HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis.

Esophageal carcinoma is amongst the prevalent malignancies worldwide, characterized by unclear molecular classifications and varying clinical outcomes. The PI3K/AKT/mTOR signaling, one of the frequently perturbed dysregulated pathways in human malignancies, has instigated the development of various inhibitory agents targeting this pathway, but many ESCC patients exhibit intrinsic or adaptive resistance to these inhibitors. Here, we aim to explore the reasons for the insensitivity of ESCC patients to mTOR inhibitors. We assessed the sensitivity to rapamycin in various ESCC cell lines by determining their respective IC50 values and found that cells with a low level of HMGA1 were more tolerant to rapamycin. Subsequent experiments have supported this finding. Through a transcriptome sequencing, we identified a crucial downstream effector of HMGA1, FKBP12, and found that FKBP12 was necessary for HMGA1-induced cell sensitivity to rapamycin. HMGA1 interacted with ETS1, and facilitated the transcription of FKBP12. Finally, we validated this regulatory axis in in vivo experiments, where HMGA1 deficiency in transplanted tumors rendered them resistance to rapamycin. Therefore, we speculate that mTOR inhibitor therapy for individuals exhibiting a reduced level of HMGA1 or FKBP12 may not work. Conversely, individuals exhibiting an elevated level of HMGA1 or FKBP12 are more suitable candidates for mTOR inhibitor treatment.

HMGA1 drives chemoresistance in esophageal squamous cell carcinoma by suppressing ferroptosis.

Chemotherapy is a primary treatment for esophageal squamous cell carcinoma (ESCC). Resistance to chemotherapeutic drugs is an important hurdle to effective treatment. Understanding the mechanisms underlying chemotherapy resistance in ESCC is an unmet medical need to improve the survival of ESCC. Herein, we demonstrate that ferroptosis triggered by inhibiting high mobility group AT-hook 1 (HMGA1) may provide a novel opportunity to gain an effective therapeutic strategy against chemoresistance in ESCC. HMGA1 is upregulated in ESCC and works as a key driver for cisplatin (DDP) resistance in ESCC by repressing ferroptosis. Inhibition of HMGA1 enhances the sensitivity of ESCC to ferroptosis. With a transcriptome analysis and following-up assays, we demonstrated that HMGA1 upregulates the expression of solute carrier family 7 member 11 (SLC7A11), a key transporter maintaining intracellular glutathione homeostasis and inhibiting the accumulation of malondialdehyde (MDA), thereby suppressing cell ferroptosis. HMGA1 acts as a chromatin remodeling factor promoting the binding of activating transcription factor 4 (ATF4) to the promoter of SLC7A11, and hence enhancing the transcription of SLC7A11 and maintaining the redox balance. We characterized that the enhanced chemosensitivity of ESCC is primarily attributed to the increased susceptibility of ferroptosis resulting from the depletion of HMGA1. Moreover, we utilized syngeneic allograft tumor models and genetically engineered mice of HMGA1 to induce ESCC and validated that depletion of HMGA1 promotes ferroptosis and restores the sensitivity of ESCC to DDP, and hence enhances the therapeutic efficacy. Our finding uncovers a critical role of HMGA1 in the repression of ferroptosis and thus in the establishment of DDP resistance in ESCC, highlighting HMGA1-based rewiring strategies as potential approaches to overcome ESCC chemotherapy resistance. Schematic depicting that HMGA1 maintains intracellular redox homeostasis against ferroptosis by assisting ATF4 to activate SLC7A11 transcription, resulting in ESCC resistance to chemotherapy.

Bioinformatics-based Study on the Effects of Umbilical Cord Mesenchymal Stem Cells on the Aging Retina.

BACKGROUND: Retinal aging is one of the common public health problems caused by population aging and has become an important cause of acquired vision loss in adults. The aim of this study was to determine the role of human umbilical cord mesenchymal stem cells (hUCMSCs) in delaying retinal ganglion cell (RGC) aging and part of the network of molecular mechanisms involved. METHODS: A retinal ganglion cell senescence model was established in vitro and treated with UCMSC. Successful establishment of the senescence system was demonstrated using ß- galactosidase staining. The ameliorative effect of MSC on senescence was demonstrated using CCK8 cell viability and Annexin V-PI apoptosis staining. The relevant targets of RGC, MSC, and senescence were mainly obtained by searching the GeneCards database. The protein interaction network among the relevant targets was constructed using the String database and Cytoscape, and 10 key target genes were calculated based on the MCC algorithm, based on which Gene ontologies (GO) enrichment and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were performed. Changes in relevant target genes were detected using real-time fluorescence quantitative PCR and the mechanism of action of UCMSC was determined by RNA interference. RESULTS: ß-galactosidase staining showed that UCMSC significantly reduced the positive results of RGC. The retinal aging process was alleviated. The bioinformatics screen yielded 201 shared genes. 10 key genes were selected by the MCC algorithm, including vascular endothelial growth factor A (VEGFA), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), albumin (ALB), interleukin- 6 (IL6), tumor necrosis factor (TNF), tumor protein P53 (TP53), insulin (INS), matrix metalloproteinase 9 (MMP9), epidermal growth factor (EGF), interleukin-1ß (IL1B), and enrichment to related transferase activity and kinase activity regulated biological processes involved in oxidative stress and inflammation related pathways. In addition, PCR results showed that all the above molecules were altered in expression after UCMSC involvement. CONCLUSION: This experiment demonstrated the role of UCMSC in delaying retinal ganglion cell senescence and further elucidated that UCMSC may be associated with the activation of VEGFA, TP53, ALB, GAPDH, IL6, IL1B, MMP9 genes and the inhibition of INS, EGF, and TNF in delaying retinal senescence.

Discovery of astragaloside IV against high glucose-induced apoptosis in retinal ganglion cells: Bioinformatics and in vitro studies.

OBJECTIVE: To examine the therapeutic mechanism of astragaloside IV (AS-IV) in the management of retinal ganglion cell (RGC) injury induced by high glucose (HG), a comprehensive approach involving the integration of network pharmacology and conducting in vitro and in vivo experiments was utilized. METHODS: A rat model of diabetic retinopathy (DR) injury was created by administering streptozotocin through intraperitoneal injection. Additionally, a model of RGC injury induced by HG was established using a glucose concentration of 0.3 mmol/mL. Optical coherence tomography (OCT) images were captured 8 weeks after the injection of AS-IV. AS-IV and FBS were added to the culture medium and incubated for 48 h. The viability of cells was assessed using a CCK-8 assay, while the content of reactive oxygen species (ROS) was measured using DCFH-DA. Apoptosis was evaluated using Annexin V-PI. To identify the targets of AS-IV, hyperglycemia, and RGC, publicly available databases were utilized. The Metascape platform was employed for conducting GO and KEGG enrichment analyses. The STRING database in conjunction with Cytoscape 3.7.2 was used to determine common targets of protein-protein interactions (PPIs) and to identify the top 10 core target proteins in the RGC based on the MCC algorithm. qRT-PCR was used to measure the mRNA expression levels of the top10 core target proteins in RGCs. RESULTS: OCT detection indicated that the thickness of the outer nucleus, and inner and outer accessory layers of the retina increased in the AS-IV treated retina compared to that in the DM group but decreased compared to that in the CON group. Coculturing RGC cells with AS-IV after HG induction resulted in a significant increase in cell viability and a decrease in ROS and apoptosis, suggesting that AS-IV can reduce damage to RGC cells caused by high glucose levels by inhibiting oxidative stress. There were 14 potential targets of AS-IV in the treatment of RGC damage induced by high glucose levels. The top 10 core target proteins identified by the MCC algorithm were HIF1α, AKT1, CTNNB1, SMAD2, IL6, SMAD3, IL1ß, PPARG, TGFß1, and NOTCH3. qRT-PCR analysis showed that AS-IV could upregulate the mRNA expression levels of SMAD3, TGF-ß1, and NOTCH3, and downregulate the mRNA expression levels of HIF1α, AKT1, CTNNB1, SMAD2, SMAD3, and IL-1ß in high glucose-induced RGC cells. CONCLUSION: The findings of this study validate the efficacy of astragaloside IV in the treatment of DR and shed light on the molecular network involved. Specifically, HIF1α, AKT1, CTNNB1, SMAD2, SMAD3, and IL-1ß were identified as the crucial candidate molecules responsible for the protective effects of astragaloside IV on RGCs.

Akkermansia muciniphila protects the intestine from irradiation-induced injury by secretion of propionic acid.

Intestinal dysbiosis frequently occurs in abdominal radiotherapy and contributes to irradiation (IR)-induced intestinal damage and inflammation. Akkermansia muciniphila (A. muciniphila) is a recently characterized probiotic, which is critical for maintaining the dynamics of the intestinal mucus layer and preserving intestinal microbiota homeostasis. However, the role of A. muciniphila in the alleviation of radiation enteritis remains unknown. In this study, we reported that the abundance of A. muciniphila was markedly reduced in the intestines of mice exposed to abdominal IR and in the feces of patients who received abdominal radiotherapy. Abundance of A. muciniphila in feces of radiotherapy patients was negatively correlated with the duration of diarrhea in patients. Administration of A. muciniphila substantially mitigated IR-induced intestinal damage and prevented mouse death. Analyzing the metabolic products of A. muciniphila revealed that propionic acid, a short-chain fatty acid secreted by the microbe, mediated the radioprotective effect. We further demonstrated that propionic acid bound to G-protein coupled receptor 43 (GRP43) on the surface of intestinal epithelia and increased histone acetylation and hence enhanced the expression of tight junction proteins occludin and ZO-1 and elevated the level of mucins, leading to enhanced integrity of intestinal epithelial barrier and reduced radiation-induced intestinal damage. Metformin, a first-line agent for the treatment of type II diabetes, promoted intestinal epithelial barrier integrity and reduced radiation intestinal damage through increasing the abundance of A. muciniphila. Together, our results demonstrated that A. muciniphila plays a critical role in the reduction of abdominal IR-induced intestinal damage. Application of probiotics or their regulators, such as metformin, could be an effective treatment for the protection of radiation exposure-damaged intestine.

Development and management of gastrointestinal symptoms in long-term COVID-19.

Background: Emerging evidence reveals that SARS-CoV-2 possesses the capability to disrupt the gastrointestinal (GI) homeostasis, resulting in the long-term symptoms such as loss of appetite, diarrhea, gastroesophageal reflux, and nausea. In the current review, we summarized recent reports regarding the long-term effects of COVID-19 (long COVID) on the gastrointestine. Objective: To provide a narrative review of abundant clinical evidence regarding the development and management of long-term GI symptoms in COVID-19 patients. Results: Long-term persistent digestive symptoms are exhibited in a majority of long-COVID patients. SARS-CoV-2 infection of intestinal epithelial cells, cytokine storm, gut dysbiosis, therapeutic drugs, psychological factors and exacerbation of primary underlying diseases lead to long-term GI symptoms in COVID-19 patients. Interventions like probiotics, prebiotics, fecal microbiota transplantation, and antibiotics are proved to be beneficial in preserving intestinal microecological homeostasis and alleviating GI symptoms. Conclusion: Timely diagnosis and treatment of GI symptoms in long-COVID patients hold great significance as they may contribute to the mitigation of severe conditions and ultimately lead to the improvement of outcomes of the patients.

Tracking tumor alteration in glioma through serum fibroblast activation protein combined with image.

PURPOSE: Detecting tumor progression of glioma continues to pose a formidable challenge. The role of fibroblast activation protein (FAP) in gliomas has been demonstrated to facilitate tumor progression. Glioma-circulating biomarkers have not yet been used in clinical practice. This study seeks to evaluate the feasibility of glioma detection through the utilization of a serum FAP marker. METHODS: We adopted enzyme-linked immunosorbent assay (ELISA) technique to quantify the relative FAP level of serum autoantibodies in a cohort of 87 gliomas. The correlation between preoperative serum autoantibody relative FAP levels and postoperative pathology, including molecular pathology was investigated. A series of FAP tests were conducted on 33 cases of malignant gliomas in order to ascertain their efficacy in monitoring the progression of the disease in relation to imaging observations. To validate the presence of FAP expression in tumors, immunohistochemistry was conducted on four gliomas employing a FAP-specific antibody. Additionally, the investigation encompassed the correlation between postoperative tumor burden, as assessed through volumetric analysis, and the relative FAP level of serum autoantibodies. RESULTS: A considerable proportion of gliomas exhibited a significantly increased level of serum autoantibody relative FAP level. This elevation was closely associated with both histopathology and molecular pathology, and demonstrated longitudinal fluctuations and variations corresponding to the progression of the disease The correlation between the rise in serum autoantibody relative FAP level and tumor progression and/or exacerbation of symptoms was observed. CONCLUSIONS: The measurement of serum autoantibody relative FAP level can be used to detect the disease as a valuable biomarker. The combined utilization of its detection alongside MR imaging has the potential to facilitate a more accurate and prompt diagnosis.

4D-DIA quantitative proteomics revealed the core mechanism of diabetic retinopathy after berberine treatment.

OBJECTIVE: To reveal the core mechanism of berberine (BBR) in the treatment of diabetic retinopathy (DR), by using Four-dimensional independent data acquisition (4D-DIA) proteomics combined bioinformatics analysis with experimental validation. METHODS: DR injury model was established by injecting streptozotocin intraperitoneally. At 8 weeks after BBR administration, optical coherence tomography (OTC) photos and Hematoxylin-eosin staining from retina in each group were performed, then the retina was collected for 4D-DIA quantitative proteomics detection. Moreover, difference protein analysis, Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, protein-protein interaction (PPI) network, as well as molecular docking was performed, respectively. In the part of experiment, Western blot (WB) and immunofluorescent staining was used to confirm the change and distribution of carbonic anhydrase 1 (CA1), one of the most important molecules from quantitative PCR detection. Lastly, RNA knockdown was used to determine the crucial role of CA1 in retinal pigment epithelial cells (RPEs) administrated with berberine. RESULTS: OCT detection showed that the outer nucleus, inner layer and outer accessory layer of RPEs were thinned in DR group, compared with in sham one, while they were thickened after berberine administration, when compared with in DR group. 10 proteins were screened out by using proteomic analysis and Venny cross plot, in which, denn domain containing 1A (DENND1A) and UTP6 small subunit processome component (UTP6) was down-regulated, while ATPase copper transporting alpha (ATP7A), periplakin (PPL), osteoglycin (OGN), nse1 Homolog (NSMCE1), membrane metalloendopeptidase (MME), lim domain only 4 (LMO4), CA1 and fibronectin 1 (FN1) was up-regulated in DR group, and the BBR treatment can effectively reverse their expressions. PPI results showed that 10 proteins shared interactions with each other, but only ATP7A, FN1 and OGN exhibited directly associated with each other. Moreover, we enlarged the linked relation up to 15 genes in network, based on 10 proteins found from proteomics detection, so as to perform deep GO and KEGG analysis. As a result, the most important biological process is involving rRNA processing; the most important cell component is small subunit processor; the most important molecular function is Phospholipid binding; the KEGG pathway was Ribosome biogenesis in eukaryotes. Moreover, molecular docking showed that LMO4, ATP7A, PPL, NSMCE1, MME, CA1 could form a stable molecular binding pattern with BBR. Of these, the mRNA expression of CA1, PPL and ATP7A and the protein level of CA1 was increased in DR, and decreased in BBR group. Lastly, CA1 RNA knockdown confirmed the crucial role of CA1 in RPE administered with BBR. CONCLUSION: The present findings confirmed the role of BBR in DR treatment and explained associated molecular network mechanism, in which, CA1 could be considered as a crucial candidate in the protection of RPEs with berberine treatment.

Recent findings in Akkermansia muciniphila-regulated metabolism and its role in intestinal diseases.

The mammalian gastrointestinal tract is colonized with a majority of gut microbes, affecting host metabolism and homeostasis. Gut microbiota plays a vital role in nutrient exchange, signaling transduction between intestinal epithelial cells, and resistance to pathogen invasion. Gut microbiota is divided into mucus layer bacteria and intestinal lumen bacteria based on the colonization distribution. Akkermansia muciniphila (A. muciniphila) prefers to colonize in the intestinal mucus layer, and specifically degrades mucins to produce short-chain fatty acids, providing energy for the host and promoting colonization of the bacterium itself. Degradation of mucins prompts the host to compensate for the production of more mucins, thereby maintaining the dynamics of these proteins. In the intestinal micro-ecosystem, A. muciniphila is non-pathogenic, and its colonization with suitable abundance contributes to the development of immune system, thus promoting intestinal health. The mechanisms by which A. muciniphila bears a protective role in the host intestine are currently unclear. In this review, we summarize the microenvironment for the colonization of A. muciniphila, physiological characteristics and pathophysiological impact of A. muciniphila on intestinal diseases, such as irritable bowel syndrome, inflammatory bowel diseases, and intestinal tumors. We also provided updates for current studies on signals that A. muciniphila enhances intestinal barrier integrity and regulates immune response. Together, we conclude that A. muciniphila is a promising probiotic, which could be a microbial target for the treatment of multiple intestinal diseases.

Effect mechanism of litter extract from Alternanthera philoxeroides on the selective absorption of heavy metal ions by amphoteric purple soil.

Plant litter causes a serious waste of resources. Thus, plant litter extract (LE) should be used in the soil remediation of heavy metals. In this study, different proportions of LE from the Alternanthera philoxeroides were used to modify dodecyl dimethyl betaine (BS)-modified purple soil (P). The basic physicochemical properties of LE + BS-modified Ps (LE + BS-Ps) were determined, and the microscopic morphology of LE + BS-Ps was studied by using scanning electron microscopy (SEM), energy dispersion spectroscopy (EDS), Fourier transform infrared (FTIR) spectroscopy, and specific surface area detection. The isothermal adsorption characteristics of heavy metal ions (Pb2+, Cu2+, and Cr6+) on different LE + BS-Ps were investigated by the batch method, and the effect mechanisms of temperature, pH, ionic strength, and LE + BS-P's property were compared. Results showed that the cation exchange capacity and specific surface area of LE + BS-Ps increased, pH of LE + BS-Ps decreased, and TOC of LE + BS-Ps increased first and then decreased with increasing proportion of LE. FTIR, SEM, and EDS results proved that LE was modified on the surface of BS-P. Langmuir and Freundlich models could be used to describe the adsorption isotherms of heavy metal ions on different LE + BS-Ps, and the fitting correlation of the Langmuir model was higher than that of the Freundlich model. The maximum adsorption capacity (qm) of Pb2+, Cu2+, and Cr6+ were 107.60-295.66, 133.00-342.11, and 33.59-75.41 mmol/kg, respectively. The qm of Pb2+, Cu2+, and Cr6+ on LE + BS-Ps all increased first and then decreased with increasing proportion of LE, and the peak value was observed in 20%LE + BS-Ps. High pH improved Pb2+ and Cu2+ adsorption but inhibited Cr6+ adsorption. The adsorption amounts of Pb2+, Cu2+, and Cr6+ all increased first and then decreased with incresing ionic strength and were maintained at the maximum value of 0.1-0.2 mol/L. The Pb2+, Cu2+, and Cr6+ adsorption mechanisms on different LE + BS-Ps showed a positive temperature effect and presented spontaneous, exothermic and entropy-adding processes.

Lomerizine 2HCl inhibits cell proliferation and induces protective autophagy in colorectal cancer via the PI3K/Akt/mTOR signaling pathway.

Colorectal cancer (CRC) is one of the most common malignancies currently. Despite advances in drug development, the survival and response rates in CRC patients are still poor. In our previous study, a library comprised of 1056 bioactive compounds was used for screening of drugs that could suppress CRC. Lomerizine 2HCl, which is an approved prophylactic drug for migraines, was selected for our studies. The results of in vitro and in vivo assays suggested that lomerizine 2HCl suppresses cell growth and promotes apoptosis in CRC cells. Moreover, lomerizine 2HCl inhibits cell migration and invasion of CRC. RNA sequencing analysis and Western blotting confirmed that lomerizine 2HCl can inhibit cell growth, migration, and invasion through PI3K/AKT/mTOR signaling pathway and induces protective autophagy in CRC. Meanwhile, autophagy inhibition by 3-methyladenine (3-MA) increases lomerizine 2HCl-induced cell apoptosis. Taken together, these results imply that lomerizine 2HCl is a potential anticancer agent, and the combination of lomerizine 2HCl and autophagy inhibitors may serve as a novel strategy to increase the antitumor efficacy of agents in the treatment of CRC.

Direct Targeting of CREB1 with Imperatorin Inhibits TGFß2-ERK Signaling to Suppress Esophageal Cancer Metastasis.

Metastasis accounts for 90% of cancer death worldwide, and effective therapeutic strategies are lacking. The aim of this work is to identify the key drivers in tumor metastasis and screen therapeutics for treatment of esophageal squamous cell carcinoma (ESCC). Gene Ontology analysis of The Cancer Genome Atlas (TCGA) gene expression datasets of ESCC patients with or without lympy metastasis identifies that TGFß2 is highly enriched in the pathways essential for tumor metastasis and upregulates in the metastatic ESCC tumors. High TGFß2 expression in ESCC correlates with metastasis and patient survival, and functionally contributes to tumor metastasis via activating extracellular signal-regulated kinases (ERK) signaling. By screening of a library consisting of 429 bioactive compounds, imperatorin is verified as a novel TGFß2 inhibitor, with robustly suppressive effect on tumor metastasis in multiple mice models. Mechanistically, direct binding of imperatorin and CREB1 inhibits phosphorylation, nuclear translocation of CREB1, and its interaction with TGFß2 promoter, represses TGFß2 expression and fibroblasts-secreted CCL2, and then inactivates ERK signaling to block cancer invasion and abrogates the paracrine effects of fibroblasts on tumor angiogenesis and metastasis. Overall, the findings suggest the use of TGFß2 as a diagnostic and prognostic biomarker and therapeutic target in ESCC, and supports the potential of imperatorin as a novel therapeutic strategy for cancer metastasis.

Tumor-associated antigen-based personalized dendritic cell vaccine in solid tumor patients.

Tumor-associated antigens (TAAs) have been tested in various clinical trials in cancer treatment but the patterns of specific T cell response to personalized TAA immunization remains to be fully understood. We report antigen-specific T cell responses in patients immunized with dendritic cell vaccines pulsed with personalized TAA panels. Tumor samples from patients were first analyzed to identify overexpressed TAAs. Autologous DCs were then transfected with pre-manufactured mRNAs encoding the full-length TAAs, overexpressed in the patients' tumors. Patients with glioblastoma multiforme (GBM) or advanced lung cancer received DC vaccines transfected with personalized TAA panels, in combination with low-dose cyclophosphamide, poly I:C, imiquimod and anti-PD-1 antibody. Antigen-specific T cell responses were measured. Safety and efficacy were evaluated. A total of ten patients were treated with DC vaccines transfected with personalized TAA panels containing 3-13 different TAAs. Among the seven patients tested for anti-TAA T cell responses, most of the TAAs induced antigen-specific CD4+ and/or CD8+ T cell responses, regardless of their expression levels in the tumor tissues. No Grade III/IV adverse events were observed among these patients. Furthermore, the treated patients were associated with favorable overall survival when compared to patients who received standard treatment in the same institution. Personalized TAA immunization-induced-specific CD4+ and CD8+ T cell responses without obvious autoimmune adverse events and was associated with favorable overall survival. These results support further studies on DC immunization with personalized TAA panels for combined immunotherapeutic regimens in solid tumor patients.Trial registration ClinicalTrials.gov, NCT02709616 (March, 2016), NCT02808364 (June 2016), NCT02808416 (June, 2016).

Long non-coding RNA MEG3 promotes cerebral ischemia-reperfusion injury through increasing pyroptosis by targeting miR-485/AIM2 axis.

OBJECTIVE: Inflammasome contributes to ischemic brain injury by inducing pyroptosis and inflammation. The aim of this study is to unravel the mechanism of long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3)-mediated regulation of absent in melanoma 2 (AIM2) inflammasome during cerebral ischemia/reperfusion (I/R). METHODS: In vivo middle cerebral artery occlusion (MCAO) rat model and in vitro oxygen-glucose deprivation/reperfusion (OGD/R)-treated neurocytes model were generated. TTC, H&E staining and TUNEL were performed to assess the cerebral ischemic injury. LDH and MTT assays were used to detect cell viability and cytotoxicity. qRT-PCR was used to detect the expression levels of MEG3, miR-485 and AIM2. Immunohistochemistry (IHC) and immunofluorescence were conducted to detect the AIM2 expression. ELISA and Western blotting were performed to determine the secretion and protein levels of inflammasome signaling proteins. Dual luciferase reporter assay and Ago2-RIP were used to validate the direct interaction among MEG3, miR-485 and AIM2. RESULTS: In both MCAO rats and OGD/R-treated neurocytes, MEG3 and AIM2 were significantly up-regulated, whereas miR-485 was down-regulated. MCAO induces pyroptosis and release of IL-1ß and IL-18 in ischemia brain. MEG3 acted as a molecular sponge to suppress miR-485, and AIM2 was identified as a direct target of miR-485. Knockdown of MEG3 inhibited OGD/R-induced pyroptosis and inflammation, and lack of MEG3 inhibited caspase1 signaling and decreased the expression of AIM2, ASC, cleaved-caspase1 and GSDMD-N. While overexpression of MEG3 exerted opposite effects. CONCLUSION: MEG3/miR-485/AIM2 axis contributes to pyroptosis via activating caspase1 signaling during cerebral I/R, suggesting that this axis may be a potent therapeutic target in ischemic stroke.

A Multi-Element Expression Score Is A Prognostic Factor In Glioblastoma Multiforme.

PURPOSE: Glioblastoma multiforme (GBM) is a highly malignant tumor of the central nervous system. Although primary GBM patients receive extensive therapies, tumors may recur within months, and there is no objective and scientific method to predict prognosis. Adoptive immunotherapy holds great promise for GBM treatment. However, the expression profiles of the tumor-associated antigens (TAAs) and tumor immune microenvironment (TME) genes used in immunotherapy of GBM patients have not been fully described. The present study aimed to develop a predictive tool to evaluate patient survival based on full analysis of the expression levels of TAAs and TME genes. METHODS: Expression profiles of a panel of 87 TAAs and 8 TME genes significantly correlated with poor prognosis were evaluated in 44 GBM patients and 10 normal brain tissues using quantitative real-time polymerase chain reaction (qRT-PCR). A linear formula (the LASSO algorithm based in the R package) weighted by regression coefficients was used to develop a multi-element expression score to predict prognosis; this formula was cross-validated by the leave-one-out method in different GBM cohorts. RESULTS: After analysis of gene expression, clinical features, and overall survival (OS), a total of 8 TAAs (CHI3L1, EZH2, TRIOBP, PCNA, PIK3R1, PRKDC, SART3 and EPCAM), 1 TME gene (FOXP3) and 4 clinical features (neutrophil-to-lymphocyte (NLR), number of basophils (BAS), age and treatment with standard radiotherapy and chemotherapy) were included in the formula. There were significant differences between high and low scoring groups identified using the formula in different GBM cohorts (TCGA (n=732) and GEO databases (n=84)), implying poor and good prognosis, respectively. CONCLUSION: The multi-element expression score was significantly associated with OS of GBM patients. The improve understanding of TAAs and TMEs and well-defined formula could be implemented in immunotherapy for GBM to provide better care.

Transformation Characteristics of Hydrogen-Donor Solvent Tetralin in the Process of Direct Coal Liquefaction.

The aim of this study is to investigate the transformation of hydrogen-donor solvent tetralin in the direct liquefaction process of coal. Pure tetralin liquid as well as mixture of tetralin and Wucaiwan coal (WCW) were separately reacted under a liquefaction condition, and constituents of liquid product were analyzed by GC-MS. The results show that after the tetralin liquid reacts with high-pressure hydrogen, 90% of the reaction product is in liquid state, the gaseous products mainly include alkane gas and COx gas. When the reaction temperatures were set at 380 and 420°C, respectively, the corresponding transformation rates of tetralin can be 34.72 and 52.74%. At 380°C, the tetralin mainly plays a role of passing active hydrogen, while at 420°C, it mainly occurs dehydrogenation transformation to provide active hydrogen, as well as generate naphthalene, methyl indan, and substituted benzene, etc. Taking tetralin as the hydrogen-donor solvent, the WCW was performed liquefaction reaction, and the obtained results show that the transformation rates of tetralin are 69.76 and 83.86% at liquefaction temperatures of 380 and 420°C, respectively. Tetralin mainly occur to dehydrogenation transformation to generate naphthalene, followed by methyl indan, where contents order of main constituents of the liquefaction products were: naphthalene> tetralin > methyl indan.

IGF2 induces CD133 expression in esophageal cancer cells to promote cancer stemness.

Failure to eradicate cancer stem cells (CSC) during primary therapy may lead to cancer recurrence. We recently reported that CD133 is a functional biomarker for CSCs in esophageal squamous cell carcinoma (ESCC) but the molecular pathways critical for maintenance of CD133-positive CSCs are largely unknown. Here, we revealed that knockdown of IGF2 or treatment with PI3K/AKT inhibitors markedly inhibited the abilities of CD133-positive ESCC cells to self-renew, resist chemotherapeutic drugs, and form tumors. Further functional analysis identified miR-377 as a downstream regulator of PI3K/AKT signaling, and a mediator of the effects of IGF2 on CD133 expression and CSC properties. We found that the expression levels of IGF2 and CD133 were positively correlated with each other in primary ESCC, and that concurrent elevation of IGF2 and CD133 expression was significantly associated with poor patient survival. Furthermore, in vivo experiments demonstrated that IGF2-neutralizing antibody enhanced the sensitivity of tumor xenografts in nude mice to 5-fluorouracil treatment. This study underpins the importance of the IGF2-PI3K/AKT-miR-377-CD133 signaling axis in the maintenance of cancer stemness and in the development of novel therapeutic strategy for treatment of esophageal cancer.

Interactions between copper(II) and DOM in the urban stormwater runoff: modeling and characterizations.

Dissolved organic matter (DOM) can strongly interact with both organic and inorganic contaminants to influence their transportation, transformation, bioavailability, toxicity and even their ultimate fate. Within this work, DOM was extracted from urban stormwater runoff samples collected from a regular sampling site of a typical residential area in Beijing, China. Copper(II) ions were selected as model to investigate the interactions between DOM and typical heavy metals. Both ultraviolet (UV) absorbance and fluorescence titration methods were introduced to determine the complex capacities (CL) and conditional stability constants (log KM) of bonding between DOM and copper (II) ions, which revealed that the values of CL were 85.62 and 87.23 µmol mg-1 and the log KM values were 5.37 and 5.48, respectively. The results suggested the successful complexation between DOM and copper(II) ions. Furthermore, morphology of the DOM binding to copper(II) ions was confirmed by both energy-dispersive X-ray spectroscopy (EDX) and X-ray photoelectron spectroscopy (XPS), which can facilitate to clarify the corresponding mechanism. The Cu 2p3/2 peak at 933.7 eV and the characteristic shake-up peaks of Cu-O were found in the XPS spectra, implying that copper(II) ions might coordinate with hydroxyl (aliphatic or phenolic) or carboxyl groups. With these profitable results, it can be concluded that DOM in urban stormwater runoff has a strong binding affinity with copper(II) ions, which may further lead to potentially significant influence on their migration and transformation.

Entanglement dynamics for two spins in an optical cavity - field interaction induced decoherence and coherence revival.

We in this paper study quantum correlations for two neutral spin-particles coupled with a single-mode optical cavity through the usual magnetic interaction. Two-spin entangled states for both antiparallel and parallel spin-polarizations are generated under the photon coherent-state assumption. Based on the quantum master equation we derive the time-dependent quantum correlation of Clauser-Horne-Shimony-Holt (CHSH) type explicitly in comparison with the well known entanglement-measure concurrence. In the two-spin singlet state, which is recognized as one eigenstate of the system, the CHSH correlation and concurrence remain in their maximum values invariant with time and independent of the average photon-numbers either. The correlation varies periodically with time in the general entangled-states for the low average photon-numbers. When the photon number increases to a certain value the oscillation becomes random and the correlations are suppressed below the Bell bound indicating the decoherence of the entangled states. In the high photon-number limit the coherence revivals periodically such that the CHSH correlation approaches the upper bound value at particular time points associated with the cavity-field period.