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Exosomes are nano-sized vesicles that serve as mediators for intercellular communication through the delivery of cargo, including protein, lipids, nucleic acids or other cellular components, to neighboring or distant cells. Exosomal cargo may vary in response to different physiological or pathological conditions. The endosomal sorting complex required for transport (ESCRT) family has been widely accepted as a key mechanism in biogenesis and cargo sorting. On the other hand, accumulating evidence show that ESCRT-independent pathways exist. Due to the critical role of exosomes in intercellular communications in delivering cargo to recipient cells, exosomes have been investigated as a vector for the delivery of endogenous or exogenous cargo for therapeutic purposes. But the number of exosomes produced by cells is limited, which hampers their application. Synthetic exosome-mimics have been fabricated and investigated as a therapeutic tool for drug delivery. This review focuses on ESCRT-independent regulation of cargo loading into exosomes, including lipid raft and ceramide-mediated mechanisms, and reported exosomes or exosome-mimics with therapeutic effects.

Non-small cell lung cancer (NSCLC) is characterized by a high incidence of metastasis and poor survival. As epithelial–mesenchymal transition (EMT) is well recognized as a major factor initiating tumor metastasis, developing EMT inhibitor could be a feasible treatment for metastatic NSCLC. Recent studies show that triptolide isolated from Tripterygium wilfordii Hook F attenuated the migration and invasion of breast cancer, colon carcinoma, and ovarian cancer cells, and EMT played important roles in this process. In the present study we investigated the effect of triptolide on the migration and invasion of NSCLC cell lines. We showed that triptolide (0.5, 1.0, 2.0 nM) concentration-dependently inhibited the migration and invasion of NCI-H1299 cells. Triptolide treatment concentration-dependently suppressed EMT in NCI-H1299 cells, evidenced by significantly elevated E-cadherin expression and reduced expression of ZEB1, vimentin, and slug. Furthermore, triptolide treatment suppressed β-catenin expression in NCI-H1299 and NCI-H460 cells, overexpression of β-catenin antagonized triptolide-caused inhibition on EMT, whereas knockout of β-catenin enhanced the inhibitory effect of triptolide on EMT. Administration of triptolide (0.75, 1.5 mg/kg per day, ip, every 2 days) for 18 days in NCI-H1299 xenograft mice dose-dependently suppressed the tumor growth, restrained EMT, and decreased lung metastasis, as evidence by significantly decreased expression of mesenchymal markers, increased expression of epithelial markers as well as reduced number of pulmonary lung metastatic foci. These results demonstrate that triptolide suppresses NSCLC metastasis by targeting EMT via reducing β-catenin expression. Our study implies that triptolide may be developed as a potential agent for the therapy of NSCLC metastasis.

Backgrounds Due to the unexpected side effects of the iodinated contrast agents, novel contrast agents for X-ray computed tomography (CT) imaging are urgently needed. Nanoparticles made by heavy metal elements are often employed, such as gold and bismuth. These nanoparticles have the advantages of long in vivo circulation time and tumor targeted ability. However, due to the long residence time in vivo, these nanoparticles may bring unexpected toxicity and, the preparation methods of these nanoparticles are complicated and time—consuming. Methods In this investigation, a small molecular bismuth chelate using diethylenetriaminepentaacetic acid (DPTA) as the chelating agent was proposed to be an ideal CT contrast agent. Results The preparation method is easy and cost—effective. Moreover, the bismuth agent show better CT imaging for kidney than iohexol in the aspect of improved CT values. Up to 500 µM, the bismuth agent show negligible toxicity to L02 cells and negligible hemolysis. And, the bismuth agent did not induce detectable morphology changes to the main organs of the mice after intravenously repeated administration at a high dose of 250 mg/kg. The pharmacokinetics of the bismuth agent follows the first—order elimination kinetics and, it has a short half—life time of 0.602 h. The rapid clearance from the body promised its excellent biocompatibility. Conclusions This bismuth agent may serve as a potential candidate for developing novel contrast agent for CT imaging in clinical applications.

Lung adenocarcinoma (LUAD) characterized by high metastasis and mortality is the leading subtype of non-small cell lung cancer. Evidence shows that some microRNAs (miRNAs) may act as oncogenes or tumor suppressor genes, leading to malignant tumor occurrence and progression. To better understand the molecular mechanism associated with miRNA methylation in LUAD progression and clinical outcomes, we investigated the correlation between miR-148a-3p methylation and the clinical features of LUAD. In the LUAD cell lines and tumor tissues from patients, miR-148a-3p was found to be significantly downregulated, while the methylation of miR-148a-3p promoter was notably increased. Importantly, miR-148a-3p hypermethylation was closely associated with lymph node metastasis. We demonstrated that mitogen-activated protein (MAP) kinase kinase kinase 9 ( MAP3K9 ) was the target of miR-148a-3p and that MAP3K9 levels were significantly increased in both LUAD cell lines and clinical tumor tissues. In A549 and NCI-H1299 cells, overexpression of miR-148a-3p or silencing MAP3K9 significantly inhibited cell growth, migration, invasion and cytoskeleton reorganization accompanied by suppressing the epithelial-mesenchymal transition. In a nude mouse xenograft assay we found that tumor growth was effectively inhibited by miR-148a-3p overexpression. Taken together, the promoter methylation-associated decrease in miR-148a-3p could lead to lung cancer metastasis by targeting MAP3K9 . This study suggests that miR-148a-3p and MAP3K9 may act as novel therapeutic targets for the treatment of LUAD and have potential clinical applications.

A circular seam cooling nozzle and its online control system have been developed to reduce the center segregation in high carbon steel billets by decreasing the superheat of the molten steel and improving the equiaxed crystal ratio based on the numerical results. An industrial experiment has been carried out on a 150 mm× 150 mm caster to investigate the effect of the circular seam cooling nozzle on the superheat removal of the molten steel. The results show that the circular seam cooling nozzle can be used to control the casting temperature in a closed loop control system. The online control system can be effectively adapted to the variation of operating parameters. The casting lasts about 4 h and about 400 t steel is successfully produced in a continuous operation. The removal of about 14 ℃ superheat and the improvement of approximate 10% equiaxed crystal ratio can be achieved by the newly developed circular seam cooling nozzle.

Aim： To evaluate the influence of the vascular endothelial growth factor A （VEGFA） polymorphisms on risk of presentation with intracerebral hemorrhage （ICH）. Methods： Nine selected VEGFA single-nucleotide polymorphisms （SNPs） were genotyped in 311 patients with brain arteriovenous malformations （BAVM） in a Chinese population. Associations between individual SNPs/haplotypes and the hemorrhage risk of BAVMs were evaluated using logistic regression analysis. Results： In the single-locus analysis, rs1547651 was associated with increased risk of ICH （adjusted 0R=2.11, 95% C1=1.01-4.42 compared with the AA genotype）o In particular, an increased risk for ICH was associated with this variant in female patients （adjusted OR=3.21, and 95% CI=0.99-10.36）. Haplotype-based analyses revealed that haplotype ＇GC＇ in block 1 and haplotype ＇ACC＇ in block 2 were associated with a 30%-38% reduction in the risk of ICH in patients with BAVMs compared to the most common haplotype （Psim=0.033 and Psim=0.005, respectively）. The protective effect of haplotype ＇ACC＇ in block 2 was more evident in male patients and subjects with BAVMs of a size 〉3 cm （adjusted OR=0.57, 95% CI=0.34-0.97 and adjusted OR=0.57, 95% CI=0.31-0.86, respectively） Conclusion： The results suggest that VEGFA gene variants may contribute to ICH risk of BAVM.

Aim： To investigate the embryotoxicity of dihydroartemisinin （DHA）, the main active metabolite of artemisinin, in zebrafish, and explore the corresponding mechanisms. Methods： The embryos of wild type and TG （flkl：GFP） transgenic zebrafish were exposed to DHA. Developmental phenotypes of the embryos were observed. Development of blood vessels was directly observed in living embryos of TG （flkl：GFP） transgenic zebrafish under fluorescence microscope. The expression of angiogenesis marker genes vegfa, ilk1, and fit1 in the embryos was detected using real-time PCR and RNA in situ hybridization assays. Results： Exposure to DHA （1-10 mg/L） dose-dependently caused abnormal zebrafish embryonic phenotypes in the early developmental stage. Furthermore, exposure to DHA （10 mg/L） resulted in more pronounced embryonic angiogenesis in TG （flkl：GFP） zebrafish line. Exposure to DHA （10 mg/L） significantly increased the mRNA expression of veEfa, flkl, and fit1 in the embryos. Knockdown of the ilk1 protein partially blocked the effects of DHA on embryogenesis. Conclusion： DHA causes abnormal embryonic phenotypes and promotes angiogenesis in zebrafish early embryonic development, demonstrating the potential embryotoxicity of DHA.

The chemical weathering can consume atmosphere/soil CO2. Human activities such as pollution, fertilization and acid precipitation have exerted a large impact on CO2 intake by carbonate weathering. Thus, based on the analysis on chemical component change of the karst groundwater in the karst ridge watershed of Conglin Village, Fuling District of Chongqing City, the influence of human activities such as fertilization, sewage discharges from mustard tuber processing, breeding industry and acid rain precipitation on carbonate weathering and CO2 intake in 1980, 2003 and 2006 was studied. The results showed that CO2 intake by carbonate rock declined with year. Because H+ derived from acid sewage discharge, fertilization and acid precipitation reacted with carbonate rock when mustard tuber production and swine breeding were developed fleetly after 2000 as well as the burning amount of high-sulfur coal augmented persistently, which led to the increase of(Ca2++Mg2+)/HCO3-. The difference on charge between Ca2++Mg2+ and HCO3- was balanced by NO3-+SO42-. The control on pollution and acid rain, especially the pre-neutralization of acid waste water, would rejuvenate the atmospheric CO2 intake strength of carbonate weathering besides the protection of water and soil environment.

Background Efforts to precisely assess tumor-specific T-cell immune responses still face major challenges, and the potential molecular mechanisms mediating hepatocellular carcinoma (HCC) microenvironment imbalance after incomplete radiofrequency ablation (iRFA) are unclear. This study aimed to provide further insight into the integrated transcriptomic and proteogenomic landscape and identify a new target involved in HCC progression following iRFA. Methods Peripheral blood and matched tissue samples were collected from 10 RFA-treated HCC patients. Multiplex immunostaining and flow cytometry were used to assess local and systemic immune responses. Differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) were explored via transcriptomic and proteogenomic analyses. Proteinase-3 (PRTN3) was identified in these analyses. And then, the ability of PRTN3 to predict overall survival (OS) was assessed in 70 HCC patients with early recurrence after RFA. In vitro CCK-8, wound healing and transwell assays were conducted to observe interactions between Kupffer cells (KCs) and HCC cells induced by PRTN3. The protein levels of multiple oncogenic factors and signaling pathway components were detected by western blotting. A xenograft mouse model was built to observe the tumorigenic effect of PRTN3 overexpression on HCC. Results Multiplex immunostaining revealed no immediate significant change in local immune cell counts in periablational tumor tissues after 30 min of iRFA. Flow cytometry showed significantly increased levels of CD4 + T cells, CD4 + CD8 + T cells, and CD4 + CD25 + CD127 − Tregs and significantly decreased the levels of CD16 + CD56 + natural killer cells on day 5 after cRFA ( p  < 0.05). Transcriptomics and proteomics revealed 389 DEGs and 20 DEPs. Pathway analysis showed that the DEP-DEGs were mainly enriched in the immunoinflammatory response, cancer progression and metabolic processes. Among the DEP-DEGs, PRTN3 was persistently upregulated and closely associated with the OS of patients with early recurrent HCC following RFA. PRTN3 expressed in KCs may affect the migration and invasion of heat stress-treated HCC cells. PRTN3 promotes tumor growth via multiple oncogenic factors and the PI3K/AKT and P38/ERK signaling pathways. Conclusions This study provides a comprehensive overview of the immune response and transcriptomic and proteogenomic landscapes of the HCC milieu induced by iRFA, revealing that PRTN3 promotes HCC progression after iRFA. Trial registration ChiCTR2200055606, http://www.chictr.org.cn/showproj.aspx?proj=32588 .

Background In a previous study, the early ripening of Kyoho grape following H 2 O 2 treatment was explored at the physiological level, but the mechanism by which H 2 O 2 promotes ripening at the molecular level is unclear. To reveal the molecular mechanism, RNA-sequencing analysis was conducted on the different developmental stages of Kyoho berry treated with H 2 O 2 . Results In the comparison of treatment and control groups, 406 genes were up-regulated and 683 were down-regulated. Time course sequencing (TCseq) analysis showed that the expression patterns of most of the genes were similar between the treatment and control, except for some genes related to chlorophyll binding and photosynthesis. Differential expression analysis and the weighted gene co-expression network were used to screen significantly differentially expressed genes and hub genes associated with oxidative stress ( heat shock protein , HSP ), cell wall deacetylation ( GDSL esterase/lipase , GDSL ), cell wall degradation ( xyloglucan endotransglucosylase/ hydrolase, XTH ), and photosynthesis ( chlorophyll a-b binding protein, CAB1 ). Gene expression was verified with RT-qPCR, and the results were largely consistent with those of RNA sequencing. Conclusions The RNA-sequencing analysis indicated that H 2 O 2 treatment promoted the early ripening of Kyoho berry by affecting the expression levels of HSP, GDSL, XTH, and CAB1 and- photosynthesis- pathways.