Cathepsins and their role in gynecological cancers: Evidence from two-sample Mendelian randomization analysis

Medicine, Journal Year: 2025, Volume and Issue: 104(10), P. e41653 - e41653

Published: March 7, 2025

Prior studies have reported connections between cathepsins (CTS) and gynecological cancers; however, the exact causal links are yet to be fully understood. Leveraging publicly accessible genome-wide association study summary datasets, we performed a two-sample bidirectional Mendelian randomization (MR) multivariate MR (MVMR) analysis, with inverse variance weighted (IVW) method as primary approach. analysis demonstrated associations CTSB cervical cancer (IVW: odds ratio [OR] = 0.9995, 95% confidence interval [CI] 0.9991-0.9999, P .0418), CTSE ovarian OR 0.9197, CI 0.8505-0.9944, .0358), CTSZ 0.9449, 0.8938-0.9990, .0459), high grade serous 0.8939, 0.8248-0.9689, .0063), 0.9269, 0.8667-0.9913, .0268). A positive correlation was identified CTSH clear cell 1.1496, 1.0368-1.2745, .0081). Nevertheless, subsequent adjustment for false discovery rate revealed that none of P-values retained statistical significance (PFDR > 0.05). MVMR results elucidated inversely associated 0.9988, 0.9981-0.9996, .0022). Moreover, noted CTSF 1.0007, 1.0000-1.0014, .0364), similarly, CTSS 1.0005, 1.0000-1.0011, .0490). CTSO exhibited non-endometrioid endometrial 1.4405, 1.1864-1.7490, < .001), positively 1.1167, 1.0131-1.2310, .0263). The findings reveal emerges protective element against cancer, whereas represent risk factors this disease. stands out factor acts cancer. This elucidates causative CTS cancers, providing innovative insights diagnostic therapeutic optimization.

Language: Английский

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Association between cathepsins and skin cancers: A bidirectional two‐sample Mendelian randomization study

Skin Research and Technology, Journal Year: 2024, Volume and Issue: 30(8)

Published: Aug. 1, 2024

Abstract Background Several cathepsins have been identified as being involved in the development of cancer. Nevertheless, connection between and skin cancers remained highly elusive. Methods A bidirectional Mendelian randomization (MR) analysis was performed to investigate causal association malignancies. The genome‐wide studies (GWAS) data for cathepsins, malignant melanoma (MM), basal cell carcinoma (BCC) were obtained from European research. primary method employed inverse variance weighted. In addition, MR‐Egger, weighted median, mode, simple mode also executed. Sensitivity using Cochran's Q test, MR‐PRESSO. Results From univariable MR (UVMR), cathepsin H, S determined a relationship with BCC. Additionally, H associated MM. Multivariable (MVMR) showed that after correcting risk factors carcinoma, detected be protective against BCC, whereas has observed factor No substantial pleiotropy heterogeneity sensitivity analysis. Conclusion This study first establish direct link Cathepsin potential serve new biomarkers offering valuable assistance prompt identification, treatment, prevention disease. additional clinical trials are required validate our findings.

Language: Английский

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Identifying and Validating Extracellular Matrix-Related Gene CTSH in Diabetic Foot Ulcer Using Bioinformatics and Machine Learning

Journal of Inflammation Research, Journal Year: 2024, Volume and Issue: Volume 17, P. 5871 - 5887

Published: Aug. 1, 2024

Background: Diabetic foot ulcer (DFU) is a serious clinical problem with high amputation and mortality rates, yet there lack of desirable therapy.While the extracellular matrix (ECM) contributes significantly to wound healing, ECM-related biomarker for DFU still unknown.The study was designed identify in using bioinformatics machine learning validate it STZ-induced mice models.Methods: GSE80178 GSE134431 microarray datasets were fetched from GEO database, differentially expressed genes (DEGs) analysis performed, respectively.By analyzing DEGs ECM genes, we identified DEGs, functional enrichment conducted.Subsequently, three algorithms (LASSO, RF SVM-RFE) applied filter key biomarkers.Next, conducted immune infiltration analysis, GSEA, correlation explore hub gene underlying mechanism.A lncRNA-miRNA-mRNA drug regulatory network constructed.Finally, validated models.Results: One hundred forty-five common adult between two identified.Taking intersection 145 964 13 DEGs.Thirteen mainly enriched pathways associated tissue remodeling, inflammation defense against infectious agents.Ultimately, CTSH as biomarker.CTSH difference cells during occurrence development DFU, influenced hedgehog, IL-17 TNF signaling pathway.Additionally, expression correlated many ECM-and immune-related genes.A constructed 10 lncRNAs, 2 miRNAs, 1 drug.Finally, animal models.Conclusion: Our found that can be used both diagnostic prognostic purposes might potential therapeutic target.

Language: Английский

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Causal effect of immune cells, metabolites, cathepsins, and vitamin therapy in diabetic retinopathy: a Mendelian randomization and cross-sectional study

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Oct. 1, 2024

Background Diabetic retinopathy (DR) is a major microvascular complication of diabetes and leading cause blindness worldwide. The pathogenesis DR involves complex interactions between metabolic disturbances, immune cells, proteolytic enzymes such as cathepsins (CATs). Despite various studies, the precise roles different CATs, metabolites, vitamins in remain unclear. Method In this study, we employed Mendelian Randomization (MR) to assess causal relationships using genetic instruments selected based on genome-wide association studies (GWAS). We two-sample mediation MR explore effects nine vitamins, DR. Additionally, study also incorporated data from NHANES survey associated relationship utilized cross-sectional analyze vitamin intake diabetic (DR), adjusting for potential confounders strengthen validity our findings. Results analysis identified CAT H significant risk factor both NPDR PDR, with no evidence reverse causality. 62 cell traits were found have 49 PDR. Enrichment revealed that pathways sphingolipid metabolism are crucial progression. Vitamins B6 E significantly reduced Cross-sectional indicated B1, B2, B6, B12, progressively decreased severity. Conclusion This first identify key DR, while showed protective effects, particularly against These findings suggest H, along E, could serve therapeutic targets Further validation through larger, multi-center recommended enhance accuracy applicability these

Language: Английский

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Multi-Level Proteomics Reveals Epigenetic Signatures in BCG-mediated Macrophage Activation

Molecular & Cellular Proteomics, Journal Year: 2024, Volume and Issue: unknown, P. 100851 - 100851

Published: Oct. 1, 2024

Language: Английский

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Acid Sphingomyelinase Deficiency Type B Patient-Derived Liver Organoids Reveals Altered Lysosomal Gene Expression and Lipid Homeostasis

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(16), P. 12645 - 12645

Published: Aug. 10, 2023

Acid sphingomyelinase deficiency (ASMD) or Niemann–Pick disease type A (NPA), B (NPB) and A/B (NPA/B), is a rare lysosomal storage characterized by progressive accumulation of sphingomyelin (SM) in the liver, lungs, bone marrow and, severe cases, neurons. model was established generating liver organoids from NPB patient carrying p.Arg610del variant SMPD1 gene. Liver were transcriptomic lipidomic analysis. We observed altered lipid homeostasis patient-derived showing predictable increase (SM), together with cholesterol esters (CE) triacylglycerides (TAG), reduction phosphatidylcholine (PC) cardiolipins (CL). Analysis gene expression pointed to 24 downregulated genes, including SMPD1, 26 upregulated genes that reflect stress typical disease. Altered revealed reduced enzymes could be involved hepatocytes sphyngoglycolipids glycoproteins, as well coding for different glycosidases cathepsins. Lipidic transcriptome changes support use hepatic ideal models ASMD investigation.

Language: Английский

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A Mendelian randomization study: Association of Cathepsin with Osteoarticular Muscle Diseases

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 3, 2024

Abstract Objective: The cathepsin present in lysosomal cells may be closely related to bone, muscle & joint diseases (BMJD)including osteoporosis and osteoarthritis, but its specific mechanism of action still needs further research exploration. aim this study is use a two-sample Mendelian randomization (MR) comprehensive analysis explore the causal relationship between risk BMJD. Method: Based on published genetic data, used method causality morbidity 9 cathepsins with rheumatoid arthritis, ankylosing spondylitis, peripheral arthritis(Crohn's disease, ulcerative colitis, postdysentery disease), psoriatic lower back pain, spinal stenosis, osteoporosis, bone necrosis, connective tissue cartilage diseases, benign tumors, myositis, synovitis tenosynovitis (radial styloid tenosynovitis), shoulder periarthritis, neuromuscular junction atrophy. Meanwhile, order reveal possibility reverse causality, we conducted analysis,using Cochran's Q test MR Egger intercept evaluate heterogeneity, horizontal pleiotropy,and stability SNPs. Result: found that B negatively correlated colitis E positively musculoskeletal G L2 Cathepsin S arthritis; through analysis, lead an increase B. In addition, did not find any synovitis, tenosynovitis, neuritis, osteoporosis,Crohn's arthritis,dysentery low pain,and cathepsin. Conclusion: large-scale population studies GWAS demonstrated close BMJD from perspective, which provide basis for pathogenesis new directions future treatment strategies.

Language: Английский

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Cathepsin in Alzheimer's Disease, Parkinson's Disease and Dementia with Lewy Bodies: Mendelian Randomization Study

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 28, 2024

Abstract Background Observational studies indicate a strong association between most neurodegenerative disorders and cathepsin, although the causative link remains unclear. Methods This research utilized Mendelian Randomization (MR) with genetic markers linked to cathepsins as instrumental variables, analyzed public Genome-Wide Association Studies (GWASs) summary data of individuals European ancestry for Alzheimer's disease (AD), Parkinson's (PD), dementia Lewy bodies (DLB) outcomes. The study applied inverse variance-weighted (IVW) method assess causal effects on AD, PD, DLB. Several sensitivity analyses heterogeneity test were conducted evaluate effectiveness results. Confounding variables accounted using multivariable MR (MVMR). Additionally, reverse was done improve forward analysis. Lastly, we utilize Bayesian Weighted (BWMR) further validate robustness Results investigation found an cathepsin H AD DLB risk. However, there negative correlation PD risk B levels. Effect estimates in MVMR BWMR remained constant. According analysis, decreased levels, negatively correlated Z no relationship cathepsins. Conclusion While higher levels associated risk, bidirectional B. By studying how influences development advancement DLB, novel methods diagnosis treatment might be investigated.

Language: Английский

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Causality between cathepsins and idiopathic pulmonary fibrosis: a Mendelian randomization study

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: April 5, 2024

Abstract Background The pathogenesis of idiopathic pulmonary fibrosis (IPF) is complex and difficult to diagnose treat clinically. Cathepsins are involved in various physiological pathological processes, observational studies have shown an association between cathepsins IPF. However, the causal relationship them remains uncertain. Our aim was assess Methods Protein quantitative trait loci (pQTL) data for were obtained from INTERVAL studies, summary statistics IPF genome-wide (GWAS) FinnGen R10 study. Univariable Mendelian randomization (UVMR), multivariable (MVMR), data-based (SMR) Bayesian colocalization analysis conducted this Results UVMR indicated that elevated cathepsin H levels reduced overall risk (OR = 0.885,95%CI 0.827 ~ 0.947, P 3.86×10 − 4). MVMR showed effect on still present after adjusting interaction 0.895,95%CI 0.834 0.961, 0.002). In addition, SMR also suggested a 0.800,95%CI 0.699 0.916, 0.001). Finally, we validated results using UK Biobank Pharma Proteomics Project (UKB-PPP) dataset 0.897,95%CI 0.836 0.963, 0.003). Conclusions This study suggests has protective may serve as potential therapeutic target IPF, providing inspiration guidance diagnosis treatment

Language: Английский

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Genetic insights into serum cathepsins as diagnostic and therapeutic targets in knee and hip osteoarthritis

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: July 30, 2024

Osteoarthritis (OA) is a chronic disease due to the deterioration of cartilage structure and function, involving progressive degradation extracellular matrix. Cathepsins, lysosomal cysteine proteases, play pivotal roles in various biological pathological processes, particularly protein degradation. Excess cathepsins levels are reported contribute development OA. However, causal relationship between cathepsin family knee hip OA remains uncertain. Therefore, this study utilized bidirectional Mendelian Randomization (MR) analyses explore association. Our results indicated that elevated serum O increase overall risk OA, while increased H enhance Conversely, reverse MR did not reveal them. In summary, different anatomical locations may genetically result from elevations isoforms, which could be as diagnostic therapeutic targets clinical practice.

Language: Английский

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