Systematic analysis of RNASET2 gene as a potential prognostic and immunological biomarker in clear cell renal cell carcinoma.

BACKGROUND: RNASET2 has been identified as an oncogene with anti-angiogenic and immunomodulatory effects in a variety of cancers, but its function in clear cell renal cell carcinoma (ccRCC) is still not well understood. METHODS: The RNASET2 expression matrix was extracted from the The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets and analyzed for diagnostic and prognostic value. RNASET2 mRNA expression was detected by quantitative polymerase chain reaction (qPCR) in ccRCC patients and renal cancer cell lines. Wound healing assay, transwell assay, western blotting, and tube formation assays were used to evaluate the function of RNASET2 in renal cancer in vitro. In addition, transcriptome sequencing was performed on knockdown RNASET2 kidney cancer cells to analyze their potential signaling pathways. Moreover, the immune microenvironment and mutational status were evaluated to predict the potential mechanisms of RNASET2 involvement in renal cancer progression. Sensitivity to common chemotherapeutic and targeted agents was assessed according to the Genomics of Drug Sensitivity in Cancer (GDSC) database. RESULTS: RNASET2 expression was significantly upregulated in ccRCC tissues and renal cancer cell lines, predicting poor prognosis for patients. In vitro experiments showed that silencing RNASET2 inhibited the migration and pro-angiogenic ability of renal cancer cells. Transcriptome sequencing suggested its possible involvement in the remodeling of the immune microenvironment in renal cell carcinoma. Furthermore, bioinformatics analysis and immunohistochemical staining showed that RNASET2 was positively correlated with the infiltration abundance of regulatory T cells. Finally, we mapped the mutational landscape of RNASET2 in ccRCC and found its predictive value for drug sensitivity. CONCLUSIONS: Our results suggest that RNASET2 is a promising biomarker and therapeutic target in ccRCC.

Bioinformatic analysis highlights SNHG6 as a putative prognostic biomarker for kidney renal papillary cell carcinoma.

PURPOSE: Kidney renal papillary cell carcinoma (KIRP) is a highly heterogeneous malignancy and current systemic therapeutic strategies are difficult to achieve a satisfactory outcome for advanced disease. Meanwhile, there is a lack of effective biomarkers to predict the prognosis of KIRP. METHODS: Using TCGA, GTEx, UALCAN, TIMER, TIMER 2.0 and STRING databases, we analyzed the relationship of SNHG6 with KIRP subtypes, tumor-infiltrating immune cells and potential target mRNAs. Based on TCGA data, ROC curves, Kaplan-Meier survival analysis and COX regression analysis were performed to evaluate the diagnostic and prognostic value of SNHG6 in KIRP. Nomogram was used to predict 3- and 5-year disease-specific survival in KIRP patients. In addition, with the help of Genetic ontology and Gene set enrichment analysis, the biological processes and signalling pathways that SNHG6 may be involved in KIRP were initially explored. RESULTS: In patients with KIRP, SNHG6 was significantly upregulated and associated with a more aggressive subtype (lymph node involvement, pathological stage IV, CIMP phenotype) and poor prognosis. The ROC curve showed good diagnostic efficacy (AUC value: 0.828) and the C-index of the Nomogram for predicting DSS at 3 and 5 years was 0.920 (0.898-0.941). In the immune microenvironment of KIRP, SNHG6 expression levels were negatively correlated with macrophage abundance and positively correlated with cancer-associated fibroblasts. Furthermore, SNHG6 may promote KIRP progression by regulating the expression of molecules such as AURKB, NDC80, UBE2C, NUF2, PTTG1, CENPH, SPC25, CDCA3, CENPM, BIRC5, TROAP, EZH2. Last, GSEA suggests that SNHG6 may be involved in the regulation of the PPAR signalling pathway and the SLIT/ROBO signalling pathway. CONCLUSIONS: Our analysis suggests that a high SNHG6 expression status in KIRP is associated with a poorer prognosis for patients, and also elucidates some potential mechanisms contributing to this poorer outcome. This may provide new insights into the treatment and management of KIRP in the foreseeable future.

Upregulation of CENPM is associated with poor clinical outcome and suppression of immune profile in clear cell renal cell carcinoma.

BACKGROUND: The response of advanced clear cell renal cell carcinoma (ccRCC) to immunotherapy is still not durable, suggesting that the immune landscape of ccRCC still needs to be refined, especially as some molecules that have synergistic effects with immune checkpoint genes need to be explored. METHODS: The expression levels of CENPM and its relationship with clinicopathological features were explored using the ccRCC dataset from TCGA and GEO databases. Quantitative polymerase chain reaction (qPCR) analysis was performed to validate the expression of CENPM in renal cancer cell lines. Kaplan-Meier analysis, COX regression analysis and Nomogram construction were used to systematically evaluate the prognostic potential of CENPM in ccRCC. Besides, single gene correlation analysis, protein-protein interaction (PPI) network, genetic ontology (GO), kyoto encyclopedia of genes and genomes (KEGG) and gene set enrichment analysis (GSEA) were used to predict the biological behaviour of CENPM and the possible signalling pathways involved. Finally, a comprehensive analysis of the crosstalk between CENPM and immune features in the tumor microenvironment was performed based on the ssGSEA algorithm, the tumor immune dysfunction and exclusion (TIDE) algorithm, the TIMER2.0 database and the TISIDB database. RESULTS: CENPM was significantly upregulated in ccRCC tissues and renal cancer cell lines and was closely associated with poor clinicopathological features and prognosis. Pathway enrichment analysis revealed that CENPM may be involved in the regulation of the cell cycle in ccRCC and may have some crosstalk with the immune microenvironment in tumors. The ssGSEA algorithm, CIBERSOPT algorithm suggests that CENPM is associated with suppressor immune cells in ccRCC such as regulatory T cells. The ssGSEA algorithm, CIBERSOPT algorithm suggests that CENPM is associated with suppressor immune cells in ccRCC such as regulatory T cells. Furthermore, the TISIDB database provides evidence that not only CENPM is positively associated with immune checkpoint genes such as CTLA4, PDCD1, LAG3, TIGIT, but also chemokines and receptors (such as CCL5, CXCL13, CXCR3, CXCR5) may be responsible for the malignant phenotype of CENPM in ccRCC. Meanwhile, predictions based on the TIDE algorithm support that patients with high CENPM expression have a worse response to immunotherapy. CONCLUSIONS: The upregulation of CENPM in ccRCC predicts a poor clinical outcome, and this malignant phenotype may be associated with its exacerbation of the immunosuppressive state in the tumor microenvironment.

Drought Stress Tolerance in Vegetables: The Functional Role of Structural Features, Key Gene Pathways, and Exogenous Hormones.

The deleterious effects of drought stress have led to a significant decline in vegetable production, ultimately affecting food security. After sensing drought stress signals, vegetables prompt multifaceted response measures, eventually leading to changes in internal cell structure and external morphology. Among them, it is important to highlight that the changes, including changes in physiological metabolism, signal transduction, key genes, and hormone regulation, significantly influence drought stress tolerance in vegetables. This article elaborates on vegetable stress tolerance, focusing on structural adaptations, key genes, drought stress signaling transduction pathways, osmotic adjustments, and antioxidants. At the same time, the mechanisms of exogenous hormones such as abscisic acid (ABA), jasmonic acid (JA), salicylic acid (SA), and ethylene (ET) toward improving the adaptive drought tolerance of vegetables were also reviewed. These insights can enhance the understanding of vegetable drought tolerance, supporting vegetable tolerance enhancement by cultivation technology improvements under changing climatic conditions, which provides theoretical support and technical reference for innovative vegetable stress tolerance breeding and food security.

Combined identification of three lncRNAs in serum as effective diagnostic and prognostic biomarkers for hepatitis B virus-related hepatocellular carcinoma.

Hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC) is a common, highly invasive malignant tumor associated with a high mortality rate. This study aimed to identify the effective diagnostic and prognostic biomarkers for HBV-related HCC. With HBV-related HCC RNA-sequencing data of The Cancer Genome Atlas (TCGA) database, 159 differentially expressed long noncoding RNAs (lncRNAs) between HBV-related HCC and para-carcinoma normal samples were identified, and 12 lncRNAs were eventually assessed for deeper research. Classification analysis developed a three-lncRNA signature of AC005332.5, ELF3-AS1 and LINC00665, which was demonstrated to be the most discriminatory with an AUC (Area under the curve) value of 0.913 (95% CI: 0.8610-0.9665) and verified in validation patients. The expression levels of AC005332.5, ELF3-AS1 and LINC00665 were significantly changed with different tumor stages or grades. Survival analysis revealed that AC005332.5, ELF3-AS1 and LINC00665 were highly associated with the prognosis of overall survival. Additionally, the lncRNA signature yielded statistical significance to predict clinical outcomes independently from other clinical variables in validation patients, as suggested in the multivariate Cox hazards analysis. Conclusively, a three-lncRNA signature of AC005332.5, ELF3-AS1 and LINC00665 may serve as an excellent diagnostic biomarker for HBV-related HCC and potential prognostic significance for HBV-related HCC sufferers.

Gamma-aminobutyric acid (GABA) alleviates salt damage in tomato by modulating Na+ uptake, the GAD gene, amino acid synthesis and reactive oxygen species metabolism.

BACKGROUND: Salt stress is a serious abiotic stress that caused crop growth inhibition and yield decline. Previous studies have reported on the the synthesis of gamma-aminobutyric acid (GABA) and its relationship with plant resistance under various abiotic stress. However, the relationship between exogenous GABA alleviating plant salt stress damage and ion flux, amino acid synthesis, and key enzyme expression remains largely unclear. We investigated plant growth, Na+ transportation and accumulation, reactive oxygen species (ROS) metabolism and evaluated the effect of GABA on amino acids, especially SlGADs gene expression and the endogenous GABA content of tomato (Solanum lycopersicum L.) seedlings treated with or without 5 mmol·L- 1 GABA under 175 mmol·L- 1 NaCl stress. RESULTS: Exogenous application of GABA significantly reduced the salt damage index and increased plant height, chlorophyll content and the dry and fresh weights of tomato plants exposed to NaCl stress. GABA significantly reduced Na+ accumulation in leaves and roots by preventing Na+ influx in roots and transportation to leaves. The transcriptional expression of SlGAD1-3 genes were induced by NaCl stress especially with GABA application. Among them, SlGAD1 expression was the most sensitive and contributed the most to the increase in glutamate decarboxylase (GAD) activity induced by NaCl and GABA application; Exogenous GABA increased GAD activity and amino acid contents in tomato leaves compared with the levels under NaCl stress alone, especially the levels of endogenous GABA, proline, glutamate and eight other amino acids. These results indicated that SlGADs transcriptional expression played an important role in tomato plant resistance to NaCl stress with GABA application by enhancing GAD activity and amino acid contents. GABA significantly alleviated the active oxygen-related injury of leaves under NaCl stress by increasing the activities of antioxidant enzymes and decreasing the contents of active oxygen species and malondialdehyde. CONCLUSION: Exogenous GABA had a positive effect on the resistance of tomato seedlings to salt stress, which was closely associated with reducing Na+ flux from root to leaves, increasing amino acid content and strengthening antioxidant metabolism. Endogenous GABA content was induced by salt and exogenous GABA at both the transcriptional and metabolic levels.

Laparoscopic ureterolithotomy, flexible ureteroscopic lithotripsy and percutaneous nephrolithotomy for treatment of upper urinary calculi in patients with autosomal dominant polycystic kidney disease.

OBJECTIVES: Patients with autosomal dominant polycystic kidney disease (ADPKD) showed relatively high incidence of urinary stones. Enlarged kidneys occupied by cysts could make the stone-removal surgery relatively difficult. This study aimed to compare the efficacy and safety of retroperitoneal laparoscopic ureterolithotomy (RPLU), flexible ureteroscopic lithotripsy (FURL) and percutaneous nephrolithotomy (PCNL) in the ADPKD patients with upper urinary stones. METHODS: In this study, 45 patients with ADPKD who underwent RPLU, FURL and PCNL procedures were evaluated. Demographic and serum parameters, stone features, outcomes and complications were analyzed. RESULTS: 45 patients were included in the present study, 13 received RPLU, 21 received FURL, and 11 received PCNL. There were no significant differences in demographic and serum parameters between the three groups. Stone-free rates of the three approaches are 100%, 85.7% and 90.9%, respectively. Patients who underwent FURL had shorter mean operative time and postoperative hospital stay. Compared to RPLU and PCNL, FURL resulted in fewer complications, but the difference is statistically non-significant. CONCLUSIONS: RPLU, FURL and PCNL are commonly used surgical methods to solve upper urinary calculi in ADPKD patients and could achieve satisfactory stone clearance. Among them, FURL showed a relative high safety and faster recovery.

Comparison of robot-assisted retroperitoneal laparoscopic adrenalectomy versus retroperitoneal laparoscopic adrenalectomy for large pheochromocytoma: a single-centre retrospective study.

BACKGROUND: To evaluate the feasibility and safety of robot-assisted retroperitoneal laparoscopic adrenalectomy (RARLA) for large pheochromocytomas (PHEOs; size≥6 cm) compared with retroperitoneal laparoscopic adrenalectomy (RLA). METHODS: Fifty-one patients who underwent adrenalectomy for large PHEOs between March 2016 and January 2019 were enrolled and divided into two groups, including 32 RLA cases and 19 RARLA cases. We compared the perioperative efficacy and long-term follow-up results between the two groups. RESULTS: Preoperative data, including demographics, comorbidities and tumour characteristics, were similar between the groups. Intraoperatively, the RARLA group had a lower incidence of haemodynamic instability (26.3% vs. 56.2%, P = 0.038) and less intraoperative blood loss (100 ml vs. Two hundred milliliter, P = 0.042) than the RLA group. The groups showed no significant differences in operative time or transfusion rates. Postoperatively, the time to diet resumption, time to ambulation, time to drainage removal and postoperative hospital stay were shorter in the RARLA group than in the RLA group (1 d vs. 2 d, P = 0.027; 1 d vs. 2 d, P = 0.034; 3 d vs. 5 d, P = 0.002; 5 d vs. 6 d, P = 0.02, respectively). The groups exhibited no significant differences in the duration of anaesthetic use, complications, or long-term follow-up results for the blood pressure (BP) improvement rate. CONCLUSIONS: Compared with RLA, RARLA is a safe, feasible and even optimized procedure for large PHEOs.

Long noncoding RNA LINC00339 promotes renal tubular epithelial pyroptosis by regulating the miR-22-3p/NLRP3 axis in calcium oxalate-induced kidney stone.

This study aims to investigate the role of long noncoding RNA (lncRNA) long intergenic nonprotein coding RNA 339 (LINC00339) in regulating renal tubular epithelial pyroptosis in kidney stones and to explore the underlying mechanism. The human renal proximal tubular epithelial (HK-2) cells were treated with calcium oxalate monohydrate (COM) for 72 hours to establish the cell model of renal tubular injury. Relative expression of LINC00339 and miR-22-3p was measured by real-time quantitative reverse transcription polymerase chain reaction. Expression of pyroptosis-related molecules was measured by Western blot analysis (NLRP3, ASC, and cleaved caspase-1 p10) and enzyme-linked immunosorbent assay (interleukin-1ß [IL-1ß] and IL-18). Pyroptosis was also determined by lactate dehydrogenase release and active caspase-1-propidium iodide double staining. Luciferase reporter assays were performed to verify whether miR-22-3p could bind to LINC00339 or NLRP3. We observed increased LINC00339, decreased miR-22-3p, NLRP3 inflammasome activation, and enhanced cell pyroptosis in COM-treated HK-2 cells. Furthermore, overexpression of both LINC00339 and NLRP3 activated NLRP3 inflammasome and promoted pyroptosis in COM-treated HK-2 cells, whereas miR-22-3p mimic and NLRP3 knockdown exerted the opposite effects. Mechanically, LINC00339 functioned as a competitive endogenous RNA by sponging miR-22-3p to facilitate NLRP3 expression. In conclusion, lncRNA LINC00339 promotes cell pyroptosis by sponging miR-22-3p to regulate NLRP3 expression in COM-treated HK-2 cells.

Expression and Regulation of Brain Natriuretic Peptide and Natriuretic Peptide Receptor A (NPR-A) in L6-S1 Dorsal Root Ganglia in a Rat Model of Chronic Nonbacterial Prostatitis.

BACKGROUND The study aimed to investigate the expression of brain natriuretic peptide (BNP) and natriuretic peptide receptor A (NPR-A) in L6-S1 dorsal root ganglia (DRG) in a rat model of chronic nonbacterial prostatitis (CNP). MATERIAL AND METHODS One hundred specific pathogen-free (SPF) male Sprague-Dawley rats were randomly divided into a control group (N=50) and a study group (N=50). The control group underwent prostatic injection of 0.1 ml of normal saline on days 3, 7, 10, 14, and 28. The study group, or rat model of CNP, underwent prostatic injection of 0.1 ml of complete Freund's adjuvant on days 3, 7, 10, 14, and 28. At the end of the study, the rats were euthanized, and the prostate tissues and L6-S1 DRG were removed. Histology was performed on the prostate tissue from the rats in the study group and control group. Real-time fluorescence-based quantitative polymerase chain reaction (PCR) and Western blot were used to study the expression of BNP and NPR-A mRNA and protein in the DRG from the rats in the study group and control group. RESULTS In the rat model of CNP, the expression of BNP and NPR-A were significantly increased in L6-S1 DRG compared with the controls. CONCLUSIONS In a rat model of CNP, the increased expression of BNP and NPR-A in L6-S1 DRG may have a role in pain signaling pathways associated with chronic prostatitis.

Retroperitoneal laparoscopic adrenalectomy with transient renal artery occlusion for large adrenal tumors (≥8 cm).

OBJECTIVES: To analyze our experience in retroperitoneal laparoscopic adrenalectomy (RLA) with transient renal artery occlusion for large adrenal tumors (≥8 cm) and to explore the safety and feasibility of this surgical procedure. METHODS: A retrospective cohort study was conducted with a surgical data review of 18 patients with large adrenal tumors who underwent RLA with transient renal artery occlusion in our hospital. RESULTS: Eighteen patients were treated by RLA with transient occlusion of the renal artery, and none were converted to open adrenalectomy. The renal artery occlusion time, operative time, estimated blood loss, perirenal drainage time, postoperative hospital stay, and postoperative drainage were 7.6 ± 1.0 min, 176.3 ± 49.7 min, 247.2 ± 274.1 mL, 4.1 ± 1.02 days, 6.3 ± 1.4 days, and 73.6 ± 47.9 mL, respectively. No severe complications occurred, with the exception of hemodynamic instability in one patient with a pheochromocytoma and one transfusion during the operation. Only one case of adrenal crisis occurred postoperatively. Pathological examination revealed 9 cases of pheochromocytoma, 6 cases of adrenal myelolipoma, 1 case of adrenal ganglioneuroma, 1 case of hygromata, and 1 case of adrenal teratoma. No recurrence or evidence of metastasis was observed during the 7-to-30-month follow-up period. CONCLUSION: RLA with transient renal artery occlusion is a feasible, effective, and safe treatment for large adrenal tumors (≥8 cm).

Comprehensive Analysis of circRNA, lncRNA, miRNA and mRNA Expression Profiles and Their Competing Endogenous RNA Networks in Hepatitis B Virus-Related Hepatocellular Carcinoma.

Pursuing knowledge about circular RNA (circRNA), long non-coding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA) expression profiles and their competing endogenous RNA (ceRNA) networks in hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC) was the focus of this research. Expression patterns of circRNAs, lncRNAs, miRNAs, and mRNAs were searched for in relation to HBV-related HCC using whole-transcriptome sequencing. The expression levels of chosen circRNA, lncRNA, miRNA, and mRNA were analyzed using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The potential connections and roles of ceRNA were deduced via bioinformatics research. The sum of 284 circRNAs, 2,927 lncRNAs, 693 miRNAs, and 5566 mRNAs were discovered to be expressed at considerably different levels in HBV-related HCC tissue and adjacent normal tissue. And the most significantly up- and down-regulated circRNAs, lncRNAs, miRNAs, and mRNAs were verified in HBV-related HCC by qRT-PCR. The circRNA/miRNA/mRNA and lncRNA/miRNA/mRNA networks of HBV-related HCC were established, and the ceRNA regulatory networks revealed the gene expression mechanisms controlled by ncRNAs. Collectively, we revealed the contribution of various circRNA, lncRNA, miRNA, and mRNA expression profiles and identified their ceRNA regulatory networks in HBV-related HCC, providing a theoretical basis for further exploration.

Types of Membrane Transporters and the Mechanisms of Interaction between Them and Reactive Oxygen Species in Plants.

Membrane transporters are proteins that mediate the entry and exit of substances through the plasma membrane and organellar membranes and are capable of recognizing and binding to specific substances, thereby facilitating substance transport. Membrane transporters are divided into different types, e.g., ion transporters, sugar transporters, amino acid transporters, and aquaporins, based on the substances they transport. These membrane transporters inhibit reactive oxygen species (ROS) generation through ion regulation, sugar and amino acid transport, hormone induction, and other mechanisms. They can also promote enzymatic and nonenzymatic reactions in plants, activate antioxidant enzyme activity, and promote ROS scavenging. Moreover, membrane transporters can transport plant growth regulators, solute proteins, redox potential regulators, and other substances involved in ROS metabolism through corresponding metabolic pathways, ultimately achieving ROS homeostasis in plants. In turn, ROS, as signaling molecules, can affect the activity of membrane transporters under abiotic stress through collaboration with ions and involvement in hormone metabolic pathways. The research described in this review provides a theoretical basis for improving plant stress resistance, promoting plant growth and development, and breeding high-quality plant varieties.

Glucagon-like peptide-1 analogs: Miracle drugs are blooming?

Glucagon-like peptide-1 (GLP-1), secreted by L cells in the small intestine, assumes a central role in managing type 2 diabetes mellitus (T2DM) and obesity. Its influence on insulin secretion and gastric emptying positions it as a therapeutic linchpin. However, the limited applicability of native GLP-1 stems from its short half-life, primarily due to glomerular filtration and the inactivating effect of dipeptidyl peptidase-IV (DPP-IV). To address this, various structural modification strategies have been developed to extend GLP-1's half-life. Despite the commendable efficacy displayed by current GLP-1 receptor agonists, inherent limitations persist. A paradigm shift emerges with the advent of unimolecular multi-agonists, such as the recently introduced tirzepatide, wherein GLP-1 is ingeniously combined with other gastrointestinal hormones. This novel approach has captured the spotlight within the diabetes and obesity research community. This review summarizes the physiological functions of GLP-1, systematically explores diverse structural modifications, delves into the realm of unimolecular multi-agonists, and provides a nuanced portrayal of the developmental prospects that lie ahead for GLP-1 analogs.

Regulatory role of BNP in the spinal center of rats with nonbacterial prostatitis.

BACKGROUND: A growing body of evidence has shown that activating spinal cord glial cells (typically astrocytes and microglial cells) is closely related to hyperpathia and persistent pain. OBJECTIVE: To investigate the expression of GFAP and CR3/CD11b in cornu dorsale medullae spinalis of rats with nonbacterial prostatitis, to explore the therapeutic efficacy and action mechanism of intrathecal injection of BNP alleviating chronic neuropathic pain. METHODS: Eighteen male SPF SD rats were randomly divided into sham operation control group, nonbacterial prostatitis group (NBP) and intrathecal injection BNP group, the NBP model was established by intraprostatic injection of CFA, and the spinal cord of L6-S1 segment was extracted seven days after intrathecal injection of BNP; The expression of GFAP and CR3/CD11b in dorsal horn of spinal cord were detected by immunofluorescence and Western blot. RESULTS: The cumulative optical density values of GFAP and CR3/CD11b immunofluorescence assay in the NBP group were higher than those in the sham operation group, with statistical significance (p⁢ï⁢»â¢ 0.01); The expression of GFAP and CR3/CD11b in intrathecal injection BNP group were lower than those in NBP group, the differences were statistically significant (p⁢ï⁢»â¢ 0.01). Western blot results showed that the expression of GFAP and CR3/CD11B in NBP group were higher than those in sham operation group, with statistical significance (p⁢ï⁢»â¢ 0.05). The expression of GFAP and CR3/CD11B in intrathecal injection BNP group were lower than those in NBP group, the differences were statistically significant (p⁢ï⁢»â¢ 0.05). CONCLUSION: Intrathecal injection of BNP can down-regulate the expressions of GFAP and CR3/CD11b in L6-S1 spinal cord of NBP rat model and to further inhibit chronic pain caused by NBP.

Multidimensional comprehensive and integrated analysis of the potential function of TMEM25 in renal clear cell carcinoma with low expression status.

BACKGROUND: Transmembrane 25(TMEM25) stands out as a potential prognostic biomarker and therapeutic target in the realm of cancer, yet its precise mechanism of action within clear cell renal cell carcinoma (ccRCC) remains unclear. MATERIALS AND METHODS: Gene expression data and clinically relevant information extracted from The Cancer Genome Atlas (TCGA) and Gene expression omnibus (GEO) databases unveil the expression patterns of TMEM25 within renal clear cell carcinoma, which reveals its prognostic and diagnostic significance. The protein expression data is available via the Human Protein Atlas (HPA) database. Further, qPCR experiments conducted on cells and tissues provide strong evidence of the gene's expression status. Additionally, they explore the correlations between TMEM25 expression and DNA methylation, gene mutations, immune cell infiltration, and drug sensitivity within this specific tumor context. RESULTS: At both the RNA and protein levels, TMEM25 displays a noteworthy downregulation in expression, which is consistently linked to an unfavorable prognosis. Receiver Operating Characteristic (ROC) curve analysis, univariate and multivariate Cox regression analyses confirmed the ability of TMEM25 to diagnose and determine prognosis in ccRCC. Its expression related closely with various immune cell types, immune checkpoints, immune inhibitors, and MHC molecules. Within ccRCC tissues, TMEM25 DNA methylation levels are observed to be elevated, and this upregulation is observed across various conditions. TMEM25 mutations also have an impact on the prognosis of ccRCC patients and the results of drug sensitivity analyses are useful for clinical decision-making. CONCLUSIONS: TMEM25 in ccRCC could potentially function as a tumor suppressor gene, holding substantial promise as a novel biomarker for diagnosing, treating, and prognosticating ccRCC patients.

A novel risk signature based on liquid-liquid phase separation-related genes reveals prognostic and tumour microenvironmental features in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma(ccRCC) is one of the most common malignancies. However, there are still many barriers to its underlying causes, early diagnostic techniques and therapeutic approaches. MATERIALS AND METHODS: The Cancer Genome Atlas (TCGA)- Kidney renal clear cell (KIRC) cohort differentially analysed liquid-liquid phase separation (LLPS)-related genes from the DrLLPS website. Univariate and multivariate Cox regression analyses and LASSO regression analyses were used to construct prognostic models. The E-MTAB-1980 cohort was used for external validation. Then, potential functions, immune infiltration analysis, and mutational landscapes were analysed for the high-risk and low-risk groups. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) experiments as well as single-cell analyses validated the genes key to the model. RESULTS: We screened 174 LLPS-related genes in ccRCC and constructed a risk signature consisting of five genes (CLIC5, MXD3, NUF2, PABPC1L, PLK1). The high-risk group was found to be associated with worse prognosis in different subgroups. A nomogram constructed by combining age and tumour stage had a strong predictive power for the prognosis of ccRCC patients. In addition, there were differences in pathway enrichment, immune cell infiltration, and mutational landscapes between the two groups. The results of qRT-PCR in renal cancer cell lines and renal cancer tissues were consistent with the biosignature prediction. Three single-cell data of GSE159115, GSE139555, and GSE121636 were analysed for differences in the presence of these five genes in different cells. CONCLUSIONS: We developed a risk signature constructed based on the five LLPS-related genes and can have a high ability to predict the prognosis of ccRCC patients, further providing a strong support for clinical decision-making.

Astaxanthin alleviates chronic prostatitis/chronic pelvic pain syndrome by increasing colonization of Akkermansia muciniphila in the intestine.

BACKGROUND: Astaxanthin (AST) is a natural compound with anti-inflammatory/immunomodulatory properties that has been found to have probiotic properties. However, the role and mechanism of AST in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) are still not fully understood. PURPOSE: The aim of this study was to evaluate the effect of AST on CP/CPPS and elucidate the mediating role of the gut microbiota. MATERIALS AND METHODS: An experimental autoimmune prostatitis (EAP) mouse model was utilized to test the potential role of AST on CP/CPPS. Antibiotic cocktail (ABX) treatment and fecal microbiota transplantation (FMT) were used to elucidate the gut microbiota-mediated effects on AST. In addition, 16S rRNA gene sequencing and qRT-PCR analyses were used to analyze changes in the gut microbiota of EAP mice and CP/CPPS patients. Finally, the mechanism by which AST exerts a protective effect on CP/CPPS was explored by untargeted metabolomics and gut barrier function assays. RESULTS: Oral administration of AST reduced prostate inflammation scores, alleviated tactile sensitization of the pelvic region in EAP mice, reduced CD4+ T cell and CD68+ macrophage infiltration in the prostatic interstitium, and inhibited the up-regulation of systemic and localized pain/pro-inflammatory mediators in the prostate. After ABX, the protective effect of AST against CP/CPPS was attenuated, whereas colonization with fecal bacteria from AST-treated EAP mice alleviated CP/CPPS. 16S rRNA gene sequencing and qRT-PCR analyses showed that Akkermansia muciniphila in the feces of EAP mice and CP/CPPS patients showed a trend toward a decrease, which was associated with poor progression of CP/CPPS. In contrast, oral administration of AST increased the relative abundance of A. muciniphila, and oral supplementation with A. muciniphila also alleviated inflammation and pain in EAP mice. Finally, we demonstrated that both AST and A. muciniphila interventions increased serum levels of SCFAs acetate, up-regulated expression of colonic tight junction markers, and decreased serum lipopolysaccharide levels in EAP mice. CONCLUSION: Our results showed that AST improved CP/CPPS by up-regulating A. muciniphila, which provides new potentially effective strategies and ideas for CP/CPPS management.

Novel GLP-1(28-36) amide-derived hybrid peptide A3 with weight loss and hypoglycemic activities.

Glucagon-like peptide-1 (GLP-1) has gained much attention in the last decade for the treatment of type 2 diabetes. Accumulating evidence indicates that some metabolites of GLP-1 have biological activities that might contribute to the pleiotropic effects of GLP-1 independent of the GLP-1 receptor. The hypoglycemic and weight-reducing effects of the reported metabolites and modifications still need to be confirmed. In this study, we started from the C-terminal nonapeptide GLP-1(28-36) amide and developed a series of GLP-1(28-36) amide-derived hybrid peptides. Our findings of biological activity evaluation in INS-1 cells, streptozotocin-induced diabetic and diet-induced obesity mice confirmed a novel hybrid peptide, A3, and provided a new perspective in the development of new drugs from peptide metabolites.

Development of a TGF-ß signaling-related genes signature to predict clinical prognosis and immunotherapy responses in clear cell renal cell carcinoma.

Background: Transforming growth factor (TGF)-ß signaling is strongly related to the development and progression of tumor. We aimed to construct a prognostic gene signature based on TGF-ß signaling-related genes for predicting clinical prognosis and immunotherapy responses of patients with clear cell renal cell carcinoma (ccRCC). Methods: The gene expression profiles and corresponding clinical information of ccRCC were collected from the TCGA and the ArrayExpress (E-MTAB-1980) databases. LASSO, univariate and multivariate Cox regression analyses were conducted to construct a prognostic signature in the TCGA cohort. The E-MTAB-1980 cohort were used for validation. Kaplan-Meier (K-M) survival and time-dependent receiver operating characteristic (ROC) were conducted to assess effectiveness and reliability of the signature. The differences in gene enrichments, immune cell infiltration, and expression of immune checkpoints in ccRCC patients showing different risks were investigated. Results: We constructed a seven gene (PML, CDKN2B, COL1A2, CHRDL1, HPGD, CGN and TGFBR3) signature, which divided the ccRCC patients into high risk group and low risk group. The K-M analysis indicated that patients in the high risk group had a significantly shorter overall survival (OS) time than that in the low risk group in the TCGA (p < 0.001) and E-MTAB-1980 (p = 0.012). The AUC of the signature reached 0.77 at 1 year, 0.7 at 3 years, and 0.71 at 5 years in the TCGA, respectively, and reached 0.69 at 1 year, 0.72 at 3 years, and 0.75 at 5 years in the E-MTAB-1980, respectively. Further analyses confirmed the risk score as an independent prognostic factor for ccRCC (p < 0.001). The results of ssGSEA that immune cell infiltration degree and the scores of immune-related functions were significantly increased in the high risk group. The CIBERSORT analysis indicated that the abundance of immune cell were significantly different between two risk groups. Furthermore, The risk score was positively related to the expression of PD-1, CTLA4 and LAG3.These results indicated that patients in the high risk group benefit more from immunotherapy. Conclusion: We constructed a novel TGF-ß signaling-related genes signature that could serve as an promising independent factor for predicting clinical prognosis and immunotherapy responses in ccRCC patients.