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BACKGROUND: Synthetic lethality (SL) emerges as a novel concept being explored to combat cancer progression and resistance to conventional therapy. Despite the efficacy of chemotherapy in select cases of colorectal cancer (CRC), a substantial proportion of patients encounter challenges, leading to an adverse prognosis of CRC patients. CRC-related SL genes offer a potential avenue for identifying therapeutic targets. METHODS: CRC-related SL genes were obtained from the SynLethDB database. The bulk RNA sequencing data, mutation data, and clinical information for treated and untreated CRC patients were enrolled from the UCSC and GEO databases. The Tumor Immunology Single Cell Center database served as the repository for collecting and analyzing single-cell RNA sequencing data. The synergistic killing effect of SL genes and chemotherapeutic drugs on resistant cells was experimentally verified. RESULTS: In the present study, pivotal SL genes associated with chemoresistance identified by using WGCNA and CRC patients categorized into two groups based on these genes. Variations between the groups were most pronounced in pathways associated with extracellular matrix remodeling. Further by integrating mutation data, five potential SL genes were discerned, which were highly expressed in the presence of TP53 or KRAS mutations, leading to a severely poor prognosis. Subsequent time series analysis revealed that the expression of GTF2H5 was gradually elevated at different stages of the transition from sensitive to resistant in CRC cells. Finally, it was preliminarily verified by experiments that GTF2H5 may play a key role in driving the drug-resistant transition within CRC cells. CONCLUSIONS: The identification of SL genes that collaboratively interact with chemotherapeutic agents could provide new insights into solving the issue of chemotherapy resistance in CRC patients. And GTF2H5 wields a fundamental influence in inducing chemoresistance in CRC, which provided a potential therapeutic target for CRC.
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Endoscopic retrograde cholangiopancreatography (ERCP) in patients with Roux-en-Y gastrectomy and an intact major duodenal papilla is challenging and difficult, with unsatisfactory outcomes using various endoscopes. Limited data are available regarding the outcomes of ERCP using a pediatric colonoscope in such patients. To evaluate the efficacy of a pediatric colonoscope in patients with Roux-en-Y gastrectomy and an major duodenal intact papilla, 93 consecutive patients with Roux-en-Y gastrectomy and an intact major duodenal papilla who underwent ERCP using a pediatric colonoscope at the Medical Center for Digestive Diseases, The Second Affiliated Hospital of Nanjing Medical University, (Nanjing, China) between January 2018 and December 2022 were retrospectively reviewed. Following the failure of bile duct cannulation, a double-guidewire or precut technique was utilized for advanced cannulation. Interventions were performed using standard ERCP therapeutic accessories. The results indicated that distal gastrectomy with Roux-en-Y reconstruction was performed in 38 out of 93 patients, while 55 patients underwent total gastrectomy with Roux-en-Y reconstruction. The success rates associated with endoscope insertion, endoscopic cannulation and therapeutic ERCP were 88.17% (82/93), 85.37% (70/82) and 95.71% (67/70), respectively, while the clinical intervention success and complication rates were 72.04% (67/93) and 7.53% (7/93), respectively. The endoscope insertion time was 40.78±10.04 min, and the ERCP procedure time was 88.55±16.38 min. Student's t-test showed that the endoscope insertion time and the ERCP procedure time in patients undergoing distal gastrectomy were longer than those in patients undergoing total gastrectomy (P<0.05). Binary logistic regression analysis showed that age and number of previous abdominal surgeries were independent risk factors associated with endoscope insertion failure. In conclusion, the present study demonstrated that the use of a pediatric colonoscope is efficacious and safe for patients with Roux-en-Y gastrectomy and an intact major duodenal papilla undergoing ERCP.
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BACKGROUND: Numerous studies have indicated that cancer-associated fibroblasts (CAFs) play a crucial role in the progression of colorectal cancer (CRC). However, there are still many unknowns regarding the exact role of CAF subtypes in CRC. METHODS: The data for this study were obtained from bulk, single-cell, and spatial transcriptomic sequencing data. Bioinformatics analysis, in vitro experiments, and machine learning methods were employed to investigate the functional characteristics of CAF subtypes and construct prognostic models. RESULTS: Our study demonstrates that Biglycan (BGN) positive cancer-associated fibroblasts (BGN + Fib) serve as a driver in colorectal cancer (CRC). The proportion of BGN + Fib increases gradually with the progression of CRC, and high infiltration of BGN + Fib is associated with poor prognosis in terms of overall survival (OS) and recurrence-free survival (RFS) in CRC. Downregulation of BGN expression in cancer-associated fibroblasts (CAFs) significantly reduces migration and proliferation of CRC cells. Among 101 combinations of 10 machine learning algorithms, the StepCox[both] + plsRcox combination was utilized to develop a BGN + Fib derived risk signature (BGNFRS). BGNFRS was identified as an independent adverse prognostic factor for CRC OS and RFS, outperforming 92 previously published risk signatures. A Nomogram model constructed based on BGNFRS and clinical-pathological features proved to be a valuable tool for predicting CRC prognosis. CONCLUSION: In summary, our study identified BGN + Fib as drivers of CRC, and the derived BGNFRS was effective in predicting the OS and RFS of CRC patients.
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Biglicano , Fibroblastos Asociados al Cáncer , Neoplasias Colorrectales , Aprendizaje Automático , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/metabolismo , Humanos , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Pronóstico , Biglicano/metabolismo , Biglicano/genética , Proliferación Celular , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Masculino , Regulación Neoplásica de la Expresión Génica , Femenino , Movimiento Celular , Microambiente TumoralRESUMEN
Currently, 80%-90% of liver cancers are hepatocellular carcinomas (HCC). HCC patients develop insidiously and have an inferior prognosis. The methyltransferase-like (METTL) family principal members are strongly associated with epigenetic and tumor progression. The present study mainly analyzed the value of METTLs (METTL1/13/18/21A/23/25/2A/2B/5/6/9) and associated mRNA risk signature for HCC. METTLs expression is upregulated in HCC and is a poor prognostic factor in HCC. METTLs were upregulated in patients older than 60 and associated with grade. Except for METTL25, the remaining 10 genes were associated with the HCC stage, invasion depth (T). In addition, METTLs showed an overall alteration rate of 50%. Except for METTL13/2A/25/9, the expression of the other seven genes was significantly associated with overall survival, disease-specific survival, and progression-free survival. Multivariate studies have shown that METTL21A/6 can be an independent prognostic marker in HCC. A total of 664 mRNAs were selected based on Pearson correlation coefficient (R > 0.5), unsupervised consensus clustering, weighted coexpression network analysis, and univariate Cox analysis. These mRNAs were significantly associated with METTLs and were poor prognostic factors in HCC patients. The least absolute shrinkage and selection operator (lasso) was used to construct the best METTLs associated with mRNA risk signature. The mRNA risk signature was significantly associated with age, stage, and t grade. The mRNA high-risk group had higher TP53 and RB1 mutations. This study constructed a nomogram with the mRNA risk profile and clinicopathological features, which could better predict the OS of individuals with HCC. We also analyzed associations between METTLs and mRNA risk signatures in epithelial-mesenchymal transition, immune checkpoints, immune cell infiltration, tumor mutational burden, microsatellite instability, cancer stem cells, tumor pathways, and drug sensitivity. In addition, this study constructed a protein interaction network network including METTLs and mRNA risk signature genes related to tumor microenvironment remodeling based on single-cell sequencing. In conclusion, this study provides a theoretical basis for the mechanism, biomarker screening, and treatment of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Transición Epitelial-Mesenquimal , Mutación/genética , Células Madre Neoplásicas , Microambiente Tumoral , MetiltransferasasRESUMEN
Background: Liver metastasis (LM) is a leading cause of cancer-related deaths in CRC patients, whereas the associated mechanisms have not yet been fully elucidated. Therefore, it is urgently needed to deeply explore novel metastasis accelerators and therapeutic targets of LM-CRC. Methods: The bulk RNA sequencing data and clinicopathological information of CRC patients were enrolled from the TCGA and GEO databases. The single-cell RNA sequencing (scRNA-seq) datasets of CRC were collected from and analyzed in the Tumor Immune Single-cell Hub (TISCH) database. The infiltration levels of cancer-associated fibroblasts (CAFs) and macrophages in CRC tissues were estimated by multiple immune deconvolution algorithms. The prognostic values of genes were identified by the Kaplan-Meier curve with a log-rank test. GSEA analysis was carried out to annotate the significantly enriched gene sets. The biological functions of cells were experimentally verified. Results: In the present study, hundreds of differentially expressed genes (DEGs) were selected in LM-CRC compared to primary CRC, and these DEGs were significantly associated with the regulation of endopeptidase activity, blood coagulation, and metabolic processes. Then, SPP1, CAV1, ANGPTL2, and COLEC11 were identified as the characteristic DEGs of LM-CRC, and higher expression levels of SPP1 and ANGPTL2 were significantly associated with worse clinical outcomes of CRC patients. In addition, ANGPTL2 and SPP1 mainly distributed in the tumor microenvironment (TME) of CRC tissues. Subsequent scRNA-seq analysis demonstrated that ANGPTL2 and SPP1 were markedly enriched in the CAFs and macrophages of CRC tissues, respectively. Moreover, we identified the significantly enriched gene sets in LM-CRC, especially those in the SPP1+macrophages and ANGPTL2+CAFs, such as the HALLMARK_EPITHELIAL_MESENCHYMAL_TRANSITION and the HALLMARK_COMPLEMENT. Finally, our in vitro experiments proved that ANGPTL2+CAFs and SPP1+macrophages promote the metastasis of CRC cells. Conclusion: Our study selected four characteristic genes of LM-CRC and identified ANGPTL2+CAFs and SPP1+macrophages subtypes as metastasis accelerators of CRC which provided a potential therapeutic target for LM-CRC.
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Fibroblastos Asociados al Cáncer , Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Algoritmos , Proteína 2 Similar a la Angiopoyetina , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Macrófagos , Osteopontina , Microambiente Tumoral/genéticaRESUMEN
Emerging evidence has suggested that circular RNAs (circRNAs) have vital functions during the initiation and progression of various diseases. However, circRNA potential mechanisms in colorectal cancer (CRC) are largely unknown. Here, we sought to investigate the role and underlying regulatory mechanism of circ0104103 in CRC. circ0104103 was validated by quantitative RT-PCR (qRT-PCR) and Sanger sequencing. Gain- and loss-of-function assays in cell lines and mouse xenograft models were utilized to investigate the effects of circ0104103 in CRC. RNA pull-down assays, RNA immunoprecipitation assays, bioinformatics analyses, RNA FISH, and luciferase reporter assays were used to elucidate the potential mechanism of circ0104103 in CRC. We identified circ0104103, which is strongly downregulated in CRC tissues and cell lines. Functional studies revealed that circ0104103 inhibited CRC cell growth, migration, and invasion both in vitro and in vivo. Mechanistically, circ0104103 binds to HuR, a functional RNA-binding protein commonly expressed in CRC. HuR binds to the 3'UTR of LACTB mRNA to facilitate stabilization and increase its expression. Moreover, circ0104103 was verified as a competing endogenous RNA (ceRNA) via negative regulation of miR-373-5p to increase LACTB expression, resulting in inhibiting the occurrence and progression of CRC. Taken together, our study revealed that circ0104103 acts as a tumor suppressor and may be a novel biomarker and therapeutic target in CRC.
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Neoplasias Colorrectales , Proteína 1 Similar a ELAV , MicroARNs , ARN Circular , Animales , Humanos , Ratones , beta-Lactamasas/genética , beta-Lactamasas/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Neoplasias Colorrectales/patología , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica/genética , Proteínas de la Membrana/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Mitocondriales/metabolismo , Interferencia de ARN , ARN Circular/genética , Proteína 1 Similar a ELAV/genética , Proteína 1 Similar a ELAV/metabolismoRESUMEN
Background: The traditional TNM staging system is often insufficient to differentiate the survival discrepancies of colorectal cancer (CRC) patients at TNM stage I/II. Our study aimed to reclassify stage I/II CRC patients into several subgroups with different prognoses and explore their suitable therapeutic methods. Methods: Single-cell RNA (scRNA) sequencing data, bulk RNA sequencing data, and clinicopathological information of CRC patients were enrolled from the TCGA and GEO databases. The tumor microenvironment of CRC tissues was accessed by the ESTIMATE algorithm. The prognostic genes were identified by Cox regression analysis. GO and KEGG analyses were conducted in the DAVID database. GSEA analysis was performed for annotation of the correlated gene sets. Results: We successfully reclassified stage I/II CRC patients into two subgroups and discovered that patients in cluster-2 underwent worse overall survival than those in cluster-1. GSEA analysis showed that immune-associated gene sets were positively enriched in cluster-2. Besides, the differentially expressed genes (DEGs) between cluster-1 and cluster-2 patients also participated in immune-related biological processes and signaling pathways. Moreover, we found that more immune cells infiltrated the microenvironment of cluster-2 patients compared to that of cluster-1 patients, such as Tregs and tumor-associated macrophages. ScRNA sequencing analysis uncovered that most of the enriched immune-associated signaling in cluster-2 patients was mainly attributed to these upregulated immune cells whose infiltration levels were also high in CRC tissues rather than in normal tissues. In addition, we demonstrated that the expression of immune checkpoint genes was significantly higher in cluster-2 patients compared to cluster-1 patients. ScRNA sequencing analysis revealed that the infiltrated CD8+T cells in CRC were naïve T cells and can be activated into effector T cells after immune checkpoint blockade (ICB) treatment. Conclusion: TNM stage I/II CRC patients can be divided into two subgroups, which have different overall survival rates, tumor microenvironment, and response to ICB therapy.
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Mounting evidence indicates that long non-coding RNAs (lncRNAs) have critical roles in colorectal cancer (CRC) progression, providing many potential diagnostic biomarkers, prognostic biomarkers, and treatment targets. Here, we sought to investigate the role and underlying regulatory mechanism of lncRNA small nucleolar RNA host gene 16 ( SNHG16) in CRC. The expressions of SNHG16 in CRC were identified by RNA-sequencing and quantitative reverse transcription PCR. The functions of SNHG16 were explored by a series of in vitro and in vivo assays (colony formation assay, flow cytometry assay, and xenograft model). Bioinformatics analysis, RNA fluorescence in situ hybridization and luciferase reporter assay were used to investigate the regulatory mechanism of effects of SNHG16. SNHG16 was found to be significantly elevated in human CRC tissues and cell lines. Functional studies suggested that SNHG16 promoted CRC cell growth both in vitro and in vivo. Mechanistically, we identified that SNHG16 is expressed predominantly in the cytoplasm. SNHG16 could interact with miR-214-3p and up-regulated its target ABCB1. This study indicated that SNHG16 plays an oncogenic role in CRC, suggesting it could be a novel biomarker and therapeutic target in CRC.
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Although invertebrates' innate immunity relies on several immune-like molecules, the diversity of these molecules and their immune response mechanisms are not well understood. Here, we show that Penaeus vannamei hemocyanin (PvHMC) undergoes specific deacetylation under Vibrio parahaemolyticus and LPS challenge. In vitro deacetylation of PvHMC increases its binding capacity with LPS and antibacterial activity against Gram-negative bacteria. Lysine residues K481 and K484 on the Ig-like domain of PvHMC are the main acetylation sites modulated by the acetyltransferase TIP60 and deacetylase HDAC3. Deacetylation of PvHMC on K481 and K484 allows PvHMC to form a positively charged binding pocket that interacts directly with LPS, whereas acetylation abrogates the positive charge to decrease PvHMC-LPS attraction. Besides, V. parahaemolyticus and LPS challenge increases the expression of Pvhdac3 to induce PvHMC deacetylation. This work indicates that, during bacterial infections, deacetylation of hemocyanin is crucial for binding with LPS to clear Gram-negative bacteria in crustaceans.
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Hemocianinas , Penaeidae , Animales , Proteínas de Artrópodos/metabolismo , Lipopolisacáridos/metabolismo , Inmunidad Innata , Bacterias Gramnegativas , Antibacterianos/metabolismoRESUMEN
Background: DNA methylation in the CpG island is associated with gastric cancer, genetic variations residue in genes involved in methylation pathway could contribute to the occurrence of gastric cancer. Here, we investigated the association between DNMTs (DNMT1/DNMT3A/DNMT3B), MTHFR genetic variations and gastric cancer risk and patients' survival. Patients and Methods: We recruited 490 gastric cancer patients and 488 age- and sex-matched healthy controls. The genotypes of the genetic variations were detected by a Mass-array platform. A commercial Helicobacter pylori (H. pylori) immunogold testing kit was used to determine the H. pylori infection. Results: We found that carriers of DNMT1 rs2228612C allele was associated with decreased gastric cancer risk (CT vs. TT: adjusted OR = 0.70, 95% CI = 0.53-0.94, P = 0.02; CT/CC vs.TT: adjusted OR = 0.73, 95% CI = 0.56-0.96, P = 0.02). Further stratified analysis showed that DNMT1 rs2228612 CT/CC were associated with a decreased gastric cancer risk in the subgroups of age ≤64 years old (adjusted OR = 0.61, 95% CI = 0.41-0.90, P = 0.01), male (adjusted OR = 0.72, 95% CI = 0.53-0.98, P = 0.03), negative H. pylori infection (adjusted OR = 0.67, 95% CI = 0.45-0.98, P = 0.04), tumor stage T3-T4 (adjusted OR = 0.69, 95% CI = 0.51-0.92, P = 0.01), and non-gastric cardiac adenocarcinoma (NGCA) (adjusted OR = 0.72, 95% CI = 0.54-0.97, P = 0.03). However, none of the genetic variations of this study was associated with overall survival. Conclusion: We concluded that the DNMT1 rs2228612C genotype is a protective factor for gastric cancer in Han Chinese population.
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The emergence of 5-Fluorouracil (5-FU) resistance is the barrier to effective clinical outcomes for colorectal cancer (CRC) patients. Autophagy was found to be involved in protecting tumor cells from 5-FU. However, the specific role of autophagy-related genes in CRC 5-FU resistance remains unclear. In this study, HSPB8 among 34 differentially expressed ARGs in CRC was identified to be the hub ARGs in 5-FU resistant which was down-regulated in CRC samples when compared with normal samples but up-regulated in CRC samples with relatively higher lymphatic invasion, later stages and poor prognosis of CRC. Mechanistic analysis demonstrated that due to the recruitment of CAFs, HSPB8 expression was enhanced in CRC cells so that HSPB8 could act together with its co-chaperone BAG3 in autophagy drived 5-FU resistance. Furthermore, the augmented expression level of HSPB8 was found to be significantly correlated to the immune cell infiltration such as Treg cells, macrophages, monocyte and dendritic cells and so on. Our results suggested CAFs driving HSPB8 induced CRC 5-FU resistance by promoting tumor autophagy would provide a new strategy in seeking potential CRC therapeutic target.
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As the most prevalent type of RNA modification in eukaryotes, N6-methyladenosine (m6A) can modulate RNA fates such as processing, splicing, maturation, export, stability, translation, and degradation. Circular RNAs (circRNAs), a novel type of non-coding RNA (ncRNAs) characterized by a covalently closed loop structure, play an essential role in various physiological and pathological processes. Extensive studies have revealed that m6A modification is widespread in circRNAs and influences their biogenesis and functions. Intriguingly, circRNAs can affect m6A modification by regulating m6A regulatory proteins. In this review, we summarize the characteristics and biological functions of m6A and circRNAs and focus on recent advances in the interaction of m6A modification and circRNAs. In addition, the potential clinical applications of m6A modification and circRNAs in diagnosis and therapeutic targets are discussed.
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BACKGROUND: A growing number of studies have shown that long non-coding RNAs (lncRNAs) play an important role in the occurrence and development of tumors. In this study, we explored the function and molecular mechanism of lncRNA SPINT1-AS1 in breast cancer progression. METHODS: A total of 30 patients and 25 healthy controls were enrolled to detect the expression of SPINT1-AS1 in the serum by RT-qPCR. CCK-8 assay, clone formation assay, EdU assay, Transwell assay, Flow cytometry for apoptosis assay and wound healing assays were used to explore the effects of SPINT1-AS1 on the proliferation and migration of breast cancer cells. Bioinformatics analysis were used to enrich the downstream target genes and related pathways of miRNAs interacting with SPINT1-AS1, construct a competitive endogenous RNA (ceRNA) network diagram. RESULTS: SPINT1-AS1 is up-regulated in the serum of breast cancer patients and breast cancer cell lines. The proliferation and migration ability of breast cancer cells were decreased significantly after SPINT1-AS1 knockdown, and it may inhibit its expression by sponging miR-let-7a/b/i-5p, thereby promoting breast cancer progression. CONCLUSIONS: SPINT1-AS1 can promote the proliferation and migration of breast cancer cells by regulating miR-let-7a/b/i-5p, suggesting that it may be an important regulator of breast cancer progression.
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Neoplasias de la Mama/metabolismo , Movimiento Celular , Proliferación Celular , MicroARNs/metabolismo , ARN Largo no Codificante/metabolismo , Anciano , Apoptosis , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Células MCF-7 , MicroARNs/genética , Persona de Mediana Edad , Metástasis de la Neoplasia , ARN Largo no Codificante/sangre , ARN Largo no Codificante/genéticaRESUMEN
MicroRNA-196a (miR-196a) was previously reported to be up-regulated in cancers, and it has the diagnostic and prognostic values in cancers. Whereas, the conclusion was still unclear according to the published data. To assess such roles of miR-196a in cancers, the present study was conducted based on published data and online cancer-related databases. To identify the relevant published data, we searched articles in databases and then the relevant data were extracted to evaluate the correlation between miR-196a expression and diagnosis, prognosis for cancer patients. The pooled results showed that miR-196a was a valuable diagnostic biomarker in cancer (area under curve (AUC) = 0.87, 95% CI: 0.84-0.90; sensitivity (SEN) = 0.73, 95% CI: 0.64-0.81; specificity (SPE) = 0.90, 95% CI: 0.81-0.95), which was consistent with the data from databases (breast cancer: miR-196a-3p: AUC = 0.77, 95% CI: 0.74-0.79; miR-196a-5p: AUC = 0.71, 95% CI: 0.66-0.75; pancreatic cancer: miR-196a-3p: AUC = 0.80, 95% CI: 0.73-0.87; miR-196a-5p: AUC = 0.61, 95% CI: 0.51-0.71). In addition, the pooled result revealed that elevated miR-196a expression in tumor tissues (HR = 2.54, 95% CI: 1.79-3.61, PHeterogeneity=0.000, I2 = 75.8%) or serum/plasma (HR = 4.06, 95% CI: 2.67-6.18, PHeterogeneity=0.668, I2 = 0%) of patients was an unfavorable survival biomarker, which was consistent with the data from databases (adrenocortical carcinoma: HR = 5.70; esophageal carcinoma: HR = 1.93; brain lower grade glioma: HR = 2.91; GSE40267: HR = 2.47, 95% CI: 1.2-5.07; TCGA: HR = 1.82, 95% CI: 1.21-2.74; GSE19783: HR = 4.24, 95% CI: 1-18.06). In short, our results demonstrated that miR-196a in tumor tissue or serum/plasma could be used as a prognostic and diagnostic values for cancers.
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Biomarcadores de Tumor/genética , MicroARNs/genética , Neoplasias/genética , Bases de Datos Genéticas , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias/diagnóstico , Neoplasias/patologíaRESUMEN
Saline is a commonly used intravenous solvent, however, its excessive infusion may increase drug-induced sodium intake. To investigate the effects of saline infusion on blood pressure variability (BPV) in patients with hypertension, a retrospective study was performed in 1010 patients with hypertension. The patients who received saline infusion before surgery for continuous 3 to 5 days were divided into 2 groups according to the saline infusion volume during the hospitalization, which are >500âmL per day group and <500âmL per day group. The overall incidence of abnormal BPV was 11.58%. As for the incidence of abnormal BPV in the <500âmL per day group with 698 patients was 9.17%, while that in the >500âmL per day group with 312 patients was as high as 16.99%. Additionally, >500âmL of daily saline infusion for continuous 3 to 5 days (P for trendâ=â.004, odds ratio [OR]â=â1.911, 95% confidence interval [CI] for OR 1.226-2.977), medical history of diabetes mellitus (Pâ<â.001, ORâ=â4.856, 95% CI for OR 3.118-7.563) and cardiovascular diseases (Pâ<â.001, ORâ=â2.498, 95% CI for OR 1.549-4.029) may be risk factors of abnormal BPV; while anti-hypertensive therapy with diuretics (Pâ<â.001, ORâ=â0.055, 95% CI for OR 0.024-0.125) may be the protective factor. Our study suggests that >500âmL of daily saline infusion for continuous 3 to 5 days may have disadvantages in the blood pressure control for hypertensive patients, especially for the patients with diabetes mellitus and cardiovascular diseases.
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Variación Biológica Poblacional/fisiología , Presión Sanguínea/efectos de los fármacos , Hipertensión/epidemiología , Solución Salina/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Presión Sanguínea/fisiología , Determinación de la Presión Sanguínea/tendencias , Enfermedades Cardiovasculares/epidemiología , Estudios de Casos y Controles , China/epidemiología , Diabetes Mellitus/epidemiología , Femenino , Humanos , Hipertensión/tratamiento farmacológico , Incidencia , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Procedimientos Ortopédicos/métodos , Procedimientos Ortopédicos/estadística & datos numéricos , Estudios Retrospectivos , Factores de Riesgo , Solución Salina/administración & dosificaciónRESUMEN
The histone deacetylase, sirtuin 6 (SIRT6), plays an essential role in the regulation of oxidative stress, mitochondrial function and inflammation in mammals. However, the specific role of SIRT6 in invertebrate immunity has not been reported. Here, we characterized for the first time, a sirtuin 6 homolog in Litopenaeus vannamei (LvSIRT6), with full-length cDNA of 2919 bp and 1536 bp open reading frame (ORF) encoding a putative protein of 511 amino acids, which contains a typical SIR2 domain. Sequence and phylogenetic analysis revealed that LvSIRT6 shares a close evolutionary relationship with SIRT6 from invertebrates. Real-time quantitative PCR analysis of LvSIRT6 transcripts revealed that they were ubiquitously expressed in shrimp and induced in hepatopancreas and hemocytes upon challenge with Vibrio parahaemolyticus, Streptococcus iniae, lipopolysaccharide (LPS), and white spot syndrome virus (WSSV), suggesting the involvement of LvSIRT6 in shrimp immune response. Moreover, knockdown of LvSIRT6 decreased mitochondrial membrane potential and increased total ROS level in hemocytes, especially upon V. parahaemolyticus challenge. Depletion of LvSIRT6 also increased hemocytes apoptosis in terms of decreased expression of pro-survival LvBcl-2, but increased expression of pro-apoptotic LvBax and LvCytochrome C, coupled with high LvCaspase3/7 activity. Shrimp were rendered more susceptible to V. parahaemolyticus infection upon LvSIRT6 knockdown. Taken together, our present data suggest that LvSIRT6 plays an important role in shrimp immune response by modulating hemocytes ROS production and apoptosis during pathogen challenge.
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Proteínas de Artrópodos/metabolismo , Hemocitos/metabolismo , Hemocitos/patología , Penaeidae/inmunología , Sirtuinas/metabolismo , Secuencia de Aminoácidos , Animales , Apoptosis/genética , Proteínas de Artrópodos/química , Proteínas de Artrópodos/genética , Secuencia de Bases , Clonación Molecular , Resistencia a la Enfermedad/genética , Regulación de la Expresión Génica , Sistemas de Lectura Abierta , Penaeidae/clasificación , Penaeidae/microbiología , Penaeidae/virología , Filogenia , Dominios Proteicos , Especies Reactivas de Oxígeno/metabolismo , Alineación de Secuencia , Sirtuinas/química , Sirtuinas/genética , Streptococcus iniae/fisiología , Vibrio parahaemolyticus/fisiología , Virus del Síndrome de la Mancha Blanca 1/fisiologíaRESUMEN
The ataxia-telangiectasia mutated (ATM) protein is regarded as the linchpin of cellular defenses to stress. Deletion of ATM results in strong oxidative stress and degenerative diseases in the nervous system. However, the role of ATM in neuronal ischemic preconditioning and lethal ischemic injury is still largely unknown. In this study, mice cortical neurons preconditioned with sublethal exposure to oxygen glucose deprivation (OGD) exhibited ATM/glucose-6-phosphate dehydrogenase pathway activation. Additionally, pharmacological inhibition of ATM prior to the preconditioning reversed neuroprotection provided by preconditioning in vitro and in vivo. Meanwhile, we found that ATM/P53 pro-apoptosis pathway was driven by lethal OGD injury, and pharmacological inhibition of ATM during fatal oxygen-glucose deprivation/reperfusion injury promoted neuronal survival. More importantly, inhibition of ATM activity after cerebral ischemia protected against cerebral ischemic-reperfusion damage in mice. In conclusion, our data show the dual role of ATM in neuronal ischemic preconditioning and lethal ischemic injury, involving in the protection of ischemic preconditioning, but promoting neuronal death in lethal ischemic injury. Thus, the present study provides new opportunity for the treatment of ischemic stroke.
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Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Isquemia Encefálica/terapia , Corteza Cerebral/irrigación sanguínea , Precondicionamiento Isquémico , Animales , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Isquemia Encefálica/metabolismo , Supervivencia Celular , Prueba de Esfuerzo , Glucosa/deficiencia , Masculino , Ratones , Ratones Endogámicos C57BL , Daño por Reperfusión/metabolismo , Daño por Reperfusión/prevención & controlRESUMEN
Chloroquine, a prototype anti-malaria drug, has been reported to possess anti-inflammatory effects. Moreover, chloroquine pretreatment could improve DNA damage repair. It is therefore reasonable to hypothesize that chloroquine pretreatment could attenuate ischemia/reperfusion injury in the brain. Considering the fact that chloroquine could also improve glucose metabolism, we speculated that the potential effects of chloroquine on ischemia/reperfusion injury might be particularly pronounced in diabetic mice. In this study, chloroquine pretreatment protected neurons from Oxygen Glucose Deprivation (OGD) induced cytotoxicity and apoptosis. In vivo, Ob/ob mice and wildtype (WT) mice were pretreated with chloroquine for 3â¯weeks. Then, ischemic stroke was induced by 60â¯min Middle Cerebral Artery Occlusion (MCAO). We found that chloroquine pretreatment normalized blood glucose in diabetic ob/ob mice, and reduced cerebral damage after ischemic stroke especially for diabetic mice. In addition, chloroquine pretreatment reduced High-mobility group box 1 (HMGB1) content in the cerebrospinal fluid (CSF) and serum and lowered myeloperoxidase (MPO) activity and inflammatory cytokines gene expression both in the ob/ob diabetic mice and WT mice. Moreover, harmful DNA damage-signaling responses, including PARP activation and p53 activation, were also attenuated by chloroquine pretreatment in these two kinds of mice. In conclusion, chloroquine pretreatment could reduce cerebral damage after ischemic stroke especially in diabetic mice through multiple mechanisms, which include reducing neural cell DNA injury, restoring euglycemia and anti-inflammatory effects. The findings may provide potential for the development of chloroquine in the prevention and treatment of stroke in diabetic high-risk patients.
Asunto(s)
Isquemia Encefálica/fisiopatología , Encéfalo/efectos de los fármacos , Cloroquina/administración & dosificación , Diabetes Mellitus/fisiopatología , Fármacos Neuroprotectores/administración & dosificación , Daño por Reperfusión/fisiopatología , Animales , Glucemia/efectos de los fármacos , Encéfalo/patología , Encéfalo/fisiopatología , Isquemia Encefálica/prevención & control , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Proteína HMGB1/líquido cefalorraquídeo , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/patología , Neuronas/fisiología , Cultivo Primario de Células , Daño por Reperfusión/prevención & controlRESUMEN
PURPOSE: MicroRNA-195 is dysregulated in different kinds of cancers and plays a pivotal role in tumorigenesis. It may function as a prognostic biomarker for cancers. However, the results from articles were not consistent. This study was designed to validate the prognostic value of microRNA-195 in human tumors. METHODS: We conducted a detailed search on PubMed until December 31, 2018. The quality of these publications was assessed on the basis of a list of key reviews presented by PRISMA statement. The pooled hazard ratios (HR) and pooled odds ratios (OR) of each 95% confidence interval (95% CI) were calculated to assess the effect. RESULTS: This meta-analysis included 12 studies involving 940 cancer patients to assess the prognostic value of miR-195 in different solid tumors. The results showed that patients with high expression of miR-195 had favorable tumor-node-metastasis (late vs early: pooled OR =0.16, 95% CI: 0.11-0.22, P<0.001), lymph node metastasis (pooled OR =0.25, 95% CI: 0.18-0.35, P<0.001) and distant metastasis (pooled OR =0.26, 95% CI: 0.13-0.52, P<0.001). At the same time, high levels of miR-195 expression were closely correlated with better overall survival (pooled HR =0.46, 95% CI: 0.36-0.58, P<0.001). CONCLUSION: Elevated microRNA-195 may serve as a potential biomarker to predict a favorable prognosis for various cancer types in China.
RESUMEN
BACKGROUND: Refractory esophageal anastomotic strictures are difficult to treat. Current treatments include esophageal stent placement (ESP) and the endoscopic incision method (EIM). This study was conducted to determine which treatment is better for patients with refractory esophageal anastomotic stricture. METHODS: This study retrospectively collected data of patients with refractory esophageal anastomotic stricture who underwent ESP or EIM between January 2012 and June 2018. Dysphagia scores before and after the procedure were recorded in both groups. The duration of relief during the follow-up period was recorded. RESULTS: Fifty patients were enrolled in this study, including 32 patients who underwent ESP and 18 who underwent EIM. Patients in the ESP group had a markedly larger diameter of dilatation than those in the EIM group (19.9±1.8 versus 11.0±1.9 mm, respectively; P0.001). However, the dysphagia score improved by 1.0±0.0 point in the ESP group and by 1.4±0.5 points in the EIM group (P<0.001). Nearly 70% of patients in the ESP group maintained lumen patency at 12 months. In contrast, only 50% of patients in the EIM group had persistent relief of stricture symptoms at 6 months and only 20% had relief at 12 months. Five patients had slight bleeding; none required blood transfusion. Thirteen patients in the ESP group had slight chest pain; seven of these required administration of a painkiller. CONCLUSIONS: EIM can rapidly relieve the symptoms of esophageal anastomotic stricture but ESP provides longer duration of relief. Both procedures are safe for patients with refractory esophageal anastomotic stricture.