Comparison of Protective Effect of Tri-circulator and Coenzyme Q10 on Myocardial Injury and the Mechanism Study by Zebrafish Model.

Tri-Circulator (TC) is a product comprising coenzyme Q10 (CoQ10), Salvia miltiorrhiza, and Panax notoginseng. Individually, each of these constituents has demonstrated protective effects on myocardial injury. The purpose of this study is to evaluate the protective efficacy of TC on heart function and compare the differential effects between CoQ10 and TC. Two myocardial injury models of zebrafish, the hypoxia-reoxygenation model (H/R) and the isoproterenol (ISO, a ß-receptor agonist) model, were used in this experiment. The zebrafish subjects were divided into 4 groups: control, H/R, TC, and CoQ10. Heart rate, stroke volume (SV), cardiac output (CO), ejection fraction (EF), fractional area change (FAC), and pericardial height were monitored to assess changes in heart function. The gene expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) was studied as markers of injury/stress. TC significantly suppresses elevated heart rate induced by H/R and prevents the decrease of heart rate induced by ISO. It alleviates the pericardial infusion induced by ISO, whereas CoQ10 does not possess a similar effect. Both TC and CoQ10 significantly inhibit the decline in SV, CO, EF, and FAC induced by H/R and ISO, and suppress the expression of ANP and BNP in cardiomyocytes induced by ISO. It is noteworthy that TC demonstrates a more pronounced effect on EF, FAC, ANP, and BNP gene expression compared to CoQ10. Both TC and CoQ10 have a protective effect on myocardial injury of zebrafish. However, TC exhibits a greater efficacy compared to CoQ10 alone in mitigating myocardial injury.

SHMT as a Potential Therapeutic Target for Renal Cell Carcinoma.

BACKGROUND: Serine hydroxymethyltransferase (SHMT) is a serine-glycine-one-carbon metabolic enzyme in which SHMT1 and SHMT2 encode the cytoplasmic and mitochondrial isoenzymes, respectively. SHMT1 and SHMT2 are key players in cancer metabolic reprogramming, and thus are attractive targets for cancer therapy. However, the role of SHMT in patients with renal cell carcinoma (RCC) has not been fully elucidated. We aimed to systematically analyze the expression, gene regulatory network, prognostic value, and target prediction of SHMT1 and SHMT2 in patients with kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), and kidney renal papillary cell carcinoma (KIRP); elucidate the association between SHMT expression and RCC; and identify potential new targets for clinical RCC treatment. METHODS: Several online databases were used for the analysis, including cBioPortal, TRRUST, GeneMANIA, GEPIA, Metascape, UALCAN, LinkedOmics, and TIMER. RESULTS: SHMT1 and SHMT2 transcript levels were significantly down- and upregulated, respectively, in patients with KICH, KIRC, and KIRP, based on sample type, individual cancer stage, sex, and patient age. Compared to men, women with KIRC and KIRP showed significantly up- and downregulated SHMT1 transcript levels, respectively. However, SHMT2 transcript levels were significantly upregulated in the patients mentioned above. KIRC and KIRP patients with high SHMT1 expression had longer survival periods than those with low SHMT1 expression. In patients with KIRC, the findings were similar to those mentioned above. However, in KICH patients, the findings were the opposite regarding SHMT2 expression. SHMT1 versus SHMT2 were altered by 9% versus 3% (n = 66 KICH patients), 4% versus 4% (n = 446 KIRC patients), and 6% versus 7% (n = 280 KIRP patients). SHMT1 versus SHMT2 promoter methylation levels were significantly up- and downregulated in patients with KIRP versus KIRC and KIRP, respectively. SHMT1, SHMT2, and their neighboring genes (NG) formed a complex network of interactions. The molecular functions of SHMT1 and its NG in patients with KICH, KIRC, and KIRP, included clathrin adaptor, metalloendopeptidase, and GTPase regulator activities; lipid binding, active transmembrane transporter activity, and lipid transporter activity; and type I interferon receptor binding, integrin binding, and protein heterodimerization, respectively. Their respective Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were involved in lysosome activity, human immunodeficiency virus 1 infection, and endocytosis; coronavirus disease 2019 and neurodegeneration pathways (multiple diseases); and RIG-I-like receptor signaling pathway, cell cycle, and actin cytoskeleton regulation. The molecular functions of SHMT2 and its NG in patients with KICH, KIRC, and KIRP included cell adhesion molecule binding and phospholipid binding; protein domain-specific binding, enzyme inhibitor activity, and endopeptidase activity; and hormone activity, integrin binding, and protein kinase regulator activity, respectively. For patients with KIRC versus KIRP, the KEGG pathways were involved in cAMP and calcium signaling pathways versus microRNAs (MiRNAs) in cancer cells and neuroactive ligand-receptor interactions, respectively. We identified the key transcription factors of SHMT1 and its NG. CONCLUSIONS: SHMT1 and SHMT2 expression levels were different in patients with RCC. SHMT1 and SHMT2 may be potential therapeutic and prognostic biomarkers in these patients. Transcription factor (MYC, STAT1, PPARG, AR, SREBF2, and SP3) and miRNA (miR-17-5P, miR-422, miR-492, miR-137, miR-30A-3P, and miR-493) regulations may be important strategies for RCC treatment.

Liver cirrhosis following oxaliplatin-based adjuvant chemotherapy for rectal cancer.

INTRODUCTION: Oxaliplatin is a third-generation platinum-based antineoplastic drug that is widely used to treat patients with colorectal cancer. Reported adverse reactions include hepatic sinusoidal obstruction syndrome and liver fibrosis, but there are few reports of cirrhosis associated with chemotherapy. In addition, the pathogenesis of cirrhosis remains unclear. CASE REPORT: We report a case of suspected oxaliplatin-induced liver cirrhosis, an adverse reaction that has not been previously reported. MANAGEMENT AND OUTCOME: A 50-year-old Chinese man was diagnosed with rectal cancer and underwent laparoscopic radical rectal cancer surgery. The patient had a history of schistosomiasis, but history and serology showed no evidence of chronic liver disease. However, after five oxaliplatin-based chemotherapy cycles, the patient presented dramatic changes in liver morphology and developed splenomegaly, massive ascites, and elevated CA125 levels. Four months after discontinuing oxaliplatin, the patient's ascites had decreased significantly and CA125 levels declined from 505.3 to 124.6 mU/mL. After 15 weeks of follow-up, CA125 levels decreased to the normal range, and there has been no increase in ascites in this patient. DISCUSSION: Oxaliplatin-induced cirrhosis may be a serious complication and should be discontinued based on clinical evidence.

Systematic analysis of the BET family in adrenocortical carcinoma: The expression, prognosis, gene regulation network, and regulation targets.

Background: Bromodomain and extracellular terminal (BET) family (including BRD2, BRD3, and BRD4) is considered to be a major driver of cancer cell growth and a new target for cancer therapy. Currently, more than 30 targeted inhibitors have shown significant inhibitory effects against various tumors in preclinical and clinical trials. However, the expression levels, gene regulatory networks, prognostic value, and target prediction of BRD2, BRD3, and BRD4 in adrenocortical carcinoma (ACC) have not been fully elucidated. Therefore, this study aimed to systematically analyze the expression, gene regulatory network, prognostic value, and target prediction of BRD2, BRD3, and BRD4 in patients with ACC, and elucidated the association between BET family expression and ACC. We also provided useful information on BRD2, BRD3, and BRD4 and potential new targets for the clinical treatment of ACC. Methods: We systematically analyzed the expression, prognosis, gene regulatory network, and regulatory targets of BRD2, BRD3, and BRD4 in ACC using multiple online databases, including cBioPortal, TRRUST, GeneMANIA, GEPIA, Metascape, UALCAN, LinkedOmics, and TIMER. Results: The expression levels of BRD3 and BRD4 were significantly upregulated in ACC patients at different cancer stages. Moreover, the expression of BRD4 was significantly correlated with the pathological stage of ACC. ACC patients with low BRD2, BRD3, and BRD4 expressions had longer survival than patients with high BRD2, BRD3, and BRD4 expressions. The expression of BRD2, BRD3, and BRD4 was altered by 5%, 5%, and 12% in 75 ACC patients, respectively. The frequency of gene alterations in the 50 most frequently altered BRD2, BRD3, and BRD4 neighboring genes in these ACC patients were ≥25.00%, ≥25.00%, and ≥44.44%, respectively. BRD2, BRD3, and BRD4 and their neighboring genes form a complex network of interactions mainly through co-expression, physical interactions, and shared protein domains. Molecular functions related to BRD2, BRD3, and BRD4 and their neighboring genes mainly include protein-macromolecule adaptor activity, cell adhesion molecule binding, and aromatase activity. Chemokine signaling pathway, thiamine metabolism, and olfactory transduction were found to be enriched as per the KEGG pathway analysis. SP1, NPM1, STAT3, and TP53 are key transcription factors for BRD2, BRD4, and their neighboring genes. MiR-142-3P, miR-484, and miR-519C were the main miRNA targets of BRD2, BRD3, BRD4, and their neighboring genes. We analyzed the mRNA sequencing data from 79 patients with ACC and found that ZSCAN12, DHX16, PRPF4B, EHMT1, CDK5RAP2, POMT1, WIZ, ZNF543, and AKAP8 were the top nine genes whose expression were positively associated with BRD2, BRD3, and BRD4 expression. The expression level of BRD2, BRD3, and BRD4 positively correlated with B cell and dendritic cell infiltration levels. BRD4-targeted drug PFI-1 and (BRD2, BRD3, and BRD4)-targeted drug I-BET-151 may have good inhibitory effects on the SW13 cell line. Conclusions: The findings of this study provide a partial basis for the role of BRD2, BRD3, and BRD4 in the occurrence and development of ACC. In addition, this study also provides new potential therapeutic targets for ACC, which can serve as a reference for future basic and clinical research.

Systematic Analysis of CXC Chemokine-Vascular Endothelial Growth Factor A Network in Colonic Adenocarcinoma from the Perspective of Angiogenesis.

Background: Tumor angiogenesis plays a vital role in tumorigenesis, proliferation, and metastasis. Recently, vascular endothelial growth factor A (VEGFA) and CXC chemokines have been shown to play vital roles in angiogenesis. Exploring the expression level, gene regulatory network, prognostic value, and target prediction of the CXC chemokine-VEGFA network in colon adenocarcinoma (COAD) is crucial from the perspective of tumor angiogenesis. Methods: In this study, we analyzed gene expression and regulation, prognostic value, target prediction, and immune infiltrates related to the CXC chemokine-VEGFA network in patients with COAD using multiple databases (cBioPortal, UALCAN, Human Protein Atlas, GeneMANIA, GEPIA, TIMER (version 2.0), TRRUST (version 2), LinkedOmics, and Metascape). Results: Our results showed that CXCL1/2/3/5/6/8/11/16/17 and VEGFA were markedly overexpressed, while CXCL12/13/14 were underexpressed in patients with COAD. Moreover, genetic alterations in the CXC chemokine-VEGFA network found at varying rates in patients with COAD were as follows: CXCL1/2/17 (2.1%), CXCL3/16 (2.6%), CXCL5/14 (2.4%), CXCL6 (3%), CXCL8 (0.8%), CXCL11/13 (1.9%), CXCL12 (0.6%), and VEGFA (1.3%). Promoter methylation of CXCL1/2/3/11/13/17 was considerably lower in patients with COAD, whereas methylation of CXCL5/6/12/14 and VEGFA was considerably higher. Furthermore, CXCL9/10/11 and VEGFA expression was notably correlated with the pathological stages of COAD. In addition, patients with COAD with high CXCL8/11/14 or low VEGFA expression levels survived longer than patients with dissimilar expression levels. CXC chemokines and VEGFA form a complex regulatory network through coexpression, colocalization, and genetic interactions. Moreover, many transcription factor targets of the CXC chemokine-VEGFA network in patients with COAD were identified: RELA, NFKB1, ZFP36, XBP1, HDAC2, SP1, ATF4, EP300, BRCA1, ESR1, HIF1A, EGR1, STAT3, and JUN. We further identified the top three miRNAs involved in regulating each CXC chemokine within the network: miR-518C, miR-369-3P, and miR-448 regulated CXCL1; miR-518C, miR-218, and miR-493 regulated CXCL2; miR-448, miR-369-3P, and miR-221 regulated CXCL3; miR-423 regulated CXCL13; miR-378, miR-381, and miR-210 regulated CXCL14; miR-369-3P, miR-382, and miR-208 regulated CXCL17; miR-486 and miR-199A regulated VEGFA. Furthermore, the CXC chemokine-VEGFA network in patients with COAD was notably associated with immune infiltration. Conclusions: This study revealed that the CXC chemokine-VEGFA network might act as a prognostic biomarker for patients with COAD. Moreover, our study provides new therapeutic targets for COAD, serving as a reference for further research in the future.

System analysis of FHIT in LUAD and LUSC: The expression, prognosis, gene regulation network, and regulation targets.

BACKGROUND: Fragile histidine triad (FHIT) is a strong tumor suppressor gene, and cells deficient in FHIT are prone to acquiring cancer-promoting mutations. Due to its location, deletions within FHIT are common in cancer. Over 50% of cancers show loss of FHIT expression. However, to date, expression levels, gene regulatory networks, prognostic value, and target prediction of FHIT in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) have not been fully reported. Therefore, systematic analysis of FHIT expression, gene regulatory network, prognostic value, and targeted prediction in patients with LUAD and LUSC has important guiding significance, providing new therapeutic targets and strategies for clinical treatment of lung cancer to further improve the therapeutic effect of lung cancer. METHODS: Multiple free online databases were used for the abovementioned analysis in this study, including cBioPortal, TRRUST, Human Protein Atlas, GeneMANIA, GEPIA, Metascape, UALCAN, LinkedOmics, and TIMER. RESULTS: FHIT was upregulated in patients with LUAD, and downregulated in patients with LUSC. Genetic alterations of FHIT were found in patients with LUAD (7%), and LUSC (10%). The promoter methylation of FHIT was lower in patients with LUAD and LUSC. FHIT expression significantly correlated with LUSC pathological stages. Furthermore, patients with LUAD and LUSC having low FHIT expression levels had a longer survival than those having high FHIT expression levels. FHIT and its neighboring genes (the 50 most frequently altered neighboring genes of FHIT) functioned in the regulation of protein kinase and DNA binding in patients with LUAD, as well as cell channels and membrane potential in patients with LUSC. Gene ontology enrichment analysis revealed that the functions of FHIT and its neighboring genes are mainly related to disordered domain-specific binding, protein kinase binding, and ion gated channel activity in patients with LUAD, as well as calcium ion binding and intracellular ligand-gated ion channel activity in patients with LUSC. Transcription factor targets of FHIT and its neighboring genes in patients with lung cancer were found: USF1, SOX6, USF2, SIRT1, VHL, LEF1, EZH2, TP53, HDAC1, ESR1, EGR1, YY1, MYC, RELA, NFKB1, and E2F1 in LUAD; and HDAC1, DNMT1, and E2F1 in LUSC. We further explored the FHIT-associated kinase (PRKCQ, AURKB and ATM in LUAD as well as PLK3 in LUSC) and FHIT-associated miRNA targets (MIR-188, MIR-323, and MIR-518A-2 in LUAD). Furthermore, the following genes had the strongest correlation with FHIT expression in patients with lung cancer: NICN1, HEMK1, and BDH2 in LUAD, and ZMAT1, TTC21A, and NICN1 in LUSC. FHIT expression was positively associated with immune cell infiltration (B cell) in patients with LUAD, as well as B cell, CD8 + T, CD4 + T cells, macrophages, and dendritic cells in patients with LUSC. Nevertheless, FHIT expression was negatively associated with CD8 + T cells and neutrophils in patients with LUAD. CONCLUSIONS: The expression, gene regulatory network, prognostic value and targeted prediction of FHIT in patients with LUAD and LUSC were systematically analyzed and revealed in this study, thereby laying a foundation for further research on the role of FHIT in LUAD and LUSC occurrence. This study provides new LUAD and LUSC therapeutic targets and prognostic biomarkers as a reference for fundamental and clinical research.

System analysis of VEGFA in renal cell carcinoma: The expression, prognosis, gene regulation network and regulation targets.

BACKGROUND: VEGFA is one of the most important regulators of angiogenesis and plays a crucial role in cancer angiogenesis and progression. Recent studies have highlighted a relationship between VEGFA expression and renal cell carcinoma occurrence. However, the expression level, gene regulation network, prognostic value, and target prediction of VEGFA in renal cell carcinoma remain unclear. Therefore, system analysis of the expression, gene regulation network, prognostic value, and target prediction of VEGFA in patients with renal cell carcinoma is of great theoretical significance as there is a clinical demand for the discovery of new renal cell carcinoma treatment targets and strategies to further improve renal cell carcinoma treatment efficacy. METHODS: This study used multiple free online databases, including cBioPortal, TRRUST, GeneMANIA, GEPIA, Metascape, UALCAN, LinkedOmics, Metascape, and TIMER for the abovementioned analysis. RESULTS: VEGFA was upregulated in patients with kidney renal clear cell carcinoma (KIRC) and kidney chromophobe (KICH), and downregulated in patients with kidney renal papillary cell carcinoma (KIRP). Moreover, genetic alterations of VEGFA were found in patients with renal cell carcinoma as follows: 4% (KIRC), 8% (KICH), and 4% (KIRP). The promoter methylation of VEGFA was lower and higher in patients with clinical stages of KIRC and stage 1 KIRP, respectively. VEGFA expression significantly correlated with KIRC and KIRP pathological stages. Furthermore, patients with KICH and KIRP having low VEGFA expression levels had a longer survival than those having high VEGFA expression levels. VEGFA and its neighboring genes functioned in the regulation of protein methylation and glycosylation, as well as muscle fiber growth and differentiation in patients with renal cell carcinoma. Gene Ontology enrichment analysis revealed that the functions of VEGFA and its neighboring genes in patients with renal cell carcinoma are mainly related to cell adhesion molecule binding, catalytic activity, acting on RNA, ATPase activity, actin filament binding, protease binding, transcription coactivator activity, cysteine-type peptidase activity, and calmodulin binding. Transcription factor targets of VEGFA and its neighboring genes in patients with renal cell carcinoma were found: HIF1A, TFAP2A, and ESR1 in KIRC; STAT3, NFKB1, and HIPK2 in KICH; and FOXO3, TFAP2A, and ETS1 in KIRP. We further explored the VEGFA-associated kinase (ATM in KICH as well as CDK1 and AURKB in KIRP) and VEGFA-associated microRNA (miRNA) targets (MIR-21 in KICH as well as MIR-213, MIR-383, and MIR-492 in KIRP). Furthermore, the following genes had the strongest correlation with VEGFA expression in patients with renal cell carcinoma: NOTCH4, GPR4, and TRIB2 in KIRC; CKMT2, RRAGD, and PPARGC1A in KICH; and FLT1, C6orf223, and ESM1 in KIRP. VEGFA expression in patients with renal cell carcinoma was positively associated with immune cell infiltration, including CD8+T cells, CD4+T cells, macrophages, neutrophils, and dendritic cells. CONCLUSIONS: This study revealed VEGFA expression and potential gene regulatory network in patients with renal cell carcinoma, thereby laying a foundation for further research on the role of VEGFA in renal cell carcinoma occurrence. Moreover, the study provides new renal cell carcinoma therapeutic targets and prognostic biomarkers as a reference for fundamental and clinical research.

PYCR in Kidney Renal Papillary Cell Carcinoma: Expression, Prognosis, Gene Regulation Network, and Regulation Targets.

BACKGROUND: Pyrroline-5-carboxylate reductase (PYCR) includes three human genes encoding three isozymes, PYCR1, PYCR2, and PYCR3 (or PYCRL), which facilitate the final step in the conversion of glutamine to proline. These genes play important roles in regulating the cell cycle and redox homeostasis as well as promoting growth signaling pathways. Proline is abnormally upregulated in a variety of cancers, and as the last key enzyme in proline production, PYCR plays an integral role in promoting tumorigenesis and cancer progression. However, its role in patients with kidney renal papillary cell carcinoma (KIRP) has not been fully elucidated. In this study, we aimed to systematically analyze the expression, gene regulatory network, prognostic value, and target prediction of PYCR in patients with KIRP, elucidate the association between PYCR expression and KIRP, and identify potential new targets for the clinical treatment of KIRP. METHODS: We systematically analyzed the expression, prognosis, gene regulatory network, and regulatory targets of PYCR1, PYCR2, and PYCRL in KIRP using multiple online databases including cBioPortal, STRING, MethSurv, GeneMANIA, Gene Expression Profiling Interactive Analysis (GEPIA), Metascape, UALCAN, LinkedOmics, and TIMER. RESULTS: The expression levels of PYCR1, PYCR2, and PYCRL were considerably upregulated in patients with KIRP based on sample type, sex, age, and individual cancer stage. PYCR1 and PYCR2 transcript levels were markedly upregulated in females than in males, and patients aged 21-40 years had higher PYCR1 and PYCR2 transcript levels than those in other age groups. Interestingly, PYCR2 transcript levels gradually decreased with age. In addition, the expressions of PYCR1 and PYCR2 were notably correlated with the pathological stage of KIRP. Patients with KIRP with low PYCR1 and PYCR2 expression had longer survival than those with high PYCR1 and PYCR2 expression. PYCR1, PYCR2, and PYCRL were altered by 4%, 7%, and 6%, respectively, in 280 patients with KIRP. The methylation levels of cytosine-phosphate-guanine (CpG) sites in PYCR were markedly correlated with the prognosis of patients with KIRP. PYCR1, PYCR2, PYCRL, and their neighboring genes form a complex network of interactions. The molecular functions of the genes, as demonstrated by their corresponding Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, included calcium channel activity, phospholipid binding, RNA polymerase II-specificity, and kinase and GTPase-regulatory activities. PYCR1, PYCR2, and PYCRL targeted miR-21, miR-221, and miR-222, resulting in a better prognosis of KIRP. We analyzed mRNA sequencing data from 290 patients with KIRP and found that ADA, NPM3, and TKT were positively associated with PYCR1 expression; PFDN2, JTB, and HAX1 were positively correlated with PYCR2 expression; SHARPIN, YDJC, and NUBP2 were positively correlated with PYCRL expression; PYCR1 was positively correlated with B cell and CD8+ T-cell infiltration levels; macrophage infiltration was negatively correlated with PYCR2 expression; and PYCRL expression was negatively correlated with B-cell, CD8+ T cell, and dendritic cell infiltration levels. CONCLUSIONS: PYCR1, PYCR2, and PYCRL may be potential therapeutic and prognostic biomarkers for patients with KIRP. The regulation of microRNAs (miRNAs), including miR-21, miR-221, and miR-222, may prove an important strategy for KIRP treatment.

Oxymatrine screened from Sophora flavescens by cell membrane immobilized chromatography relieves histamine-independent itch.

OBJECTIVES: This study aimed to discover the active compounds of Sophora flavescens Ait. (SF), the anti-itch effects and underlying mechanisms of oxymatrine (OMT), one of the bioactive compounds from SF. METHODS: Dorsal root ganglion cell membrane immobilized chromatography was used to screen potential anti-pruritic active compounds from SF. The scratching behaviour was analysed to systematically study the anti-pruritic effects of OMT in chloroquine- (CQ), peptide Ser-Leu-Ile-Gly-Arg-Leu- (SLIGRL), histamine- (HIS) and allyl-isothiocyanate-(AITC)-induced itch mice models. Real-time quantitative PCR, in-vivo study and molecular docking were employed to explore the underlying mechanisms. KEY FINDINGS: All in all, 21 compounds of SF were identified and 5 potential bioactive compounds were discovered. OMT significantly reduced scratching bouts in two HIS-independent itch models induced by CQ and SLIGRL but was not effective in the HIS-induced itch model. OMT reduced scratching bouts in a dose-dependent manner and decreased the messenger RNA (mRNA) expression of transient receptor potential ankyrin 1 (TRPA1) channel in two HIS-independent itch models; in addition, OMT reduced the wipes and scratching bouts induced by AITC. CONCLUSIONS: This study discovered five potential anti-pruritic compounds including OMT in the SF extract, and OMT has strong anti-pruritic effects in HIS-independent itch via TRPA1 channel.