Cellular senescence: a promising therapeutic target in colorectal cancer.

Colorectal cancer is one of the most malignant cancers worldwide, and efforts have been made to elucidate the mechanism of colorectal carcinogenesis. Cellular senescence is a physiological process in cell life, but it is also found in cancer initiation and progression. Lines of evidence show that senescence may influence the development and progression of colorectal carcinogenesis. Here, the authors review the characteristics of senescence and the recent findings of a relationship between senescence and colorectal cancer.

Cancer is a leading cause of death worldwide; out of the top ten most common cancers in 2020, the incidence and mortality rate of colorectal cancer (CRC) ranked third and second, respectively. Based on statistics, it was estimated that more than 1.9 million CRC cases occurred in 2020. In terms of CRC, a prominent risk factor is age, and studies suggest that the aging process plays a role in CRC initiation and progression. This review discusses how aging contributes to CRC carcinogenesis and summarizes recent findings on potential therapeutics.

[Molecular mechanism of astragaloside â £ against atherosclerosis by regulating miR-17-5p and PCSK9/VLDLR signal pathway].

This study explores the regulatory effect of astragaloside Ⅳ on miR-17-5 p and its downstream proprotein convertase subtillisin/kexin type 9(PCSK9)/very low density lipoprotein receptor(VLDLR) signal pathway, aiming at elucidating the mechanism of astragaloside Ⅳ against atherosclerosis(AS). In cell experiment, oxidized low-density lipoprotein(ox-LDL) was used for endothelial cell injury modeling with vascular smooth muscle cells(VSMCs). Then cells were classified into the model group, miR-17-5 p inhibitor group, blank serum group, and astragaloside Ⅳ-containing serum group based on the invention. Afterward, cell viability and the expression of miR-17-5 p, VLDLR, and PCSK9 mRNA and protein in cells in each group were detected. In animal experiment, 15 C57 BL/6 mice were used as the control group, and 45 ApoE~(-/-) mice were classified into the model group, miR-17-5 p inhibitor group, and astragaloside Ⅳ group, with 15 mice in each group. After 8 weeks of intervention, the peripheral serum levels of interleukin-6(IL-6), interleukin-10(IL-10), and tumor necrosis factor-α(TNF-α), and the expression of miR-17-5 p, VLDLR, and PCSK9 mRNA in the aorta of mice were detected. The pathological changes of mice in each group were observed. According to the cell experiment, VSMC viability in the miR-17-5 p inhibitor group and the astragaloside Ⅳ-containing serum group was higher than that in the model group(P<0.05). The mRNA and protein expression of miR-17-5 p and VLDLR in VSMCs in the miR-17-5 p inhibitor group and the astragaloside Ⅳ-containing serum group was lower than that in the model group(P<0.05), but the mRNA and protein expression of PCSK9 was higher than that in the model group(P<0.05). As for the animal experiment, the levels of IL-6 and TNF-α in the peripheral serum of the miR-17-5 p inhibitor group and the astragaloside Ⅳ group were lower(P<0.05) and the serum level of IL-10 was higher(P<0.05) than that of the model group. The mRNA expression of miR-17-5 p and VLDLR in the aorta in the miR-17-5 p inhibitor group and the astragaloside Ⅳ group was lower(P<0.05), and PCSK9 mRNA expression was higher(P<0.05) than that in the model group. Pathological observation showed mild AS in the miR-17-5 p inhibitor group and the astragaloside Ⅳ group. In summary, astragaloside Ⅳ can prevent the occurrence and development of AS. The mechanism is that it performs targeted regulation of miR-17-5 p, further affecting the PCSK9/VLDLR signal pathway, inhibiting vascular inflammation, and thus alleviating endothelial cell injury.

miR-340 Inhibits Proliferation and Induces Apoptosis in Gastric Cancer Cell Line SGC-7901, Possibly via the AKT Pathway.

BACKGROUND Gastric cancer is among the most common types of cancer, with high morbidity and mortality. MicroRNAs (miRNAs) play vital roles in the tumorigenesis and biology of gastric cancer. This study aimed to reveal the role of miR-340 in gastric cancer cell proliferation and apoptosis and to elucidate the potential mechanisms. MATERIAL AND METHODS Human gastric cancer cells SGC-7901 were used in this study for cell transfection with miR-340 mimic or inhibitor. After transfection, cell viability, proliferation, and apoptosis were examined by MTT, BrdU, and flow cytometry assays, respectively. The protein level changes of p27, p21, Caspase 3 (CASP3), B cell lymphoma 2 (BCL2), BCL2-associated X protein (BAX), and v-AKT murine thymoma viral oncogene (AKT) were detected by Western blot. RESULTS Overexpression of miR-340 significantly reduced cell viability and proliferation (P<0.01), and induced cell apoptosis (P<0.01) of SGC-7901. miR-340 elevated the protein level of cell cycle inhibitor p27, but did not affect the level of p21. Apoptosis-related factors pro-CASP3, cleaved-CASP3, and BAX were promoted, and BCL2 was inhibited by miR-340. miR-340 also suppressed the phosphorylation of AKT. Opposite effects were detected when SGC-7901 cells were transfected with miR-340 inhibitor. CONCLUSIONS These results indicate that miR-340 can inhibit proliferation and induce apoptosis of SGC-7901 cells, suggesting its roles in protecting against gastric cancer. The roles of miR-340 in gastric cancer cells may be associated with its regulation of the AKT pathway. Thus, miR-340 may be a potential therapeutic strategy for gastric cancer treatment.

Knockdown of Minichromosome Maintenance Proteins Inhibits Foci Forming of Mediator of DNA-Damage Checkpoint 1 in Response to DNA Damage in Human Esophageal Squamous Cell Carcinoma TE-1 Cells.

Esophageal squamous cell carcinoma (ESCC) has a high morbidity in China and its treatment depends greatly on adjuvant chemotherapy. However, DNA damage repair in cancer cells severely affects the outcome of treatment. This study investigated the potential mechanism regarding mediator of DNA-damage checkpoint 1 (MDC1) and minichromosome maintenance proteins (MCMs) during DNA damage in ESCC. Recombinant vectors of MDC1 and MCMs with tags were constructed and transfected into human ESCC cell line TE-1. Immunoprecipitation and mass spectrometry were performed to screen the MCMs interacting with MDC1, and direct interaction was confirmed by glutathione S-transferase (GST) pull-down assay in vitro. MCM2 and MCM6 were knocked down by shRNAs, after which chromatin fraction and foci forming of MDC1 upon bleomycin-induced DNA damage were examined. The results showed that MCM2/3/5/6 were immunoprecipitated by antibodies against the tag of MDC1 in TE-1 nuclei, and the GST pull-down assay indicated the direct interaction. Knockdown of MCM2 or MCM6 reduced the chromatin fraction of MDC1 according to Western blot results. Moreover, knockdown of MCM2 or MCM6 could significantly inhibit foci forming of MDC1 in TE-1 nuclei in response to bleomycin-induced DNA damage (p < 0.001). This study indicates the direct interaction between MDC1 and MCMs in TE-1 nuclei. Downregulation of MCMs can inhibit chromatin fraction and foci forming of MDC1 in TE-1 cells upon DNA damage, which suggests MCMs and MDC1 as potential targets to improve the outcome of chemotherapy in ESCC.

Metabolome Profiling of Malignant Ascites Identifies Candidate Metabolic Biomarkers of Hepatocellular Carcinoma.

BACKGROUND: Malignant ascites is one of the severe complications of hepatocellular carcinoma, which can be regarded as a unique tumor microenvironment of hepatocellular carcinoma. The identification of novel biomarkers in malignant ascites could be crucial to differentiate patients with hepatocellular carcinoma and cirrhotic ascites. OBJECTIVE: The study aimed to distinguish the metabolomics of malignant ascites in patients with hepatocellular carcinoma from that of non-malignant ascites (cirrhotic ascites). METHODS: Liquid chromatography-mass spectrometry was performed to analyze the differentially distributed biomarkers in patients with malignant ascites and hepatocellular carcinoma (n = 39), as well as in patients with cirrhotic ascites, which were taken as controls (n = 36). RESULTS: A total of 20 differential metabolites associated with malignant ascites were identified, of which 8 metabolites were upregulated and 12 metabolites were downregulated (ratio < 0.5 or > 1.5, respectively). Moreover, pathway and enrichment analyses revealed nitrogen metabolism, urea cycle, phenylalanine, and tyrosine metabolism to be implicated in the formation of malignant ascites in patients with hepatocellular carcinoma. CONCLUSION: Our results suggest that the key factors associated with pathways, such as arachidonic acid, phenylalanine, and glutamic acid pathways, are potential ascitic fluidbased biomarkers for differentiating hepatocellular carcinoma with cirrhosis ascites; the results also provide a clinical pathophysiological interpretation of biomarkers and metabolic pathways relevant to disease status.

Combining non-invasive liquid biopsy and a methylation analysis to assess surgical risk for early esophageal cancer.

Background: While the widespread use of endoscopic submucosal dissection (ESD) has significantly reduced the incidence of early esophageal cancer (ESCA), the limited ability of ESD to strip deep infiltrating esophageal lesions results in a considerable risk of intraoperative perforation. Circulating-free DNA (cfDNA) is widely used in modern tumor screening due to its non-invasive detection capabilities. A methylation analysis offers vital insights into the condition and advancement of malignancies due to its unique positioning, such as a marker of cancer. This study investigated the potential of combining a non-invasive liquid biopsy technique, along with a methylation analysis, to assess the surgical perforation risk of ESCA patients. Methods: In this study, we conducted an analysis of gene expression differences between stage I esophageal squamous carcinoma samples and healthy tissue samples using data from The Cancer Genome Atlas (TCGA) database. We also identified the genes associated with progression-free survival (PFS) in esophageal squamous carcinoma. Integrating the framework of the methylation analysis, we explored the methylated sites of these distinct genes. To refine this process, we used the Shiny Methylation Analysis Resource Tool (SMART) to conduct a comprehensive analysis of these sites. We then confirmed the stability of the methylation sites in different lesion conditions using methylation-specific quantitative polymerase chain reaction (MS-qPCR) with paraffin tissue samples collected after ESD. Results: We analyzed RNA-sequencing data from 42 early stage ESCA patients and 17 controls, identifying 1,263 up-regulated and 460 down-regulated genes. Functional analyses revealed involvement in key pathways such as cell cycle regulation and immune responses. Furthermore, we identified 38 differentially expressed genes associated with PFS. Using SMART analysis, we found 217 hyper-methylated regions in 38 genes, suggesting potential early markers for ESCA. Validation experiments confirmed the reliability of 29 hyper-methylated regions in FFPE tissue samples and 6 regions in cfDNA. A LunaCAM model showed high accuracy [area under the curve (AUC) =0.89] in discriminating early ESCA. Integrated assessment of six highly methylated regions significantly improved predictive performance, with 90.56% sensitivity, highlighting the importance of combinatorial biomarker evaluation for early cancer detection. Conclusions: This study established a novel approach that integrates non-invasive testing with a methylation analysis to assess the surgical risk of early ESCA patients. The significance of changes in methylation sites in relation to lesion status should not be underestimated, as they have the potential to offer vital insights for proactive risk assessments before surgery.

MAGED4B is a Poor Prognostic Marker of Stomach Adenocarcinoma and a Potential Therapeutic Target for Stomach Adenocarcinoma Tumorigenesis.

Background: Gastric cancer is the second most common cause of cancer death worldwide with poor overall prognosis. It is important to study the molecular mechanism of stomach adenocarcinoma (STAD). MAGED4B, a member of the melanoma antigen gene (MAGE) family, is highly expressed in many tumor cells and is associated with tumor progression. Its prognostic value in and the function of the encoded protein are still unclear. Methods: The data of 415 STAD tissues was retrieved from TCGA database, and the expression level of MAGED4B mRNA was evaluated. The correlation between the expression of MAGED4B mRNA and the progression free survival (PFS) time of STAD patients was evaluated by Kaplan Meier analysis. The STAD cell lines with overexpressed and silent MAGED4B were constructed, and the effects of MAGED4B on the viability, migration and proliferation were evaluated by the CCK-8, scratch test and EDU test. The flow cytometry was used to detect apoptosis with overexpressed and silent MAGED4B under the cisplatin treatment, and WB was used to detect the expressions of related proteins, such as TNF-α. Results: The expression level of MAGED4B mRNA in the STAD tissues was higher than that in the normal tissues, and its high expression was related to poor PFS. The overexpression of MAGED4B in the STAD cell lines can promote the vitality, motility and proliferation of the STAD cells, while the silencing of MAGED4B can inhibit the above three cell functions of the STAD cells. The overexpression of MAGED4B can reduce the cisplatin induced apoptosis and increase the cisplatin IC50; the silencing of MAGED4B can promote the cisplatin induced apoptosis and reduce the cisplatin IC50. The overexpression of MAGED4B reduced the protein levels of TRIM27 and TNF- α. Conclusion: MAGED4B could be a valuable prognostic biomarker and a therapeutic target for gastric adenocarcinoma of great interest.

A Study on the Static Magnetic and Electromagnetic Properties of Silica-Coated Carbonyl Iron Powder after Heat Treatment for Improving Thermal Stability.

In order to study the thermal stability of coated carbonyl iron powder (CIP) and its influence on magnetic properties, carbonyl iron powder was coated with a silica layer and then annealed in an air atmosphere at elevated temperatures. Transmission electron microscopy (TEM) analysis and Fourier transform infrared spectroscopy confirmed the existence of a silicon dioxide layer with a thickness of approximately 80~100 nm. Compared with uncoated CIP, the silicon-coated CIP still maintained a higher absorption performance after annealing, and the calculated impedance matching value Z only slightly decreased. It is worth noting that when the annealing temperature reached 300 °C, coercivity (Hc) increased, and the real and imaginary parts of the permeability decreased, which means that the silicon dioxide layer began to lose its effectiveness. On the contrary, the significant decrease in microwave absorption ability and impedance matching value Z of uncoated CIP after annealing were mainly because the newly formed oxide on the interface became the active polarization center, leading to an abnormal increase in permittivity. In terms of the incremental mass ratio after annealing, 2% was a tipping point for permeability reduction.

Transcriptomic and network pharmacology approaches revealed possible mechanisms underlying the 5-fluorouracil (5-FU)-sensitizing effect of Xuan-Fu-Hua decoction treatment on liver cancer cells.

Background: Xuan-Fu-Hua decoction is a traditional Chinese medicine formula widely used for the treatment of inflammation-related disease in the lung and liver. This study aimed to investigate the effect of Xuan-Fu-Hua decoction treatment on liver cancer cells and its mechanism of action. Methods: The impact of Xuan-Fu-Hua decoction treatment on the proliferation and apoptosis of SMMC-7721 liver cancer cells with or without 5-fluorouracil (5-FU) cotreatment was determined in both in vitro and in vivo settings. Alterations in gene expression patterns in SMMC-7721 cells induced by Xuan-Fu-Hua decoction treatment were explored by transcriptomic sequencing. Effective components of Xuan-Fu-Hua decoction and their target proteins were investigated using network pharmacology approaches. Results: Xuan-Fu-Hua decoction alone did not significantly influence SMMC-7721 liver cancer cell growth, but it significantly increased the 5-Fu-induced growth inhibition and apoptosis of SMMC-7721 liver cancer cells in vitro and in vivo. Most differentially expressed genes in SMMC-7721 liver cancer cells with or without Xuan-Fu-Hua decoction treatment were enriched in cell apoptosis-related pathways. Xuan-Fu-Hua decoction treatment significantly increased the transcription levels of DDIT3, PMAIP1, and ZMAT3 genes while decreasing that of WNT4, AXIN2, NFE2L2, TGFBR1, MITF, and IGFBP3 genes. An interaction network between the effective components and their possible target proteins was constructed by predicting compound-target protein and protein-protein interactions. Gene set enrichment analysis revealed the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway as well as Bcl-2 and Mcl-1 proteins as potential regulatory targets of Xuan-Fu-Hua decoction in sensitizing SMMC-7721 cells to the cytotoxicity of 5-FU treatment. Conclusions: Xuan-Fu-Hua decoction increased the sensitivity of liver cancer cells to the cytotoxicity of 5-FU treatment, possibly by potentiating cell apoptosis and inhibiting the prosurvival machinery.

Endoscopic tightening of the cardia mucosa in gastroesophageal reflux disease: A case series of 120 patients up to 1-year follow-up.

Background and Aim: A technique of endoscopic tightening of the cardia mucosa for the treatment of gastroesophageal reflux disease (GERD) was developed and its clinical efficacy was observed. Methods: 120 patients with GERD who underwent endoscopic tightening surgery from December 2017 to December 2019 were included in this study. GERD-Q score and constitution type of patients were evaluated preoperatively and at 1 month, 3 months, 6 months, and 1 year after surgery. In addition, effectiveness and side effects of the procedure were graded based on gastroesophageal flap valve (GEFV) function. Results: GERD-Q score of 1 month, 3 months, 6 months, and 1 year after surgery were significantly decreased (P<0.01) compared with preoperative score. There were no significant differences between GERD-Q score of 1 month, 3 months, 6 months, and 1 year after surgery. The surgery proves to be effective in all GEFV grades, especially in Hill-III. Conclusion: Endoscopic tightening is an effective method for the treatment of patients with GERD, especially of Hill-III patients. Attention should be paid to cardia width, ligation ring depth, and ring number during operation. Relevance for Patients: ETCM is a safe endoscopic procedure with minimal trauma, which has been proved effective for patients who are diagnosed with GERD.

Endoscopic tightening of the cardia mucosa in gastroesophageal reflux disease: A case series of 120 patients up to 1-year follow-up.

Background and Aim: A technique of endoscopic tightening of the cardia mucosa for the treatment of gastroesophageal reflux disease (GERD) was developed and its clinical efficacy was observed. Methods: 120 patients with GERD who underwent endoscopic tightening surgery from December 2017 to December 2019 were included in this study. GERD-Q score and constitution type of patients were evaluated preoperatively and at 1 month, 3 months, 6 months, and 1 year after surgery. In addition, effectiveness and side effects of the procedure were graded based on gastroesophageal flap valve (GEFV) function. Results: GERD-Q score of 1 month, 3 months, 6 months, and 1 year after surgery were significantly decreased (P<0.01) compared with preoperative score. There were no significant differences between GERD-Q score of 1 month, 3 months, 6 months, and 1 year after surgery. The surgery proves to be effective in all GEFV grades, especially in Hill-III. Conclusion: Endoscopic tightening is an effective method for the treatment of patients with GERD, especially of Hill-III patients. Attention should be paid to cardia width, ligation ring depth, and ring number during operation. Relevance for Patients: ETCM is a safe endoscopic procedure with minimal trauma, which has been proved effective for patients who are diagnosed with GERD.

Diagnostic accuracy of linked colour imaging versus white light imaging for early gastric cancers: a prospective, multicentre, randomized controlled trial study.

BACKGROUND: Linked colour imaging (LCI) is a novel new image-enhanced endoscopy (IEE) technology that produces bright and vivid images. The aim of this study was to assess the ability of LCI to improve the diagnostic accuracy of early gastric cancer (EGC) relative to white light imaging (WLI). MATERIALS AND METHODS: We performed this study on patients undergoing screening endoscopy from 12 medical institutions in China. Patients were randomly assigned to receive WLI followed by LCI or LCI followed by WLI. The primary outcome was to compared the diagnostic accuracy between LCI and WLI for EGC/high-grade intraepithelial neoplasms. Secondary outcomes included the numbers of suspicious lesions, neoplastic lesions and examination time by using LCI detected versus using WLI. RESULTS: A total of 1924 patients were randomly selected, and 1828 were included in the analysis. The diagnostic accuracy for EGC, which was 78.8% by using LCI and 68.4% by using WLI (p < .0001). More suspicious lesions were detected by LCI than by WLI (n = 1235 vs. 1036, p = .031), especially among differentiated EGC (p = .013). LCI greatly shortened the examination time compared with WLI (p = .019). CONCLUSIONS: LCI has better accuracy and shorter examination time in diagnosing EGC than WLI (Clinical trial registration: NCT03092414).Key messagesCompared with white light imaging (WLI), the diagnostic accuracy, sensitivity and specificity increased by using LCI.More lesions were detected by LCI alone than by WLI alone, especially among differentiated EGC.LCI may be used as a screening tool for routine clinical observation.

1,3,5,7-Tetra-bromo-adamantane.

In the pyramidal-shaped mol-ecule of the title compound, C(10)H(12)Br(4), the four terminal Br-C bond distances are nearly identical, ranging from 1.964 (4) to 1.974 (4) Å. The Br⋯Br distance of 3.6553 (7) Šindicates van der Waals contacts between mol-ecules in the crystal structure.

Safety of potassium-bearing citrate in patients with renal transplantation: A case report.

RATIONALE: Urinary lithiasis is one of severe postoperative complications in patients undergoing renal transplantation, possibly leading to anuria, urinary infection, or even acute renal failure. Potassium sodium hydrogen citrate (PSHC), a potassium-bearing citrate, is commonly prescribed to prevent stone formation. PATIENT CONCERNS: A 25-year-old man (patient 1) and a 31-year-old man (patient 2) receiving renal transplantation for end-stage renal disease (ESRD) were enrolled in this study. They were given 10 g/day of PSHC granules from the ninth day to the 17th day after surgery. Patient 1 presented chest tightness, nausea, muscle weakness, and ascending paralysis on the 10th day. Patient 2 presented weak waves on EGG on the 17th day. Moreover, their serum potassium concentrations (SPCs) were 7.67 and 6.05 mmol/L, respectively. DIAGNOSIS: Acute hyperkalemia. INTERVENTIONS: Hemo-filtration was performed for patient 1, while patient 2 received 10% calcium gluconate 10 mL, 5% NaHCO3 125 mL, and 10% glucose 500 mL with the addition of 10 units of insulin through intravenous drip. OUTCOMES: Their SPCs dropped to the normal range. LESSONS: Physicians should pay close attentions to potential risks caused by PSHC, and monitor the SPCs to minimize the occurrence of hyperkalemia.