A comprehensive survival and prognosis analysis of GPR55 expression in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common subtype, accounting for about 90% of all primary liver cancers. The liver is rich in a large number of immune cells, thus forming a special immune microenvironment, which plays a key role in the occurrence and development of hepatocellular carcinoma. Nowadays, tumor immunotherapy has become one of the most promising cancer treatment methods. Immune checkpoint inhibitors (ICIs) combined with VEGF inhibitors are listed as first-line treatment options for advanced HCC. Therefore, the search for a potential biomarker to predict the response to immunotherapy in HCC patients is urgently needed. The G protein-coupled receptor 55 (GPR55), a lysophosphatidylinositol (LPI) receptor, has recently emerged as a potential new target for anti-tumor therapy. Previous studies have found that GPR55 is highly expressed in breast cancer, pancreatic cancer, skin cancer and cholangiocarcinoma, and is involved in tumor proliferation and migration. However, the role and mechanism of GPR55 in HCC has not been elucidated. Therefore, this article discusses the clinical significance of GPR55 in HCC and its correlation with the immune response of HCC patients, so as to provide theoretical basis for improving the prognosis of HCC.

Classification and clinical significance of the posterior group of renal calyces.

To study the anatomical orientation of the posterior group of calyces based on reconstructed images of computerized tomography urography (CTU) and provide a novel classification with its clinical significance. Clinical data of a total of 1321 patients, who underwent CTU examination in our hospital were retrospectively analyzed. Among these, a total of 2642 3-dimensional reconstructed images of CTU scans were considered in this study. Based on the morphology of the renal calyces and the influence on the establishment of surgical access, the posterior group renal calyces are classified into 3 major types including pot-belly type, classically branched and elongated branched. The classically branched type is further classified into 3 sub-types: a, b and c, based on the association of minor calyces of the posterior group to the major calyces. Type a is derived from 1 group of major calyces only, type b is derived from 2 groups of major calyces simultaneously, and type c is derived from 3 groups of major calyces simultaneously. Statistical findings revealed that all kidneys possess posterior group calyces. The percentage of occurrence of pot-belly type, classically branched and elongated branched is 8.06%, 73.13%, and 18.81%, respectively. The anatomical typing of the classical branching type occurred in 19.36%, 68.17%, and 12.47% for types a, b, and c, respectively. In this study, the posterior group calyces were found to be present across all patients. The posterior group calyces were highest in the classical branching type, of which anatomical typing was highest in type b. The typing of the posterior group of calyces could provide an anatomical basis for percutaneous nephrolithotomy (PCNL) puncture from the posterior group.

MiR-132-3p activation aggravates renal ischemia-reperfusion injury by targeting Sirt1/PGC1alpha axis.

The pathogenesis of renal ischemic diseases remains unclear. In this study, we demonstrate the induction of microRNA-132-3p (miR-132-3p) in ischemic acute kidney injury (AKI) and cultured renal tubular cells under oxidative stress. miR-132-3p mimic increased apoptosis in renal tubular cells and enhanced ischemic AKI in mice, whereas miR-132-3p inhibition offered protective effects. We analyzed miR-132-3p target genes through bioinformatic analysis and Sirt1 was predicted as the target gene of miR-132-3p. Luciferase microRNA target reporter assay further verified Sirt1 as a direct target of miR-132-3p. In cultured tubular cells and mouse kidneys, IRI and H2O2 treatment repressed Sirt1 and PGC-1α/NRF2/HO-1 expression, whereas anti-miR-132-3p preserved Sirt1 and PGC-1α/NRF2/HO-1 expression. In renal tubular, Sirt1 inhibitor suppressed PGC1-1α/NRF2/HO-1 expression and aggravated tubular apoptosis. Together, the results suggest that miR-132-3p induction aggravates ischemic AKI and oxidative stress by repressing Sirt1 expression, and miR-132-3p inhibition offers renal protection and may be a potential therapeutic target.

Analysis of potential immune-related genes involved in the pathogenesis of ischemia-reperfusion injury following liver transplantation.

Background: Hepatic ischemia-reperfusion (I/R) injury is an unavoidable pathological process that occurs after liver transplantation. However, the immune-related molecular mechanism still remains unclear. This study aims to further explore the biological mechanisms of immune-related genes in hepatic I/R injury. Methods: Gene microarray data was downloaded from the Gene Expression Omnibus (GEO) expression profile database and the differentially expressed genes (DEGs) were taken for intersection. After identifying common DEGs, functional annotation, protein-protein interaction (PPI) network, and modular construction were performed. The immune-related hub genes were obtained, which their upstream transcription factors and non-RNAs were predicted. Validation of the hub genes expression and immune infiltration were performed in a mouse model of hepatic I/R injury. Results: A total of 71 common DEGs were obtained from three datasets (GSE12720, GSE14951, GSE15480). The GO and KEGG enrichment analysis results indicated that immune and inflammatory response played an important role in hepatic I/R injury. Finally, 9 immune-related hub genes were identified by intersecting cytoHubba with immune-related genes, including SOCS3, JUND, CCL4, NFKBIA, CXCL8, ICAM1, IRF1, TNFAIP3, and JUN. Conclusion: Our study revealed the importance of the immune and inflammatory response in I/R injury following liver transplantation and provided new insights into the therapeutic of hepatic I/R injury.

Effect of transmembrane protein 100 on prostate cancer progression by regulating SCNN1D through the FAK/PI3K/AKT pathway.

The effects of transmembrane (TMEM) proteins in the progression of prostate cancer (PCa) remain unknown. This study aims to explore the functions of TMEM100 in PCa. To explore the expression, regulation, and effects of TMEM100 in PCa, two PCa cell lines and 30 PCa tissue samples with adjacent control tissues were examined. Online databases, immunohistochemistry, immunofluorescence, western blot, flow cytometry, colony formation, wound healing, transwell assays, and xenograft mouse models were used to explore effects of TMEM100 relevant to PCa. TMEM100 expression was shown to decrease in PCa patients, and low TMEM100 expression was associated with tumor stage and metastasis. Overexpression of TMEM100 suppressed PCa progression by inhibiting the FAK/PI3K/AKT signaling pathway. Tumor size was smaller in TMEM100 overexpressing PCa cells in xenograft mice than in control mice. We also found that TMEM100 could regulate SCNN1D by inhibiting FAK/PI3K/AKT signaling in PCa cell lines. Taken together, our findings indicate that TMEM100 is a tumor suppressor that plays a vital role in preventing PCa proliferation, migration, and invasion through inhibition of FAK/PI3K/AKT signaling. These studies suggest that TMEM100 can be used as a predictive biomarker and therapeutic target.

Ferroptosis-A New Dawn in the Treatment of Organ Ischemia-Reperfusion Injury.

Ischemia-reperfusion (I/R) is a common pathological phenomenon that occurs in numerous organs and diseases. It generally results from secondary damage caused by the recovery of blood flow and reoxygenation, followed by ischemia of organ tissues, which is often accompanied by severe cellular damage and death. Currently, effective treatments for I/R injury (IRI) are limited. Ferroptosis, a new type of regulated cell death (RCD), is characterized by iron overload and iron-dependent lipid peroxidation. Mounting evidence has indicated a close relationship between ferroptosis and IRI. Ferroptosis plays a significantly detrimental role in the progression of IRI, and targeting ferroptosis may be a promising approach for treatment of IRI. Considering the substantial progress made in the study of ferroptosis in IRI, in this review, we summarize the pathological mechanisms and therapeutic targets of ferroptosis in IRI.

TFAP2C Knockdown Sensitizes Bladder Cancer Cells to Cisplatin Treatment via Regulation of EGFR and NF-κB.

Cisplatin is the first-line chemotherapy for advanced or metastatic bladder cancer. Nevertheless, approximately half of patients with BCa are insensitive to cisplatin therapy or develop cisplatin resistance during the treatment process. Therefore, it is especially crucial to investigate ways to enhance the sensitivity of tumor cells to cisplatin. Transcription factor AP-2 gamma (TFAP2C) is involved in cancer development and chemotherapy sensitivity. However, its relationship with chemotherapy has not been studied in BCa. In this study, we aimed to investigate the therapeutic potential of TFAP2C in human BCa. Results based on TCGA (The Cancer Genome Atlas), GTEx (The Genotype-Tissue Expression) and GEO (Gene Expression Omnibus) data showed that TFAP2C expression was upregulated in BCa tissues and that its high expression was associated with poor prognosis. Meanwhile, we demonstrated the overexpression of TFAP2C in BCa clinical specimens. Subsequently, in vitro, we knocked down TFAP2C in BCa cells and found that TFAP2C knockdown further increased cell cycle arrest and apoptosis caused by cisplatin. In addition, the inhibitory effect of cisplatin on BCa cell migration and invasion was enhanced by TFAP2C knockdown. Our data indicated that cisplatin increased epidermal growth factor receptor (EGFR) and nuclear factor-kappaB (NF-κB) activation levels, but TFAP2C knockdown suppressed this effect. Finally, in vivo data further validated these findings. Our study showed that TFAP2C knockdown affected the activation levels of EGFR and NF-κB and enhanced the anti-tumor effects of cisplatin in vivo and in vitro. This provides a new direction to improve the efficacy of traditional cisplatin chemotherapy.

HO-1 Contributes to Luteolin-Triggered Ferroptosis in Clear Cell Renal Cell Carcinoma via Increasing the Labile Iron Pool and Promoting Lipid Peroxidation.

Ferroptosis, a novel form of regulated cell death characterized by disrupted iron metabolism and the accumulation of lipid peroxides, has exhibited enormous potential in the therapy of cancer particularly clear cell renal cell carcinoma (ccRCC). Luteolin (Lut), a natural flavonoid widely existing in various fruits and vegetables, has been proven to exert potent anticancer activity in vitro and in vivo. However, previous studies on the anticancer mechanism of Lut have been shown in apoptosis but not ferroptosis. In the present study, we identified that Lut substantially inhibited the survival of ccRCC in vitro and in vivo, and this phenomenon was accompanied by excessively increased intracellular Fe2+ and abnormal depletion of GSH. In addition, Lut induced the imbalance of mitochondrial membrane potential, classical morphological alterations of mitochondrial ferroptosis, generation of ROS, and occurrence of lipid peroxidation in an iron-dependent manner in ccRCC cells. However, these alterations induced by Lut could be reversed to some extent by the iron ion chelator deferiprone or the ferroptosis inhibitor ferrostatin-1, indicating that ccRCC cells treated with Lut underwent ferroptosis. Mechanistically, molecular docking further established that Lut probably promoted the heme degradation and accumulation of labile iron pool (LIP) by excessively upregulating the HO-1 expression, which led to the Fenton reaction, GSH depletion, and lipid peroxidation in ccRCC, whereas blocking this signaling pathway evidently rescued the Lut-induced cell death of ccRCC by inhibiting ferroptosis. Altogether, the current study shows that the natural compound monomer Lut exerted anticancer efficacy by excessively upregulating HO-1 expression and activating LIP to trigger ferroptosis in ccRCC and could be a promising and potent drug candidate for ccRCC treatment.

microRNA-486-5p is implicated in the cisplatin-induced apoptosis and acute inflammation response of renal tubular epithelial cells by targeting HAT1.

The proinflammatory property of cisplatin is potentially destructive and contributes to the pathogenesis of acute kidney injury (AKI). The role and upstream regulatory mechanism of histone acetyltransferase 1 (HAT1) in acute kidney inflammation are still unknown. We performed RNA sequencing to filter differentially expressed microRNAs (miRNAs) in the kidney tissue of mice with AKI induced by cisplatin and ischemia-reperfusion. Here, we found that miR-486-5p was upregulated and that the expression of HAT1 was reduced in AKI mouse models and injured human renal proximal tubular epithelial cell (HK-2) model induced by cisplatin. miR-486-5p is implicated in cisplatin-induced kidney damage in vivo. Bioinformatics analysis predicted a potential binding site between miR-486-5p and HAT1. The Luciferase reporter assay and Western blot confirmed that miR-486-5p directly targeted the 3'-untranslated region of HAT1 mRNA and inhibited its expression in the cytoplasm of HK-2 cells. In the in vitro study, inhibiting miR-486-5p reduced apoptosis, and the expression of proinflammatory mediators was induced by cisplatin in HK-2 cells. Simultaneously, the downregulation of miR-486-5p inhibited the activation of the toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB). We further found that HAT1 could inhibit apoptosis and the activation of cisplatin on the TLR4/NF-κB pathway and that the upregulation of miR-486-5p reversed this effect. Therefore, the upregulation of miR-486-5p targeting HAT1 promoted the cisplatin-induced apoptosis and acute inflammation response of renal tubular epithelial cells by activating the TLR4/NF-κB pathway, providing a new basis to highlight the potential intervention of regulating the miR-486-5p/HAT1 axis.

Identification of inflammatory response and alternative splicing in acute kidney injury and experimental verification of the involvement of RNA­binding protein RBFOX1 in this disease.

An increasing number of inflammatory responses and alternative splicing (AS) have been recently reported to be associated with various kidney diseases. The effect of inflammatory response on acute kidney injury (AKI) has not been fully clarified. In the present study, a mouse model of AKI induced by cisplatin and ischemia­reperfusion (IR) was established and genome­wide profiling analysis and identification of differentially expressed genes (DEGs) in kidney tissue was conducted by Gene Ontology (GO) functional analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, protein­protein interaction (PPI) network analysis and RT­qPCR. The results revealed that common DEGs in AKI induced by cisplatin and IR were enriched in the inflammatory response pathway, including hub genes CSF­1, CXCL1, CXCL10, IL­1ß, IL­34, IL­6 and TLR2. AS in AKI was initially reported. Cisplatin­induced AS was enriched in the phosphorylation pathway, involving regulated AS genes CSNK1A1, PAK2, CRK, ADK and IKBKB. IR­induced AS was enriched in apoptosis and proliferation pathways, including DEGs ZDHHC16, BCL2L1 and FGF1 regulated by AS. The ability of RNA­binding proteins (RBPs) to regulate AS was coordinated with the function of context­dependent genetic mechanisms. A total of 49 common differentially expressed RBP genes were screened. RNA binding fox­1 homolog 1 (RBFOX1) was revealed to be the top downregulated gene. The relative levels of RBFOX1 in the nuclei of mouse renal tubular epithelial cells in mRNA and proteins were downregulated by cisplatin and IR. Moreover, the biological functions of RBFOX1 were investigated in human renal proximal tubular epithelial cells (HK­2 cells). Results of in vitro experiments revealed that exogenous RBFOX1 inhibited inflammation and oxidative stress to reduce hypoxia/reoxygenation­induced apoptosis of HK­2 cells. This phenomenon may be related to the inhibition of NF­κB and the activation of the NRF2/HO­1 signaling pathway. In conclusion, the inflammatory cytokines, AS and RBPs in AKI were analyzed in the present study via whole transcriptome sequencing. It was revealed that the RBP gene RBFOX1 was involved in the pathogenesis of AKI. Thus, the present study provided novel insights into the mechanism of AKI pathogenesis.

miR-132-3p promotes the cisplatin-induced apoptosis and inflammatory response of renal tubular epithelial cells by targeting SIRT1 via the NF-κB pathway.

Cisplatin is a highly effective and broad-spectrum anticancer drug for the clinical treatment of solid tumors. However, it causes acute kidney injury (AKI) in patients with cancer. Consequently, its clinical application is limited. The occurrence, development, and prognosis of AKI are closely associated with microRNA (miRNA), which needs validation as a biomarker, especially for the early stages of cisplatin-induced AKI. An example of miRNA is miR-132-3p, which plays important roles in inflammatory responses, cell proliferation, and apoptosis in a variety of diseases. However, variations in its expression, potential mechanisms, and downstream targets in cisplatin-induced AKI remain unclear. This study aimed to investigate the functions of miR-132-3p in cisplatin-induced AKI. Sequencing and qRT-PCR revealed that miR-132-3p was significantly upregulated in cisplatin-induced AKI models of mouse and human proximal renal tubular epithelial (HK-2) cells. Apoptosis and inflammatory responses were significantly suppressed by the inhibition of the miR-132-3p expression in cisplatin-stimulated HK-2 cells, and this suppression was blocked by miR-132-3p mimics. Bioinformatics and dual luciferase reporter gene assay identified the 3'- UTR of SIRT1 mRNA as a direct target of miR-132-3p. RNA-FISH and immunofluorescence co-localization demonstrated that miR-132-3p and SIRT1 directly combined and interacted in the cytoplasm of HK-2 cells. Mechanistically, the SIRT1 expression was suppressed and the NF-κB signaling pathway was activated by the upregulation of miR-132-3p in cisplatin-induced AKI. By contrast, the SIRT1 expression was upregulated after the inhibition of miR-132-3p. The ratios of p-p65/p65 and p-IκBα/IκBα were significantly reduced, and the expression levels of inflammatory biomarkers and apoptotic proteins induced by cisplatin were obviously attenuated. Our results suggested that miR-132-3p exacerbated cisplatin-induced AKI by negatively regulating SIRT1 and activating the NF-κB signaling pathway. Therefore, targeting miR-132-3p might be a potential adjuvant therapy for ameliorating AKI in cisplatin-treated patients.