Sepsis is a systemic inflammatory response syndrome caused by infection, resulting in organ dysfunction. Sepsis‐induced acute kidney injury (AKI) is one of the most common potential complications. ...Increasing reports have shown that M1 and M2 macrophages both take part in the progress of AKI by influencing the level of inflammatory factors and the cell death, including pyroptosis. However, whether M1 and M2 macrophages regulate AKI by secreting exosome remains unknown. In the present study, we isolated the exosomes from M1 and M2 macrophages and used Western blot and enzyme‐linked immunosorbent assay (ELISA) to investigate the effect of M1 and M2 exosomes on cell pyroptosis. miRNA sequencing was used to identify the different miRNA in M1 and M2 exosomes. Luciferase reporter assay was used to verify the target gene of miRNA. We confirmed that exosomes excreted by macrophages regulated cell pyroptosis in vitro by using Western blot and ELISA. miRNA sequencing revealed the differentially expressed level of miRNAs in M1 and M2 exosomes, among which miR‐93‐5p was involved in the regulation of pyroptosis. By using bioinformatics predictions and luciferase reporter assay, we found that thioredoxin–interacting protein (TXNIP) was a direct target of miR‐93‐5p. Further in vitro and in vivo experiments indicated that exosomal miR‐93‐5p regulated the TXNIP directly to influence the pyroptosis in renal epithelial cells, which explained the functional difference between different phenotypes of macrophages. This study might provide new targets for the treatment of sepsis‐induced AKI.
The TET2 DNA dioxygenase regulates gene expression by catalyzing demethylation of 5-methylcytosine, thus epigenetically modulating the genome. TET2 does not contain a sequence-specific DNA-binding ...domain, and how it is recruited to specific genomic sites is not fully understood. Here we carried out a mammalian two-hybrid screen and identified multiple transcriptional regulators potentially interacting with TET2. The SMAD nuclear interacting protein 1 (SNIP1) physically interacts with TET2 and bridges TET2 to bind several transcription factors, including c-MYC. SNIP1 recruits TET2 to the promoters of c-MYC target genes, including those involved in DNA damage response and cell viability. TET2 protects cells from DNA damage-induced apoptosis dependending on SNIP1. Our observations uncover a mechanism for targeting TET2 to specific promoters through a ternary interaction with a co-activator and many sequence-specific DNA-binding factors. This study also reveals a TET2-SNIP1-c-MYC pathway in mediating DNA damage response, thereby connecting epigenetic control to maintenance of genome stability.
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•SNIP1 bridges TET2 to interact with multiple transcription factors, including c-MYC•TET2 protects cells from DNA damage-induced apoptosis in a SNIP1-dependent manner•The TET2-SNIP1-c-MYC axis supports the DNA sequence-specific recruitment of TET2
Chen et al. show SNIP1 recruits TET2 to the promoters of c-MYC target genes, including those involved in DNA damage response and cell viability. This study uncovers a mechanism for targeting TET2 to specific promoters through a ternary interaction with a co-activator and sequence-specific DNA-binding factors and also reveals a TET2-SNIP1-c-MYC pathway in mediating DNA damage response, thereby connecting epigenetic control to maintenance of genome stability.
Bronchopulmonary dysplasia (BPD) is a severe complication of preterm infants characterized by increased alveolarization and inflammation. Premature exposure to hyperoxia is believed to be a key ...contributor to the pathogenesis of BPD. No effective preventive or therapeutic agents have been created. Stimulator of interferon gene (STING) is associated with inflammation and apoptosis in various lung diseases. Long non‐coding RNA MALAT1 has been reported to be involved in BPD. However, how MALAT1 regulates STING expression remains unknown. In this study, we assessed that STING and MALAT1 were up‐regulated in the lung tissue from BPD neonates, hyperoxia‐based rat models and lung epithelial cell lines. Then, using the flow cytometry and cell proliferation assay, we found that down‐regulating of STING or MALAT1 inhibited the apoptosis and promoted the proliferation of hyperoxia‐treated cells. Subsequently, qRT‐PCR, Western blotting and dual‐luciferase reporter assays showed that suppressing MALAT1 decreased the expression and promoter activity of STING. Moreover, transcription factor CREB showed its regulatory role in the transcription of STING via a chromatin immunoprecipitation. In conclusion, MALAT1 interacts with CREB to regulate STING transcription in BPD neonates. STING, CREB and MALAT1 may be promising therapeutic targets in the prevention and treatment of BPD.
Background and Purpose
Aseptic prosthesis loosening, caused by wear particles, is one of the most common causes of arthroplasty failure. Extensive and over‐activated osteoclast formation and ...physiological functioning are regarded as the mechanism of prosthesis loosening. Therapeutic modalities based on inhibiting osteoclast formation and bone resorption have been confirmed to be an effective way of preventing aseptic prosthesis loosening. In this study, we have investigated the effects of sophocarpine (SPC, derived from Sophora flavescens) on preventing implant loosening and further explored the underlying mechanisms.
Experimental Approach
The effects of SPC in inhibiting osteoclastogenesis and bone resorption were evaluated in osteoclast formation, induced in vitro by the receptor activator of NF‐κB ligand (RANKL). A rat femoral particle‐induced peri‐implant osteolysis model was established. Subsequently, micro‐CT, histology, mechanical testing and bone turnover were used to assess the effects of SPC in preventing implant loosening.
Key Results
In vitro, we found that SPC suppressed osteoclast formation, bone resorption, F‐actin ring formation and osteoclast‐associated gene expression by inhibiting NF‐κB signalling, specifically by targeting IκB kinases. Our in vivo study showed that SPC prevented particle‐induced prosthesis loosening by inhibiting osteoclast formation, resulting in reduced periprosthetic bone loss, diminished pseudomembrane formation, improved bone‐implant contact, reduced bone resorption‐related turnover and enhanced stability of implants. Inhibition of NF‐κB signalling by SPC was confirmed in vivo.
Conclusion and Implications
SPC can prevent implant loosening through inhibiting osteoclast formation and bone resorption. Thus, SPC might be a novel therapeutic agent to prevent prosthesis loosening and for osteolytic diseases.
Thyroid cancer is a common endocrine malignancy with a rapidly increasing incidence worldwide. Although its mortality is steady or declining because of earlier diagnoses, its survival rate varies ...because of different tumour types. Thus, the aim of this study was to identify key biomarkers and novel therapeutic targets in thyroid cancer. The expression profiles of GSE3467, GSE5364, GSE29265 and GSE53157 were downloaded from the Gene Expression Omnibus database, which included a total of 97 thyroid cancer and 48 normal samples. After screening significant differentially expressed genes (DEGs) in each data set, we used the robust rank aggregation method to identify 358 robust DEGs, including 135 upregulated and 224 downregulated genes, in four datasets. Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes pathway enrichment analyses of DEGs were performed by DAVID and the KOBAS online database, respectively. The results showed that these DEGs were significantly enriched in various cancer‐related functions and pathways. Then, the STRING database was used to construct the protein–protein interaction network, and modules analysis was performed. Finally, we filtered out five hub genes, including LPAR5, NMU, FN1, NPY1R, and CXCL12, from the whole network. Expression validation and survival analysis of these hub genes based on the The Cancer Genome Atlas database suggested the robustness of the above results. In conclusion, these results provided novel and reliable biomarkers for thyroid cancer, which will be useful for further clinical applications in thyroid cancer diagnosis, prognosis and targeted therapy.
Identification of key genes and pathways of thyroid cancer by integrated bioinformatics analysis.
•Ultrahigh resolution mass spectrometry was applied to characterize the HTLWWs.•Biopolymers (HMW PS and PN) were the most refractory sub-fractions during AD process.•Recalcitrant compounds, like ...nitrogenous compounds were identified.
Anaerobic digestion (AD) has shown potential to convert hydrothermal liquefaction wastewater (HTLWW) into biogas in previous studies. However, the identification of refractory components and further insights into the molecular transformations of organics in HTLWW are essential for developing more efficient AD processes. In this study, two HTLWWs were obtained from the temperature-derived hydrothermal liquefaction of sewage sludge at 170 ℃ and 320 ℃. Their molecular compositions, as well as their modifications in the subsequent AD process, were characterized using a suite of advanced molecular tools. The dissolved organic matter (DOM) in the high temperature-derived HTLWW was lower in molecular weight, less saturated, less oxidized, and enhanced in nitrogenous substances. During the AD process, most of the volatile compounds and low molecular weight (LMW) neutrals were removed, while biopolymers were the most refractory. Carboxylic-rich alicyclic molecules (CRAM), particularly those containing 3 to 5 N for low temperature-derived DOM and 1 to 3 N for high temperature-derived DOM, were resistant to anaerobic biodegradation. Meanwhile, compounds with fewer nitrogens and more carboxyl groups were preferentially produced. This molecular characterization of HTLWW-derived DOM and examination of its transformation during AD will contribute to the development of efficient methods for HTLWW treatment in the future.
It is traditionally believed that cerebral amyloid-beta (Aβ) deposits are derived from the brain itself in Alzheimer's disease (AD). Peripheral cells such as blood cells also produce Aβ. The role of ...peripherally produced Aβ in the pathogenesis of AD remains unknown. In this study, we established a bone marrow transplantation model to investigate the contribution of blood cell-produced Aβ to AD pathogenesis. We found that bone marrow cells (BMCs) transplanted from APPswe/PS1dE9 transgenic mice into wild-type (Wt) mice at 3 months of age continuously expressed human Aβ in the blood, and caused AD phenotypes including Aβ plaques, cerebral amyloid angiopathy (CAA), tau hyperphosphorylation, neuronal degeneration, neuroinflammation, and behavioral deficits in the Wt recipient mice at 12 months after transplantation. Bone marrow reconstitution in APPswe/PS1dE9 mice with Wt-BMCs at 3 months of age reduced blood Aβ levels, and alleviated brain Aβ burden, neuronal degeneration, neuroinflammation, and behavioral deficits in the AD model mice at 12 months after transplantation. Our study demonstrated that blood cell-produced Aβ plays a significant role in AD pathogenesis, and the elimination of peripheral production of Aβ can decrease brain Aβ deposition and represents a novel therapeutic approach for AD.
Herein, a small series of 3-pyrrolin-2-ones was efficiently synthesized through a three-step Ugi cascade sequence. This method features readily available substrates, simple aqueous workup procedures ...and good yields, dramatically improving generality of reaction. Importantly, the newly product N-benzyl-2-(3-(4-chlorophenyl)-4-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)-2-phen-ylacetamide exhibited potent anti-proliferation in prostate cancer cell line through G1/S cell cycle arrest and targeted in PI3K/AKT/TSC2 signal pathway.
Steroid-associated osteonecrosis (SAON) might induce bone collapse and subsequently lead to joint arthroplasty. Core decompression (CD) is regarded as an effective therapy for early-stage SAON, but ...the prognosis is unsatisfactory due to incomplete bone repair. Parathyroid hormone1-34 (PTH1-34) has demonstrated positive efficacy in promoting bone formation. We therefore evaluated the effects of PTH on improving the effects of CD in Early-Stage SAON. Distal femoral CD was performed two weeks after osteonecrosis induction or vehicle injection, with ten of the ON-induced rabbits being subjected to six-week PTH1-34 treatment and the others, including ON-induced and non-induced rabbits, being treated with vehicle. MRI confirmed that intermittent PTH administration improved SAON after CD therapy. Micro-CT showed increased bone formation within the tunnel. Bone repair was enhanced with decreased empty osteocyte lacunae and necrosis foci area, resulting in enhanced peak load and stiffness of the tunnel. Additionally, PTH enlarged the mean diameter of vessels in the marrow and increased the number of vessels within the tunnels, as well as elevated the expression of BMP-2, RUNX2, IGF-1, bFGF and VEGF, together with serum OCN and VEGF levels. Therefore, PTH1-34 enhances the efficacy of CD on osteogenesis and neovascularization, thus promoting bone and blood vessels repair in the SAON model.
To identify whether Dickkopf-1 (DKK1) could be a potential biomarker for early detection and prognosis in patients with pancreatic cancer (PC).
Serum was collected from 140 patients with pancreatic ...adenocarcinoma and 92 control patients without pancreatic adenocarcinoma. Serological levels of DKK1 were examined by enzyme-linked immunosorbent assay (ELISA). The sensitivity and specificity was compared with carbohydrate antigen 19-9 (CA19-9). A 2-year follow-up was monitored to evaluate the correlation between DKK1 serum levels and overall survival. The expression of DKK1 in PC tumor tissues was also evaluated using immunohistochemistry staining.
Serum levels of DKK1 and CA19-9 were elevated in PC patients in the early-stage cases. These levels increased with the advancement of clinical stage. There was significant difference in DKK1 serum levels between early and advanced PC stages. Receiver operating characteristic curve (ROCC) analysis showed that DKK1 was significantly better than CA19-9 in differentiating patients with PC from the controls (area under the curve (AUC) 0.919 versus 0.853, respectively), especially in distinguishing early-stage cancer from chronic pancreatitis (CP). The expression of DKK1 in PC tissues correlated with its expression in serum samples. The overall survival rate was 24.4% in the group with higher DKK1 levels and was found to be significantly different from the group with lower DKK1 levels (33.3%).
DKK1 may be a novel diagnostic/prognostic biomarker for PC.
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