As a novel class of noncoding RNAs, circRNAs have been recently identified to regulate tumorigenesis and aggressiveness. However, the function of circRNAs in colorectal cancer (CRC) metastasis ...remains unclear. We aimed to identify circRNAs that are upregulated in CRC tissues from patients and study their function in CRC metastasis.
We compared six pairs of CRC tissues and their matched adjacent non-tumor tissues by using circRNA microarray. We first evaluated the expression of circPTK2 (hsa_circ_0005273) in fresh tissues from CRC tumors and corresponding adjacent tissues by qPCR analysis. CircPTK2 expression levels in the tissue microarray with 5 years of survival information were determined by RNA-ISH analysis. Meanwhile, the expression levels of circulating circPTK2 were further analyzed according to the patients' clinical features. We analyzed cell apoptosis, colony formation, migration, and invasion in CRC cells. To further elucidate the effect of circPTK2 in CRC metastasis, we also conducted a colon cancer hepatic and pulmonary metastasis experiment. We used RNA biotin-labeled pull down and mass spectrometry to identify the target of circPTK2. We established a PDTX model to evaluate the effect of shRNA specifically targeting circPTK2 on tumor metastasis.
We identified a novel circRNA, circPTK2, which is back-spliced of three exons (exons 27, 28 and 29) of PTK2 by using circRNA microarray, bioinformatics and functional studies. CircPTK2 was elevated in CRC tissues and positively associated with tumor growth and metastasis. CRC patients with increased circPTK2 expression were positively correlated with poorer survival rates. Furthermore, our studies showed that circPTK2 could promote EMT of CRC cells in vitro and in vivo by binding to vimentin protein on sites Ser38, Ser55 and Ser82. We further demonstrated the interaction of circPTK2 and vimentin mediated the regulation of CRC by knockdown or overexpression of vimentin. In addition, we revealed that tail vein injection of shRNA specifically targeting circPTK2 blunt tumor metastasis in a patient-derived CRC xenograft model.
Collectively, these results demonstrate that circPTK2 exerts critical roles in CRC growth and metastasis and may serve as a potential therapeutic target for CRC metastasis, and also a promising biomarker for early diagnosis of metastasis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Exposure to ambient fine particulate matter (PM2.5) has been linked to a higher pulmonary fibrosis risk. Dysregulation of the epitranscriptome results in abnormal expression of mRNAs during fibrosis ...development. N4-acetylcytidine (ac4C) is one of the most frequent RNA epigenetic alterations, however, its function in PM2.5-triggered fibrosis is yet unknown. In this study, lung epithelial and murine models were established and exposed to PM2.5 to analyze the function of ac4C alteration in pulmonary fibrosis and underlying mechanisms. Meanwhile, the expression levels of only known ac4C “writer” protein, N-acetyltransferase 10 (NAT10), were significantly induced in pulmonary epithelia, relative to the control. Subsequently, NAT10 enhanced the stability of transforming growth factor beta 1 (TGFB1) mRNA as well as protein levels. As an up-stream driver, TGFB1 accelerated EMT and fibrosis process. Inhibition of NAT10 significantly protected against pulmonary EMT and fibrosis driven by PM2.5 exposure, whereas TGFB1 overexpression reversed the protective effects of NAT10 inhibition. Thus, NAT10 accelerated PM2.5-triggered pulmonary fibrosis via increasing TGFB1 mRNA stability in an ac4C-dependent manner. Our results reveal a pivotal role of NAT10-regulated mRNA ac4C acetylation in PM2.5-triggered pulmonary fibrosis and uncover the potential epitranscriptional mechanism.
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•NAT10-mediated RNA acetylation accelerates PM2.5-induced pulmonary fibrosis.•NAT10 enhances TGFB1 mRNA stability in an RNA acetylation-dependent manner.•TGFB1 reverses the protection of NAT10 depletion on PM2.5-induced pulmonary fibrosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Chimeric antigen receptor (CAR) - T cell therapy is a new class of cellular immunotherapies, which has made great achievements in the treatment of malignant tumors. Despite improvements in colorectal ...cancer (CRC) therapy, treatment of many patients fails because of metastasis and recurrence. The human epidermal growth factor receptor 2 (HER2) is a substantiated target for CAR-T therapy, and has been reported recently to be over-expressed in CRC, which may provide a potential therapeutic target for CRC treatment. Herein, HER2 was a promising target of metastatic colorectal cancer (mCRC) in CAR-T therapy as assessed by flow cytometry and tissue microarray (TMA) with 9-year survival follow-up data. Furthermore, HER2-specific CAR-T cells exhibited strong cytotoxicity and cytokine-secreting ability against CRC cells in vitro. Moreover, through the tumor-bearing model of the NOD-Prkdc
Il2rg
/Nju (NCG) mice, HER2 CAR-T cells showed signs of effectively preventing CRC progression in three different xenograft models. Notably, HER2 CAR-T cells displayed greater aggressiveness in HER2
CRC in the patient-derived tumor xenograft (PDX) models and had potent immunotherapeutic capacity for mCRC in the metastatic xenograft mouse models. In conclusion, our studies provide scientific evidence that HER2 CAR-T cells represent an emerging immunotherapy for the treatment of mCRC.
Abstract
Background
Maize (
Zea mays
L.) is at the vanguard facing the upcoming breeding challenges. However, both a super pan-genome for the
Zea
genus and a comprehensive genetic variation map for ...maize breeding are still lacking.
Results
Here, we construct an approximately 6.71-Gb pan-
Zea
genome that contains around 4.57-Gb non-B73 reference sequences from fragmented de novo assemblies of 721 pan-
Zea
individuals. We annotate a total of 58,944 pan-
Zea
genes and find around 44.34% of them are dispensable in the pan-
Zea
population. Moreover, 255,821 common structural variations are identified and genotyped in a maize association mapping panel. Further analyses reveal gene presence/absence variants and their potential roles during domestication of maize. Combining genetic analyses with multi-omics data, we demonstrate how structural variants are associated with complex agronomic traits.
Conclusions
Our results highlight the underexplored role of the pan-
Zea
genome and structural variations to further understand domestication of maize and explore their potential utilization in crop improvement.
Chronic obstructive pulmonary disease (COPD) has been linked to particulate matter (PM) exposure. Using transcriptomic analysis, we demonstrate that diesel exhaust particles, one of the major sources ...of particulate emission, down-regulated genes located in mitochondrial complexes I and V and induced experimental COPD in a mouse model. 1-Nitropyrene was identified as a major toxic component of PM-induced COPD. In the panel study, COPD patients were found to be more susceptible to PM than individuals with normal lung function due to an increased inflammatory response. Mechanistically, exposure to PM in human bronchial epithelial cells led to a decline in CCAAT/enhancer-binding protein alpha (C/EBPα), which triggered aberrant expression of NADH dehydrogenase genes and ultimately led to enhanced autophagy. ATG7-deficient mice, which have lower autophagy rates, were protected from PM-induced experimental COPD. Using metabolomics analysis, we further established that treatment with taurine and 3-methyladenine completely restored mitochondrial gene expression levels, thereby ameliorating the PM-induced emphysema. Our studies suggest a potential therapeutic intervention for the C/EBPα/mitochondria/autophagy axis in PM-induced COPD.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
•Integrated analysis of meteorological-soil-groundwater information based on two typical monitoring sites and the plain area of Jilin Province, China.•Reveals the prerequisite that groundwater levels ...are influenced by freeze–thaw processes.•The main influencing factors controlling water level fluctuations during freeze–thaw periods are revealed and their importance is quantified.
Studying the dynamic mechanism of water-level variations during the freeze–thaw period in seasonally frozen soil regions is an important premise and foundation for winter agricultural irrigation and groundwater resource assessment. Freezing and thawing-induced groundwater-level variations have been observed in regions with a shallow water table depth. However, whether the groundwater level is affected by the freeze–thaw process and the extent of this effect should be verified and discussed on a wider spatiotemporal scale. To this end, this study selected the plain area of Jilin Province, China as an example, and based on a comprehensive analysis of dynamic groundwater-level monitoring data from 114 monitoring wells, the distribution of the meteorological data and soil types and two typical experimental monitoring sites in the area, the dynamic characteristics and influencing factors of groundwater-level variations during the freeze–thaw period were identified. Combined with a multi-factor statistical analysis of the monitoring data at the regional scale of the plain area of Jilin Province, China, the response mechanism of the groundwater level to the freeze–thaw process in the seasonally frozen plain area was summarized. The results showed that: (1) The dynamic phenomenon where the groundwater level falls in the freezing period and rises in the thawing period due to the freeze–thaw process was widespread in seasonally frozen soil regions; (2) The depth threshold of the groundwater level affected by the freeze–thaw process was the sum of the maximum frozen soil depth and the maximum capillary rise height; (3) The main factors controlling the groundwater-level variation during the freeze–thaw period were the initial water-level depth and the maximum snow cover thickness; based on a random forest model, the groundwater-level variation during the freeze–thaw process could be accurately calculated with these main controlling factors; (4) The groundwater-level dynamics during the freeze–thaw process was mainly controlled by the exchange of water between the groundwater and the vadose zone system, and the rise in the water level was only partially replenished by the snowmelt water. The research results have an important guiding significance for winter agricultural irrigation and groundwater recharge resource evaluation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•DEPs-induced neural disorders are triggered by sustained activation of microglia.•Inhibition of NLRP3 inflammasome activation ameliorates the neural disorders.•Taurine protects mice from ...DEPs-induced neural disorders.
The major components of traffic pollution particulate matter, diesel exhaust particles (DEPs), are airborne ultrafine particles (UFPs). DEPs can enter the central nervous system (CNS), where they may cause neurotoxicity.
We established murine models with intranasal DEPs instillation in male C57BL/6 and Nlrp3 knock-out (Nlrp3−/−) mice to investigate the effects of DEPs exposure on murine neurobehaviors and related mechanisms. Morris water maze (MWM) tests were performed to evaluate the learning and memory behaviors of mice following DEPs instillation. Metabolomics were assessed using an gas chromatography system coupled to a mass spectrometer. Real-time PCR and immunohistochemistry assays were used to analyze the mRNA and protein expression levels of target genes. Murine microglia, BV2 cells were employed to assay the effects of DEPs exposure in vitro.
Intranasal administration of DEPs in mice led to impairment in hippocampal-dependent learning and memory. Moreover, this phenotype was linked to increased number of Iba-1+ microglia and NLRP3 inflammasome, as well as suppression of mitochondrial gene expression in the hippocampus of mice exposed to DEPs. Nlrp3−/− mice were resistant to DEPs-induced learning and memory impairment, concomitant with protection against the suppression of mitochondrial gene expression. Murine microglia cells (BV2) were exposed to DEPs in vitro and taurine was identified as one of the significantly suppressed metabolites in DEPs-treated microglia by metabolomics analysis. Supplementation with taurine efficiently rescued learning, memory and mitochondrial gene expression levels in the hippocampus of DEPs-exposed mice.
Mechanistically, our study revealed that microglia-mediated NLRP3 inflammasome activation plays a deleterious role in DEPs-induced neurotoxicity by inhibiting mitochondrial gene expression. These results shed novel light on the potential value of nutritional supplementation against DEPs-induced neurotoxicity in individuals exposed to severe airborne traffic-related air pollutions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Air pollution has been intensively associated with acute exacerbation in COPD patients. In this study, we characterize COPD acute exacerbation (aeCOPD) in response to PM2.5 exposure and report that ...elevated hsa_circ_0005045 expression, non-smoking and group C are valuable clues to predict aeCOPD during air pollution episodes. The physical interaction between circRNA and proteins (PRDX2) promoted alveolar destruction, which is the underlying mechanism.
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Ambient fine particulate matter (PM2.5) is linked to an increased risk of chronic obstructive pulmonary disease (COPD) exacerbations, which significantly increase the risk of mortality in COPD patients. Identifying the subtype of COPD patients who are sensitive to environmental aggressions is necessary. Using in vitro and in vivo PM2.5 exposure models, we demonstrate that exosomal hsa_circ_0005045 is upregulated by PM2.5 and binds to the protein cargo peroxiredoxin2, which functionally aggravates hallmarks of COPD by recruiting neutrophil elastase and triggering in situ release of tumor necrosis factor (TNF)-α by inflammatory cells. The biological function of hsa_circ_0005045 associated with aggravation of COPD is validated using exosome-transplantation and conditional circRNA-knockdown murine models. By sorting the major components of PM2.5, we find that PM2.5-bound heavy metals, which are distinguishable from the components of cigarette smoke, trigger the elevation of exosomal hsa_circ_0005045. Finally, using machine learning models in a cohort with 327 COPD patients, the PM2.5 exposure-sensitive COPD patients are characterized by relatively high hsa_circ_0005045 expression, non-smoking, and group C (mMRC 0–1 (or CAT < 10) and ≥ 2 exacerbations (or ≥ 1 exacerbation leading to hospital admission) in the past year). Thus, our results suggest that environmental reduction in PM2.5 emission provides a targeted approach to protecting non-smoking COPD patients against air pollution-related disease exacerbation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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