RUNX1, FUS, and ELAVL1-induced circPTPN22 promote gastric cancer cell proliferation, migration, and invasion through miR-6788-5p/PAK1 axis-mediated autophagy.

BACKGROUND: An increasing number of studies have demonstrated the association of circular RNAs (circRNAs) with the pathological processes of various diseases and their involvement in the onset and progression of multiple cancers. Nevertheless, the functional roles and underlying mechanisms of circRNAs in the autophagy regulation of gastric cancer (GC) have not been fully elucidated. METHODS: We used transmission electron microscopy and the mRFP-GFP-LC3 dual fluorescent autophagy indicator to investigate autophagy regulation. The cell counting kit-8 assay, colony formation assay, 5-ethynyl-2'-deoxyuridine incorporation assay, Transwell assay, and Western blot assay were conducted to confirm circPTPN22's influence on GC progression. Dual luciferase reporter assays validated the binding between circPTPN22 and miR-6788-5p, as well as miR-6788-5p and p21-activated kinase-1 (PAK1). Functional rescue experiments assessed whether circPTPN22 modulates PAK1 expression by competitively binding miR-6788-5p, affecting autophagy and other biological processes in GC cells. We investigated the impact of circPTPN22 on in vivo GC tumors using a nude mouse xenograft model. Bioinformatics tools predicted upstream regulatory transcription factors and binding proteins of circPTPN22, while chromatin immunoprecipitation and ribonucleoprotein immunoprecipitation assays confirmed the binding status. RESULTS: Upregulation of circPTPN22 in GC has been shown to inhibit autophagy and promote cell proliferation, migration, and invasion. Mechanistically, circPTPN22 directly binds to miR-6788-5p, subsequently regulating the expression of PAK1, which activates protein kinase B (Akt) and extracellular signal-regulated kinase (Erk) phosphorylation. This modulation ultimately affects autophagy levels in GC cells. Additionally, runt-related transcription factor 1 (RUNX1) negatively regulates circPTPN22 expression, while RNA-binding proteins such as FUS (fused in sarcoma) and ELAVL1 (recombinant ELAV-like protein 1) positively regulate its expression. Inhibition of the autophagy pathway can increase FUS expression, further upregulating circPTPN22 in GC cells, thereby exacerbating the progression of GC. CONCLUSION: Under the regulation of the transcription factor RUNX1 and RNA-binding proteins FUS and ELAVL1, circPTPN22 activates the phosphorylation of Akt and Erk through the miR-6788-5p/PAK1 axis, thereby modulating autophagy in GC cells. Inhibition of autophagy increases FUS, which in turn upregulates circPTPN22, forming a positive feedback loop that ultimately accelerates the progression of GC.

Cytotoxic jatrophane diterpenoids from the aerial parts of Euphorbia helioscopia.

A phytochemical study of 80% ethanol extract from the aerial parts of Euphorbia helioscopia led to the isolation of three new jatrophane diterpenoids, euphoheliphanes A-C (1-3). Their structures were established on the basis of spectroscopic data (NMR, IR, UV, and MS). The isolated diterpenoids were tested in vitro for cytotoxic potentials against 6 renal cancer cell lines. As a result, compounds 1-3 exhibited some cytotoxic activities against all the tested tumor cell lines with IC50 values less than 50 µM.[Formula: see text].

Prognostic value and potential function of a novel heme-related LncRNAs signature in gastric cancer.

Heme is a coordination complex formed by the binding of iron ions and porphyrin rings. Its metabolic processes are associated with various cancers, including gastric cancer (GC). In recent years, long non-coding RNAs (LncRNAs) have been identified as key regulatory factors in GC. However, the role of LncRNAs associated with heme metabolism in GC and their relationship with prognosis have not been reported. In this study, we constructed a novel LncRNAs signature related to heme metabolism (HMlncSig) and validated its prognostic value for predicting the survival of GC patients through training, test, and entire cohorts. Kaplan-Meier analysis demonstrated that patients in the high-risk group had shorter survival times. Univariate and multivariate Cox regression analysis showed that HMlncSig was an independent prognostic indicator for GC patients, regardless of other clinical pathological features. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis and gene set variation analysis pathways showed that the activation of these markers may be involved in tumor progression, influencing the survival of GC patients. The nomogram, based on HMlncSig score and clinical features, demonstrated the strong predictive ability of this signature. Additionally, significant differences were observed between the high-risk and low-risk groups in terms of immune cell subtypes, expression of immune checkpoint genes, and response to chemotherapy and immunotherapy. Through clinical validation, we found that the risk score and heme levels of GC patients were both significantly elevated and correlated with the degree of malignancy. Furthermore, we found that AP000692.1, a key gene in this signature, promoted the proliferation, migration, and invasion of GC cells. In conclusion, our HMlncSig model has significant predictive value for the prognosis of GC patients and can provide clinical guidance for personalized immunotherapy.

Targeting the MCP-GPX4/HMGB1 Axis for Effectively Triggering Immunogenic Ferroptosis in Pancreatic Ductal Adenocarcinoma.

Induction of ferroptosis can inhibit cancer cells in vitro, however, the role of ferroptosis in treatment in vivo is controversial. The immunosuppressive cells activated by the ferroptotic tumor cells can promote the growth of residual tumor cells, hindering the application of ferroptosis stimulation in tumor treatment. In this study, a new strategy is aimed to be identified for effectively triggering immunogenic ferroptosis in pancreatic ductal adenocarcinoma (PDAC) and simultaneously stimulating antitumor immune responses. Toward this, several molecular and biochemical experiments are performed using patient-derived organoid models and a KPC mouse model (LSL-KrasG12D /+, LSL-Trp53R172H/+, Pdx-1-Cre). It is observed that the inhibition of macrophage-capping protein (MCP) suppressed the ubiquitin fold modifier (UFM)ylation of pirin (PIR), a newly identified substrate of UFM1, thereby decreasing the transcription of GPX4, a marker of ferroptosis, and promoting the cytoplasmic transportation of HMGB1, a damage-associated molecular pattern. GPX4 deficiency triggered ferroptosis, and the pre-accumulated cytosolic HMGB1 is released rapidly. This altered release pattern of HMGB1 facilitated the pro-inflammatory M1-like polarization of macrophages. Thus, therapeutic inhibition of MCP yielded dual antitumor effects by stimulating ferroptosis and activating antitumor pro-inflammatory M1-like macrophages. The nanosystem developed for specifically silencing MCP is a promising tool for treating PDAC.

Identification of hub biomarkers and exploring the roles of immunity, M6A, ferroptosis, or cuproptosis in rats with diabetic erectile dysfunction.

BACKGROUND: Currently, patients with diabetic erectile dysfunction (DMED) were not satisfied with the effects of first-line phosphodiesterase type 5 inhibitors (PDE5Is). Hence, this paper was designed to mine hub biomarkers in DMED and explore its potential mechanisms. METHODS: Gene expression matrix of DMED was downloaded from the gene expression omnibus (GEO; GSE2457) dataset. The top 20 genes were selected based on the connectivity degrees in protein-protein interaction (PPI) network. Functional enrichment analysis was utilized to reveal DMED-related signaling pathways. We also explored the roles of immunity, m6A, ferroptosis, or cuproptosis in DMED and constructed Sprague Dawley (SD) rats DMED model to verify gene expressions by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Based on the threshold, a total of 122 differently expressed genes (DEGs) were identified in DMED, including 39 up-regulated and 83 down-regulated genes. Functional enrichment analysis implied that these DEGs were significantly enriched in peroxisome proliferator-activated receptors, ferroptosis, hypoxia-inducible factor 1 signaling pathways, and so on. SD rats DMED model was also successfully established by us and validated by intracavernous pressure/mean arterial pressure, Masson's trichrome staining, and immunohistochemical analysis. We further verified the expression of these top 20 genes from the PPI network by qRT-PCR in the SD rats DMED model and finally identified Sparc, Lox, Srebf1, and Mmp3 as hub biomarkers (all p < 0.05). As for immunity and cuproptosis, our analysis indicated that DMED had nothing to do with them (all p > 0.05). Actually, DMED was markedly associated with m6A regulators and ferroptosis. CONCLUSIONS: We identified Sparc, Lox, Srebf1, and Mmp3 as potential hub biomarkers in the SD rats DMED model for future drug development and found its significant associations with m6A regulators and ferroptosis, but not with immunity or cuproptosis.

Meat, vegetable, and fruit consumption among urban and rural elders aged 60+ years in regional China: a population-level nutritional study.

The aim was to assess epidemiological characteristics of the most recent consumption patterns of meat, vegetable, and fruit among representative urban and rural residents aged 60+ years in regional China. In this cross-sectional survey conducted in mid-2018, participants aged 60+ years were randomly chosen from urban and rural communities in Nanjing municipality of China. Meat, vegetable, and fruit intake were assessed with a validated food frequency questionnaire. Multivariate logistic regression models were applied to compute odds ratio (OR) and 95 % confidence interval (CI) to investigate the association of socio-demographic characteristics with a likelihood of meeting intake recommendation. Among the 20 867 participants, 49⋅5 % were men and 45⋅0 % urban elders, and 6⋅5 % aged 80+ years. The mean values of consumption frequency of red meat, white meat, vegetable, and fruit were 2⋅99 ± 2⋅28, 1⋅37 ± 1⋅13, 5⋅24 ± 6⋅43, and 2⋅64 ± 2⋅91 times/week, respectively, among overall participants. Moreover, there were 14⋅9, 23⋅7, and 12⋅1 % of participants meeting intake recommendations of meat, vegetable, and fruit, separately, in this study. After adjustment for potential confounders, age, gender, residence area, and educational attainment each was associated with the likelihood of meeting intake recommendation of meat, vegetable, or fruit. The consumption frequency and proportion of participants meeting intake recommendations of meat, vegetable, or fruit were not high among elders in regional China. Socio-demographic characteristics were associated with intake recommendations of meat, vegetables, and fruit. It has public health implications that participants' socio-demographic attributes shall be considered for precision intervention on meat, vegetable, and fruit consumption in healthy eating campaigns among elders in China.

Light Addressable Potentiometric Sensors for Biochemical Imaging on Microscale: A Review on Optimization of Imaging Speed and Spatial Resolution.

Light addressable potentiometric sensors (LAPS) are a competitive tool for unmarked biochemical imaging, especially imaging on microscale. It is essential to optimize the imaging speed and spatial resolution of LAPS since the imaging targets of LAPS, such as cell, microfluidic channel, etc., require LAPS to image at the micrometer level, and a fast enough imaging speed is a prerequisite for the dynamic process involved in biochemical imaging. In this study, we discuss the improvement of LAPS in terms of imaging speed and spatial resolution. The development of LAPS in imaging speed and spatial resolution is demonstrated by the latest applications of biochemistry monitoring and imaging on the microscale.

Survival Prognosis, Tumor Immune Landscape, and Immune Responses of PPP1R18 in Kidney Renal Clear Cell Carcinoma and Its Potentially Double Mechanisms.

Background: The aim of this study was to investigate the immunological and prognostic roles of protein phosphatase 1 regulatory subunit 18 (PPP1R18) for overall survival (OS) in kidney renal clear cell carcinoma (KIRC) patients, as well as the prediction of its potential mechanisms. Methods: Based on PPP1R18 single gene expression matrices and clinical information from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and GSE6344 datasets, the relationships between PPP1R18 and prognosis/immunity were fully explored. Univariate and multivariate Cox regression analyses were applied to assess its independent prognostic ability and gene set enrichment analysis (GSEA) was implemented to find its related pathways. Besides, we also explored possible mechanisms of PPP1R18 involved in KIRC. Results: PPP1R18 was highly expressed in KIRC samples than in non-tumor tissues in TCGA, ICGC and GSE6344 datasets, with validations from quantitative real-time polymerase chain reaction (qRT-PCR) in both cell lines and KIRC tissues (all P < 0.05). Univariate and multivariate Cox regression analyses indicated that PPP1R18 was also considered to be with independent prognostic ability in KIRC (both P < 0.01). GSEA results showed that PPP1R18 gene expression was significantly related to Chemokine, JAK STAT, MAPK, and NOTCH pathways. Furthermore, PPP1R18 was also firmly associated with microsatellite instability (MSI), tumor mutational burden (TMB), immune microenvironment, immune cells, immune checkpoints and immune infiltration (all P < 0.05). Analysis of tumor immune dysfunction and exclusion (TIDE) and Imvigor210 datasets suggested that patients with low PPP1R18 expression are more likely to benefit from immunotherapy. Finally, we identified two potential mechanisms of a classical competing endogenous RNA (ceRNA) mechanism and an RNA-binding protein (RBP) involved mechanism of PPP1R18 in KIRC. Conclusions: PPP1R18 played oncogenic and immunological roles of OS in KIRC, offering potential antigens for developing KIRC mRNA vaccines.

Immune-related gene TM4SF18 could promote the metastasis of gastric cancer cells and predict the prognosis of gastric cancer patients.

Gastric cancer (GC) is one of the most common malignancies in the world, and the search for better markers has become one of the challenges today. It has been found that the L6 superfamily regulates the biological functions of numerous tumors, but transmembrane 4 L six family member 18 (TM4SF18) has been rarely reported. We found that TM4SF18 expression is upregulated in GC tissues and cells, which can be effectively diagnosed and dynamically monitored to assess the prognosis of GC patients. Furthermore, knockdown of TM4SF18 effectively inhibited proliferation, migration, and invasion of GC cells, and affected the epithelial-mesenchymal transition process. TM4SF18 was found to be an independent prognostic factor for GC by univariate and multifactorial Cox analyses as well as by establishing nomogram plots. In addition, in TM4SF18 and immune correlation analysis, TM4SF18 expression levels were found to be negatively correlated with most immune cell marker genes and associated with numerous immune cells and immune pathways, resulting in less benefit from treatment with immune checkpoint inhibitors. In summary, we found that TM4SF18 is a promising GC biomarker that promotes the proliferation, migration, and invasion abilities of GC cells, and is associated with immune response.

Survival Prognosis, Tumor Immune Landscape, and Immune Responses of ADAMTS14 in Clear Cell Renal Cell Carcinoma and Its Potential Mechanisms.

Background: ADAMTS14 played a crucial role in the formation and development of various cancers. Currently, no associations had been revealed between ADAMTS14 and clear cell renal cell carcinoma (ccRCC). Hence, this study was designed to assess the prognostic values and immunological roles of ADAMTS14 in ccRCC and to reveal its potential mechanisms. Methods: ADAMTS14-related expression profiles and related clinical data were downloaded from The Cancer Genome Atlas (TCGA) dataset, validated by the ICGC dataset, qRT-PCR, and immunohistochemistry. We utilized gene set enrichment analysis (GSEA) to find potentially ADAMTS14-related pathways and applied univariate/multivariate Cox regression analyses to identify independent factors significantly related to overall survival (OS) for ccRCC. A nomogram consisted of independent prognostic factors was also conducted. We further explored the associations between ADAMTS14 with immunity and revealed its potential mechanisms. Results: ADAMTS14 displayed a higher expression in ccRCC tumor than in adjacent normal tissues, and further validated results of the ICGC dataset; qRT-PCR and immunohistochemistry remained consistent (all p < 0.05). Moreover, elevated ADAMTS14 expression was significantly associated with poor OS (p < 0.001). Through univariate/multivariate Cox regression analyses, ADAMTS14 was found to be an independent prognostic factor for ccRCC (both p < 0.05) and GSEA identified several signaling pathways including INSULIN, MTOR, and PPAR pathways. The nomogram based on independent prognostic factors was successfully established and well evaluated. Moreover, the expression of ADAMTS14 was remarkably associated with immune checkpoint molecules, tumor mutational burden (TMB), immune cells, and tumor immune microenvironment (all p < 0.05). Results from TIDE and TCIA showed that highly expressed ADAMTS14 could predict worse efficacy of immunotherapy (all p < 0.05). As for its potential mechanisms, we also revealed several LncRNA/RNA binding protein (RBP)/ADAMTS14 mRNA networks. Conclusions: ADAMTS14 was found to play oncogenic roles in ccRCC and to be significantly associated with immunity. Several LncRNA/RBP/ADAMTS14 mRNA networks were also identified for its potential mechanisms.

The Prognostic Assessment of CDC20 in Patients with Renal Clear Cell Carcinoma and Its Relationship with Body Immunity.

This article analyzes the relationship between cell division cycle (CDC20) molecules and oncology outcomes in patients with renal clear cell carcinoma (KIRC). CDC20 appears to act as a regulatory protein interacting with many other proteins at multiple points in the cycle. The RNA sequencing data and corresponding clinical information of CDC20 molecules were obtained from The Cancer Genome Atlas (TCGA) database. The expression of CDC20 in kidney renal clear cell carcinoma tissue and adjacent normal tissue was detected by immunohistochemical methods. Logistic analysis was performed to analyze the role of CDC20 in the clinicopathological characteristics and prognosis of KIRC. Gene Set Enrichment Analysis (GSEA) was used to identify the signal pathways which were related to CDC20. Independent prognostic factors were evaluated using univariate and multivariate Cox regression analysis. A nomogram involved in CDC20 expression and clinicopathological variables was conducted to predict overall survival (OS) in KIRC patients at 1, 3, and 5 years. Furthermore, the relation between CDC20 and immunity was also studied. Our results showed that CDC20 was upregulated in kidney renal clear cell carcinoma tissues, accompanying shorter OS (all P < 0.05). According to the results obtained by immunohistochemistry and TCGA database, CDC20 was significantly upregulated in kidney renal clear cell carcinoma tissues compared with neighboring normal kidney tissues. Univariate and multivariate Cox regression analysis showed that high expression of CDC20 was an independent prognostic factor of poor prognosis in kidney renal clear cell carcinoma patients (all P < 0.05). GSEA analysis suggested that the high expression of CDC20 was related to eight multiple signaling pathways. In addition, CDC20 was linked to tumour mutation burden (TMB), immune checkpoint molecules, tumour microenvironment, and immunological infiltration.

Chromatin regulators-related lncRNA signature predicting the prognosis of kidney renal clear cell carcinoma and its relationship with immune microenvironment: A study based on bioinformatics and experimental validation.

Background: Kidney Renal Clear cell carcinoma (KIRC) is a major concern in the urinary system. A lot of researches were focused on Chromatin Regulators (CRs) in tumors. In this study, CRs-related lncRNAs (CRlncRNAs) were investigated for their potential impact on the prognosis of KIRC and the immune microenvironment. Methods: The TCGA database was used to obtain transcriptome and related clinical information. CRs were obtained from previous studies, whereas CRlncRNAs were obtained by differential and correlation analysis. We screened the lncRNAs for the signature construction using regression analysis and LASSO regression analysis. The effectiveness of the signature was evaluated using the Kaplan-Meier (K-M) curve and Receiver Operating Characteristic curve (ROC). Additionally, we examined the associations between the signature and Tumor Microenvironment (TME), and the efficacy of drug therapy. Finally, we further verified whether these lncRNAs could affect the biological function of KIRC cells by functional experiments such as CCK8 and transwell assay. Results: A signature consisting of 8 CRlncRNAs was constructed to predict the prognosis of KIRC. Quantitative Real-Time PCR verified the expression of 8 lncRNAs at the cell line and tissue level. The signature was found to be an independent prognostic indicator for KIRC in regression analysis. This signature was found to predict Overall Survival (OS) better for patients in the subgroups of age, gender, grade, stage, M, N0, and T. Furthermore, a significant correlation was found between riskScore and immune cell infiltration and immune checkpoint. Finally, we discovered several drugs with different IC50 values in different risk groups using drug sensitivity analysis. And functional experiments showed that Z97200.1 could affect the proliferation, migration and invasion of KIRC cells. Conclusion: Overall, the signature comprised of these 8 lncRNAs were reliable prognostic biomarkers for KIRC. Moreover, the signature had significant potential for assessing the immunological landscape of tumors and providing individualized treatment.

A Novel Nine Apoptosis-Related Genes Signature Predicting Overall Survival for Kidney Renal Clear Cell Carcinoma and its Associations with Immune Infiltration.

Background: This study was designed to establish a sensitive prognostic model based on apoptosis-related genes to predict overall survival (OS) in patients with clear cell renal cell carcinoma (ccRCC). Methods: Obtaining the expression of apoptosis-related genes and associated clinical parameters from online datasets (The Cancer Genome Atlas, TCGA), their biological function analyses were performed through differently expressed genes. By means of LASSO, unadjusted and adjusted Cox regression analyses, this predictive signature was constructed and validated by internal and external databases (both TCGA and ArrayExpress). Results: A total of nine apoptosis-related genes (SLC27A2, TNFAIP2, IFI44, CSF2, IL4, MDK, DOCK8, WNT5A, APP) were ultimately screened as associated hub genes and utilized to construct a prognosis model. Then our constructed riskScore model significantly passed the validation in both the internal and external datasets of OS (all p < 0.05) and verified their expressions by qRT-PCR. Moreover, we conducted the Receiver Operating Characteristic (ROC), finding the area under the ROC curves (AUCs) were all above 0.70 which indicated that riskScore was a stable independent prognostic factor (p < 0.05). Furthermore, prognostic nomograms were established to figure out the relationship between 1-, 3- and 5-year OS and individual parameters for ccRCC patients. Additionally, survival analyses indicated that our riskScore worked well in predicting OS in subgroups of age, gender, grade, stage, T, M, N0, White (all p < 0.05), except for African, Asian and N1 (p > 0.05). We also explored its association with immune infiltration and applied cMap database to seek out highly correlated small molecule drugs. Conclusion: Our study successfully constructed a prognostic model containing nine hub apoptosis-related genes for ccRCC, helping clinicians predict patients' OS and making the prognostic assessment more standardized. Future prospective studies are required to validate our findings.

CircHAS2 promotes the proliferation, migration, and invasion of gastric cancer cells by regulating PPM1E mediated by hsa-miR-944.

Gastric cancer (GC) is considered one of the most common gastrointestinal malignancies worldwide. Circular RNAs (circRNAs) are a new class of endogenous noncoding RNAs, which can be used as biomarkers and therapeutic targets for many tumors. However, the role and potential regulatory mechanisms of circRNAs in GC remain unclear. In this study, we demonstrated that a specific circRNA, circHAS2, was upregulated in GC tissues and cells and was positively correlated with tumor metastasis. In vitro experiments demonstrated that circHAS2 knockdown or the addition of hsa-miR-944 mimics inhibited the proliferation, migration, and invasion ability of GC cells and affected the epithelial-mesenchymal transition. In addition, hsa-miR-944 interacted with protein phosphatase, Mg2+/Mn2+-dependent 1E (PPM1E), and was found to be a target gene of circHAS2. The upregulation of PPM1E reversed the effects of circHAS2 knockout on GC cells. The circHAS2/hsa-miR-944/PPM1E axis may be involved in the progression of GC; thus, circHAS2 may be a potential biomarker and therapeutic target for GC.

Persulfate enhanced electrochemical oxidation of highly toxic cyanide-containing organic wastewater using boron-doped diamond anode.

Cyanide-containing organic wastewater is discharged in large quantities by coking, electroplating and pharmaceutical industries, which seriously endangers environmental safety and human health. In this paper, Electrochemical Oxidation-Persulfate (EO-PS) Advanced Oxidation Process (AOP) was firstly used to treat high concentration cyanide-containing organic wastewater obtained from a chemical enterprise. The potential application of this process in the treatment of high concentration cyanide-containing organic wastewater was explored for the first time, and the effects of current density, initial pH, temperature and initial concentration on chemical oxygen demand (COD), total organic carbon (TOC) and total cyanide (CN-) removal in wastewater were systematically investigated. The results shown that the EO-PS process had an excellent removal effect on organics and cyanide in high concentration cyanide-containing organic wastewater which contained 11,290 mg L-1 COD, 4456 mg L-1 TOC and 1280.15 mg L-1 CN-. The COD, TOC and CN- removal at optimized operating parameters for 24 h were 95.8%, 87.8% and 98.4%, respectively. The corresponding electrical energy per order was only 41.6 kWh m-3 order-1. In addition, the pollutants removal can be accelerated under conditions of high current density, acidic solution, appropriate temperature and low pollutant concentration, among which low current density, low pH, appropriate temperature and low pollutant concentration can effectively diminish energy consumption. Cyanide, COD and TOC degradation in all reaction conditions followed the pseudo-first-order kinetic model.