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Copper and Gastric Cancer: Looking Back from the Perspective of Cuproptosis
No full textCopper (Cu), an essential trace element, plays a crucial role in various physiological processes within the human body. Recently, cuproptosis, a novel form of cell death induced by copper overload, has been identified. Despite numerous studies investigating the association between copper and gastric cancer (GC), a comprehensive review of the existing literature on this topic is notably lacking. This review provides a retrospective analysis of the correlation between copper and gastric cancer, outlines the aberrant copper metabolism in gastric cancer and its potential mechanisms, and synthesizes current bioinformatics research on cuproptosis in gastric cancer. Furthermore, the review delves into copper-related synthetic materials and drugs that have been pivotal in the diagnosis and treatment of gastric cancer. We have emphasized that the association between copper and gastric cancer has not been fully investigated, indicating the possibility of discovering copper-related synthetic materials, chelating agents, and complexing agents as potential therapeutic approaches for gastric cancer
Anti-Angiogenic Effect of Bortezomib Treatment in Multiple Myeloma is Associated with Lower NF-κB and OPN Expression
No full textBackground: Multiple myeloma (MM) is a malignant clonal plasma cell disorder in the bone marrow and is the second-most common hematologic malignancy in adults. It proliferates by inducing neovascularization of the bone marrow stroma. Both nuclear factor kappa B (NF-κB) and osteopontin (OPN) pathways are considered crucial in the development of various tumors, including MM. Bortezomib is a proteasome inhibitor well established as a first-line treatment in MM. This study aimed to demonstrate in vivo anti-angiogenic effects of bortezomib in MM patients who responded to therapy by analyzing whether the expression of NF-κB was associated with OPN and microvessel density (MVD) as well as overall survival (OS). Methods: Thirty patients who were newly diagnosed MM were enrolled in a study to investigate possible associations between neovascularization, expressed as microvessel density, NF-κB, and osteopontin expression in myeloma cells from bone marrow biopsy (BMB) pretreatment and posttreatment samples. This study used paraffin-embedded BMB before and after therapy with bortezomib. Immunohistochemical staining was performed to analyze the samples. Results: After bortezomib treatment, BMB samples showed significantly fewer plasma cell infiltrates (PCI) (p < 0.001), lower percentages of NF-κB (p < 0.001), and OPN (p = 0.023) in plasma cells, and reduced MVD (p = 0.009) compared to pretreatment. A significant positive correlation was observed between NF-κB and OPN expression in plasma cells before and after bortezomib treatment in BMB samples (rs = 0.57, p = 0.002; and rs = 0.50, p = 0.007; respectively). Additionally, significant positive correlations were observed between NF-κB and OPN with MVD in pretreatment BMB samples (rs = 0.500, p = 0.018; and rs = 0.502, p = 0.017; respectively). Patients with higher MVD posttreatment had significantly shorter overall survival (OS) rates (p = 0.025). Conclusions: Bortezomib treatment results in a significant decrease of MVD (angiogenesis) and PCI in BMBs of MM patients who responded to treatment. Furthermore, lower posttreatment MVD is associated with a longer OS. It seems that NF-κB and OPN inhibition could be the new therapeutic targets for MM patients, whilst MVD assessment before and after treatment with bortezomib (and other proteasome inhibitors) should be incorporated into routine diagnostic procedures
Dietary Fiber Improves Lipid Metabolism through Changes in Gut Microbiota and their Metabolites in High-Fat Diet Fed Rats
No full textBackground and Aims: A high-fat diet can induce hepatic steatosis, hyperlipidemia, obesity, diabetes, and other lipid metabolism disorders through the regulation of lipid metabolism signaling pathways in the liver. The objective of this study was to investigate the influence of dietary fiber on the composition of the intestinal microbiota to improve lipid metabolism. Materials and Methods: Male Sprague Dawley (SD) rats were divided into four groups: a Control group (ZC), a high-fat diet group (HF), a fiber diet group (GQ), and a combination of high-fat and fiber diet group (GZGQ). Following four weeks of feeding with experimental diets, the rats were euthanized, and the blood sample was collected from the abdominal aorta. Plasma levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were assessed. Furthermore, total DNA was extracted from a 100 mg stool sample. The 16S ribosomal RNA gene sequencing and quadrupole time-of-flight mass spectrometry coupled with high-performance liquid chromatography to detect the structure and metabolites of rat intestinal gut flora. Linear discriminant analysis effect size was used to determine the major communities or species across various experimental groups. Results: Using high-throughput 16S rRNA gene sequencing, 8, 6, 2, and 5 unique bacteria were observed in the ZC, GQ, HF, and GZGQ group, respectively. Compared to the Control group, the proportion of thick-walled phyla decreased in the GQ and GZGQ groups and increased in the HF group. The relative abundance of Bacteroidales S24-7 group, Bacteroides, and Ruminococcus gnavus group was significantly higher in the GQ and GZGQ groups (p < 0.05), whereas the relative abundance of some bacteria was elevated in the HF group. Moreover, it was found that the atorvastatin-induced metabolites were elevated in the HF group. Furthermore, choline content was significantly increased in the GZGQ group, and levocarnitine content was significantly lower in both the GQ and GZGQ groups. Additionally, dietary fiber reduced the levels of TC, TG, and LDL-C in high-fat rats. Conclusions: These findings indicate that through the gut microbiota, dietary fiber regulates dyslipidemia, increases choline and L-carnitine, and reduces the risk of diseases associated with a high-fat diet
Oncogene RPP25 Promotes Glioblastoma Progression by Inhibiting Ferroptosis and Oxidative Stress
No full textBackground: Glioblastoma (GBM) are the most prevalent malignant brain tumors with extensive morphological and genetic heterogeneity. The objective of this study was to investigate the role of the oncogene Ribonuclease P/MRP Subunit P25 (RPP25) in GBM progression and its underlying molecular mechanisms. Methods: Glioma cell lines were used to evaluate the effects of RPP25 on ferroptosis-related proteins, oxidative stress levels, and reactive oxygen species (ROS) content. In addition, GBM mouse models were established, including an RPP25 overexpression group (OE-RPP25) and an RPP25 overexpression with integrin beta-8 (ITGB8) knockdown group (OE-RPP25+sh-ITGB8). Tumor volume and weight were measured to assess tumor growth. The levels of ferroptosis and oxidative stress were also evaluated using lipid peroxidation and ROS content assays. Results: It was observed that RPP25 overexpression significantly elevated both tumor volume and weight (p < 0.05) compared to the control group. However, when ITGB8 was knocked down in the OE-RPP25 group, tumor volume and weight were reduced. Furthermore, RPP25 overexpression upregulated the expression of ITGB8, hypoxia-inducible factor (FIH1), and glutathione peroxidase 4 (GPX4), while ITGB8 knockdown reversed these effects. Additionally, RPP25 overexpression suppressed the expression of apoptosis-related proteins B-cell lymphoma-2 associated X (Bax) and Caspase-3 and increased (p < 0.05) the expression of anti-apoptotic protein B-cell lymphoma-2 (Bcl-2). However, ITGB8 knockdown promoted apoptosis in tumor cells by counteracting these effects. Moreover, RPP25 overexpression inhibited ferroptosis and oxidative stress, while ITGB8 knockdown reversed these effects, promoting lipid peroxidation and glutathione depletion. Conclusions: These findings suggest that RPP25 plays a crucial role in GBM progression by upregulating the ITGB8/transforming growth factor-beta (TGF-β)/Smad4 axis, inhibiting ferroptosis and oxidative stress, and suppressing apoptosis. These findings provide important insights into the interaction between RPP25 and ITGB8 and their potential applications in GBM therapy. Targeting the RPP25-ITGB8 axis may represent a promising strategy for the treatment of GBM by modulating ferroptosis and apoptosis pathways. The findings also suggest that ferroptosis and oxidative stress may be potential targets for GBM therapy
ADMET Analysis, Antibacterial and Modified Antibiotic Activities of Thiadiazine Derivatives
No full textBackground: Infections caused by multi-resistant microorganisms are a public health issue. Synthetic products have been studied as a therapeutic alternative for these cases, with the aim of antibacterial activity or enhancing existing antibiotics. Methods: This study aimed to evaluate the antibacterial activity upon modifying antibiotic actions and to perform a pharmacokinetic analysis of compounds derived from thiadiazine. The products were synthesised, and a chemical analysis was performed using thin-layer chromatography (TLC). Results: After obtaining the compounds, minimum inhibitory concentration (MIC) and modified antibiotic activity tests were performed, in which norfloxacin and gentamicin antibiotics were used against multidrug-resistant (MDR) bacterial strains of Staphylococcus aureus 10 (S. aureus 10) and Pseudomonas aeruginosa 24 (P. aeruginosa 24) using the microdilution method. We also performed topological analyses, a similarity evaluation with drugs, and in-silico absorption, distribution, metabolism, excretion and toxicity (ADMET) analyses. Only two compounds showed antibacterial activity against the examined strains. However, all compounds showed activity against the S. aureus strain when associated with norfloxacin. The in-silico analysis showed that the compounds have high lipophilicity and non-toxic characteristics. Conclusions: Therefore, the thiadiazine-derived compounds potentiate the antibiotic activity against S. aureus 10 bacteria and have ADMET properties, which are favourable for further studies on these compounds as potential low-toxicity sources for the MDR bacteria problem
LINC00861 Promotes Immune Response in the Tumor Microenvironment and Inhibits Prostate Cancer Tumor Growth by Regulating PD-L1
No full textBackground: Prostate cancer (PC) ranks as the fifth deadliest tumor in the world and has been regarded as a serious threat for the life and health of middle-aged and elderly men. Some studies have shown that LINC00861 regulated the anti-tumor immune response, and may have a certain impact on tumor immunotherapy. Therefore, to explore the related role of LINC00861 in PC, we detected the expression of LINC00861 in PC, and regulated the expression of LINC00861 after confirming its expression. This study aimed to explore the potential of LINC00861 in promoting the immunity of cytotoxic T cells and influencing the biological behavior of PC cells and tumor growth by regulating programmed cell death 1 ligand 1 (PD-L1). Methods: Expression of LINC00861 and PD-L1 was detected in 10 cases of PC and adjacent tissues. Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) analysis was performed to assess the expression level of LINC00861 in cancer cells. Cell lines with differential expression were selected for interference and overexpression of LINC00861, followed by grouping. The vitality of PC cells was observed, and measurements were taken for cell proliferation, migration, invasion, PD-L1, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and expression of inflammatory factors such as Interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α in the cells. To establish the subcutaneous PC tumor model, PC cells from each group were subcutaneously implanted in the right flank of BALB/c mice using 100 μL of phosphate-buffered saline (PBS). Mouse tumor tissues were collected to observe tumor size, assess tumor-infiltrating lymphocytes, and evaluate the infiltration of cytotoxic T cells (CD3+ and CD8+). Results: In PC tissues and cells, PC-3 cells were selected for subsequent experiments through cell screening. Successful transfection of LINC00861 inhibition and overexpression vectors was achieved in PC cells. Inhibiting the expression of LINC00861 upregulated the expression of PD-L1, enhanced cell growth vitality, proliferation, migration, invasion, and cytokine production capabilities, and reduced apoptosis. Overexpression reversed these effects. In in vivo experiments, inhibiting LINC00861 expression resulted in rapid tumor growth, accompanied by increased tumor volume and dense tumor tissue cells. Overexpression of LINC00861 produced the opposite results for these effects. The findings also indicated that inhibiting LINC00861 led to a significant increase in PD-L1 expression in tumor tissues and a significant decrease in CD3+ T and CD8+ T levels (p < 0.05). When LINC00861 was overexpressed, PD-L1 levels were reduced, while CD3+ T and CD8+ T levels were improved. Conclusions: LINC00861 is down-regulated in PC tissues. The inhibition of LINC00861 increases the expression of PD-L1, inhibits cytotoxic T cells immunity, and enhances the growth of PC cells and tumor growth and metastasis. Overexpression inhibits the development of PC
Dihydroartemisinin Mitigates Osimertinib Resistance in Lung Adenocarcinoma through Modulation of the EMT Transcription Factor Slug
No full textBackground: Osimertinib, a third-generation tyrosine kinase inhibitor (TKI), is associated with a complex array of resistance pathways. Epithelial-mesenchymal transition (EMT) represents a mechanism contributing to resistance development in epidermal growth factor receptor (EGFR)-TKI treatment. Previous research suggests that the downregulation of Snail, a transcription factor linked to EMT, can delay the onset of osimertinib resistance. Slug, another member of the Snail family, remains underexplored in its impact on EMT-related osimertinib resistance. Dihydroartemisinin (DHA) has demonstrated efficacy in inhibiting the proliferation, invasion, and metastasis of various types of tumor cells, including lung cancer. This study confirmed that DHA could downregulate Slug expression and inhibit the metastasis and invasion of tumor cells. Methods: The cultured osimertinib-resistant lung adenocarcinoma cell line was named H1975/OE. Real-time polymerase chain reaction (RT-PCR), western blotting, and Transwell assays were employed to confirm EMT occurrence in H1975/OE cells. To investigate the mechanism of EMT in osimertinib resistance, we evaluated EMT-related markers in H1975 parental cells and H1975/OE-resistant cells. Complete silencing of the regulator Slug in H1975/OE cells using small interfering RNA (siRNA) was followed by an examination of alterations in the expression levels of EMT-associated markers. Finally, DHA, a natural inhibitor, was used to assess its interference with osimertinib resistance linked to EMT. Results: Evaluation of EMT-specific markers in the H1975 parental cell line and H1975/OE resistant cell line revealed upregulated N-cadherin expression and downregulated E-cadherin expression in H1975/OE cells. The enhanced invasiveness of H1975/OE indicated that EMT occurred in the resistant cell line. Subsequent experiments confirmed that Slug expression was upregulated in the resistant cell line and that knockout of Slug facilitated a delay in the occurrence of osimertinib resistance in H1975/OE cells. Further investigation demonstrated that DHA could inhibit Slug expression, alleviating osimertinib resistance associated with EMT. Conclusions: Slug plays a pivotal role in osimertinib resistance associated with EMT. DHA effectively overcomes osimertinib resistance linked to EMT by inhibiting Slug expression
Effects of Gamma Knife Irradiation on the Expression of CREB in the Brain of Chronic Epileptic Rats
Get PDFBackground: Epilepsy surgery has seen numerous technological advances in diagnostic and therapeutic procedures in recent years. However, further understanding of how to integrate traditional and emerging technologies into epilepsy treatment is needed to develop this area. The purpose of this study is to observe the antiepileptic effect of gamma knife irradiation on chronic epileptic rats and the expression of cyclic adenosine monophosphate response element binding protein (CREB) in the brain. Methods: Sixty Wistar rats were randomly divided into four groups: the control group, the control + gamma knife group, the pentylenetetrazole (PTZ) group and the PTZ + gamma knife group. The rats were injected intraperitoneally with PTZ to establish the epileptic models. Gamma knife irradiation was performed on the bilateral frontal cortex of rats. After 12 weeks of irradiation, the Morris water maze test was used on each group of rats to test their ability to learn and remember, and the expression of CREB in the cortex and hippocampus was detected. Results: The epileptic seizures of rats in the PTZ + gamma knife group were significantly reduced by the 12th week after low-dose gamma knife irradiation (p < 0.05). Compared with the PTZ group, the swimming distance was significantly shorter in the PTZ + gamma knife group (p < 0.05). Compared with the PTZ group, the daily escape latency in the Morris water maze of the PTZ + gamma knife group on days 3–5 was significantly shortened (p < 0.05). Compared with the PTZ group, the number of times the Morris water maze crossed the platform and the percentage swimming time in the platform quadrant were both significantly higher in the PTZ + gamma knife group (p < 0.05). Conclusion: The cognitive function and the expression of CREB decreased in the brains of epileptic rats, which was increased after low-dose gamma knife irradiation. This may suggest a possible molecular mechanism underlying the effects of gamma knife irradiation on epileptic seizures
Identification of Differentiation-Related Biomarkers in Liposarcoma Tissues Using Weighted Gene Co-Expression Network Analysis
No full textBackground: A thorough diagnosis of liposarcoma is essential to develop an optimal therapy. This study aimed to identify differentiation-related biomarkers in liposarcoma. Methods: Expression profiling data were downloaded from the Gene Expression Omnibus (GEO) database. Modules correlated with dedifferentiated liposarcoma were identified using weighted gene co-expression network analysis (WGCNA). Differentially-expressed genes were identified utilizing the limma R package. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted with the clusterProfiler R package. Hub genes were identified by least absolute shrinkage and selection operator (LASSO) analysis. Survival analysis was performed using survival and survminer R packages. Results: The brown module was the most positively correlated module with dedifferentiated liposarcoma, while the turquoise module exhibited the strongest negative correlation with dedifferentiated liposarcoma. Forty-nine upregulated common genes were found by intersecting the upregulated differentially-expressed genes with the co-expressed genes in the brown module, and 177 downregulated common genes were found by intersecting the downregulated differentially-expressed genes with the co-expressed genes in the turquoise module. GO and KEGG analyses revealed that upregulated common genes were abundant in cell division and tumor-related pathways, while downregulated common genes were involved in cellular metabolism and metabolism-related pathways. ADIPOQ, UBE2C, and PRC1 were screened out as biomarkers which might distinguish dedifferentiated and well-differentiated liposarcoma. Dedifferentiated liposarcoma patients with low ADIPOQ levels displayed a significantly shorter distant recurrence-free survival than those with high ADIPOQ levels. Conclusion: ADIPOQ, UBE2C, and PRC1 are potential differentiation-related biomarkers in liposarcoma tissues. ADIPOQ has the potential to be a novel prognostic biomarker for patients with dedifferentiated liposarcoma
The Repression of the Candida albicans Growth and Pseudomycelium Formation by Thiomonoterpenoid
Get PDFBackground: In the last decade, the wide spread of the multidrug resistant yeast C. albicans has challenged the development of new approaches to treatment. Among various options, the use of natural and synthetic terpenes as antifungals or enhancers of conventional drugs has been offered in many works. Here we show the effect of the recently synthesized compound isobornane sulfide named KS1 on C. albicans and discuss its potential mechanism of action. Methods: To characterize the impact of the compound on the yeast minimum inhibitory concentration (MIC) determination on clinical isolates, quantitative PCR with reverse transcriptase (qRT-PCR) of efflux genes expression, cytotoxicity determination on eukaryotic cells, bright-field and fluorescent microscopy with KS1 conjugate with BODIPY fluorophore have been used. The in silico prediction of KS1 properties has been performed using the ADMET server, and molecular docking was used for the modeling of KS1 interaction with putative targets. Results: While exhibiting moderate antifungal activity as compared to fluconazole and terbinafine, KS1 has a synergy with both antifungals on resistant clinical isolates while not stimulating the expression of the CDR1 and MDR1 efflux genes. Moreover, KS1 represses hypha formation by C. albicans, reducing the number of germ tubes more than twice compared to the control. It readily penetrates the cell, as shown by confocal microscopy using the created KS1-BODIPY fluorophore conjugate, apparently thereby facilitating the penetration of antifungals into the cell. As judged by the ADMET server, KS1 falls into the category of drug-like compounds and neither inhibits the isoforms of cytochrome P450 nor manifests mutagenicity or carcinogenicity that fits with in vitro data. The molecular docking showed that KS1 has a high affinity for the transcription activator transcription activator (Tec1) protein of C. albicans, responsible for invasion and hypha formation, which fits with the in vitro data. Conclusions: These findings suggest KS1 as promising both a solely antifungal and an enhancer of conventional antimycotics blocking fungal virulence