Hereditas最新文献

Background: Cervical cancer (CC) is a prevalent gynecological malignancy, contributing to a substantial number of fatalities among women. MicroRNAs (miRNAs) have emerged as promising biomarkers with significant potential for the early detection and prognosis of CC.

Objective: This study aimed to explore the clinical significance and biological role of miR-615-5p in CC, with the goal of identifying novel biomarkers for this disease.

Materials and methods: The levels of miR-615-5p and TMIGD2 mRNA in tissue samples and cells were quantified through quantitative reverse transcription real-time PCR, followed by statistical analyses to investigate the correlation between miR-615-5p and clinical data. The effects of miR-615-5p on the proliferation and metastasis of CC cells were evaluated using the Cell Counting Kit-8 and Transwell assays. The potential mechanism of miR-615-5p was elucidated by bioinformatics analyses and Dual-luciferase reporter assay. Western blotting was employed to measure the protein levels of TMIGD2.

Results: In CC, the downregulation of miR-615-5p was related to poor prognosis and emerged as an independent prognostic factor. The levels of miR-615-5p were reduced in CC cells. miR-615-5p overexpression restrained the proliferation and metastasis of CC cells. Furthermore, TMIGD2 was identified as a target gene regulated by miR-615-5p, and its expression was notably elevated in CC. The influence of miR-615-5p on the biological behaviors of CC cells was mediated through the modulation of TMIGD2.

Conclusions: Downregulation of miR-615-5p was a prognostic indicator of poor prognosis in CC. miR-615-5p exerted its tumor-suppressive effects by inhibiting cell growth and metastasis through the regulation of TMIGD2.

Objective: Previous observational studies on the association between aspirin use, bone mineral density (BMD), and fracture risk have yielded controversial results. This study explored the causal relationship between aspirin use, BMD, and fracture risk using Mendelian randomization (MR).

Methods: Summary data for aspirin use and BMD of five different body parts (femoral neck, lumbar spine, forearm, heel, and ultra distal forearm) and fractures were obtained from the integrative epidemiology unit open genome-wide association studies database for bidirectional MR analysis. An appropriate model was chosen based on Cochran's Q test, with inverse variance-weighted as the primary method for MR analysis, supplemented by the weighted-median and MR-Egger methods. MR-Egger and MR-PRESSO were used to test for horizontal pleiotropy and exclude significant outliers that could bias the results. Various sensitivity analyses, including leave-one-out analysis, were conducted to ensure the robustness of the findings.

Results: Aspirin use significantly increased lumbar spine BMD (odds ratio [OR] = 4.660; 95% confidence interval [CI]: 1.365-15.906; P = 0.014). No significant causal association was found between aspirin use and fracture risk (beta = 59.951; 95% CI: -265.189-385.091; P = 0.718). No significant reverse causality was observed.

Conclusion: This study indicates that aspirin use does not significantly affect fracture risk but has a significant protective effect on lumbar spine BMD, revealing a potential benefit of aspirin against osteoporosis.

Background: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder, with antibody-mediated immune responses to infectious diseases agents potentially playing a decisive role in its pathophysiological process. However, the causal relationship between antibodies and AD remains unclear.

Methods: A two-sample Mendelian randomization (MR) analysis was conducted to investigate the causal link between antibody-mediated immune responses to infectious diseases agents and the risk of AD. Genetic variations associated with these antibodies obtained from UK Biobank, and data on AD were obtained from the Finnish databases, utilizing its extensive repository of genome-wide association studies (GWAS) for a comprehensive analysis. The MR analysis employed the inverse variance-weighted, MR-Egger, and weighted median methods. Sensitivity analysis was also performed using MR-Egger regression, MR-pleiotropy residual sum, and outlier tests.

Results: Two causal associations were identified between antibody-mediated immune responses to infectious diseases agents and AD. Varicella zoster virus glycoproteins E and I antibody suggest a protective association with AD. Conversely, higher levels of Epstein-Barr virus EBNA-1 antibody appear to be associated with an increased risk of AD.

Conclusion: Our MR analysis has revealed a causal relationship between antibody-mediated immune responses to specific infectious disease agents and AD. These findings provide valuable insights into the pathophysiological mechanisms underlying AD.

Endometriosis is a complex gynecological condition characterized by abnormal immune responses. This study aims to explore the immunomodulatory effects of monoterpene glycosides from Paeonia lactiflora on endometriosis. Using the ssGSEA algorithm, we assessed immune cell infiltration levels between normal and endometriosis groups. Key targets were identified through differential expression analysis of the GSE51981 dataset. Potential immunomodulatory targets of Paeonia lactiflora compounds were identified through Venn diagram analysis, followed by enrichment and machine learning analyses. A nomogram was developed for predicting endometriosis, while molecular docking explored compound-target interactions. Significant differences in immune cell infiltration were observed, with increased CD8 T cells, cytotoxic cells, and others in endometriosis. Differential expression analysis identified 43 potential targets. Enrichment analysis highlighted pathways involved in immune and inflammatory responses. Machine learning identified SSTR5, CASP3, FABP2, and SYK as critical targets, contributing to a nomogram that demonstrated good predictive performance for endometriosis risk. Molecular docking revealed strong interactions between Paeoniflorigenone and CASP3. Our findings suggest that monoterpene glycosides have therapeutic effects on endometriosis by modulating key immune-related targets and pathways, providing a basis for further investigation into Paeonia lactiflora's potential as a treatment for this condition.

Background: Previous studies have shown that bone mineral density (BMD) has a certain impact on scoliosis. However, up to now, there is no clear evidence that there is a causal association between the two. The aim of this study is to investigate whether there is a causal association between BMD at different body positions and scoliosis by two-sample Mendelian randomization (MR).

Methods: Genetic variants (SNPS) strongly associated with BMD (total body BMD (TB-BMD), lumbar spine BMD (LS-BMD), femoral neck BMD (FN-BMD), heel BMD (HE-BMD), and forearm BMD (FA-BMD)) were extracted from GEFOS and genome-wide association analysis (GWAS) databases SNPs) were used as instrumental variables (IVs). Scoliosis was also selected from the Finnish database as the outcome. Inverse variance weighting (IVW) method was used as the main analysis method, and multiple sensitivity analysis was performed by combining weighted median, MR-Egger, MR Multi-effect residuals and outliers.

Results: IVW results showed that TB-BMD (OR = 0.83, 95%CI: 0.66-1.55 P = 0.13), LS-BMD (OR = 0.72, 95%CI: 0.52-0.99, P = 0.04), FN-BMD (OR = 0.74, 95%CI: 0.50-1.09, P = 0.13), FA-BMD (OR = 0.95,95%CI: 0.70-1.28, P = 0.75), HE-BMD (OR = 0.91, 95%CI: 0.77-1.08, P = 0.29). Sensitivity analyses showed no evidence of pleiotropy or heterogeneity (p > 0.05) (MR-PRESSO and Cochrane). The results were further validated by leave-one-out test and MR-Egger intercept, which confirmed the robustness of the study results.

Conclusion: In conclusion, the present study demonstrates that the causal role of genetic prediction of scoliosis increases with decreasing lumbar BMD. There was no evidence that BMD at the remaining sites has a significant causal effect on scoliosis. Our results suggest that the lumbar spine BMD should be routinely measured in the population at high risk of scoliosis. If osteoporosis occurs, appropriate treatment should be given to reduce the incidence of scoliosis.

Clinical trial number: Not applicable.

Background: Considering that the treatment of gout is poor, we performed a Mendelian randomization (MR) study to identify candidate biomarkers and therapeutic targets for gout.

Methods: A drug-targeted MR study was performed for gout by integrating the gout genome-wide association studies (GWAS) summary data and cis expression quantitative trait loci of 2,633 druggable genes from multiple cohorts. Summary data-based Mendelian randomization (SMR) analyses based on transcript and protein levels were further implemented to validate the reliability of the identified potential therapeutic targets for gout. Phenome-wide MR (Phe-MR) analysis was conducted in 1403 diseases to investigate incidental side effects of potential therapeutic targets for gout.

Results: Eight potential therapeutic targets (ALDH3B1, FCGR2B, IL2RB, NRBP1, RCE1, SLC7A7, SUMF1, THBS3) for gout were identified in the discovery cohort using MR analysis. Replication analysis and meta-analysis implemented in the replication cohort validated the robustness of the MR findings (P < 0.05). Evidence from the SMR analysis (P < 0.05) further strengthened the reliability of the 8 potential therapeutic targets for gout also revealed that high levels of ALDH3B1 reduced the gout risk possibly modified by the methylation site cg25402137. SMR analysis (P < 0.05) at the protein level added emphasis on the impact of the risk genes NRBP1 and SUMF1 on gout. Phe-MR analysis indicated significant causality between 7 gout causal genes and 45 diseases.

Conclusion: This study identified several biomarkers associated with gout risk, providing new insights into the etiology of gout and promising targets for the development of therapeutic agents.

Background: Cisplatin (DDP) resistance has long posed a challenge in the clinical treatment of lung cancer (LC). Insulin-like growth factor 2 binding protein 2 (IGF2BP2) has been identified as an oncogenic factor in LC, whereas its specific role in DDP resistance in LC remains unclear.

Results: In this study, we investigated the role of IGF2BP2 on DDP resistance in DDP-resistant A549 cells (A549/DDP) in vitro and in a DDP-resistant lung tumor-bearing mouse model in vivo. Additionally, methylated RNA immunoprecipitation sequencing (MeRIP-seq) was conducted to identify the potential mRNAs regulated by IGF2BP2, an N6-methyladenosine (m6A) regulator, in the tumor tissues of mice. Compared to normal tissues, IGF2BP2 levels were increased in LC tissues and in relapsed/resistant LC tissues. Most importantly, IGF2BP2 levels were significantly higher in relapsed/resistant LC tissues than in LC tissues. Significantly, knockdown of IGF2BP2 or DDP treatment inhibited A549 cell viability, migration, and cell cycle progression. Consistently, DDP treatment suppressed the viability and migration and triggered cell cycle arrest in A549/DDP cells in vitro, as well as reduced tumor volume and weight of A549/DDP tumor-bearing mice; meanwhile, the combination of DDP and IGF2BP2 siRNA further significantly inhibited A549/DDP cell growth in vitro and in vivo compared to DDP treatment alone. Furthermore, MeRIP-seq data showed that IGF2BP2 downregulation remarkably elevated m6A levels of spondin 2 (Spon2) and reduced mRNA levels of Spon2 in tumor tissues from A549 tumor-bearing mice. Meanwhile, the combination of DDP and IGF2BP2 siRNA notably reduced Spon2 levels, as well as inhibited the viability and induced apoptosis in A549/DDP cells; however, these effects were reversed by Spon2 overexpression.

Conclusion: Collectively, downregulation of IGF2BP2 could overcome DDP resistance in LC through declining the Spon2 gene expression in an m6A-dependent manner. These results may provide a new strategy for overcoming DDP resistance in LC.

Background: Conventional treatments, including surgery, radiotherapy and chemotherapy, have many limitations in the prognosis of glioma patients. Atorvastatin (ATOR) has a significant inhibitory effect on glioma malignancy. Thus, ATOR may play a key role in the search for new drugs for the effective treatment of gliomas.

Methods: U87 cells were treated with different doses of ATOR and transfected. Viability was assessed using MTT, proliferative ability was determined using the colony formation test, Bax and Bcl-2 were identified using Western blot, apoptosis was identified using flow cytometry, and U87 cell migration and invasion were detected using the Transwell assay. Glucose uptake, lactate secretion, and ATP production in U87 cell culture medium were quantified. The positive rates of IFN-γ and TNF-α in CD8T were measured through flow cytometry. Subcutaneous injection of U87 cells was carried out to construct an in vivo mouse model of gliom, followed by HE staining to assess the effects of ATOR and miR-125a-5p on tumor development.

Results: ATOR blocked the viability, proliferation, migration, and invasion of U87 cells through the miR-125a-5p/TXLNA axis, and suppressed glycolysis and immune escape of glioma cells. Furthermore, overexpressing miR-125a-5p enhanced the anti-tumor effect of ATOR in vivo.

Conclusion: ATOR blocks glioma progression by modulating the miR-125a-5p/TXLNA axis, further demonstrating that ATOR provides an effective therapeutic target for the treatment of glioma.

Background: Breast cancer is the most prevalent cancer among women worldwide. Most breast cancer-related deaths result from metastasis and drug resistance. Novel therapies are imperative for targeting metastatic and drug-resistant breast cancer cells. Accumulating evidence suggests that dysregulated microRNAs (miRNAs) promote breast cancer progression, metastasis, and drug resistance. Compared with healthy breast tissue, miR-660-5p is notably overexpressed in breast cancer tumor tissues. However, the downstream effectors of miR-660-5p in breast cancer cells have not been fully elucidated. Our aim was to investigate the role of miR-660-5p in breast cancer cell proliferation, migration, invasion, and angiogenesis and to identify its potential targets.

Results: Our findings revealed significant upregulation of miR-660-5p in MDA-MB-231 and MCF-7 cells compared with MCF-10 A cells. Furthermore, inhibiting miR-660-5p led to notable decreases in the proliferation, migration, and invasion of breast cancer cells, as well as angiogenesis, in HUVEC cells. Through bioinformatics analysis, we identified 15 potential targets of miR-660-5p. We validated TMEM41B as a direct target of miR-660-5p via Western blot and dual-luciferase reporter assays.

Conclusions: Our study highlights the upregulation and involvement of miR-660-5p in breast cancer cell proliferation, migration, invasion, and angiogenesis. Additionally, we identified TMEM41B as a direct target of miR-660-5p in breast cancer cells.

Background: Glioma is a malignancy with challenging clinical treatment and poor prognosis. Platelets are closely associated with tumor growth, propagation, invasion, and angiogenesis. However, the role of platelet-related genes in glioma treatment and prognosis remains unclear.

Results: A prognostic risk model was established using nine platelet-related prognostic signature genes (CAPG, CLIC1, GLB1, GNG12, KIF20A, PDIA4, SULF2, TAGLN2, and WEE1), and the risk score of samples were calculated. Subsequently, the glioma samples were divided into high- and low-risk groups based on the median values of risk scores. scRNA-seq analysis revealed that the prognostic genes were primarily located in astrocytes and natural killer cells. The immune infiltration proportions of most immune cells differed significantly between high- and low-risk groups. Moreover, we found AZD7762 as a potential candidate for glioma treatment.

Conclusion: Nine platelet-related prognostic genes identified as prognostic signatures for glioma were closely associated with the TME and may aid in directing the clinical treatment and prognosis of gliomas.