Sestrin2 remedies neuroinflammatory response by inhibiting A1 astrocyte conversion via autophagy.

Most central nervous diseases are accompanied by astrocyte activation. Autophagy, an important pathway for cells to protect themselves and maintain homeostasis, is widely involved in regulation of astrocyte activation. Reactive astrocytes may play a protective or harmful role in different diseases due to different phenotypes of astrocytes. It is an urgent task to clarify the formation mechanisms of inflammatory astrocyte phenotype, A1 astrocytes. Sestrin2 is a highly conserved protein that can be induced under a variety of stress conditions as a potential protective role in oxidative damage process. However, whether Sestrin2 can affect autophagy and involve in A1 astrocyte conversion is still uncovered. In this study, we reported that Sestrin2 and autophagy were significantly induced in mouse hippocampus after multiple intraperitoneal injections of lipopolysaccharide, with the elevation of A1 astrocyte conversion and inflammatory mediators. Knockdown Sestrin2 in C8-D1A astrocytes promoted the levels of A1 astrocyte marker C3 mRNA and inflammatory factors, which was rescued by autophagy inducer rapamycin. Overexpression of Sestrin2 in C8-D1A astrocytes attenuated A1 astrocyte conversion and reduced inflammatory factor levels via abundant autophagy. Moreover, Sestrin2 overexpression improved mitochondrial structure and morphology. These results suggest that Sestrin2 can suppress neuroinflammation by inhibiting A1 astrocyte conversion via autophagy, which is a potential drug target for treating neuroinflammation.

Identification and analysis of a CD8+ T cell-related prognostic signature for colorectal cancer based on bulk RNA sequencing and scRNA sequencing data: A STROBE-compliant retrospective study.

Colorectal cancer (CRC) is one of the most common malignancies worldwide, leading to a large number of cancer-related mortalities. Aberrant CD8+ T cell infiltration plays a critical role in tumor progression and patient prognosis. This study aimed to identify a prognostic model for CRC based on CD8+ T cell-related genes. The infiltration levels of immune cells in CRC tissues were accessed by the ESTIMATE algorithm. Weighted gene co-expression network analysis (WGCNA) analysis was used to select CD8+ T cell-related genes. Prognostic genes were identified using Cox regression analysis and Kaplan-Meier curves. The least absolute shrinkage and selection operator (LASSO) algorithm was used to construct prognostic models. Gene set enrichment analysis (GSEA) was performed to annotate enriched gene sets. Single-cell RNA (scRNA) sequencing analysis was used to examine gene expression in different cell types. We found that the downregulated infiltration level of CD8+ T cells was an independent prognostic factor for CRC and selected a cluster of differentially expressed genes correlated with CD8+ T cell infiltration (CD8TDEGs). Subsequently, we identified 18 prognostic CD8TDEGs, according to which patients were reclassified into two clusters with distinct overall survival. Seven prognostic CD8TDEGs were selected to calculate the constructed prognostic model's risk scores. Interestingly, although CRC tissues with higher risk scores had higher infiltration levels of CD8+ T cells, the level of immune checkpoint genes was also high. Moreover, the scRNA-sequencing analysis showed that the expression levels of CD8TDEGs in the prognostic model varied among different types of cells. This study constructed a novel prognostic model for CRC and provided a foundation for targeting CD8+ T cell infiltration to improve the survival of CRC patients.

Artificial intelligence for detecting superficial esophageal squamous cell carcinoma under multiple endoscopic imaging modalities: A multicenter study.

BACKGROUND AND AIM: Diagnosis of esophageal squamous cell carcinoma (ESCC) is complicated and requires substantial expertise and experience. This study aimed to develop an artificial intelligence (AI) system for detecting superficial ESCC under multiple endoscopic imaging modalities. METHODS: Endoscopic images were retrospectively collected from West China Hospital, Sichuan University as a training dataset and an independent internal validation dataset. Images from other four hospitals were used as an external validation dataset. The AI system was compared with 11 experienced endoscopists. Furthermore, videos were collected to assess the performance of the AI system. RESULTS: A total of 53 933 images from 2621 patients and 142 videos from 19 patients were used to develop and validate the AI system. In the internal and external validation datasets, the performance of the AI system under all or different endoscopic imaging modalities was satisfactory, with sensitivity of 92.5-99.7%, specificity of 78.5-89.0%, and area under the receiver operating characteristic curves of 0.906-0.989. The AI system achieved comparable performance with experienced endoscopists. Regarding superficial ESCC confined to the epithelium, the AI system was more sensitive than experienced endoscopists on white-light imaging (90.8% vs 82.5%, P = 0.022). Moreover, the AI system exhibited good performance in videos, with sensitivity of 89.5-100% and specificity of 73.7-89.5%. CONCLUSIONS: We developed an AI system that showed comparable performance with experienced endoscopists in detecting superficial ESCC under multiple endoscopic imaging modalities and might provide valuable support for inexperienced endoscopists, despite requiring further evaluation.

Comparison of postoperative recovery of patients who underwent laparoscopic-assisted radical resection of right colon cancer with modified triangular anastomosis or tubular anastomosis: a retrospective cohort study.

BACKGROUND: We compared the advantages and disadvantages of modified triangular anastomosis and tubular anastomosis for digestive tract reconstruction in patients undergoing laparoscopic-assisted radical resection of right colon cancer. METHODS: This was a retrospective cohort analysis of 92 cases of laparoscopic-assisted resection of right colon cancer, treated from June 2017 to June 2018, at the Huai'an No. 1 People's Hospital in China. Patients were divided into a modified triangular anastomosis group (n = 33) and a tubular anastomosis group (n = 59). In the modified triangular anastomosis group, digestive tract reconstruction was conducted using side-to-side anastomosis of the ileo-transverse colon with a 60-mm linear stapler. The common entry hole was closed with a running suture. The tubular anastomosis group underwent end-to-side anastomosis of the ileo-transverse colon with a tubular stapler anchor placed at the end of the ileum. RESULTS: At baseline and perioperatively, there were no significant between-group differences in age, sex, body mass index, tumor location, pathological stage, or tumour size (P > 0.05). There were also no significant between-group differences in operation time, estimated blood loss, the number of harvested lymph nodes, the first postoperative flatulence time, hospitalisation time, or postoperative complications (P > 0.05); however, the total cost of hospitalization for the triangular anastomosis group was significantly lower than the tubular anastomosis group (P < 0.05). CONCLUSION: Modified triangular anastomosis is a safe and feasible procedure for laparoscopic-assisted radical resection of right colon cancer. These results affirm the safety and effectiveness of total laparoscopic radical resection of right colon cancer. Given the equivalent outcomes between the two procedures, the modified triangular procedure may be more a more cost-effective option for clinical application.

MicroRNA­592 promotes cell proliferation, migration and invasion in colorectal cancer by directly targeting SPARC.

Colorectal cancer (CRC), one of the most common cancer types, causes a large number of cancer­related mortalities annually worldwide. Dysregulated microRNAs (miRNAs/miR) are closely associated with the malignant progression of CRC. Therefore, the present study aimed to investigate the expression and regulatory role of miR­592 in CRC. It was found that miR­592 expression was significantly elevated in CRC tissues and cell lines, and was associated with the prognosis of patients. Cellular phenotype assays demonstrated that miR­592 could promote CRC cell proliferation, migration and invasion. Bioinformatics analysis demonstrated that miR­592 mainly participated in the positive regulation of transcription, as well as the regulation of cell motility. Moreover, miR­592 targets were enriched in several signaling pathways, such as the 'mTOR' and 'FoxO' signaling pathways. In addition, secreted protein acidic and rich in cysteine (SPARC) was identified as a target of miR­592 in CRC. The present results suggested that miR­592 acts as an oncogene in CRC, in part, by directly inhibiting SPARC expression. Collectively, the present study provides a novel potential therapeutic strategy for CRC.

CircPDZD8 promotes gastric cancer progression by regulating CHD9 via sponging miR-197-5p.

CircRNAs have been shown to be associated with gastric cancer tumorigenesis. But little was known about the role of circPDZD8 in gastric cancer. CircPDZD8 was up-regulated in gastric cancer tissues and cells, Kaplan-Meier survival analysis indicated that gastric patients had a poor overall survival when circPDZD8 levels were high. CircPDZD8 knockdown could hinder proliferation and migration of gastric cancer cells. MiR-197-5p, which was down-regulated in gastric cancer, was shown to be a target of circPDZD8 and was inversely correlated with circPDZD8 expression. CHD9, as a target gene of miR-197-5p, was negatively regulated by miR-197-5p and positively correlated with circPDZD8 expression. Importantly, circPDZD8 could up-regulate CHD9 expression by sponging miR-197-5p, and modulate cell progression by regulation of the miR-197-5p/CHD9 axis in gastric cancer. CircPDZD8 knockdown repressed the progression of gastric cancer cells by sponging miR-197-5p and down-regulating CHD9.

Serum microRNA-592 serves as a novel potential biomarker for early diagnosis of colorectal cancer.

Colorectal cancer (CRC) is the second leading cause of cancer-associated mortality worldwide. Currently, available diagnostic biomarkers are neither sensitive nor specific. Thus, the present study aimed to identify novel circulating microRNAs (miRNAs) as biomarkers for the early diagnosis of CRC. All samples were provided by The Second Affiliated Hospital of Nanjing Medical University (Nanjing, China). Analysis of the GSE108153 and GSE55139 datasets, downloaded from the Gene Expression Omnibus (GEO) database was performed using the online tool, GEO2R. Reverse transcription-quantitative PCR was performed to determine miR-592 expression in CRC tissues, cells and serums of patients. Subsequently, the diagnostic value of serum miR-592 was assessed via receiver operating characteristic (ROC) curve analysis. Both the assessment of clinical samples and bioinformatics analysis demonstrated that miR-592 expression levels were significantly upregulated in the tissues and serum of patients with CRC, suggesting that elevated serum miR-592 may be tumor-derived. ROC analysis indicated that serum miR-592 levels may differentiate patients with early stage CRC and advanced adenoma from healthy individuals, with area under the curve values of 0.801 and 0.747, respectively. Taken together, the results of the present study suggest that serum miR-592 may be implicated as a potential biomarker for the early diagnosis of CRC.

CircSMC3 regulates gastric cancer tumorigenesis by targeting miR-4720-3p/TJP1 axis.

Circular RNAs (circRNAs) are identified to play an evident role in many human cancers, such as gastric cancer. However, the potential mechanisms underlying the circRNA-induced pathogenesis in gastric cancers are still elusive. The present study is designed to unfold the mechanism by which circRNAs involve in gastric cancer progression. Using circRNAs microarray, we detected the dysregulated circRNAs and identified an upregulated circRNA, circSMC3 (hsa_circ_0000260), in gastric cancer tissues. Patients with high circSMC3 expression levels had a poor overall survival via Kaplan-Meier survival analysis implied that gastric cancer. Functionally, loss of circSMC3 abolished the proliferation and motility of gastric cancer cells. Mechanically, circSMC3 decreased miR-4720-3p expression by acting as a miRNA sponge, and tight junction protein 1 (TJP1) 3'UTR was identified to be the target of miR-4720-3p, contributing to a circSMC3/miR-4720-3p/TJP1 axis. Thus, our results indicate that circSMC3 promotes gastric cancer cell proliferation and motility through miR-4720-3p/TJP1.

Optimal pathways involved in the treatment of sevoflurane or propofol for patients undergoing coronary artery bypass graft surgery.

The cardio-protection mechanisms of sevoflurane and propofol still remain unclear in patients undergoing coronary artery bypass grafting (CABG). We designed the present study to identify the optimal pathways through integrating differential co-expressed network (DCN)-based guilt by association (GBA) principle based on the expression data of E-GEOD-4386 downloaded from EMBL-EBI. Differentially expressed genes (DEGs) were firstly identified and then DCN and sub-DCN were established. The seed pathways were predicted through GBA principle using the area under the curve (AUC) for pathway categories, and the pathway terms with AUC >0.9 were defined as the seed pathways. KEGG pathway analysis was applied to the DEGs based on DAVIA to detect significant pathways. The final optimal pathways were identified based on the traditional pathway analysis and network-based pathway inference approach. There were 83 common, 99 sevoflurane-specific and 4 propofol-specific DEGs in the expression profile of artial samples. Finally, 8 and 4 pathway terms having the AUC >0.9 were identified and determined as the seed pathways in the propofol and sevoflurane group, respectively. TNF signaling pathway, NF-κB signaling pathway, as well as NOD-like receptor signaling pathway were the common optimal ones in these two groups. Only the pathway of cytokine-cytokine receptor interaction was unique to sevoflurane, and no pathway was specific to propofol. Our results suggested that sevoflurane and propofol might synergistically possess some cardio-protective properties in patients undergoing CABG.

SARM1 deletion restrains NAFLD induced by high fat diet (HFD) through reducing inflammation, oxidative stress and lipid accumulation.

SARM1 (Sterile alpha and armadillo motif-containing protein 1) is the recently identified TIR domain-containing cytosolic protein, which is involved in toll-like receptors (TLRs) signaling transduction. In the present study, the role of SARM1 in high fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) progression was explored. We found that SARM1 was expressed highly in fatty liver. And SARM1-knockout (KO) reduced steatohepatitis and metabolic disorders induced by HFD. SARM1-deletion decreased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in HFD-fed mice. Additionally, inflammatory response caused by HFD was alleviated by SARM1-deletion through inactivating TLR4/7/9 and nuclear factor kappa B (NF-κB) pathways. Of note, SARM1-deletion also reduced the expressions of inflammation-associated molecules in hypothalamus of HFD-fed mice. Furthermore, HFD administration led to oxidative stress in liver of mice, while being decreased in SARM1-KO mice. Moreover, SARM1-ablation improved lipid dyslipidemia by suppressing the mRNA levels of genes, linked to glycolysis, lipogenesis and transcriptional regulation. Insulin resistance was also attenuated by SARM1-deficiency through enhancing the activation of liver Akt/glycogen synthase kinase-3ß (GSK3ß) and insulin receptor substrate-1 (IRS1)/FOXO1 pathways in HFD-fed mice. Also, SARM1-knockout improved neuropeptide Y (NPY), Pro-Opiomelanocortins (POMC), Agouti-related Protein (AGRP) and Cocaine-and-Amphetamine Responsive Transcript 1 (CART1) expressions in hypothalamus of mice after HFD administration. In vitro, we found that the reduction of inflammatory response, oxidative stress and dyslipidemia induced by SARM1-knockout in primary hepatocytes after fructose stimulation was largely attributed to its suppression to TLR4/7/9. Together, the findings demonstrated that SARM1 might be an effective target for developing effective therapeutic strategies against NAFLD.

Irigenin sensitizes TRAIL-induced apoptosis via enhancing pro-apoptotic molecules in gastric cancer cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) holds promising value for cancer therapy due to its capacity to induce apoptosis in cancer cells. Nevertheless, TRAIL therapy is greatly hampered by its resistance. Irigenin (Iri), isoflavonoids, can be isolated from the rhizome of Belamcanda chinensis, and has been shown anti-cancer properties. In this study, we explored if Iri could enhance TRAIL-regulated apoptosis in TRAIL resistant gastric cancer cells. Iri significantly potentiated TRAIL-triggered cytotoxicity. Iri alone and TRAIL alone showed no effective role in apoptosis induction, whereas combined treatment with Iri and TRAIL markedly induced apoptosis in cancer cells, as evidenced by the up-regulation of cleaved Caspase-8/-9/-3 and PARP. Additionally, the sensitization to TRAIL was along with the enhancement of pro-apoptotic proteins, including FAS-associated protein with death domain (FADD), death receptor 5 (DR5) and Bax. And suppressing FADD, DR5 and Bax by si RNA significantly reduced the apoptosis and enhanced the cell viability induced by the co-application of Iri and TRAIL. Moreover, the sensitization to TRAIL was accompanied by the decrease of Cellular-FLICE inhibitory protein (c-FLIP), Bcl-2 and Survivin. Additionally, Iri could sensitize TRAIL to produce reactive oxygen species (ROS). Pre-treatment of N-acetyl-cysteine (NAC), ROS scavenger, attenuated Iri plus TRAIL-induced apoptosis and improved cell viability. Finally, combination of Iri and TRAIL inhibited tumor growth in the xenograft model. Collectively, our present study gave new insights into the effects of Iri on potentiating TRAIL-sensitivity, and suggested that Iri could be a potential candidate for sensitizer of TRAIL-resistant cancer cell treatment.

GSK3ß mediates pancreatic cancer cell invasion in vitro via the CXCR4/MMP-2 Pathway.

BACKGROUND: Glycogen synthase kinase-3ß (GSK3ß) expression and activity are upregulated in pancreatic cancer tissues. In our previous study, we found that stromal cell-derived factor-1/ chemokine receptor C-X-C motif chemokine receptor 4 (SDF-1α/CXCR4) upregulated matrix metalloproteinase 2 (MMP-2) and promoted invasion in PANC1 and SW-1990 pancreatic cancer cells by activating p38 mitogen-activated protein kinase (p38 MAPK). Additionally, inhibition of GSK3ß reduced MMP-2 secretion. METHODS: To investigate the molecular mechanism of GSK3ß in pancreatic cancer tissues, we created stable PANC1 cells up-regulation of GSK3ß by transfecting GSK3ß overexpression plasmid, and down-regulation of GSK3ß using two different types of RNA interference. RESULTS: Western blotting showed that overexpression of GSK3ß up-regulated CXCR4 and MMP-2 expression; suppression of GSK3ß down-regulated CXCR4 and MMP-2 protein expression. Up-regulation of MMP2 induced by overexpression of GSK3ß was blocked by inhibition of CXCR4. Overexpression of GSK3ß promoted PANC1 cell invasion, and down-regulation of GSK3ß suppressed PANC1 cell invasion in the transwell invasion assays. However, inhibition of CXCR4 using shRNA attenuated the ability of GSK3ß to promote PANC1 cell invasion. CONCLUSIONS: This study demonstrated that GSK3ß promotes PANC1 cell invasion via the CXCR4/MMP-2 pathway.

[Limb preservation surgery combined with perioperative rehabilitation for the treatment of 7 patients with stage II to III giant cell tumor of bone in the proximal humerus].

OBJECTIVE: To study the effects of the extensive resection of the tumor-loading segment and artificial humerus head replacement combined with perioperative rehabilitation for the treatment of stage II to III giant cell tumor of bone in the proximal humerus. METHODS: From March 2007 to March 2010, 7 patients with stage II to III giant cell tumor of bone in the proximal humerus were treated. Among the patients, 3 patients were male and 4 patients were female with a mean age of 34.6 years (ranged, 18 to 49 years). The mean course of disease was 19 months (ranged, 6 to 35 months). All the patients were confirmed to suffer stage II to III giant cell tumor of bone in the proximal humerus by pathology and X-ray examinations. Clinical manifestations of the patients included persistence aggravated pain of the shoulder, swelling in the proximate arm with obviously tenderness, activity limited of the joint. All the patients were treated with extensive resection of the tumor-loading segment and artificial humerus head replacement combined with perioperative rehabilitation. CMS and OSIS score system were used to evaluate shoulder function and shoulder stability. RESULTS: All the patients were followed up, and the duration ranged from 14 to 35 months, with an average of 17 months. There were no serious complications or recurrence in all cases. One year after the surgery CMS and OSIS score system were 70.7 scores (ranged,63 to 82 scores) and 25.1 scores (ranged, 18 to 29 scores) respectively. According to evaluation for shoulder function, 2 patients got an excellent result and 5 good. According to evaluation of shoulder stability, 1 patient got an excellent result and 6 good. CONCLUSION: Extensive resection of the tumor-loading segment and artificial humerus head replacement combined with perioperative rehabilitation for the treatment of stage II to III giant cell tumor of bone in the proximal humerus would not only preserve the upper extremity but also preserve the function of upper extremity.