Autophagy is a degradative pathway that delivers cellular components to the lysosome for degradation. The role of autophagy in cell differentiation is poorly understood. Here we show that CaMKII can ...directly phosphorylate Beclin 1 at Ser90 to promote K63-linked ubiquitination of Beclin 1 and activation of autophagy. Meanwhile, CaMKII can also promote K63-linked ubiquitination of inhibitor of differentiation 1/2 (Id-1/2) by catalyzing phosphorylation of Id proteins and recruiting TRAF-6. Ubiquitinated Id-1/Id-2 can then bind to p62 and be transported to autolysosomes for degradation. Id degradation promotes the differentiation of neuroblastoma cells and reduces the proportion of stem-like cells. Our study proposes a mechanism by which autophagic degradation of Id proteins can regulate cell differentiation. This suggests that targeting of CaMKII and the regulation of autophagic degradation of Id may be an effective therapeutic strategy to induce cell differentiation in neuroblastoma.
The integration of heterometallic units and nanostructures into metal–organic frameworks (MOFs) used for the oxygen evolution reaction (OER) can enhance the electrocatalytic performance and help ...elucidate underlying mechanisms. We have synthesized a series of stable MOFs (CTGU‐10a1–d1) based on trinuclear metal carboxylate clusters and a hexadentate carboxylate ligand with a (6,6)‐connected nia net. We also present a strategy to synthesize hierarchical bimetallic MOF nanostructures (CTGU‐10a2–d2). Among these, CTGU‐10c2 is the best material for the OER, with an overpotential of 240 mV at a current density of 10 mA cm−2 and a Tafel slope of 58 mV dec−1. This is superior to RuO2 and confirms CTGU‐10c2 as one of the few known high‐performing pure‐phase MOF‐OER electrocatalysts. Notably, bimetallic CTGU‐10b2 and c2 show an improved OER activity over monometallic CTGU‐10a2 and d2. Both DFT and experiments show that the remarkable OER performance of CTGU‐10c2 is due to the presence of unsaturated metal sites, a hierarchical nanobelt architecture, and the Ni–Co coupling effect.
Finding the right balance: The integration of heterometallic clusters and nanostructures into stable hierarchical nanosheet‐based bimetal–organic frameworks allows to increase the oxygen evolution reaction performance of electrocatalysts. The ideal ratio between Co and Ni leads to one of the best performances of pure‐phase MOF–OER electrocatalysts.
Two cycles in one pot! The synthesis of biologically important phenanthridinones has been achieved by the one‐pot formation of CC and CN bonds through a palladium‐catalyzed dual CH activation, ...which involves four bond ruptures and two bond formations (see scheme). The conversion of phenanthridinones into natural product like derivatives further demonstrates the utility of this synthetic achievement.
Inflammation triggers pulmonary vascular remodelling. Ferroptosis, a nonapoptotic form of cell death that is triggered by iron-dependent lipid peroxidation and contributes to the pathogenesis of ...several inflammation-related diseases, but its role in pulmonary hypertension (PH) has not been studied. We examined endothelial cell ferroptosis in PH and the potential mechanisms. Pulmonary artery endothelial cells (PAECs) and lung tissues from monocrotaline (MCT)-induced PH rats were analysed for ferroptosis markers, including lipid peroxidation, the labile iron pool (LIP) and the protein expression of glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1) and NADPH oxidase-4 (NOX4). The effects of the ferroptosis inhibitor ferrostatin-1 (Fer-1) on endothelial cell ferroptosis and pulmonary vascular remodelling in MCT-induced rats were studied in vitro and in vivo. Ferroptosis was observed in PAECs from MCT-induced PH rats in vitro and in vivo and was characterized by a decline in cell viability accompanied by increases in the LIP and lipid peroxidation, the downregulation of GPX4 and FTH1 expression and the upregulation of NOX4 expression. High-mobility group box 1 (HMGB1)/Toll-like receptor 4 (TLR4)/NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signalling was measured by western blotting. These changes were significantly blocked by Fer-1 administration in vitro and in vivo. These results suggest that Fer-1 plays a role in inhibiting ferroptosis-mediated PAEC loss during the progression of PH. The ferroptosis-induced inflammatory response depended on the activation of HMGB1/TLR4 signalling, which activated the NLRP3 inflammasome in vivo. We are the first to suggest that pulmonary artery endothelial ferroptosis triggers inflammatory responses via the HMGB1/TLR4/NLRP3 inflammasome signalling pathway in MCT-induced rats. Treating PH with a ferroptosis inhibitor and exploring new treatments based on ferroptosis regulation might be promising therapeutic strategies for PH.
Transport through the cell membrane can be divided into active, passive and vesicular types (exosomes). Exosomes are nano‐sized vesicles released by a variety of cells. Emerging evidence shows that ...exosomes play a critical role in cancers. Exosomes mediate communication between stroma and cancer cells through the transfer of nucleic acid and proteins. It is demonstrated that the contents and the quantity of exosomes will change after occurrence of cancers. Over the last decade, growing attention has been paid to the role of exosomes in the development of breast cancer, the most life‐threatening cancer in women. Breast cancer could induce salivary glands to secret specific exosomes, which could be used as biomarkers in the diagnosis of early breast cancer. Exosome‐delivered nucleic acid and proteins partly facilitate the tumorigenesis, metastasis and resistance of breast cancer. Exosomes could also transmit anti‐cancer drugs outside breast cancer cells, therefore leading to drug resistance. However, exosomes are effective tools for transportation of anti‐cancer drugs with lower immunogenicity and toxicity. This is a promising way to establish a drug delivery system.
Exosomes are nano‐sized vesicles released by a variety of cells. Exosomes function as versatile promoters in the tumorigenesis, metastasis and drug resistance of breast cancer. In this review, we summarize the current knowledge about the functions of exosomes in the diagnosis, tumorigenesis, metastasis, microenvironment, drug resistance and therapy of breast cancer.
Fall armyworm has invaded China and colonized its populations in tropical and sub-tropical regions of South China since December 2018. Chemical spray has been widely used to control the pest, which ...shall lead to resistance evolution. In this research, we collected five populations of the pest from Yunnan, Hainan, Tibet, and Fujian of China, and tested their susceptibilities to pyrethroid, organophosphorus, oxadiazine, diamide, antibiotics and other types of insecticides (14 insecticides totally) in the laboratory. Based on the susceptible baseline published from the previous studies, the resistance ratio was 615–1 068-fold to chlorpyrifos, 60–388-fold to spinosad, 26–317-fold to lambda-cyhalothrin, 13–29-fold to malathion, 9–33-fold to fenvalerate, 8–20-fold to deltamethrin, 3–8-fold to emamectin benzoate and 1–2-fold to chlorantraniliprole, respectively. The median lethal concentration (LC50) of other six insecticides without the susceptible baselines was 148.27–220.96 μg mL−1 for beta-cypermethrin, 87.03–128.43 μg mL−1 for chlorfenapyr, 16.35–99.67 μg mL−1 for indoxacarb, 10.55–51.01 μg mL−1 for phoxim, 7.08–8.78 μg mL−1 for M-EBI (the mixed insecticide of emamectin benzoate and indoxcarb) and 1.49–4.64 μg mL−1 for cyantraniliprole. This study can be helpful for chemical control as well as for resistance monitoring and management of the pest in China.
Circular RNAs (circRNAs) have received increasing attention in human tumor research. However, there are still a large number of unknown circRNAs that need to be deciphered. The aim of this study is ...to unearth novel circRNAs as well as their action mechanisms in hepatocellular carcinoma (HCC).
A combinative strategy of big data mining, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and computational biology was employed to dig HCC-related circRNAs and to explore their potential action mechanisms. A connectivity map (CMap) analysis was conducted to identify potential therapeutic agents for HCC.
Six differently expressed circRNAs were obtained from three Gene Expression Omnibus microarray datasets (GSE78520, GSE94508 and GSE97332) using the RobustRankAggreg method. Following the RT-qPCR corroboration, three circRNAs (hsa_circRNA_102166, hsa_circRNA_100291 and hsa_circRNA_104515) were selected for further analysis. miRNA response elements of the three circRNAs were predicted. Five circRNA-miRNA interactions including two circRNAs (hsa_circRNA_104515 and hsa_circRNA_100291) and five miRNAs (hsa-miR-1303, hsa-miR-142-5p, hsa-miR-877-5p, hsa-miR-583 and hsa-miR-1276) were identified. Then, 1424 target genes of the above five miRNAs and 3278 differently expressed genes (DEGs) on HCC were collected. By intersecting the miRNA target genes and the DEGs, we acquired 172 overlapped genes. A protein-protein interaction network based on the 172 genes was established, with seven hubgenes (JUN, MYCN, AR, ESR1, FOXO1, IGF1 and CD34) determined from the network. The Gene Oncology, Kyoto Encyclopedia of Genes and Genomes and Reactome enrichment analyses revealed that the seven hubgenes were linked with some cancer-related biological functions and pathways. Additionally, three bioactive chemicals (decitabine, BW-B70C and gefitinib) based on the seven hubgenes were identified as therapeutic options for HCC by the CMap analysis.
Our study provides a novel insight into the pathogenesis and therapy of HCC from the circRNA-miRNA-mRNA network view.
Nonviral episomal vectors present attractive alternative vehicles for gene therapy applications. Previously, we have established a new type of nonviral episomal vector‐mediated by the characteristic ...motifs of matrix attachment regions (MARs), which is driven by the cytomegalovirus (CMV) promoter. However, the CMV promoter is intrinsically susceptible to silencing, resulting in declined productivity during long‐term culture. In this study, Chinese hamster ovary (CHO) cells and DNA methyltransferase‐deficient (Dnmt3a‐deficient) CHO cells were transfected with plasmid‐mediated by MAR, or CHO cells were treated with the DNA methylation inhibitor 5‐Aza‐2′‐deoxycytidine. Flow cytometry, plasmid rescue experiments, fluorescence in‐situ hybridization (FISH), and bisulfite sequencing were performed to observe transgene expression, its state of existence, and the CpG methylation level of the CMV promoter. The results indicated that all DNA methylation inhibitor and methyltransferase deficient cells could increase transgene expression levels and stability in the presence or absence of selection pressure after a 60‐generation culture. Plasmid rescue assay and FISH analysis showed that the vector still existed episomally after long‐time culture. Moreover, a relatively lower CMV promoter methylation level was observed in Dnmt3a‐deficient cell lines and CHO cells treated with 5‐Aza‐2′‐deoxycytidine. In addition, Dnmt3a‐deficient cells were superior to the DNA methylation inhibitor treatment regarding the transgene expression and long‐term stability. Our study provides the first evidence that lower DNA methyltransferase can enhance expression level and stability of transgenes mediated by episomal vectors in transfected CHO cells.
DNA methyltransferase‐deficient (Dnmt3a‐deficient) Chinese hamster ovary cells and DNA methylation inhibitor 5‐Aza‐2`‐deoxycytidine could increase transgene expression levels and stability of episomal vector. Moreover, Dnmt3a‐deficient cells were superior to the DNA methylation inhibitor in regarding the transgene expression and long‐term stability.
Background
Computed tomography (CT) or MR images may cause the severity of early acute pancreatitis (AP) to be underestimated. As an innovative image analysis method, radiomics may have potential ...clinical value in early prediction of AP severity.
Purpose
To develop a contrast‐enhanced (CE) MRI‐based radiomics model for the early prediction of AP severity.
Study Type
Retrospective.
Subjects
A total of 259 early AP patients were divided into two cohorts, a training cohort (99 nonsevere, 81 severe), and a validation cohort (43 nonsevere, 36 severe).
Field Strength/Sequence
3.0T, T1‐weighted CE‐MRI.
Assessment
Radiomics features were extracted from the portal venous‐phase images. The "Boruta" algorithm was used for feature selection and a support vector machine model was established with optimal features. The MR severity index (MRSI), the Acute Physiology and Chronic Health Evaluation (APACHE) II, and the bedside index for severity in acute pancreatitis (BISAP) were calculated to predict the severity of AP.
Statistical Tests
Independent t‐test, Mann–Whitney U‐test, chi‐square test, Fisher's exact tests, Boruta algorithm, receiver operating characteristic analysis, DeLong test.
Results
Eleven potential features were chosen to develop the radiomics model. In the training cohort, the area under the curve (AUC) of the radiomics model, APACHE II, BISAP, and MRSI were 0.917, 0.750, 0.744, and 0.749, and the P value of AUC comparisons between the radiomics model and scoring systems were all less than 0.001. In the validation cohort, the AUC of the radiomics model, APACHE II, BISAP, and MRSI were 0.848, 0.725, 0.708, and 0.719, respectively, and the P value of AUC comparisons were 0.96 (radiomics vs. APACHE II), 0.40 (radiomics vs. BISAP), and 0.46 (radiomics vs. MRSI).
Data Conclusion
The radiomics model had good performance in the early prediction of AP severity.
Level of Evidence: 3
Technical Efficacy Stage: 2
J. Magn. Reson. Imaging 2020;51:397–406.
Background/Aims: The rejuvenation properties of nanofat grafting have been described in recent years. However, it is not clear whether the clinical efficacy of the procedure is attributable to stem ...cells or linked to other components of adipose tissue. In this study we isolated nanofat-derived stem cells (NFSCs) to observe their biological characteristics and evaluate the efficacy of precise intradermal injection of nanofat combined with platelet-rich fibrin (PRF) in patients undergoing facial rejuvenation treatment. Methods: Third-passage NFSCs were isolated and cultured using a mechanical emulsification method and their surface CD markers were analyzed by flow cytometry. The adipogenic and osteogenic nature and chondrogenic differentiation capacity of NFSCs were determined using Oil Red O staining, alizarin red staining, and Alcian blue staining, respectively. Paracrine function of NFSCs was evaluated by enzyme-linked immunosorbent assay (ELISA) at 1, 3, 7, 14, and 28 days after establishing the culture. Then, the effects of PRF on NFSC proliferation were assessed in vitro. Finally, we compared the outcome in 103 patients with facial skin aging who underwent both nanofat and intradermal PRF injection (treatment group) and 128 patients who underwent hyaluronic acid (HA) injection treatment (control group). Outcomes in the two groups were compared by assessing pictures taken at the same angle before and after treatment, postoperative recovery, incidence of local absorption and cysts, and skin quality before treatment, and at 1, 12, 24 months after treatment using the VISIA Skin Image Analyzer and a SOFT5.5 skin test instrument. Results: NFSCs expressed CD29, CD44, CD49d, CD73, CD90, and CD105, but did not express CD34, CD45, and CD106. NFSCs also differentiated into adipocytes, osteoblasts, and chondrocytes under appropriate induction conditions. NFSCs released large amounts of growth factors such as VEGF, bFGF, EGF, and others, and growth factor levels increased in a time-dependent manner. At the same time, PRF enhanced proliferation of NFSCs in vitro in a dose-dependent manner, and the growth curves under different concentrations of PRF all showed plateaus 6d after seeding. Facial skin texture was improved to a greater extent after combined injection of nanofat and PRF than after control injection of HA. The nanofat-PRF group had a higher satisfaction rate. Neither treatment caused any complications such as infection, anaphylaxis, or paresthesia during long-term follow-up. Conclusion: NFSCs demonstrate excellent multipotential differentiation and paracrine function, and PRF promotes proliferation of NFSCs during the early stage after seeding. Both nanofat-PRF and HA injection improve facial skin status without serious complications, but the former was associated with greater patient satisfaction, implying that nanofat-PRF injection is a safe, highly effective, and long-lasting method for skin rejuvenation.
PDF
