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Effect of HIF-PHI on Vascular Calcification and Apoptosis in High Phosphate-Induced VSMCs
No full textBackground: Vascular calcification (VC) is a significant risk factor for cardiovascular disease. The pathogenesis involves various factors such as hyperphosphatemia, oxidative stress, inflammation, and apoptotic cell death, leading to phenotypic changes in vascular smooth muscle cells (VSMCs) and subsequent calcification. This study aims to investigate the impact of roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), on the development of calcification in VSMCs induced by hyperphosphatemia in mice. Methods: Aortic VSMCs were cultured and exposed to high phosphate conditions to induce calcification. The cells were divided into control, high phosphate, and HIF-PHI plus high phosphate groups. Cell viability was assessed using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay, and calcium content was measured through Von Kossa staining and the bicinchoninic acid (BCA) assay. The apoptotic rate was determined by flow cytometry, alkaline phosphatase concentration was determined by enzyme-linked immunosorbent assay (ELISA), and mitochondrial reactive oxygen species (ROS) levels were determined by Dichlorodihydrofluorescein acetoacetate (DCFH-DA). Protein expression levels were evaluated using immunoblotting techniques. Results: Compared to the control group, calcium deposition, calcium content, alkaline phosphatase, Runt-related Transcription Factor 2 (RUNX2) expression and apoptotic rate were significantly higher, while Alpha Smooth Muscle Actin (α-SMA) expression was significantly lower in the high phosphate group (p < 0.05). The HIF-PHI group showed an opposite trend to the high phosphate group in a dose-dependent manner (p < 0.05). The mitochondrial ROS and BCL2/adenovirus E1B 19kDa protein-interacting protein 3-like (BNIP3L) expression were significantly higher in the high phosphate group than in the control group (p < 0.05). Compared to the high phosphate group, the mitochondrial ROS was lower, while the protein expression levels of BNIP3L and Bcl-2 Interacting Protein 1 (Beclin-1) were higher in the HIF-PHI group (p < 0.05). HIF-1α protein expression was significantly higher in the high phosphate group than in the control group, which was increased by the treatment of HIF-PHI (p < 0.05). Conclusions: HIF-PHI ameliorates vascular calcification and apoptosis in high-phosphate induced viability of VSMCs by upregulation of HIF-1α expression, reduced mitochondrial ROS production and increased expression of autophagy-related proteins
DTYMK Induces Metastasis and Propagation of Bladder Cancer Cells and Acts as a Predictive Biomarker
No full textBackground: Bladder cancer (BLCA) is a common malignancy with rising incidence worldwide. The deoxythymidylate kinase (DTYMK) plays a crucial role in the progression of cancers. However, its precise function and significance in the diagnosis of BLCA are yet to be properly explored. This study aimed to elucidate the correlation between DTYMK and BLCA. Methods: The Cancer Genome Atlas Program (TCGA) database was utilized to verify the DTYMK expression. The expression levels of DTYMK in bladder tissues were assessed using quantitative real-time polymerase chain reaction (qRT-PCR), Western blot analysis, and immunohistochemistry. Moreover, the relationship between DTYMK and the prognosis of bladder cancer was analyzed using the KM-plotter and Ualcan databases. DTYMK was knocked down in bladder cancer cells by transfecting with a lentivirus vector to investigate the role of DTYMK both in vitro and in vivo. Additional analyses were performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and GeneMania online tools to explore the underlying mechanisms in the progression of bladder cancer. Results: DTYMK expression was significantly increased in bladder cancer tissues compared to the paracancerous tissues (p < 0.01) and found associated with the degree of differentiation (p < 0.05), lymph node metastasis (p < 0.01), tumor node metastasis (TNM) stage (p < 0.01), and poor prognosis in bladder cancer patients. Functional studies demonstrated that down-regulation of DTYMK inhibited cell proliferation and migration in vitro and suppressed xenograft tumor formation in vivo (p < 0.01). GO and KEGG results associated DTYMK with certain physiological events, such as neuroactive ligand-receptor interaction and retinol metabolism. Additionally, 20 genes exhibited a synergistic effect and 10 genes showed interaction with DTYMK in bladder cancer. Conclusions: DTYMK expression was significantly increased in bladder cancer cells. The elevated expression was associated with the degree of differentiation, lymph node metastasis, tumor node metastasis (TNM) stage, and poor prognosis in bladder cancer patients. These findings suggest its potential as a novel predictive biomarker. These findings offer evidence for the potential use of DTYMK as a targeted therapy for bladder cancer
RARB Enhances the Sensitivity of Cisplatin-Resistant Non-Small Cell Lung Cancer Cells by Downregulating NCOA3
No full textBackground: Drug resistance in non-small cell lung cancer (NSCLC) cells will affect the therapeutic efficacy of cisplatin (DDP) in treatment. Retinoic acid receptor beta (RARB) has been implicated in the prognosis of NSCLC. This study aimed to investigate the mechanism of RARB in the drug resistance of NSCLC cells. Methods: Differential gene expression in drug-resistant NSCLC cells was analyzed using bioinformatics. DDP-resistant NSCLC cells were generated through continuous exposure to DDP over six months. mRNA and protein levels of RARB, nuclear receptor coactivator 3 (NCOA3), and phosphorylated p65 (p-p65) were quantified using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Cell viability was assessed using the cell counting kit-8 (CCK-8) assay, and the half-maximal inhibitory concentration (IC50) of DDP was determined. Cell apoptosis was analyzed via flow cytometry. A rescue experiment was conducted to explore whether the regulatory effect of RARB on DDP-resistant NSCLC cell sensitivity was mediated by NCOA3 regulation. Results: RARB expression was downregulated in DDP-resistant NSCLC cells, while NCOA3 and p-p65 expressions were upregulated. RARB overexpression (RARB-OE) inhibited cell viability and enhanced the sensitivity and apoptosis of DDP-resistant NSCLC cells, whereas overexpression of NCOA3 (NCOA3-OE) had the opposite effect. Additionally, RARB-OE reduced NCOA3 and p-p65 levels in DDP-resistant NSCLC cells, while NCOA3-OE increased p-p65 levels. Notably, the impact of RARB-OE and NCOA3-OE on DDP-resistant NSCLC cells was reversed following co-transfection. Conclusion: RARB enhances the sensitivity of DDP-resistant NSCLC cells by downregulating NCOA3
Immunomodulatory and Protective Effects of Stem Cells from Human Exfoliated Deciduous Teeth on Mice with Sepsis
No full textBackground: Sepsis characterized by an uncontrolled inflammatory response is a common clinical syndrome which can cause organ dysfunction, shock, and often death. Importantly, no specific treatment for sepsis exists. Little is known about the therapeutic effects of stem cells from human exfoliated deciduous teeth (SHEDs) on sepsis. The study aims to investigate immunomodulatory and protective effects of SHEDs against sepsis. Methods: Polymicrobial sepsis was induced in mice via cecal ligation and puncture (CLP). SHEDs or normal saline was intravenously injected 30 min after CLP. Seventy-five adult male C57BL/6 mice were randomized into three groups (n = 25/group): (1) Sham-CLP; (2) CLP; (3) CLP+SHED. Mice (20/group) were monitored for 96 h post-CLP for survival. Five mice/group were euthanized at 24 h post-CLP; blood and tissues (lung, liver, kidney, spleen, and intestine) were harvested for pathophysiological study. A cytometric bead array assay was employed to assess plasma concentrations of cytokines [interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), monocytechemoattractant protein-1 (MCP-1), IL-10], and an automatic biochemical analyzer was used to assess liver and kidney function. Hematoxylin and eosin (H&E) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining were performed to evaluate organ injuries. Immunofluorescence staining and E. coli colony-forming units (CFUs) counts of the spleen were also employed. Results: Kaplan-Meier survival analysis revealed a significantly lower survival rate in CLP than in Sham-CLP mice, and a significantly better survival rate in CLP+SHED mice than in CLP mice (p = 0.021). At 24 h post-CLP, serum IL-6, MCP-1, TNF-α, and IL-10 were significantly lower in the CLP+SHED group than in the CLP group (all p < 0.05). When compared to CLP mice, CLP+SHED mice had altered distribution of cluster of differentiation 3+ (CD3+) T cells and CD11c+ dendrocytes in the spleen, decreased the number of TUNEL+ cells in the kidneys and lungs, and altered TUNEL+ cell distribution in the intestine and spleen. Compared to CLP mice, TUNEL+ cells in kidney, lung and spleen of CLP-SHEDs group were attenuated although without significance (p = 0.079, 0.045 and 0.075 respectively). However, the distribution of TUNEL+ cells in intestine were altered in CLP+SHED mice when compared to CLP mice. The E. coli clearance in spleen was improved (p = 0.075) in the CLP+SHED mice when compared to CLP group. Conclusions: SHEDs treatment 30 min after sepsis induction improves survival in mice with CLP-related sepsis. It has potential to be a new therapeutic option for sepsis
Genome-Wide Profiling of Extracellular Vesicles Derived from B16 Melanoma Cells Reflects Dynamic Changes in Mutation Profiles of Melanoma Cells
Full text linkBackground: Extracellular vesicles (EVs) are carriers of DNA derived from parental cells, presenting a promising avenue for monitoring tumor progression. This aimed to investigate the relationship between EV DNA and the parental cell genome to establish a theoretical foundation for utilizing EVs to dynamically monitor tumor progression. Methods: Utilizing a classical model of cell tumor evolution, B16 melanoma cell lines (B16-F0, B16-F1, and B16-F10) with varying metastatic potentials, we demonstrated that EVs derived from these cells harbor stable double-stranded (dsDNA) fragments ranging from 15 to 10,000 bp. DNase I enzyme digestion, SYBR Green I staining, and TapeStation system were employed for characterization. Whole genome profiling analysis revealed a high concordance between EV DNA and the mutant spectrum of parent cells, particularly regarding single nucleotide polymorphisms (SNPs). EVs contained evolutionary relevant mutation profile of melanoma cells with different metastatic potentials and had a comparable evolutionary relationship with the parent cells. Results: (1) EVs derived from B16 melanoma cells contained stable dsDNA fragments ranging from 15 to 10,000 bp. (2) EVs DNA comprehensively covered the entire genome of parent cells. (3) EVs DNA exhibited strong consistency with small fragment mutations (SNPs, Inserts/Deletions) of parent cells, with decreasing consistency as mutation length increased. (4) EVs carried mutant gene profiles associated with melanoma cell progression and had similar evolutionary relationships with parent cells. Conclusions: This study underscores the ability of EVs DNA to reflect the mutation status of parental cells and emphasizes their potential as biomarkers for monitoring tumor evolution. These findings offer a theoretical foundation for the dynamic monitoring of tumor progression using EVs DNA
The Role of FCRLB in Predicting Thyroid Cancer Prognosis and Regulating Thyroid Cancer Cell Proliferation and Apoptosis
No full textBackground: Immunogenic cell death (ICD)-related gene signatures demonstrate prognostic significance across multiple cancer types. Nevertheless, the differential expression of these genes in thyroid carcinoma (THCA) and their application in predicting the survival outcomes of individuals with THCA remain poorly understood. Therefore, this study aimed to explore the role of ICD-related genes in predicting the survival outcomes of THCA patients. Methods: The expression of ICD-related genes was analyzed using RNA-seq data and compared with clinicopathological features from The Cancer Genome Atlas-thyroid carcinoma cohort. The role of Fc receptor-like B (FCRLB) in thyroid cancer was identified using Methyl Thiazolyl Tetrazolium (MTT) assay, 7-amino-actinomycin D staining, and Annexin V-fluorescein isothiocyanate staining assay. Results: We identified FCRLB as a novel marker for predicting THCA survival. Moreover, bioinformatic analyses revealed a significant correlation between elevated FCRLB expression and increased levels of immune infiltration and somatic mutations, potentially contributing to a poorer prognosis in THCA (p < 0.05). Furthermore, we observed overexpression of FCRLB in THCA cells compared to thyroid epithelial cells (p < 0.05). Additionally, reduced proliferation, cell cycle arrest, and enhanced apoptosis were the outcomes of FCRLB knockdown in TPC-1 THCA cells (p < 0.05). Conclusions: These findings suggest that FCRLB overexpression predicts poor THCA survival and might contribute to THCA development
Metabolomics of Human Seminal Fluid Reveals Aging-Related Increase in the Amino Acid Content
No full textBackground: Aging is the progressive decline in an organisms structural and functional characteristics. Aging has also been linked to a reduction in male reproductive potential. In contemporary societies where delayed parenthood is prevalent, there is a burgeoning interest in comprehending the age-related decline in male fertility and its implications for offspring. This study delves into investigating the metabolome of human seminal fluid, aiming to unveil potential metabolite biomarkers of male reproductive potential during the aging process, employing a Nuclear Magnetic Resonance (NMR)-based metabolomics approach. Methods: Seminal samples from 31 healthy normozoospermic men (age range from 25 to 50 years old) undergoing fertility treatment were examined. Routine semen analyses were performed on fresh semen samples to determine the sperm parameters according to the World Health Organization guidelines. Seminal fluid was separated from spermatozoa and the metabolic profile was analyzed through 1H-Nuclear Magnetic Resonance (1H-NMR). The samples were separated into two groups based on age (<35 years and ≥35 years) and multivariate analysis was performed on the quantified metabolites. Results: Employing this NMR-based metabolomics approach, we identified 37 small metabolites across all seminal fluid samples. Partial least squares-discriminant analysis unveiled a clustering trend between age groups. Notably, a significant age-associated increase in the amino acids serine and aspartate was observed. Moreover, a propensity for increased levels of various amino acids in seminal fluid with advancing age was observed. Conversely, seminal levels of malate exhibited a decline in older individuals. Conclusions: Our findings provide compelling evidence of age exerting a discernible influence on the comprehensive seminal metabolome. These results underscore the potential for future omics studies, focusing on unraveling the intricate molecular mechanisms that underlie the age-associated decline in male fertility
Research Progress in Understanding the Role of the Intestinal Barrier in Liver Diseases via the Gut-Liver Axis: A Comprehensive Review
No full textThe gut-liver axis has emerged as a fundamental concept in elucidating liver diseases. Central to this axis is the intestinal barrier, which exerts a significant influence on the progression of various liver conditions, including non-alcoholic fatty liver disease, alcoholic liver disease, viral liver diseases, autoimmune liver diseases, and cirrhosis. This review synthesizes domestic and international literature to explore the intricate association between the intestinal barrier and liver diseases. Mechanistic insights into how the intestinal barrier modulates liver pathology are elucidated, emphasizing its role in mediating the systemic effects of intestinal contents on liver health. Additionally, this paper sheds light on the potential clinical and scientific implications of targeting the intestinal barrier in liver disease management. The review highlights the imperative for continued research efforts to unravel the intricate connections between the intestinal barrier and liver diseases to unveil novel therapeutic strategies to alleviate the burden of these conditions
PYCR2 Knockdown Suppresses the Proliferation, Migration, and Invasion of Esophageal Squamous Cell Carcinoma by the KEAP1-Nrf2 Pathway to Induce Ferroptosis
No full textBackground: Pyrroline-5-Carboxylate Reductase 2 (PYCR2) demonstrates abnormal expression in various tumors and is intricately associated with tumor progression and prognosis. However, its expression and roles in esophageal squamous cell carcinoma (ESCC) remain unknown. The objective of this research is to explore the expression, effects, and underlying mechanisms of PYCR2 in ESCC. Methods: In this study, we performed immunohistochemical analysis on ESCC tissues to assess PYCR2 expression levels and their correlation with clinical parameters. Subsequently, we utilized in vitro assays and RNA sequencing to elucidate the functional roles of PYCR2 in ESCC cells. The primary objective was to comprehend the impact of PYCR2 on key cellular processes, including proliferation, migration, invasion, apoptosis, and its potential involvement in ferroptosis through the kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid-2 (NRF2) pathway. Results: Our findings suggest an upregulation of PYCR2 expression in ESCC, which correlates with a poorer prognosis in patients exhibiting increased PYCR2 levels (p < 0.05). Knocking down PYCR2 inhibits proliferation, migration, invasion, and epithelial-mesenchymal transformation (EMT), while concurrently promoting apoptosis (p < 0.05). Furthermore, our results indicate that PYCR2 knockdown induces ferroptosis by inhibiting the KEAP1-Nrf2 pathway. Conclusion: In conclusion, this study suggests that PYCR2 plays a crucial role in the malignant progression of ESCC and emerges as a promising new biomarker and potential therapeutic target in ESCC
Diagnostic Value of 64-Slice Spiral CT Combined with Serum Tumor Markers in Lymph Node and Distant Metastasis of Gastric Cancer
No full textBackground: Preoperative staging is of great significance in determining treatment strategies and outcome evaluation. This study aims to investigate the diagnostic value of 64-slice spiral computed tomography (CT) in combination with serum tumor markers for lymph nodes and distant metastasis in gastric cancer. Methods: We retrospectively analyzed the clinical data of 124 gastric cancer patients who underwent surgical treatment between April 2015 and April 2020. Based on the occurrence of lymph nodes and distant metastasis, the differences in CT examination results and tumor markers such as carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), and CA125 were compared. Results: The serum CEA and CA199 levels and the rate of positive lymph node identified through CT were significantly lower in the N0 group compared to the N1-3 group (p < 0.05). Similarly, the serum CEA, CA125 levels, and the rate of the positive lymph node were significantly lower in the M0 group than those in the M1 group (p < 0.05). Additionally, in diagnosing preoperative lymph node metastasis in gastric cancer, the areas under the curve of serum CEA, CA199 levels, and their combined detection were 0.602, 0.694, and 0.708, respectively. The areas under the curve of serum CEA and CA125 levels and their combined detection in the diagnosis of preoperative distant metastasis of gastric cancer were 0.657, 0.838, and 0.888, respectively. The sensitivity, specificity, and accuracy of 64-slice spiral CT in the diagnosis of preoperative lymph node metastasis in gastric cancer were 87.32%, 90.56%, and 88.71%, respectively. The combined diagnosis with serum CEA and CA199 levels exhibited a sensitivity of 91.55%, a specificity of 86.79%, and an accuracy of 89.52%. The sensitivity, specificity, and accuracy of 64-slice spiral CT in the diagnosis of preoperative distant metastasis in gastric cancer were 71.43%, 90.63%, and 86.29%, respectively. The combined diagnosis with serum CEA and CA125 levels demonstrated a sensitivity of 92.86%, a specificity of 88.54%, and an accuracy of 89.52%. Conclusion: 64-slice spiral CT combined with serum tumor markers can improve the diagnostic value of lymph node and distant metastasis of gastric cancer