FOXP4 is a Direct YAP1 Target that Promotes Gastric Cancer Stemness and Drives Metastasis.

The Hippo-YAP1 pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration. Dysregulation of Hippo-YAP1 signaling promotes initiation and progression of several types of cancer, including gastric cancer (GC). As the Hippo-YAP1 pathway regulates expression of thousands of genes, it is important to establish which target genes contribute to the oncogenic program driven by YAP1 to identify strategies to circumvent it. Here, we identified a vital role of FOXP4 in YAP1-driven gastric carcinogenesis by maintaining stemness and promoting peritoneal metastasis. Loss of FOXP4 impaired GC spheroid formation and reduced stemness marker expression, while FOXP4 upregulation potentiated cancer cell stemness. RNA-seq analysis revealed SOX12 as downstream target of FOXP4, and functional studies established that SOX12 supports stemness in YAP1-induced carcinogenesis. A small molecule screen identified 42-(2-Tetrazolyl)rapamycin as a FOXP4 inhibitor, and targeting FOXP4 suppressed GC tumor growth and enhanced the efficacy of 5-FU chemotherapy in vivo. Collectively, these findings revealed that FOXP4 upregulation by YAP1 in GC regulates stemness and tumorigenesis by upregulating SOX12. Targeting the YAP1-FOXP4-SOX12 axis represents a potential therapeutic strategy for GC.

Coenzyme Q deficiency may predispose to sudden unexplained death via an increased risk of cardiac arrhythmia.

Cardiac arrhythmia is currently considered to be the direct cause of death in a majority of sudden unexplained death (SUD) cases, yet the genetic predisposition and corresponding endophenotypes contributing to SUD remain incompletely understood. In this study, we aimed to investigate the involvement of Coenzyme Q (CoQ) deficiency in SUD. First, we re-analyzed the exome sequencing data of 45 SUD and 151 sudden infant death syndrome (SIDS) cases from our previous studies, focusing on previously overlooked genetic variants in 44 human CoQ deficiency-related genes. A considerable proportion of the SUD (38%) and SIDS (37%) cases were found to harbor rare variants with likely functional effects. Subsequent burden testing, including all rare exonic and untranslated region variants identified in our case cohorts, further confirmed the existence of significant genetic burden. Based on the genetic findings, the influence of CoQ deficiency on electrophysiological and morphological properties was further examined in a mouse model. A significantly prolonged PR interval and an increased occurrence of atrioventricular block were observed in the 4-nitrobenzoate induced CoQ deficiency mouse group, suggesting that CoQ deficiency may predispose individuals to sudden death through an increased risk of cardiac arrhythmia. Overall, our findings suggest that CoQ deficiency-related genes should also be considered in the molecular autopsy of SUD.

Biomarkers Screening and Mechanisms Analysis of the Restraint Stress-Induced Myocardial Injury in Hyperlipidemia ApoE-/- Mice.

OBJECTIVES: To explore the biomarkers and potential mechanisms of chronic restraint stress-induced myocardial injury in hyperlipidemia ApoE-/- mice. METHODS: The hyperlipidemia combined with the chronic stress model was established by restraining the ApoE-/- mice. Proteomics and bioinformatics techniques were used to describe the characteristic molecular changes and related regulatory mechanisms of chronic stress-induced myocardial injury in hyperlipidemia mice and to explore potential diagnostic biomarkers. RESULTS: Proteomic analysis showed that there were 43 significantly up-regulated and 58 significantly down-regulated differentially expressed proteins in hyperlipidemia combined with the restraint stress group compared with the hyperlipidemia group. Among them, GBP2, TAOK3, TFR1 and UCP1 were biomarkers with great diagnostic potential. KEGG pathway enrichment analysis indicated that ferroptosis was a significant pathway that accelerated the myocardial injury in hyperlipidemia combined with restraint stress-induced model. The mmu_circ_0001567/miR-7a/Tfr-1 and mmu_circ_0001042/miR-7a/Tfr-1 might be important circRNA-miRNA-mRNA regulatory networks related to ferroptosis in this model. CONCLUSIONS: Chronic restraint stress may aggravate myocardial injury in hyperlipidemia mice via ferroptosis. Four potential biomarkers are selected for myocardial injury diagnosis, providing a new direction for sudden cardiac death (SCD) caused by hyperlipidemia combined with the restraint stress.

The decision-making process of palliative care among male caregivers of chronically ill patients-A grounded theory study.

BACKGROUND: Family caregivers have a vital role to play in palliative care for chronically ill patients. In Taiwan, caregiver demographics are evolving, with the number of male caregivers increasing. Gender differences influence psychosocial behaviours, thought processes and communication styles. In healthcare, acknowledgement of gender differences facilitates effective delivery of high-quality care. AIM: The aim of this study is to explore male caregivers' decision-making process for palliative care for chronically ill family members. METHODS: This study employed grounded theory to generate a substantive theory of male caregivers' decision-making process for palliative care for chronically ill family members. We recruited 22 male participants from three inner-city teaching hospitals in Taiwan. FINDINGS: Regarding the decision-making process of palliative care of chronic ill family, where male caregivers do not want their loved ones suffering anymore, the male caregivers' decision-making process was impacted, first, by caregivers' views on the last stage of life; second, by their wish for good care during the end of life; and third, by their conviction that the patients' wishes should be respected. Furthermore, caregivers' philosophy of life and death is also a supportive ground for decision-making. This philosophy was influenced by their education in palliative care, financial status and religious beliefs and practices. The core category emerging from this study is encapsulated by a participant's assertion, 'How difficult is it? There are no male and female differences'. CONCLUSION: We found that palliative care experiences of male caregivers are important for the decision-making process for palliative care for their chronically ill family members. Caregivers want their loved ones to receive good care as the last step in life, to respect their wishes and no more suffering for the patient. Therefore, health professionals should be familiar with the palliative care process that caregivers go through to offer updated information when needed.

Analysis of Salt Stress on Soil Microbial Community Composition and Its Correlation with Active Components in the Rhizosphere of Acanthopanax senticosus.

Salt stress can adversely affect plant seed germination, growth and development, and eventually lead to slow growth and even death of plants. The purpose of this study was to investigate the effects of different concentrations of NaCl and Na2SO4 stress on the physicochemical properties, enzyme activities, rhizosphere microbial community and seven active components (L-phenylalanine, Protocatechuic acid, Eleutheroside B, Chlorogenic acid, Caffeic acid, Eleutheroside E, Isofraxidin) of Acanthopanax senticosus rhizosphere soil. Statistical analysis was used to explore the correlation between the rhizosphere ecological factors of Acanthopanax senticosus and its active components. Compared with Acanthopanax senticosus under NaCl stress, Na2SO4 generally had a greater effect on Acanthopanax senticosus, which reduced the richness of fungi in rhizosphere soil and adversely affected the content of multiple active components. Pearson analysis showed that pH, organic matter, ammonium nitrogen, available phosphorus, available potassium, catalase and urease were significantly correlated with active components such as Caffeic acid and Isofraxidin. There were 11 known bacterial genera, 12 unknown bacterial genera, 9 known fungal genera and 1 unknown fungal genus significantly associated with the active ingredient. Salt stress had great changes in the physicochemical properties, enzyme activities and microorganisms of the rhizosphere soil of Acanthopanax senticosus. In conclusion, different types and concentrations of salts had different effects on Acanthopanax senticosus, and the active components of Acanthopanax senticosus were regulated by rhizosphere soil ecological factors.

Discussion on the relationship between gut microbiota and glioma through Mendelian randomization test based on the brain gut axis.

BACKGROUND: In the realm of Gut-Brain axis research, existing evidence points to a complex bidirectional regulatory mechanism between gut microbiota and the brain. However, the question of whether a causal relationship exists between gut microbiota and specific types of brain tumors, such as gliomas, remains unresolved. To address this gap, we employed publicly available Genome-Wide Association Study (GWAS) and MIOBEN databases, conducting an in-depth analysis using Two-Sample Mendelian Randomization (MR). METHOD: We carried out two sets of MR analyses. The preliminary analysis included fewer instrumental variables due to a high genome-wide statistical significance threshold (5×10-8). To enable a more comprehensive and detailed analysis, we adjusted the significance threshold to 1×10-5. We performed linkage disequilibrium analysis (R2 <0.001, clumping distance = 10,000kb) and detailed screening of palindromic SNPs, followed by MR analysis and validation through sensitivity analysis. RESULTS: Our findings reveal a causal relationship between gut microbiota and gliomas. Further confirmation via Inverse Variance Weighting (IVW) identified eight specific microbial communities related to gliomas. Notably, the Peptostreptococcaceae and Olsenella communities appear to have a protective effect, reducing glioma risk. CONCLUSION: This study not only confirms the causal link between gut microbiota and gliomas but also suggests a new avenue for future glioma treatment.

Causal relationships of Helicobacter pylori and related gastrointestinal diseases on Type 2 diabetes: Univariable and Multivariable Mendelian randomization.

BACKGROUND: Previous observational studies have demonstrated a connection between the risk of Type 2 diabetes mellitus (T2DM) and gastrointestinal problems brought on by Helicobacter pylori (H. pylori) infection. However, little is understood about how these factors impact on T2DM. METHOD: This study used data from the GWAS database on H. pylori antibodies, gastroduodenal ulcers, chronic gastritis, gastric cancer, T2DM and information on potential mediators: obesity, glycosylated hemoglobin (HbA1c) and blood glucose levels. Using univariate Mendelian randomization (MR) and multivariate MR (MVMR) analyses to evaluate the relationship between H. pylori and associated gastrointestinal diseases with the risk of developing of T2DM and explore the presence of mediators to ascertain the probable mechanisms. RESULTS: Genetic evidence suggests that H. pylori IgG antibody (P = 0.006, b = 0.0945, OR = 1.0995, 95% CI = 1.023-1.176), H. pylori GroEL antibody (P = 0.028, OR = 1.033, 95% CI = 1.004-1.064), gastroduodenal ulcers (P = 0.019, OR = 1.036, 95% CI = 1.006-1.068) and chronic gastritis (P = 0.005, OR = 1.042, 95% CI = 1.012-1.074) are all linked to an increased risk of T2DM, additionally, H. pylori IgG antibody is associated with obesity (P = 0.034, OR = 1.03, 95% CI = 1.002-1.055). The results of MVMR showed that the pathogenic relationship between H. pylori GroEL antibody and gastroduodenal ulcer in T2DM is mediated by blood glucose level and obesity, respectively. CONCLUSION: Our study found that H. pylori IgG antibody, H. pylori GroEL antibody, gastroduodenal ulcer and chronic gastritis are all related to t T2DM, and blood glucose level and obesity mediate the development of H. pylori GroEL antibody and gastroduodenal ulcer on T2DM, respectively. These findings may inform new prevention and intervention strategies for T2DM.

Tunable and switchable multifunctional terahertz meta-mirror based on graphene and vanadium dioxide.

We design a multifunctional THz polarization modulation meta-mirror integrated with polarization conversion and dichroism functions switched by temperature and voltage. The meta-mirror is composed of two-layered graphene metasurfaces and a layer of vanadium dioxide (VO2) on a gold film substrate. Linear-to-linear polarization conversion and linear dichroism (LD) can be switched by temperature control in the VO2 film and Fermi level adjustments in the graphene metasurfaces, where the polarization conversion ratio (PCR) is higher than 0.9 in the range of 2.89 THz to 4.02 THz, LD value reached a maximum of 0.6 at 3.84 THz, and linear-to-circular polarization conversion and circular dichroism (CD) can also be tuned with ellipticity higher than 0.9 in the range of 2.32 THz to 2.69 THz and CD value as high as 0.71 at 2.45 THz. The proposed meta-mirror is the first THz metamaterial device integrating four switchable functions, including linear-to-linear polarization conversion, linear-to-circular polarization conversion, linear dichroism and circular dichroism. The meta-mirror is a promising design for compact system integration in THz imaging, sensing and biological detection applications.

M2 Tumor-Associated Macrophages-Derived Exosomal MALAT1 Promotes Glycolysis and Gastric Cancer Progression.

M2-polarized tumor-associated macrophages (M2 TAMs) promote cancer progression. Exosomes mediate cellular communication in the tumor microenvironment (TME). However, the roles of exosomes from M2 TAMs in gastric cancer progression are unclear. Herein, it is reported that M2 TAMs-derived exosomes induced aerobic glycolysis in gastric cancer cells and enhanced their proliferation, metastasis, and chemoresistance in a glycolysis-dependent manner. It is identified that MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) is enriched in M2 TAM exosomes and confirmed that MALAT1 transfer from M2 TAMs to gastric cancer cells via exosomes mediates this effect. Mechanistically, MALAT1 interacted with the δ-catenin protein and suppressed its ubiquitination and degradation by ß-TRCP. In addition, MALAT1 upregulated HIF-1α expression by acting as a sponge for miR-217-5p. The activation of ß-catenin and HIF-1α signaling pathways by M2 TAM exosomes collectively led to enhanced aerobic glycolysis in gastric cancer cells. Finally, a dual-targeted inhibition of MALAT1 in both gastric cancer cells and macrophages by exosome-mediated delivery of siRNA remarkably suppressed gastric cancer growth and improved chemosensitivity in mouse tumor models. Taken together, these results suggest that M2 TAMs-derived exosomes promote gastric cancer progression via MALAT1-mediated regulation of glycolysis. The findings offer a potential target for gastric cancer therapy.

Discovery and structural mechanism of DNA endonucleases guided by RAGATH-18-derived RNAs.

CRISPR-Cas systems and IS200/IS605 transposon-associated TnpBs have been utilized for the development of genome editing technologies. Using bioinformatics analysis and biochemical experiments, here we present a new family of RNA-guided DNA endonucleases. Our bioinformatics analysis initially identifies the stable co-occurrence of conserved RAGATH-18-derived RNAs (reRNAs) and their upstream IS607 TnpBs with an average length of 390 amino acids. IS607 TnpBs form programmable DNases through interaction with reRNAs. We discover the robust dsDNA interference activity of IS607 TnpB systems in bacteria and human cells. Further characterization of the Firmicutes bacteria IS607 TnpB system (ISFba1 TnpB) reveals that its dsDNA cleavage activity is remarkably sensitive to single mismatches between the guide and target sequences in human cells. Our findings demonstrate that a length of 20 nt in the guide sequence of reRNA achieves the highest DNA cleavage activity for ISFba1 TnpB. A cryo-EM structure of the ISFba1 TnpB effector protein bound by its cognate RAGATH-18 motif-containing reRNA and a dsDNA target reveals the mechanisms underlying reRNA recognition by ISFba1 TnpB, reRNA-guided dsDNA targeting, and the sensitivity of the ISFba1 TnpB system to base mismatches between the guide and target DNA. Collectively, this study identifies the IS607 TnpB family of compact and specific RNA-guided DNases with great potential for application in gene editing.

Peripheral artery disease mediating the effect of metabolic syndrome related diseases on lower limb ulcers: Mendelian randomization analysis.

Background: Previous observational studies have demonstrated a correlation between metabolic syndrome related diseases and an elevated susceptibility to ulcers of lower limb. It has been suggested that this causal relationship may be influenced by the presence of peripheral artery disease (PAD). Nevertheless, the precise contribution of these factors as determinants of ulcers of lower limb remains largely unexplored. Method: This research incorporated information on hypertension, BMI, hyperuricemia, type 2 diabetes, PAD, and ulcers of lower limb sourced from the GWAS database. Univariate Mendelian randomization (SVMR) and multivariate Mendelian randomization (MVMR) methods were employed to assess the association between metabolic syndrome related diseases, including hypertension, obesity, hyperuricemia, and type 2 diabetes, as well as to investigate whether this association was influenced by PAD. Results: Univariate Mendelian randomization analysis showed that genetically predicted hypertension, BMI, and type 2 diabetes were associated with an increased risk of PAD and ulcers of lower limb, and PAD was associated with an increased risk of ulcers of lower limb, but there is no causal relationship between hyperuricemia and ulcers of lower limb. The results of multivariate Mendelian randomization showed that PAD mediated the causal relationship between hypertension, obesity and ulcers of lower limb, but the relationship between type 2 diabetes and ulcers of lower limb was not mediated by PAD. Conclusion: Hypertension, BMI and type 2 diabetes can increase the risk of ulcers of lower limb, and PAD can be used as a mediator of hypertension and obesity leading to ulcers of lower limb, These findings may inform prevention and intervention strategies directed toward metabolic syndrome and ulcers of lower limb.

[Corrigendum] Genistein exerts growth inhibition on human osteosarcoma MG-63 cells via PPARγ pathway.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that, in Fig. 1D on p. 1134, the data panels showing the results for the 'Control' and '1 µmol/l GW9662' experiments (on the left hand side of the figure) were overlapping, such that these data had been derived from the same original source where they were intended to show the results from differently performed experiments. The authors were able to re­examine their original data, and realize that the data for the '1 µmol/l GW9662' panel had been selected incorrectly. The corrected version of Fig. 1, now featuring the correct data for the '1 µmol/l GW9662' experiment in Fig. 1D, is shown on the next page, The authors confirm their error did not grossly affect either the results of the conclusions reported in the paper, and are grateful to the Editor of International Journal of Oncology for allowing them this opportunity to publish a Corrigendum. They also apologize to the readership for any inconvenience caused. [International Journal of Oncology 46: 1131-1140, 2015; DOI: 10.3892/ijo.2015.2829].

Establishment of skin cutaneous melanoma prognosis model based on vascular mimicry risk score.

Studies have indicated that Vascular mimicry (VM) could contribute to the unfavorable prognosis of skin cutaneous melanoma (SKCM). Thus, the objective of this study was to identify therapeutic targets associated with VM in SKCM and develop a novel prognostic model. Gene expression data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) were utilized to identify differentially expressed genes (DEGs). By intersecting these DEGs with VM genes, we acquired VM-related DEGs specific to SKCM, and then identified prognostic-related VM genes. A VM risk score system was established based on these prognosis-associated VM genes, and patients were then categorized into high- and low-score groups using the median score. Subsequently, differences in clinical characteristics, gene set enrichment analysis (GSEA), and other analyses were further presented between the 2 groups of patients. Finally, a novel prognostic model for SKCM was established using the VM score and clinical characteristics. 26 VM-related DEGs were identified in SKCM, among the identified DEGs associated with VM in SKCM, 5 genes were found to be prognostic-related. The VM risk score system, comprised of these genes, is an independent prognostic risk factor. There were significant differences between the 2 patient groups in terms of age, pathological stage, and T stage. VM risk scores are associated with epithelial biological processes, angiogenesis, regulation of the SKCM immune microenvironment, and sensitivity to targeted drugs. The novel prognostic model demonstrates excellent predictive ability. Our study identified VM-related prognostic markers and therapeutic targets for SKCM, providing novel insights for clinical diagnosis and treatment.

Crystal Structure and Optical Properties Characterization in Quasi-0D Lead-Free Bromide Crystals (C6H14N)3Bi2Br9·H2O and (C6H14N)3Sb3Br12.

Low dimensional organic inorganic metal halide materials have shown broadband emission and large Stokes shift, making them widely used in various fields and a promising candidate material. Here, the zero-dimensional lead-free bromide single crystals (C6H14N)3Bi2Br9·H2O (1) and (C6H14N)3Sb3Br12 (2) were synthesized. They crystallized in the monoclinic crystal system with the space group of P21 and P21/n, respectively. Through ultraviolet-visible-near-infrared (UV-vis-NIR) absorption analysis, the band gaps of (C6H14N)3Bi2Br9·H2O and (C6H14N)3Sb3Br12 are found to be 2.75 and 2.83 eV, respectively. Upon photoexcitation, (C6H14N)3Bi2Br9·H2O exhibit broad-band red emission peaking at 640 nm with a large Stokes shift of 180 nm and a lifetime of 2.94 ns, and the emission spectrum of (C6H14N)3Sb3Br12 are similar to those of (C6H14N)3Bi2Br9·H2O. This exclusive red emission is ascribed to the self-trapping exciton transition caused by lattice distortion, which is confirmed through both experiments and first-principles calculations. In addition, due to the polar space group structure and the large spin-orbit coupling (SOC) associated with the heavy elements of Bi and Br of crystal 1, an obvious Rashba effect was observed. The discovery of organic inorganic metal bromide material provides a critical foundation for uncovering the connection between 0D metal halide materials' structures and properties.

Registered nurses' perceptions and experience of working in aged care: A qualitative approach.

AIM: To understand and report on the perceptions and experiences of registered nurses in the aged care sector. DESIGN: An exploratory qualitative study. METHODS: Semi-structured telephone interviews were utilised as the primary data collection method. Fifteen registered nurses were interviewed. All interviews were recorded, transcribed verbatim and analysed using conventional content analysis. Participants were quoted verbatim to ensure authenticity. RESULTS: The results indicated a demand for increased administrative and staffing support in the aged care workplace. Poor morale and unethical practices contributed to negative perceptions and attitudes among nurses towards aged care. Managing and communicating with older people was reported as challenging, which impacts nursing staff recruitment and retention. Future work is needed to ensure that outstanding clinical role models and leadership support nursing staff recruitment and retention. Incorporating aged care content into the nursing curriculum and providing professional development opportunities to aged care professionals would be the foundation towards solutions, as the study primarily explored nurses' perspectives.

Erratum: [Corrigendum] Resveratrol reverses P­glycoprotein­mediated multidrug resistance of U2OS/ADR cells by suppressing the activation of the NF­κB and p38 MAPK signaling pathways.

[This corrects the article DOI: 10.3892/ol.2016.5136.].

An mRNA profiling assay incorporating coding region InDels for body fluid identification and the inference of the donor in mixed samples.

Biological traces discovered at crime scenes hold significant significance in forensic investigations. In cases involving mixed body fluid stains, the evidentiary value of DNA profiles depends on the type of body fluid from which the DNA was obtained. Recently, coding region polymorphism analysis has proved to be a promising method for directly linking specific body fluids to their respective DNA contributors in mixtures, which may help to avoid "association fallacy" between separate DNA and RNA evidence. In this study, we present an update on previously reported coding region Single Nucleotide Polymorphisms (cSNPs) by exploring the potential application of coding region Insertion/Deletion polymorphisms (cInDels). Nine promising cInDels, selected from 70 mRNA markers based on stringent screening criteria, were integrated into an existing mRNA profiling assay. Subsequently, the body fluid specificity of our cInDel assay and the genotyping consistency between complementary DNA (cDNA) and genomic DNA (gDNA) were examined. Our study demonstrates that cInDels can function as important multifunctional genetic markers, as they provide not only the ability to confirm the presence of forensically relevant body fluids, but also the ability to associate/dissociate specific body fluids with particular donors.

Adults' perspectives of experiences and preferences for end-of-life care.

BACKGROUND: Decisions about end-of-life care often raise clinical and ethical challenges, especially when the person's capacity to contribute in the decision making at the end of life is limited. AIM: This study aimed to explore Taiwanese adults' preferences associated with communication, healthcare planning, life-sustaining treatments and palliative care and experiences of end-of-life care. METHODS: Semi-structured interviews were conducted with 16 adults aged 20 years and above. The sampling approach was a convenience strategy in a community centre located in a metropolitan area in the Southern region of Taiwan. A qualitative content analysis approach was used to elicit key themes from the data. RESULTS: Significant findings related to the two main themes of adults' experiences, including the observed distress of those who were dying and the distress experienced by the family. Other key findings pertain to personal preferences for end-of-life care, such as preferred end-of-life communication, preparing for the end-of-life and maintenance of quality of life. CONCLUSIONS: This exploratory study offers insight into 16 Taiwanese community-dwelling adults' views of preferences regarding end-of-life communication, preparation for the end of life and maintenance of quality of life, as well as their experiences of end-of-life care. A further exploration is suggested to elicit how personal end-of-life experiences shape individuals' health practices in advance care planning for end-of-life care.

Identification of angiogenesis-related genes in diabetic foot ulcer using machine learning algorithms.

Background: Diabetic foot ulcers (DFUs) are among the most prevalent and dangerous complications of diabetes. Angiogenesis is pivotal for wound healing; however, its role in the chronic wound healing process in DFU requires further investigation. We aimed to investigate the pathogenic processes of angiogenesis in DFU from a molecular biology standpoint and to offer insightful information about DFU prevention and therapy. Methods: Differential gene and weighted gene co-expression network analyses (WGCNA) were employed to screen for genes related to DFU using the downloaded and collated GSES147890 datasets. With the goal of identifying hub genes, an interaction among proteins (PPI) network was constructed, and enrichment analysis was carried out. Utilizing a variety of machine learning techniques, including Boruta, Support Vector Machine Recursive Feature Elimination (SVM-RFE), and Least Absolute Shrinkage and Selection Operator (LASSO), we were able to determine which hub genes most strongly correspond to DFU. This allowed us to create an ideally suited DFU forecasting model that was validated via an external dataset. Finally, by merging 36 angiogenesis-related genes (ARGs) and machine learning models, we identified the genes involved in DFU-related angiogenesis. Results: By merging 260 genes located in the green module and 59 differentially expressed genes (DEGs), 35 candidate genes highly associated with DFU were found for more investigation. 35 candidate genes were enriched in epidermal growth factor receptor binding, nuclear division regulation, fluid shear stress, atherosclerosis, and negative regulation of chromosomal structure for the enrichment study. Fifteen hub genes were found with the aid of the CytoHubba plug. The LASSO method scored better in terms of prediction performance (GSE134341) (LASSO:0.89, SVM:0.65, Boruta:0.66) based on the validation of the external datasets. We identified thrombomodulin (THBD) as a key target gene that potentially regulates angiogenesis during DFU development. Based on the external validation dataset (GSE80178 and GSE29221), receiver operating characteristic (ROC) curves with higher efficiency were generated to confirm the potential of THBD as a biomarker of angiogenesis in DFU. Furthermore supporting this finding were the results of Western blot and real-time quantitative polymerase chain reaction (RT-qPCR), which showed decreased THBD expression in human umbilical vein endothelial cells (HUVECs) cultivated under high glucose. Conclusions: The findings implicate that THBD may influence DFU progression as a potential target for regulating angiogenesis, providing a valuable direction for future studies.