLRL) method to alleviate the above problems. First, MSCLRL generates a corresponding low-dimensional latent representation for each omics data, which can effectively retain the unique information of each omics and improve the robustness and accuracy of the similarity matrix. Second, the obtained latent representations are assigned appropriate weights by MSCLRL, and global similarity learning is performed to generate an integrated similarity matrix. Third, the integrated similarity matrix is used to feed back and update the low-dimensional representation of each omics. Finally, the final integrated similarity matrix is used for clustering. In 10 benchmark multi-omics datasets and 2 separate cancer case studies, the experiments confirmed that the proposed method obtained statistically and biologically meaningful cancer subtypes.

Urine metabolomic characteristics of female patients with occupational chronic cadmium poisoning after 15 years of treatment.

Occupational chronic cadmium poisoning (OCCP) can cause irreversible organ damage. Currently, no effective treatment is available for OCCP, and effective and sensitive biomarkers for treatment evaluation are still lacking. In this study, metabolomics techniques were used to analyze changes in endogenous metabolites in the urine of patients with OCCP after 15 years of treatment. Thirty urine samples from female patients with OCCP and healthy female controls (n = 15 per group) were assessed using gas chromatography-time-of-flight mass spectrometry and ultra-high-performance liquid chromatography-Q-Exactive mass spectrometry. The OCCP group had higher concentrations of blood urea nitrogen and urinary cadmium but near-normal urinary concentrations of ß2 -microglobulin and retinol-binding protein. Compared with the control group, the OCCP group had 66 significantly different metabolites with a variable importance in projection score >1 and p < 0.05. These differential metabolites were involved in various metabolic pathways, such as creatine metabolism, nicotinate and nicotinamide metabolism, the pentose phosphate pathway, d-glutamine and d-glutamate metabolism, and amino acid metabolism. Compared with the control group, the OCCP group had significantly higher urinary concentrations of creatine, glutamic acid, quinolinic acid and nicotinic acid. In a receiver operator characteristic analysis, the area under the curve of creatine was higher than those for glutamic acid, quinolinic acid and nicotinic acid, indicating that urinary concentrations of creatine could be used as a sensitive biomarker for the diagnosis and prognosis of OCCP and for monitoring its treatment.

Extracellular HSP90α promotes cellular senescence by modulating TGF-ß signaling in pulmonary fibrosis.

Recent findings suggest that extracellular heat shock protein 90α (eHSP90α) promotes pulmonary fibrosis, but the underlying mechanisms are not well understood. Aging, especially cellular senescence, is a critical risk factor for idiopathic pulmonary fibrosis (IPF). Here, we aim to investigate the role of eHSP90α on cellular senescence in IPF. Our results found that eHSP90α was upregulated in bleomycin (BLM)-induced mice, which correlated with the expression of senescence markers. This increase in eHSP90α mediated fibroblast senescence and facilitated mitochondrial dysfunction. eHSP90α activated TGF-ß signaling through the phosphorylation of the SMAD complex. The SMAD complex binding to p53 and p21 promoters triggered their transcription. In vivo, the blockade of eHSP90α with 1G6-D7, a specific eHSP90α antibody, in old mice attenuated the BLM-induced lung fibrosis. Our findings elucidate a crucial mechanism underlying eHSP90α-induced cellular senescence, providing a framework for aging-related fibrosis interventions.

Abnormal neutrophil polarization in chronic obstructive pulmonary disease and how cigarette smoke extracts attract neutrophils.

Background: Airway inflammation produced by neutrophils is a critical factor in the development of chronic obstructive pulmonary disease (COPD). Poor or excessive neutrophil polarization and chemotaxis may lead to pathogen accumulation and tissue damage. However, it is unclear how cigarette smoke extract (CSE) attracts neutrophils and to what extent COPD is affected by the improper polarization of these abnormal neutrophils. This study sought to assess the polarization and migration dynamics of neutrophils isolated from patients with different severities of COPD compared to healthy smoking and non-smoking control subjects, and to detect how CSE triggers the polarization of neutrophils. Methods: The neutrophils were freshly isolated using standard isolation protocol. The polarization of the neutrophils was observed using a Zigmond chamber when stimulated by a linear concentration gradient of CSE or N-formyl-methionine-leucine-phenylalanine (fMLP). Confocal laser-scanning microscopy was used to observe the intracellular calcium of the neutrophils. The experimental data are presented as the mean ± standard deviation. SPSS 20.0 software was used for the statistical analysis. A P value <0.05 was considered statistically significant. Results: The neutrophils from the COPD patients showed a higher frequency of spontaneous polarization and a lower prevalence of directionality polarization than those from the healthy control (HC) and smoker subjects. The abnormal polarization of the neutrophils from the COPD patients was altered by the influence of store-operated calcium entry (SOCE) component matrix interaction molecules 1 and 2 and calcium release-activated calcium channel protein 1 [stromal interaction molecule 1 (STIM1), Stromal interaction molecule 2 (STIM2), and calcium release-activated calcium modulator 1 (ORAI1)]. Conclusions: The COPD neutrophils exhibited unique polarization and migration patterns compared to those of the cells examined from other populations. The attraction of CSEs to neutrophils was mediated by the SOCE/Akt/Src pathway.

HDM induce airway epithelial cell ferroptosis and promote inflammation by activating ferritinophagy in asthma.

Asthma is a disease characterized by airway epithelial barrier destruction, chronic airway inflammation, and airway remodeling. Repeated damage to airway epithelial cells by allergens in the environment plays an important role in the pathophysiology of asthma. Ferroptosis is a novel form of regulated cell death mediated by lipid peroxidation in association with free iron-mediated Fenton reactions. In this study, we explored the contribution of ferroptosis to house dust mite (HDM)-induced asthma models. Our in vivo and in vitro models showed labile iron accumulation and enhanced lipid peroxidation with concomitant nonapoptotic cell death upon HDM exposure. Treatment with ferroptosis inhibitors deferoxamine (DFO) and ferrostatin-1 (Fer-1) illuminated the role of ferroptosis and related damage-associated molecular patterns in HDM-treated airway epithelial cells. Furthermore, DFO and Fer-1 reduced HDM-induced airway inflammation in model mice. Mechanistically, NCOA4-mediated ferritin-selective autophagy (ferritinophagy) was initiated during ferritin degradation in response to HDM exposure. Together, these data suggest that ferroptosis plays an important role in HDM-induced asthma and that ferroptosis may be a potential treatment target for HDM-induced asthma.

Anti-PD-L1 antibody alleviates pulmonary fibrosis by inducing autophagy via inhibition of the PI3K/Akt/mTOR pathway.

Pulmonary fibrosis is a fatal lung disease for which no effective treatment is available. Previous studies have shown that the expression of programmed cell death-Ligand (PD-L1) is significantly increased in pulmonary fibrosis, and that this is related to the occurrence of this disease. However, the underlying mechanism is not clear. To clarify the efficacy and mechanism of an anti-PD-L1 monoclonal antibody (anti-PD-L1 mAb) as a treatment for pulmonary fibrosis, we conducted histopathological, molecular, and functional analyses in a mouse model of bleomycin-induced pulmonary fibrosis and a cell model of fibrosis induced by transforming growth factor-beta 1 (TGF-ß1). Our results indicate that PD-L1 is highly expressed in the lung fibrosis model. The anti-PD-L1 mAb significantly alleviated bleomycin-induced lung structural disorders and collagen deposition in mice and inhibited the proliferation, migration, activation and extracellular matrix deposition of TGF-ß1-induced lung fibroblasts. Interestingly, the anti-PD-L1 mAb could also alleviate the autophagy impairment observed in pulmonary fibrosis. The potential mechanism is through the downregulation of the PI3K/Akt/mTOR signaling pathway. Our study provides evidence of the crucial ability of anti-PD-L1 mAbs to activate autophagy in the context of pulmonary fibrosis, providing a new strategy for the treatment of this disease.

LncRNAs PSMG3-AS1 and MEG3 negatively regulate each other to participate in endometrial carcinoma cell proliferation.

Endometrial carcinoma (EC), also known as corpus cancer or corpus uterine cancer, is the most frequently diagnosed genital cancer among women in developed countries. Our preliminary RNA-seq analysis revealed the inverse correlation between the expression of PSMG3-AS1 and MEG3 across EC tissues, indicating the possible interaction between them. This study aimed to explore the interaction between two long non-coding RNAs (lncRNAs) PSMG3-AS1 and MEG3 in EC. Investigation of the interaction between two lncRNAs in cancer biology is a novel topic. The expression of PSMG3-AS1 and MEG3 in EC and paired non-tumor tissues from 60 EC patients were determined by RT-qPCR. Correlations between them were analyzed by Pearson's correlation coefficient. PSMG3-AS1 and MEG3 were overexpressed in EC cells to study the relationship between them. The roles of PSMG3-AS1 and MEG3 in regulating the proliferation of EC cells were assessed by CCK-8 assay. PSMG3-AS1 was upregulated, while MEG3 was downregulated in EC. Across EC tissues, the expression of PSMG3-AS1 and MEG3 were inversely correlated. In EC cells, overexpression of PSMG3-AS1 and MEG3 resulted in the downregulation of each other. In cell proliferation assay, PSMG3-AS1 promoted cell proliferation, and MEG3 inhibited cell proliferation. Moreover, the proliferation rate of cells co-transfected with PSMG3-AS1 and MEG3 expression vectors was not different from that in cells without transfections. In conclusion, PSMG3-AS1 and MEG3 may negatively regulate each other to regulate EC cell proliferation.

Joint toxicity of lead and cadmium on the behavior of zebrafish larvae: An antagonism.

Although the individual toxicity of lead (Pb) and cadmium (Cd) was intensively studied, little is known about their joint toxicity on the development of circadian behavioral rhythm. Therefore, we co-exposed zebrafish to Pb and Cd to investigate the alterations of behavioral rhythm and the potential mechanism. Inductively coupled plasma mass spectrometry analysis was used to detect the internal exposure level of heavy metals. The behavioral rhythm was monitored by a video-track tracking system. The changes of gene expression regarding melatonin-related molecules and clock genes were analyzed by quantitative polymerase chain reaction and JTK-Cycle analysis. The results showed that the level of Pb2+ and Cd2+ accumulated in the co-exposure group were significantly lower than that in the Pb or Cd group. Exposed to Pb reduced the locomotor activity; the behavioral rhythms were disrupted by Cd, while the pattern in the co-exposure group showed an antagonistic effect on locomotor activity and behavioral rhythm. The expression rhythm of aanat1 was disturbed and the expression levels of mtnr1aa and mtnr1bb were decreased by co-exposure treatment, but mtnr1c was increased in Pb and Cd group, respectively. Exposure to Cd caused the disruption of expression rhythm in clock genes, like clock1b, clock2, and cry1b, while only the rhythm of clock2 was disrupted in the co-exposure group. The results suggest that the behavioral rhythm disruption caused by Cd exposure is associated with the disturbance of certain circadian genes, whereas Pb exposure only abates the locomotor activity; an antagonistic effect on the behavioral pattern when co-exposed zebrafish larvae to Pb and Cd.

NLRP3 induces the autocrine secretion of IL-1ß to promote epithelial-mesenchymal transition and metastasis in breast cancer.

Tumor metastasis is a leading cause of mortality in patients with breast cancer (BC). As a predominant component of inflammasome, Nod-like receptor protein 3 (NLRP3) was found to be required for tumor progression, while the role of NLRP3 in BC metastasis remains largely undefined. In current study, we found that invasive BC had aberrant upregulation of NLRP3 expression, especially in the claudin-low subtype. And higher expression of NLRP3 predicted poor survival of BC patients. Further investigation suggested that NLRP3 promotes the migration and invasion, as well as the metastasis of BC cells. Moreover, we revealed that NLRP3 induces the autocrine secretion of IL-1ß to promote epithelial-mesenchymal transition via a Caspase-1-dependent manner. Hence, this study suggested that upregulation of NLRP3 in BC induces the autocrine secretion of IL-1ß and promotes EMT and metastasis of BC cells.