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Fatty acid desaturases (FADs) are enzymes that transform carboncarbon single bonds into carboncarbon double bonds within acyl chains, resulting in the production of unsaturated FAs (UFAs). They are crucial for plant growth, development, and adaptation to environmental stress. In our research, we identified 40 FAD candidates in the Salix matsudana genome, grouping them into seven categories. Exon-intron structures and conserved motifs of SmFADs within the same group showed significant conservation. Cis-Element analysis revealed SmFADs are responsive to hormones and stress. Additionally, GO and KEGG analyses linked SmFADs closely with lipid biosynthesis and UFA biosynthesis, which were crucial for the plant's response to environmental stress. Notably, the SmFAB2.4, SmADS1, SmFAD7.5, and SmFAD8.2 were predicted to participate in submergence tolerance, whereas SmFAD8.1 and SmFAD7.1 played an essential role in salt stress response. The diverse expression profiles of SmFADs across willow varieties, in various tissues, and throughout the willow bud development stages revealed a spectrum of functional diversity for these genes. Moreover, specific SmFADs might play a crucial role in callus development and the response to culturing conditions in various willow cultivars. This research underscored the importance of SmFAD profiles and functions and identified potential genes for enhancing forest resilience.
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Vasculogenic mimicry (VM) serves as a vascular-like channel that provides important substances for tumor growth and is a primary factor in glioblastoma (GBM) drug resistance. Human Antigen R (HuR)-an mRNA-binding protein-is highly expressed in GBM, closely related to tumor progression, and deemed a potential drug target. Although some small-molecule compounds have been identified to disrupt HuR binding to target mRNA, they remain in the preclinical research stage, suggesting the need for further validation and development of HuR inhibitors. In our study, we aim to screen for potential HuR inhibitors and investigate their efficacy and molecular mechanisms in GBM. We employed the fluorescence polarization method to identify HuR inhibitors from a natural compound library, confirming the efficacy of juglone in effectively inhibiting the binding of HuR to AREVegf-a. Further validation of the binding of juglone to HuR at the protein level was conducted through electrophoretic mobility shift analysis, surface plasmon resonance, and molecular docking. Furthermore, juglone demonstrated inhibitory effects on glioma growth and VM formation in vitro and in vivo. Moreover, it was observed that juglone reversed epithelial-mesenchymal transition by inhibiting the VEGF-A/VEGFR2/AKT/SNAIL signaling pathway. Finally, we established the capability of juglone to target HuR in U251 cells through HuR knockdown, mRNA stability, and cell thermal shift assays. Therefore, this study identifies juglone as a novel HuR inhibitor, potentially offering promise as a lead compound for anti-VM therapy in GBM by targeting HuR. Abbreviations: AKT, protein kinase B; ARE, adenine-and uridine-rich elements; CETSA, cellular thermal shift assay; DMEM, Dulbecco's modified Eagle's medium; ELISA, enzyme linked immune sorbent assay; EMSA, electrophoretic mobility shift assay; EMT, epithelial mesenchymal transition; FP, fluorescence polarization; GBM, glioblastoma; HTS, high-throughput screening; HuR, human antigen R; IF, Immunofluorescence; PAS, periodic acid-Schiff; PI3K, phosphoinositide-3 kinase; qRT-PCR, quantitative real-time PCR; RRMs, RNA recognition motifs; SPR, surface plasmon resonance. TMZ, temozolomide; VM, vasculogenic mimicry; VEGF-A, Vascular endothelial growth factor-A; VEGFR2, Vascular endothelial growth factor receptor-2.
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Proteína 1 Similar a ELAV , Naftoquinonas , Factor A de Crecimiento Endotelial Vascular , Humanos , Proteína 1 Similar a ELAV/metabolismo , Proteína 1 Similar a ELAV/genética , Proteína 1 Similar a ELAV/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Naftoquinonas/farmacología , Animales , Ratones , Línea Celular Tumoral , Ratones Desnudos , Glioma/metabolismo , Glioma/tratamiento farmacológico , Glioma/patología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
BACKGROUND: Poisonings caused by plant toxins and mycotoxins occur frequently, which do great harm to human health and social public health safety. When a poisoning incident occurs, biological samples are commonly be used to conduct the detection of toxic substances and their metabolites for targeted clinical treatment and incident analysis. OBJECTIVE: To establish an efficient and accurate analysis method of 39 phytotoxins and mycotoxins in blood and urine by high performance liquid chromatography quadrupole tandem orbitrap mass spectrometry (HPLC-Orbitrap MS). METHOD: After 3 mL of methanol being added to 1 mL blood and urine respectively for extraction and protein precipitation, the supernatant was injected into HPLC-Orbitrap MS for analysis. The phytotoxins and mycotoxins were separated by Hypersil GOLD PFP column with gradient elution using methanol-5 mmol/L ammonium acetate as mobile phase. The data were collected in ESI positive ion mode using Full MS/dd-MS2 for mass spectrometry detection. RESULT: The mass database of 39 phytotoxins and mycotoxins was developed, and accurate qualitative analysis can be obtained by matching with the database using the proposed identification criteria. Limit of detections (LODs) were 1.34 × 10-4 â¼ 1.92 ng/mL and 1.92 × 10-4 â¼ 9.80 ng/mL for blood and urine samples, respectively. Limits of quantification (LOQ) of toxins in blood and urine ranged from 4.47 × 10-4 â¼ 6.32 ng/mL and 6.39 × 10-4 â¼ 32.67 ng/mL, respectively. Intra-day relative standard deviations (RSDs) were 0.79 % â¼ 10.90 %, and inter-day RSDs were 1.08 % â¼ 18.93 %. The recoveries can reach 90 % â¼ 110 % with matrix matching calibration curves. CONCLUSION: The established method is simple and rapid to operate, which can complete the sample analysis within 30 min, providing technical support for clinical poisoning treatment and public health poisoning analysis.
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Límite de Detección , Micotoxinas , Micotoxinas/orina , Micotoxinas/sangre , Humanos , Cromatografía Líquida de Alta Presión/métodos , Reproducibilidad de los Resultados , Modelos Lineales , Espectrometría de Masas en Tándem/métodosRESUMEN
Colorectal Carcinoma (CRC) is one of the most common malignant tumors of the digestive tract, with a high mortality rate. DPY30 is one of the core subunits of the histone methyltransferase complex, which was involved in many cancer processes. However, the role of DPY30 in the occurrence and progression of CRC remains unclear. In this study, we sought to evaluate the role and mechanism of DPY30 in CRC cells apoptosis. Here, we identified that knockdown of DPY30 significantly inhibited the HT29 and HCT116 cells proliferation in vitro. Moreover, the knockdown of DPY30 significantly increased the apoptosis rate and promoted the expression of apoptosis-related proteins in CRC cells. Meanwhile, DPY30 knockdown promoted CRC cells apoptosis through endogenous programmed death and in a caspase activation-dependent manner. Furthermore, RNA-seq analysis revealed that the action of DPY30 is closely related to the apoptosis biological processes, and screened its potential effectors Raf1. Mechanistically, DPY30 downregulation promotes MST2-induced apoptosis by inhibiting Raf1 transcriptional activity through histone H3 lysine 4 trimethylation (H3K4me3). In vivo experiments showed that DPY30 was correlated with Raf1 in nude mouse subcutaneous xenografts tissues significantly. Clinical colorectal specimens further confirmed that overexpression of DPY30 in malignant tissues was significantly correlated with Raf1 level. The vital role of the DPY30/Raf1/MST2 signaling axis in the cell death and survival rate of CRC cells was disclosed, which provides potential new targets for early diagnosis and clinical treatment of CRC.
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DPY30 belongs to the core subunit of components of the histone lysine methyltransferase complex, which is implicated in tumorigenesis, cell senescence, and other biological events. However, its contribution to colorectal carcinoma (CRC) progression and metastasis has yet to be elucidated. Therefore, this study aimed to investigate the biological function of DPY30 in CRC metastasis both in vitro and in vivo. Herein, our results revealed that DPY30 overexpression is significantly positively correlated with positive lymph nodes, epithelial-mesenchymal transition (EMT), and CRC metastasis. Moreover, DPY30 knockdown in HT29 and SW480 cells markedly decreased EMT progression, as well as the migratory and invasive abilities of CRC cells in vitro and lung tumor metastasis in vivo. Mechanistically, DPY30 increased histone H3K4me3 level and promoted EMT and CRC metastasis by upregulating the transcriptional expression of ZEB1. Taken together, our findings indicate that DPY30 may serve as a therapeutic target and prognostic marker for CRC.
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DPY30, a core subunit of the SET1/MLL histone H3K4 methyltransferase complexes, plays an important role in diverse biological functions through the epigenetic regulation of gene transcription, especially in cancer development. However, its involvement in human colorectal carcinoma (CRC) has not been elucidated yet. Here we demonstrated that DPY30 was overexpressed in CRC tissues, and significantly associated with pathological grading, tumor size, TNM stage, and tumor location. Furthermore, DPY30 knockdown remarkably suppressed the CRC cell proliferation through downregulation of PCNA and Ki67 in vitro and in vivo, simultaneously induced cell cycle arrest at S phase by downregulating Cyclin A2. In the mechanistic study, RNA-Seq analysis revealed that enriched gene ontology of cell proliferation and cell growth was significantly affected. And ChIP result indicated that DPY30 knockdown inhibited H3 lysine 4 trimethylation (H3K4me3) and attenuated interactions between H3K4me3 with PCNA, Ki67 and cyclin A2 respectively, which led to the decrease of H3K4me3 establishment on their promoter regions. Taken together, our results demonstrate overexpression of DPY30 promotes CRC cell proliferation and cell cycle progression by facilitating the transcription of PCNA, Ki67 and cyclin A2 via mediating H3K4me3. It suggests that DPY30 may serve as a potential therapeutic molecular target for CRC.
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Neoplasias Colorrectales , Ciclina A2 , Humanos , Ciclina A2/genética , Factores de Transcripción , Epigénesis Genética , Antígeno Ki-67 , Antígeno Nuclear de Célula en Proliferación , Proliferación Celular/genética , Ciclo Celular/genética , Neoplasias Colorrectales/genéticaRESUMEN
Sexual dimorphism has commonly been found in many species. The phenotypes of Salix matsudana females and males are different under salinity stress. An F1 population was selected to compare the differences between males and females. As a result, males showed stronger roots and heavier dry weights than females. The unique molecular mechanisms of males and females under salinity stress were further analyzed based on the root transcriptome of males and females. Both males and females up-regulated systemic acquired resistance genes, such as ADH and oxygenase-related genes, to resist salt. Moreover, many other abiotic stress response genes were up-regulated in males to adjust to salinity stress, while females showed more down-regulation of nitrogen metabolism-related genes to decrease the harm from salinity stress. The research on salinity tolerance in Salix matsudana males and females would help to further understand sexual dimorphism under selection pressure and provide benefits to the ecological environment.
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A rapid and sensitive high-performance liquid chromatography-high-resolution orbitrap mass spectrometry method was developed for the simultaneous screening of 354 organic poisons and metabolites in blood and urine, including drugs, medications, pesticides, rodenticides, veterinary drugs, alkaloids, and mycotoxins with a multi-toxicant chromatography-mass spectrometry information library. The method and library showed good prospects in clinical poisoning screening and forensic toxicological identification. Blood and urine samples were extracted successively with ethyl acetate in acidic and alkaline conditions; then, the extract was blown to nearly dry by nitrogen gas and redissolved with methanol-aqueous solution (v:v, 50:50), and the dissolved solution was analyzed by LC-MS/MS after filtering. Precursor ions' m/z was set for identification, retention time, fragment ions, and isotopic pattern which were used for confirmation. No interference peaks were found in the blank samples, showing good specificity. The LODs of toxicants in urine and blood were 1.00×10-3-50.0 ng/mL and 2.07×10-3-50.0 ng/mL, respectively, while the LOQs were 3.30×10-3-1.67×102 ng/mL and 6.91×10-3-1.67×102 ng/mL. The intra-day precision and inter-day precision of urine samples were 2.31-9.13% and 4.75-12.3%, respectively, which were 1.92-10.8% and 2.01-12.1% in blood samples. The established method was applied to analyze 9 cases of clinical poisoning patients, and bromadiolone, carbofuran, and amanitins were detected, respectively. A total of 382 biospecimens from drug abusers were analyzed with the proposed method, which indicated that some drugs were detected in 62 cases, mainly including methamphetamine, heroin, and MDMA. The results were consistent with the information from traditional liquid chromatography-triple quadrupole mass spectrometry.
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Líquidos Corporales , Plaguicidas , Humanos , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Líquidos Corporales/química , Plaguicidas/toxicidad , Plaguicidas/análisis , Sustancias Peligrosas/análisisRESUMEN
Objective: To establish a method for quantitative analysis of haloacetic acids (HAAs), disinfection byproducts, in tap water with reversed-phase ultra-performance liquid chromatography-quadrupole-orbitrap high resolution mass spectrometry. Methods: Tap water samples were collected and 0.70 g/L ascorbic acid was added to eliminate residual chlorine. Then, the water samples were directly injected into the instrument for analysis after filtration. After separation on a pentafluorobenzene (PFP) column with an inner diameter of 1.0 mm at a higher linear velocity and a lower volume flow rate compared with those of a narrow-bore column, nine HAAs, namely, monochloroacetic acid (MCAA), monobromoacetic acid (MBAA), dichloroacetic acid (DCAA), bromochloroacetic acid (BCAA), dibromoacetic acid (DBAA), trichloroacetic acid (TCAA), bromodichloroacetic acidï¼BDCAA), chlorodibromoacetic acid (CDBAA) and tribromoacetic acid (TBAA), were examined by negative electrospray ionization and full MS/dd-MS 2 acquisition mode. In order to adjust for the matrix effect, matrix matching calibration curves were used to quantitate the nine HAAs. Results: Good linearity was obtained for each of the nine HAAs within their respective linear ranges. The detection limits and quantification limits of the method were 0.020-1.0 µg/L and 0.060-3.0 µg/L. The recoveries were 69.8%-119%. Conclusion: The proposed method showed strengths in separation speed and qualitative accuracy. It did not require for complicated pretreatment procedures and can meet the need of tap water sample analysis.
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Desinfección , Agua , Cromatografía Liquida , Espectrometría de Masas en Tándem/métodos , Agua/análisis , Agua/químicaRESUMEN
With the increasing incidence of antibiotic resistance, there is an urgent need to develop new antibiotics with excellent activity against drug-resistant bacteria. Three novel series of tylosin semisynthetic derivatives were designed, synthesized and evaluated for their antibacterial activities against various Gram-positive and Gram-negative bacteria. Among these derivatives, compound C-2 demonstrated potent antibacterial activity against both gram-positive and gram negative bacteria, and non mutagenic. More importantly, compound C-2 displayed high antimicrobial potency against Gram-positive bacteria in a murine model, and was found to be more efficient than tildipirosin. Thus, compound C-2 had great potential as a promising lead compound for the treatment of bacterial infection.
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Bacterias Gramnegativas , Bacterias Grampositivas , Animales , Antibacterianos/farmacología , Leucomicinas , Ratones , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
Objective: To establish a high-performance liquid chromatography orbital trap mass spectrometry (HPLC-Obitrap MS) method for screening 34 common drugs and metabolites in biological samples. Methods: The target analytes in urine and blood samples were extracted with ethyl acetate, concentrated by nitrogen blowing and redissolved. The hair samples were washed with water and acetone, dried and cut into bits of about 1 mm, and then crushed in a freezing grinder. The analytes were extracted with methanol, and after filtration, the filtrate was used for instrumental analysis. Hypersil Gold PFP (2.1 mm×100 mm, 3 µm) column was used for chromatographic separation. Methanol and 5 mmol/L ammonium acetate solution were used as mobile phase with gradient elution at a flow rate of 400 µL/min. Mass spectrometry was done by electrospray positive and negative ion alternation mode. The data were collected using Full MS and Full MS/dd-MS2 mode. Xcalibur 4.0 software was used to control instruments and to collect data, and TraceFinder 3.3 was used for screening and identification. Results: The method's detection limits for 34 drugs and their metabolites in blood, urine and hair samples were 3.30-10700 ng/L, 4.43-5440 ng/L, 0.0350-4.21 µg/kg, respectively. The intra-day and inter-day precisions of the spiked samples at the levels of 5.0, 10, and 20 µg/L were 3.50%-6.00% and 4.18%-9.90%, respectively. A total of 1125 biological samples of urine, blood and hair were collected and screened. The results showed that 96.7% of the drug users were taking a single drug, while 3.3% were mixed drug users. The main types of drug of abuse were methamphetamine (75.8%), heroin (18.5%), ketamine (2.4%) and other drugs (3.3%), and 87.9% of the positive samples were from male users. Compared with the results of high-performance liquid chromatography triple quadrupole mass spectrometry, this method can be used to identify more types of drugs in one run and to conduct retrospective analysis. Conclusion: The method established in the study is simple and sensitive and is well suited for the screening of common drugs and metabolites in biological samples.
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Cabello , Espectrometría de Masas en Tándem , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida , Humanos , Masculino , Estudios Retrospectivos , Espectrometría de Masas en Tándem/métodosRESUMEN
OBJECTIVE: To establish a method for determination of the common and emerging halogenated carboxylic acids(HCAs) in drinking water by ion chromatography(IC) and quadrupole-orbitrap(Q-Orbitrap) high resolution mass spectrometry(HRMS) combined the traditional quantitative detection with semi-target analysis. METHODS: Effects on the type of chromatographic column, the composition of mobile phase, the flow rate of acetonitrile added post column, the column temperature, and the injection volume were studied in detail for IC-HRMS method, also for HRMS conditions. Drinking water sample was directly injected into IC-HRMS for analysis after filtration. The chromatography separation was performed on an AS21 anion exchange chromatography column(2 mm×250 mm) with the gradient elution using 800 mmol/L methylamine-water as mobile phase, and acetonitrile was added after column. The detection was conducted on HRMS with the electrospray ionization negative mode. And the quantitative analysis of 8 haloacetic acids(HAAs) and semi-target screening of 19 HCAs were achieved by full MS/dd-MS~2 mode. RESULTS: Good linearity(r>0.996) was obtained for each of 8 HAAs for IC-HRMS. The method detection limits(MDLs) and method quantification limits(MQLs) were in the range of 0.50-2.5 µg/L and 1.7-8.3 µg/L, respectively. Intra-and inter-day relative standard deviations(RSDs) were in the range of 1.50%-11.0% and 4.58%-10.9%, respectively. The recoveries were in the range of 61.3%-117%(n=6). The proposed method was applied to analyze 39 drinking water samples, and dichloroacetic acid and trichloroacetic acid were detected and quantified, with concentrations ranging from 1.35 to 48.0 µg/L. Besides, five HCAs(difluoroacetic acid, trifluoroacetic acid, bromochloroacetic acid, monochloropropionic acid and dichloropropionic acid) were preliminary identified with semi-target screening method. CONCLUSION: The developed method was simple, rapid, no sample preparation except filtration and low reagent cosumption, which could meet the need of drinking water monitoring and achieve comprehensive screening of HCAs in drinking water. In addition, full MS/dd-MS~2 data acquisition mode could provide retrospective analysis of existing data by adding the emerging or interesting HCAs into the screening compound database.
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Agua Potable , Ácidos Carboxílicos/análisis , Cromatografía Líquida de Alta Presión , Estudios Retrospectivos , Espectrometría de Masas en TándemRESUMEN
Pathogenic bacteria use an intercellular chemical communication system called quorum sensing (QS) to control the expression of cellular functions such as virulence factors, biofilm formation, toxin production, and antibiotic resistance in a manner that is highly dependent on population density. Hence, since the emergence of QS, there has been a great interest in exploiting the QS mechanism as a new drug target. Therefore, blocking the QS mechanism can be an effective strategy to control infection and solve the problem of drug resistance. So far, there is no clinically approved anti-QS drug that can disable the circuits of QS systems. This review discusses the quorum-sensing network systems and novel anti-QS inhibitors in some Gram-negative bacteria.
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Acil-Butirolactonas/farmacología , Antibacterianos/farmacología , Antineoplásicos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Acil-Butirolactonas/química , Antibacterianos/química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Bacterias Gramnegativas/metabolismo , Humanos , Estructura Molecular , Percepción de Quorum/efectos de los fármacosRESUMEN
Hepatocellular carcinoma (HCC) belongs to the most frequent cancer with a high death rate worldwide. Thousands of long non-coding RNAs (lncRNAs) have been confirmed to influence the development of human cancers, including HCC. Nevertheless, the biological role of PRR34 antisense RNA 1 (PRR34-AS1) in HCC remains obscure. Here, we observed via quantitative real-time reverse transcriptase polymerase chain reaction (quantitative real-time RT-PCR) that PRR34-AS1 was highly expressed in HCC cells. Functional assays revealed that PRR34-AS1 promoted HCC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) process in vitro and facilitated tumor growth in vivo. In addition, western blot analysis and TOP Flash/FOP Flash reporter assays verified that PRR34-AS1 stimulated Wnt/ß-catenin pathway in HCC cells. Furthermore, RNA immunoprecipitation (RIP), RNA pull-down, and luciferase reporter assays uncovered that PRR34-AS1 sequestered microRNA-296-5p (miR-296-5p) to positively modulate E2F transcription factor 2 (E2F2) and SRY-box transcription factor 12 (SOX12) in HCC cells. Importantly, chromatin immunoprecipitation (ChIP) and luciferase reporter assays uncovered that E2F2 transcriptionally activated PRR34-AS1 in turn. Further, rescue experiments reflected that PRR34-AS1 affected HCC progression through targeting miR-296-5p/E2F2/SOX12/Wnt/ß-catenin axis. Our findings found that PRR34-AS1 elicited oncogenic functions in HCC, which indicated that PRR34-AS1 might be a novel therapeutic target for HCC.
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Hepatocellular carcinoma (HCC) is one of the most common malignancies globally and the second leading cause of cancer-related death. Low-density lipoprotein (LDL) receptor-related protein 1B (LRP1B) is one of the commonly mutated genes in HCC, but its role in HCC remains unclear. In this study, we analyzed the role of LRP1B mutation in HCC. The bioinformatics results show that LRP1B had a frequency of mutation in HCC patients, and LRP1B mutation was associated with a higher tumor mutation burden (TMB), and survival analysis proved that the prognosis of HCC patients with LRP1B mutation was poor. Univariate and multivariate COX regression analysis indicated that LRP1B mutation was an independent risk factor in evaluating HCC patients' prognosis. Correlation analysis showed that LRP1B mutation status was associated with the infiltration of 2 types of immune cells and higher expression of immune checkpoint gene human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) in HCC patients. In summary, the results show that LRP1B mutation is associated with the higher TMB and poor prognosis of patients with HCC, and it was an independent risk factor for clinical outcomes of HCC patients. LRP1B gene mutations can serve as predictors in HCC patients with higher TMB and higher expression of HHLA2. The results of this study will be beneficial to future studies on targeted therapy and immunotherapy for HCC.
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In this study, we determined the involvement of SOX2 and its downstream signaling molecules in hepatocellular carcinoma (HCC) progression. We carried out lentiviral transfection in HepG2 cells to determine the roles of SOX2, CCAT1, EGFR, miR-222-5p, and CYLD in HepG2 cells. We first determined the interaction between SOX2 and CCAT1 and that between miR-222-5p and CYLD and their effect on tumor growth in vivo was analyzed in HCC-xenograft bearing nude mice xenografts. SOX2 and CCAT1 were highly expressed in HCC tissues and HepG2 cells. SOX2 bound to the regulatory site of CCAT1. Silencing of SOX2 or CCAT1 inhibited HepG2 cell proliferation, migration, and invasion as well as decreased the expression of CCAT1 and EGFR. CCAT1 silencing reduced EGFR expression, but EGFR expression was increased in HCC tissues and HepG2 cells, which promoted proliferation, migration, and invasion in vitro. EGFR upregulated miR-222-5p, leading to downregulation of CYLD. miR-222-5p inhibition or CYLD overexpression repressed cell functions in HepG2 cells. SOX2 silencing decreased CCAT1, EGFR, and miR-222-5p expression but increased CYLD expression. Loss of SOX2 also reduced the growth rate of tumor xenografts. In summary, SOX2-mediated HCC progression through an axis involving CCAT1, EGFR, and miR-222-5p upregulation and CYLD downregulation.
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Carcinoma Hepatocelular/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/genética , ARN Largo no Codificante/genética , Factores de Transcripción SOXB1/metabolismo , Adulto , Anciano , Animales , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Estudios de Casos y Controles , Movimiento Celular/genética , Proliferación Celular/genética , Enzima Desubiquitinante CYLD/genética , Progresión de la Enfermedad , Regulación hacia Abajo , Receptores ErbB/genética , Femenino , Técnicas de Silenciamiento del Gen , Voluntarios Sanos , Células Hep G2 , Hepatectomía , Humanos , Hígado/patología , Hígado/cirugía , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Masculino , Ratones , MicroARNs/metabolismo , Persona de Mediana Edad , ARN Largo no Codificante/metabolismo , Factores de Transcripción SOXB1/genética , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Isoquinoline analogs are an important, structurally diverse class of compounds that are extensively used as pharmaceuticals. Derivatives containing the isoquinoline scaffold have become a focus of therapeutic research because of their wide range of biological characteristics. Examples of these drugs, many of which are in clinical application or at the pre-clinical stage, are used to treat a broad swathe of ailments, such as tumors, respiratory diseases, infections, nervous system diseases, cardiovascular and cerebrovascular diseases, endocrine and metabolic diseases. METHODS: Data were collected from PubMed, Web of Science, and SciFinder, through searches of drug names. RESULTS: At least 38 isoquinoline-based therapeutic drugs are in clinical application or clinical trials, and their chemical structure and pharmacokinetics are described in detail. CONCLUSION: The isoquinoline ring is a privileged scaffold which is often preferred as a structural basis for drug design, and plays an important role in drug discovery. This review provides a guide for pharmacologists to find effective preclinical/clinical drugs and examines recent progress in the application of the isoquinoline scaffold.
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Trastornos Cerebrovasculares/tratamiento farmacológico , Isoquinolinas/uso terapéutico , Enfermedades Metabólicas/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Trastornos Respiratorios/tratamiento farmacológico , Humanos , Isoquinolinas/química , Estructura MolecularRESUMEN
Background: LINC02560 is a new 477 bp long non-coding RNA located in 19q13.43. However, the expression of LINC02560 in colorectal cancer (CRC) has not been reported, and its correlation with tumor development and function is still unclear. Methods: The expression of LINC02560 in CRC was first analyzed in the cancer genome atlas (TCGA) combined with The Genotype-Tissue Expression(GTEx) databases and then validated by clinical CRC samples and cell lines. The association between LINC02560 expression and clinicopathologic variables was analyzed by the Wilcoxon Rank SUM test. Cox regression analysis and Kaplan-Meier plots were used to assess the prognostic value of LINC02560 in CRC. The correlation between the expression level of LINC02560 and the 24 immune cells in tumor microenvironment (TME) was analyzed by single sample gene set enrichment analysis (ssGSEA). Gene set enrichment analysis (GSEA) was conducted to detect potential biological processes associated with LINC02560 in CRC. Results: LINC02560 was significantly up-regulated in CRC in comparison to normal samples. There are significant differences in the expression of LINC02560 in different subgroups of N stage, M stage, carcinoembryonic antigen (CEA) level, residual tumor, TP53 status and pathological stage. The high LINC02560 expression indicated poor overall survival (OS) and progress free interval (PFI) in patients with CRC. Moreover, the multivariate Cox analysis demonstrated that the expression of LINC02560 was an independent prognosis-predicting factor for OS in CRC patients. GSEA indicated that high expression of LINC02560 was involved in MAPK, Wnt, and PPAR signaling pathways and participated in humoral immune processes. We also identified that LINC02560 expression had a negative correlation with 4 kinds of immune cells. Conclusions: In summary, our research results indicate that LINC02560 may be a potential prognostic biomarker. It is involved in the occurrence and development of CRC and may affect the prognosis of CRC patients by regulating immune cells in the TME.
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Hepatocellular carcinoma (HCC) is one of the common malignant tumors. The prognosis and five-year survival rate of HCC are not promising due to tumor recurrence and metastasis. Exploring markers that contribute to the early diagnosis of HCC, markers for prognostic evaluation of HCC patients, and effective targets for treating HCC patients are in the spotlight of HCC therapy. Zinc Finger CCHC-Type Containing 17 (ZCCHC17) encodes the RNA binding protein ZCCHC17, but its role in HCC is still unclear. Here, 90 paraffin-embedded specimens combined with bioinformatics were used to comprehensively clarify the value of ZCCHC17 in the diagnosis and prognosis of HCC and its potential functions. Paraffin-embedded specimens were used to assess ZCCHC17 protein expression and its correlation with prognosis in 90 HCC patients. the public data sets of HCC patients from TCGA, ICG, and GEO databases were also used for further analysis. It was found that protein and mRNA levels of ZCCHC17 in HCC tissues were significantly higher than those in normal tissues. The abnormally high expression may be related to the abnormal DNA methylation of ZCCHC17 in tumor tissues. The high expression of ZCCHC17 is related to AFP, histologic grade, tumor status, vascular invasion, and pathological stage. Multi-data set analysis showed that patients with high ZCCHC17 expression had a worse prognosis, and multivariate cox regression analysis showed an independent prognostic significance of ZCCHC17. The results of functional analysis, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA), indicate that ZCCHC17 is mainly involved in immune regulation. Subsequently, further single-sample gene set enrichment analysis (ssGSEA) showed that the expression of ZCCHC17 was related to the infiltration of immune cells. Importantly, we also analyzed the relationship between ZCCHC17 and immune checkpoint genes, tumor mutation burden (TMB), microsatellite instability (MSI) and TP53 status in HCC patients and evaluated the role of ZCCHC17 in cancer immunotherapy. In summary, ZCCHC17 is a novel marker for the diagnosis and prognostic evaluation of HCC. Concurrently, it regulates immune cells in the tumor microenvironment (TME) of HCC patients, which has a specific reference value for the immunotherapy of HCC.