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• FLNA and FLNB were the two most frequently mutated disulfidptosis cell death genes in cancer. • UCEC and SKCM were the two cancer types that have the highest mutation rates while the mutation of ACTN4 was associated with worse survival of CESC and ESCA. • The correlation between CNV and survival across multiple cancer types found that UCEC, KIRP, LGG, and KIRC were the top cancer types where the CNV level was associated with survival. • There was a negative correlation between expression and methylation for most of the genes. • About half of the disulfidptosis-related cell death proteins were associated with the activation of EMT. • Disulfidptosis genes were correlated to immune cell infiltration levels in cancers. • Multiple compounds were identified as potential drugs that might be affected by disulfidptosis-related cell death for future study. A recent study has identified a novel programmed cell death pathway, termed disulfidptosis, which is based on disulfide proteins. This discovery provides new insight into the mechanisms of cell death and may have implications for therapeutic strategies targeting cell death pathways. This study aimed to evaluate the pan-cancer genomics and clinical association of disulfidptosis and disulfidptosis-related cell death genes, including SLC7A11, INF2, CD2AP, PDLIM1, ACTN4, MYH9, MYH10, IQGAP1, FLNA, FLNB, TLN1, MYL6, ACTB, DSTN, and CAPZB. Using multi-omics profiling data, this study provides a comprehensive and systematic characterization of disulfidptosis genes across more than 9000 samples of over 30 types of cancer. FLNA and FLNB were the two most frequently mutated disulfidptosis cell death genes in cancer. UCEC and SKCM were the two cancer types that have the highest mutation rates while the mutation of ACTN4 was associated with worse survival of CESC and ESCA. Breast cancer was potentially affected by disulfidptosis because its subtypes are different in disulfidptosis gene expression. Similarly, KIRC might also be associated with disulfidptosis. Additionally, the association of disulfidptosis-related cell death genes with survival was analyzed, with MESO and LGG as the top cancer types with survival associated with disulfidptosis cell death genes. The correlation between CNV and survival across multiple cancer types found that UCEC, KIRP, LGG, and KIRC were the top cancer types where the CNV level was associated with survival. There was a negative correlation between expression and methylation for most of the genes and there was only a slight correlation between methylation levels and survival of cancer in LGG. About half of the disulfidptosis-related cell death proteins were associated with the activation of EMT. Disulfidptosis genes were correlated to immune cell infiltration levels in cancers. Multiple compounds were identified as potential drugs that might be affected by disulfidptosis-related cell death for future study. Disulfidptosis cell death genes are potentially involved in many cancer types and can be developed as candidates for cancer diagnosis, prognosis, and therapeutic biomarkers. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The response to retention hypothesis of atherogenesis proposes that atherosclerosis is initiated via the retention of atherogenic lipoproteins by vascular proteoglycans. Co-localization studies suggest that of all the vascular proteoglycans, biglycan is the one most closely co-localized with LDL. The goal of this study was to determine if over-expression of biglycan in hyperlipidemic mice would increase atherosclerosis development. Methods: Transgenic mice were developed by expressing biglycan under control of the smooth muscle actin promoter, and were crossed to the LDL receptor deficient (C57BL/6 background) atherosclerotic mouse model. Biglycan transgenic and non-transgenic control mice were fed an atherogenic Western diet for 4–12 weeks. Results: LDL receptor deficient mice overexpressing biglycan under control of the smooth muscle alpha actin promoter had increased atherosclerosis development that correlated with vascular biglycan content. Conclusion: Increased vascular biglycan content predisposes to increased lipid retention and increased atherosclerosis development. [Copyright &y& Elsevier]

Pancreatic carcinoma is a highly lethal malignancy with an extremely poor prognosis. Recent genome-wide studies have implicated axon guidance pathways, including the SLIT/ROBO pathway, in pancreatic tumor development and progression. Here we showed that ROBO3 expression is up-regulated in pancreatic cancer tissue samples and cell lines. Over-expression of ROBO3 promotes pancreatic cancer cell growth, invasion and metastasis in vitro and in mouse xenograft tumor models. We identified miR-383 as a suppressor of ROBO3, and revealed its expression to be inversely correlated with ROBO3. Over-expression of ROBO3 activates Wnt pathway components, β-catenin and GSK-3, and the expression of markers indicating an EMT. By means of immunoprecipitation, we revealed an interaction between Wnt inhibitor SFRP and ROBO3 in pancreatic cancer cell lines. Our work suggests that ROBO3 may contribute to the progression of pancreatic cancer by sequestering Wnt inhibitor SFRP, which in turn leads to increased Wnt/β-catenin pathway activity. We also confirmed that ROBO3 increases with clinical grade and miR-383 expression is inversely correlated to that of ROBO3. [ABSTRACT FROM AUTHOR]

Abstract Ethnopharmacological relevance Rhubarb is a traditional Chinese medicine(TCM), that possesses neuroprotective, anti-inflammatory, antibacterial, antioxidative, purgative and anticancer properties, and has been used to treat intracerebral hemorrhage (ICH) and many other diseases. Aims of the study This study aimed to investigate the changes of brain protein in ICH rats treated with rhubarb and to explore the multi-target mechanism of rhubarb in the treatment of ICH via bioinformatics analysis of differentially expressed proteins (DEPs). Materials and methods Rats were subjected to collagenase-induced ICH and then treated orally with 3 or 12 g/kg rhubarb daily for 2 days following ICH. After sacrifice, total protein of brain tissue was extracted, and isobaric tag for relative and absolute quantification (iTRAQ)-based liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was employed to quantitatively identify of the DEPs in two treatment groups compared with the vehicle group. The DEPs were analyzed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and STRING databases. Bioinformatics Analysis Tool for Molecular mechanism of TCM (BATMAN-TCM) was used to predict the target of rhubarb and western blotting was used for verification. Results In total, 1356 proteins were identified with a 1% false discovery rate (FDR). Among them, 55 DEPs were significantly altered in the sham, vehicle, low dose rhubarb group (LDR, 3 g/kg), and high dose rhubarb group (HDR, 12 g/kg). Enrichment analysis of GO annotations indicated that rhubarb mainly regulated expression of some neuron projection proteins involved in the response to drug and nervous system development. The dopaminergic synapse pathway was found to be the most significant DEP in the combined analysis of the KEGG and BATMAN-TCM databases. Based on the results of the STRING analysis, oxidative stress (OS), calcium binding protein regulation, vascularization, and energy metabolism were important in the rhubarb therapeutic process. Conclusion Rhubarb achieves its effects mainly through the dopaminergic synapse pathway in ICH treatment. The ICH-treating mechanisms of rhubarb may also involve anti-OS, calcium binding protein regulation, angiogenic regulation, and energy metabolism improvement. This study adds new evidence to clinical applications of rhubarb for ICH. Highlights • iTRAQ-based quantitative proteomics was utilized to detect proteins in ICH rats treated with rhubarb. • Rhubarb regulated 55 DEPs that mainly included OS, calcium binding protein regulation, vascularization, energy metabolism, and the dopaminergic synapse pathway. • This work adds new evidence to clinical applications of rhubarb for ICH. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Background and Aims: Increasing studies show that messenger RNA (mRNA) levels of local IGF-system are overexpressed in cancer tissue of patients with colorectal cancer (CRC). However, the influence of type 2 diabetes (T2DM) on the expression of insulin-like growth factor-1 (IGF-1) and IGF-1 receptor (IGF-1R) mRNA in colorectal cancer tissue and adjacent non-cancerous tissue (ANCT) is unknown. The aim of this study was to assess mRNA expression of IGF-1 and IGF-1R in paired samples of cancer tissue and ANCT between colorectal adenocarcinoma (CA) patients with and without T2DM. Methods: To quantify the levels of IGF-1 and IGF-1R mRNA in CA, we analyzed the expression of IGF-1 and IGF-1R mRNA levels in paired samples of cancer tissue and ANCT in CA patients with and without T2DM using real-time reverse transcription-polymerase chain reaction (RT-PCR). Results: mRNA levels of IGF-1 and IGF-1R were significantly higher in cancer tissue compared with its ANCT in CA patients with and without T2DM. Compared with the CA group, significantly higher levels of IGF-1 and IGF-1R mRNA were observed in cancer tissue in CA with T2DM group. No significant differences were observed in the role of cancer locations, Dukes stages and diabetes duration on mRNA expression of IGF-1. After adjusting for age, gender and Dukes stages, multivariate analysis indicated IGF-1 mRNA level was a risk factor for prognosis (p <0.05). Conclusions: Our results support the hypothesis that IGF system plays an important role in CRC. Further larger studies are needed. [Copyright &y& Elsevier]

• TET2 is the most regulated 5mC demethylase during 3 T3-L1 differentiation. • TET2 is identified as an anti-adipogenic demethylase by loss-of function and gain-of function assays. • TET2 inhibits lipid accumulation by promoter demethylation of Adrb3. • Vitamin C was found to decrease 5mC level and repress lipid production. To explore its roles in adipogenesis, the levels of genomic 5mC methylation were examined across the adipocyte differentiation of 3 T3-L1 cells. This led to the identification of an up-regulating 5mC profile during the process. To further explore the regulation, gene expression assay was performed with a set of 5mC metabolic enzymes. Among them, TET2 was found to be the most regulated 5mC demethylase, in addition to a well-investigated 5mC methylase DNMT1. In the process, the expression of Tet2 increased for over 16-fold, suggesting its implications in the differentiation. Therefore, loss-of-function and gain-of-function assays were performed with Tet2. It was found that in relative to the differentiation of wild-type cells, knockdown of Tet2 expression led to greatly enhanced differentiation process, while over-expression of the gene resulted in repressed differentiation. Pathway study found that during the differentiation, TET2 demethylates Adrb3 promoter to up-regulate its expression. This led to enhanced lipolysis and decreased lipid production. To the upstream pathway, vitamin C treatment was found to enhance the activity of TETs, decrease 5mC levels and repress lipid production. Taken together, TET2 was characterized as an anti-adipogenic demethylase in adipocyte differentiation of 3 T3-L1 cells. [ABSTRACT FROM AUTHOR]