Angiogenesis-related Genes Research Articles

Construction and validation of a prognostic model of angiogenesis-related genes in multiple myeloma

BackgroundAngiogenesis is associated with tumour growth, infiltration, and metastasis. This study aimed to detect the mechanisms of angiogenesis-related genes (ARGs) in multiple myeloma (MM) and to construct a new prognostic model.MethodsMM research foundation (MMRF)-CoMMpass cohort, GSE47552, GSE57317, and ARGs were sourced from public databases. Differentially expressed genes (DEGs) in the tumour and control cohorts in GSE47552 were determined through differential expression analysis and were enriched with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Weighted gene coexpression network analysis (WGCNA) was applied to derive modules linked to the ARG scores and obtain module genes in GSE47552. Differentially expressed ARGs (DE-ARGs) were selected for subsequent analyses by overlapping DEGs and module genes. Furthermore, prognostic genes were selected using univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analyses. Depending on the prognostic genes, a risk model was constructed, and risk scores were determined. Moreover, MM samples from MMRF-CoMMpass were sorted into high- and low-risk teams on account of the median risk score. Additionally, correlations among clinical characteristics, gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), immune analysis, immunotherapy predictions and the mRNA‒miRNA‒lncRNA network were carried out.ResultsA total of 898 DEGs, 211 module genes, 24 DE-ARGs and three prognostic genes (AKAP12, C11orf80 and EMP1) were selected for this study. Enrichment analysis revealed that the DEGs were related to 86 GO terms, such as ‘cytoplasmic translation’, and 41 KEGG pathways, such as ‘small cell lung cancer’. A prognostic gene-based risk model was created in MMRF-CoMMpass and confirmed with the GSE57317 dataset. Moreover, a nomogram was established on the basis of independent prognostic factors that have proven to be good predictors. In addition, the immune cell infiltration results suggested that memory B cells were enriched in the high-risk group and that immature B cells were enriched in the low-risk group. Finally, the mRNA‒miRNA‒lncRNA network demonstrated that hsa-miR-508-5p was tightly associated with EMP1 and AKAP12. RT‒qPCR was used to validate the expression of the genes associated with prognosis.ConclusionA new prognostic model of MM associated with ARGs was created and validated, providing a new perspective for exploring the connection between ARGs and MM.

Bioenergetic-active photoluminescent bioactive Nanodressing for proangiogenic MRSA infected wound repair and microenviroment monitoring

Multidrug-resistant bacterial infected wound repair and real-time microenvironment monitoring are still critical challenges, due to the infection-induced inflammation and poor angiogenesis capacity, as well as the complicate wound microenvironment. Herein, we report a multifunctional photoluminescent bioactive hydrogel (GMCB) with cell bioenergy-supplying and excellent antioxidant activities for achieving infection inflammation wound repair and microenvironment monitoring. GMCB was constructed through a bioenergy-supplying poly(citrate-borate) nanomicelle, antioxidant myricetin and gelatin matrix. GMCB possesses injectable, adhesive, photoluminescent and biodegradable properties, demonstrating excellent cellular biocompatibility. GMCB also shows a pH-responsive photoluminescent change based on the reversible crosslinking between borate and myricetin, which would have the potential to monitoring the pH values of wounds. GMCB significantly promotes the cell migration, upregulates the expression of angiogenesis-related genes, efficiently clears reactive oxygen species, and inhibits the expression of inflammatory factors. Importantly, GMCB could release citrate to accelerate the cellular bioenergetics by enhancing mitochondrial membrane potential and ATP levels providing energy for multiple biological activities of cells. GMCB accelerates the repair of methicillin-resistant Staphylococcus aureus (MRSA) infected inflammatory wounds by inhibiting early-stage inflammation, promoting neovascularization and collagen deposition. This work provides a feasible strategy to design bioenergy-reinforcing and intelligent dressing for wound repair-monitoring integration.

Genome-wide profiling of long non-coding RNA following ozone exposure: A randomized, controlled exposure trial

BackgroundExposure to ambient ozone has been associated with extrapulmonary health, but the underlying mechanisms remain to be understood. LncRNAs are involved in the regulation of gene expression, but their regulatory mechanisms in ozone-related health effects are scarcely explored. ObjectiveTo investigate genome-wide lncRNA changes after short-term ozone exposure and their regulatory roles in ozone exposure and gene expression. MethodWe conducted a randomized, crossover, controlled exposure trial in 32 healthy college students in Shanghai, China. Each participant received both 200-ppb ozone exposure and filtered air exposure for 2 h in a random order with a 14-day washout period. Blood samples were collected after each exposure and used for lncRNA sequencing. Differentially expressed lncRNAs between the two exposures were identified using orthogonal partial least squares discriminant analysis and linear regression analysis. LncRNAs-targeted mRNAs were mapped and subjected to enrichment analyses. We also constructed lncRNA-miRNA-mRNA networks. ResultsA total of 90 lncRNAs were differentially expressed after exposure to ozone, with 49 up-regulated and 41 down-regulated. Enrichment analyses suggested that these dysregulated lncRNAs were involved in a variety of biological processes, including those related to oxidative stress, inflammation response, and cell proliferation, development, and differentiation. Multiple pathways such as IL-17 signaling, NF-kB signaling, and Rho GTPases signaling were also enriched. Furthermore, the lncRNA-miRNA-mRNA network revealed that specific lncRNAs may regulate the expression of inflammation- and angiogenesis-related genes by interacting with miRNAs, such as NEAT1/hsa-miR-500a-3p/SIGLEC8, NEAT1/hsa-miR-6835–3p/SLC16A14, OIP5-AS1/miR-183–5p/EGR1, and SNHG25/hsa-miR-663a/FOSB axes. ConclusionThis study characterized a thorough profile of human lncRNAs following short-term ozone exposure and suggested the regulatory roles of these lncRNAs in ozone-induced inflammatory responses and angiogenesis, providing novel epigenetic insights into the mechanisms of the health effects of ozone exposure.

Facile synthesis of in situ bismuth-doped calcium phosphate nanocomposite integrated injectable biopolymer hydrogel slurry for bone regeneration

The bionics of natural bone structures plays an essential role in the selection of materials for bone tissue engineering. Although the content of trace metallic elements in bone is low, they have significant effects on the process of bone growth and metabolism. Up to now, the applications of “green” heavy metals in bone regeneration are limited. Herein, in this study, we present a straightforward one-pot strategy for the synthesis of in situ bismuth-doped amorphous calcium phosphate nanocomposites (RBCP), effectively integrating the beneficial properties of each component. The characterization of these products can be readily optimized by adjusting reaction parameters. Our in vitro studies show that under coordination of each component, the RBCP biomaterial demonstrates distinguished biocompatibility and significantly accelerates vascular pattern formation within just 4 h by stimulating the expression of angiogenesis-related genes in human umbilical vein endothelial cells (HUVECs). In vivo experiments indicate that the incorporation of bismuth effectively enhances bone regeneration and osseointegration in a rat femur defect model. In conclusion, the as-prepared RBCP biomaterials hold promising prospects for treating segmental bone defects, owing to the facile, cost-effective, and eco-friendly preparation process, along with their remarkable capabilities.

Bioinformatics Identification and Validation of Angiogenesis-Related Genes in Myocardial Ischemic Reperfusion Injury.

Angiogenesis plays a critical protective role in myocardial ischemia-reperfusion injury (MIRI); however, therapeutic targeting of associated genes remains constrained. To bridge this gap, we conducted bioinformatics analysis to identify pivotal angiogenesis-related genes in MIRI, potentially applicable for preventive and therapeutic interventions. We collected two mouse heart I/R expression datasets (GSE61592 and GSE83472) from Gene Expression Omnibus, utilizing the Limma package to identify differentially expressed genes (DEGs). Angiogenesis-related genes (ARGs) were extracted from GeneCards, and their overlap with DEGs produced differentially expressed ARGs (ARDEGs). Further analyses included Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and disease ontology to explore biological functions. Weighted gene correlation network analysis (WGCNA) was used to investigate molecular modules linked to MIRI. Additionally, a protein-protein interaction (PPI) network was constructed to pinpoint hub genes relevant to MIRI. Receiver operating characteristic curves were used to assess the diagnostic efficacy of these hub genes for MIRI. An ischemia-reperfusion injury model was established using human cardiac microvascular endothelial cells (HCMECs), with the expression of hub genes validated within this experimental framework. We identified 47 ARDEGs, 41 upregulated and 6 downregulated. PPI network analysis revealed suppressor of cytokine signaling 3 (Socs3), C-X-C motif chemokine ligand 1 (Cxcl1), interleukin 1 beta (Il1b), and matrix metallopeptidase 9 (Mmp9) as hub genes. Receiver operating characteristic (ROC) curve analysis demonstrated strong diagnostic potential for Socs3, Cxcl1, Il1b, and Mmp9. In vitro validation corroborated the mRNA and protein expression predictions. Our study highlights the pivotal role of Socs3, Cxcl1, Il1b, and Mmp9 in MIRI development, their significance in immune cell infiltration, and their diagnostic accuracy. These findings offer valuable insights for MIRI diagnosis and treatment, presenting potential molecular targets for future research.

Development and experimental verification of novel angiogenesis related prognostic model and immune infiltration characterization in osteosarcoma

BackgroundAs the most common primary bone cancer, osteosarcoma (OS) still lacks satisfactory therapeutic outcomes. Therefore, it is crucial to further evaluate OS at different risk levels and identify new intervention targets. Many evidences suggest the important role of angiogenesis in OS, but further exploration is needed.MethodsWe utilized public databases TARGET and GEO and employed bioinformatics algorithms such as LASSO, univariate and multivariate Cox regression analyses, and unsupervised consensus clustering to explore the role of angiogenesis-related genes (AGRGs) in OS. By calculating AGRG scores, we further analyzed OS molecular subtypes based on AGRGs. The correlation between AGRG scores and immune infiltration was subsequently examined. In vitro experiments, including WB, PCR, siRNA, migration, and invasion assays, were used to determine the value of the selected targets for OS.ResultsUltimately, we established an OS prognosis model based on five AGRGs (COL5A2, CXCL6, FSTL1, NRP1, and TNFRSF21) that can independently validate prognosis levels. In vitro experiments confirmed the aberrant expression of CXCL6 in OS and its potential role in migration and invasion.ConclusionOur study reveals the impact of angiogenesis on OS from a novel perspective and provides potential intervention targets.

Gene expression networks in endothelial cells from failing human hearts.

Chronic heart failure is associated with adverse remodeling of the heart that is typically characterized by cardiomyocyte hypertrophy. This requires the formation of new capillaries to maintain oxygen supply. Insufficient angiogenesis promotes the transition from compensated hypertrophy into heart failure. The aim of this study was to identify angiogenesis-related gene networks and corresponding regulatory hubs in endothelial cells from failing human hearts. We isolated left ventricular endothelial cells from patients with advanced heart failure undergoing left ventricular assist device surgery (n = 15) and healthy organ donors (n = 2) and performed RNA sequencing. Subgroup analysis revealed no impact of comorbidities on gene expression. In a weighted gene coexpression network analysis, we found 26 gene clusters, of which 9 clusters showed a significant positive or negative correlation with the presence of heart failure. We identified the transcription factors CASZ1 (castor zinc finger 1), ZNF523 (zinc finger protein 523), and NFE2L1 (nuclear factor erythroid 2-related factor 1) as hub genes of a cluster related to angiogenesis. Knockdown of CASZ1, ZNF523, or NFE2L1 in human umbilical vein endothelial cells led to a downregulation of genes from the respective cluster, including CD34 and platelet-derived growth factor-β, confirming their regulatory function. In conclusion, we assessed gene networks in endothelial cells and identified transcription factors CASZ1, ZNF532, and NFE2L1 as potential regulators of angiogenesis in failing human hearts. Our study provides insights into the transcriptional regulation of angiogenesis beyond the classical vascular endothelial growth factor signaling pathway.NEW & NOTEWORTHY Gene coexpression network analysis defined 26 gene clusters expressed in endothelial cells from failing human hearts. Transcription factors CASZ1, ZNF523, and NFE2L1 were identified as hub genes of a cluster related to angiogenesis. Knockdown of CASZ1, ZNF523, or NFE2L1 in human umbilical vein endothelial cells led to a downregulation of genes from the respective cluster, confirming their regulatory function. This provides insights into the transcriptional regulation of angiogenesis in heart failure beyond classical signaling pathways.

Artificial Intelligence in Advance Angiogenesis and Inflammation Research: A Breakthrough in Disease Prediction and Therapy

Background: Angiogenesis and inflammation are fundamental biological processes, crucial to human health. Dysregulation of these processes is implicated in diseases such as cancer, cardiovascular disorders, and autoimmune diseases. Despite advances in research, the complexity of these interactions has been challenging to understand. Recent developments in artificial intelligence (AI) offer a promising approach for overcoming these challenges, especially in big data analysis. This study explores AI applications in quantifying angiogenesis and inflammatory markers and predicting disease progression. Methods: AI algorithms, including machine learning (ML) and deep learning (DL), were employed to analyze high-throughput biological data. The study applied Lasso regression for biomarker discovery, Long Short-Term Memory (LSTM) networks for predicting disease progression, and Gaussian Mixture Models (GMM) for patient subgroup identification. Image analysis using DeepLabv3+ was conducted to assess angiogenesis and inflammatory markers in histological images. Model performance was evaluated using R-squared (R²), Mean Squared Error (MSE), and Root Mean Squared Error (RMSE) metrics. Results: The AI framework demonstrated high accuracy in predicting disease progression, with notable R² values and low MSE and RMSE values. The application of AI led to the successful identification of angiogenesis-related genes and biomarkers in various diseases, including diabetic foot ulcers and chronic obstructive pulmonary disease. AI-based image analysis also provided precise quantification of angiogenesis and inflammation, enhancing the understanding of disease mechanisms. Conclusion: AI-driven approaches significantly improve the analysis of complex biological processes, offering new insights into angiogenesis and inflammation. The high predictive accuracy of the AI models underscores their potential in clinical applications, such as personalized treatment strategies and disease monitoring. As AI continues to evolve, its integration into biomedical research will likely yield further advancements in disease prediction, diagnosis, and treatment.

Serum proteomic profiling of physical activity reveals CD300LG as a novel exerkine with a potential causal link to glucose homeostasis

Background:Physical activity has been associated with preventing the development of type 2 diabetes and atherosclerotic cardiovascular disease. However, our understanding of the precise molecular mechanisms underlying these effects remains incomplete and good biomarkers to objectively assess physical activity are lacking.Methods:We analyzed 3072 serum proteins in 26 men, normal weight or overweight, undergoing 12 weeks of a combined strength and endurance exercise intervention. We estimated insulin sensitivity with hyperinsulinemic euglycemic clamp, maximum oxygen uptake, muscle strength, and used MRI/MRS to evaluate body composition and organ fat depots. Muscle and subcutaneous adipose tissue biopsies were used for mRNA sequencing. Additional association analyses were performed in samples from up to 47,747 individuals in the UK Biobank, as well as using two-sample Mendelian randomization and mice models.Results:Following 12 weeks of exercise intervention, we observed significant changes in 283 serum proteins. Notably, 66 of these proteins were elevated in overweight men and positively associated with liver fat before the exercise regimen, but were normalized after exercise. Furthermore, for 19.7 and 12.1% of the exercise-responsive proteins, corresponding changes in mRNA expression levels in muscle and fat, respectively, were shown. The protein CD300LG displayed consistent alterations in blood, muscle, and fat. Serum CD300LG exhibited positive associations with insulin sensitivity, and to angiogenesis-related gene expression in both muscle and fat. Furthermore, serum CD300LG was positively associated with physical activity and negatively associated with glucose levels in the UK Biobank. In this sample, the association between serum CD300LG and physical activity was significantly stronger in men than in women. Mendelian randomization analysis suggested potential causal relationships between levels of serum CD300LG and fasting glucose, 2 hr glucose after an oral glucose tolerance test, and HbA1c. Additionally, Cd300lg responded to exercise in a mouse model, and we observed signs of impaired glucose tolerance in male, but not female, Cd300lg knockout mice.Conclusions:Our study identified several novel proteins in serum whose levels change in response to prolonged exercise and were significantly associated with body composition, liver fat, and glucose homeostasis. Serum CD300LG increased with physical activity and is a potential causal link to improved glucose levels. CD300LG may be a promising exercise biomarker and a therapeutic target in type 2 diabetes.Funding:South-Eastern Norway Regional Health Authority, Simon Fougners Fund, Diabetesforbundet, Johan Selmer Kvanes’ legat til forskning og bekjempelse av sukkersyke. The UK Biobank resource reference 53641. Australian National Health and Medical Research Council Investigator Grant (APP2017942). Australian Research Council Discovery Early Career Award (DE220101226). Research Council of Norway (Project grant: 325640 and Mobility grant: 287198). The Medical Student Research Program at the University of Oslo. Novo Nordisk Fonden Excellence Emerging Grant in Endocrinology and Metabolism 2023 (NNF23OC0082123).Clinical trial number:clinicaltrials.gov: NCT01803568.

Implementing microfluidic flow device model in utilizing dural substitutes as pulp capping materials for vital pulp therapy

Vital pulp therapy (VPT) has gained prominence with the increasing trends towards conservative dental treatment with specific indications for preserving tooth vitality by selectively removing the inflamed tissue instead of the entire dental pulp. Although VPT has shown high success rates in long-term follow-up, adverse effects have been reported due to the calcification of tooth canals by mineral trioxide aggregates, which are commonly used in VPT. Canal calcification poses challenges for accessing instruments during retreatment procedures. To address this issue, this study evaluated the mechanical properties of dural substitute intended to alleviate intra-pulp pressure caused by inflammation, along with assessing the biological responses of human dental pulp stem cells (hDPSC) and human umbilical vein endothelial cells (HUVEC), both of which play crucial roles in dental pulp. The study examined the application of dural substitutes as pulp capping materials, replacing mineral trioxide aggregate (MTA). This assessment was conducted using a microfluidic flow device model that replicated the blood flow environment within the dental pulp. Computational fluid dynamics simulations were employed to ensure that the fluid flow velocity within the microfluidic flow device matched the actual blood flow velocity within the dental pulp. Furthermore, the dural substitutes (Biodesign; BD and Neuro-Patch; NP) exhibited resistance to penetration by 2-hydroxypropyl methacrylate (HEMA) released from the upper restorative materials and bonding agents. Finally, while MTA increased the expression of angiogenesis-related and hard tissue-related genes in HUVEC and hDPSCS, respectively, BD and NP did not alter gene expression and preserved the original characteristics of both cell types. Hence, dural substitutes have emerged as promising alternatives for VPT owing to their resistance to HEMA penetration and the maintenance of stemness. Moreover, the microfluidic flow device model closely replicated the cellular responses observed in live pulp chambers, thereby indicating its potential use as an in vivo testing platform.

Identification of angiogenesis-related subtypes and risk models for predicting the prognosis of gastric cancer patients

Gastric cancer (GC) is a leading cause of cancer-related mortality and is characterized by significant heterogeneity, highlighting the need for further studies aimed at personalized treatment strategies. Tumor angiogenesis is critical for tumor development and metastasis, yet its role in molecular subtyping and prognosis prediction remains underexplored. This study aims to identify angiogenesis-related subtypes and develop a prognostic model for GC patients. Using data from The Cancer Genome Atlas (TCGA), we performed consensus cluster analysis on differentially expressed angiogenesis-related genes (ARGs), identifying two patient subtypes with distinct survival outcomes. Differentially expressed genes between the subtypes were analyzed via Cox and LASSO regression, leading to the establishment of a subtype-based prognostic model using a machine learning algorithm. Patients were classified into high- and low-risk groups based on the risk score. Validation was performed using independent datasets (ICGC and GSE15459). We utilized a deconvolution algorithm to investigate the tumor immune microenvironment in different risk groups and conducted analyses on genetic profiling, sensitivity and combination of anti-tumor drug. Our study identified ten prognostic signature genes, enabling the calculation of a risk score to predict prognosis and overall survival. This provides critical data for stratified diagnosis and treatment upon patient admission, monitoring disease progression throughout the entire course, evaluating immunotherapy efficacy, and selecting personalized medications for GC patients.

Epigenetics and Control of Tumor Angiogenesis in Melanoma: An Update with Therapeutic Implications.

Angiogenesis, the formation of new blood vessels from pre-existing ones, is a crucial process in the progression and metastasis of melanoma. Recent research has highlighted the significant role of epigenetic modifications in regulating angiogenesis. This review comprehensively examines the current understanding of how epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, influence angiogenic pathways in melanoma. DNA methylation, a key epigenetic modification, can silence angiogenesis inhibitors such as thrombospondin-1 and TIMP3 while promoting pro-angiogenic factors like vascular endothelial growth factor (VEGF). Histone modifications, including methylation and acetylation, also play a pivotal role in regulating the expression of angiogenesis-related genes. For instance, the acetylation of histones H3 and H4 is associated with the upregulation of pro-angiogenic genes, whereas histone methylation patterns can either enhance or repress angiogenic signals, depending on the specific histone mark and context. Non-coding RNAs, particularly microRNAs (miRNAs) further modulate angiogenesis. miRNAs, such as miR-210, have been identified as key regulators, with miR-9 promoting angiogenesis by targeting E-cadherin and enhancing the expression of VEGF. This review also discusses the therapeutic potential of targeting epigenetic modifications to inhibit angiogenesis in melanoma. Epigenetic drugs, such as DNA methyltransferase inhibitors (e.g., 5-azacytidine) and histone deacetylase inhibitors (e.g., Vorinostat), have shown promise in preclinical models by reactivating angiogenesis inhibitors and downregulating pro-angiogenic factors. Moreover, the modulation of miRNAs and lncRNAs presents a novel approach for anti-angiogenic therapy.

Nuclear receptor 4A1 ameliorates renal fibrosis by inhibiting vascular endothelial growth factor A induced angiogenesis in UUO rats

IntroductionAngiogenesis is closely related to renal fibrosis; however, its basic mechanism remains unclear. In our study, we found that nuclear receptor 4A1 (NR4A1) inhibits vascular endothelial growth factor A (VEGFA)-induced angiogenesis, ameliorating renal fibrosis. MethodsWe prepared a renal fibrosis animal model with unilateral ureteral obstruction (UUO) and NR4A1 knockdown UUO mice model, Using Human umbilical vein endothelial cells (HUVECs) to conduct all in vitro experiments. We then detected and analyzed the expression levels of NR4A1 and other genes related to angiogenesis and fibrosis. ResultsThe angiogenesis related genes, such as VEGFA, vascular endothelial growth factor receptor-2 (VEGFR-2), endoglin (CD105), as well as the expression of fibrosis related genes that included, α-smooth muscle actin (α-SMA), Vimentin, and Collagen I are all significantly increased in the UUO rat model. In addition, the expression of NR4A1 of the kidney tissue of UUO rats was significantly reduced. Therefore, according to the above results, we speculated that angiogenesis may exacerbate renal fibrosis and NR4A1 may repress renal fibrosis by inhibiting angiogenesis. To further verify the above results, we used VEGFA to stimulate HUVECs with (or without) overexpression or knockdown of NR4A1. The results showed that with prolonged stimulation using VEGFA, the expression of NR4A1 decreases. Overexpression of NR4A1 significantly inhibits the expression of related indicators of angiogenesis and renal fibrosis. Furthermore, knockdown of NR4A1 induces endothelial cell proliferation and migration; therefore, exacerbating angiogenesis and fibrosis. Finally, the results of NR4A1 knockdown UUO mice showed that knockdown of NR4A1 can aggravating kidney damage and induce the expression of angiogenesis and renal fibrosis related indicators, while UUO can significantly induce kidney damage, angiogenesis and renal fibrosis. When knockdown of NR4A1, renal kidney damage, angiogenesis and fibrosis becomes more severe than UUO. Thus, all of these results indicate that NR4A1 can ameliorate renal fibrosis by inhibiting angiogenesis. ConclusionsNR4A1 can inhibit angiogenesis to ameliorate renal fibrosis.

Maleimide conjugated PEGylated liposomal antibiotic to combat multi-drug resistant Escherichia coli and Klebsiella pneumoniae with enhanced wound healing potential

Antibiotic resistance is a significant threat, leaving us vulnerable to bacterial infections. Novel strategies are needed to combat bacterial resistance beyond discovering new antibiotics. This research focuses on using maleimide conjugated PEGylated liposomes (Mal-PL-Ab) to individually encapsulate a variety of antibiotics (ceftriaxone, cephalexin, doxycycline, piperacillin, ampicillin, and ceftazidime) and enhance their delivery against multi-drug resistant (MDR) bacteria like Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae). Mal-PL-Ab, with an average size of 84.2 nm ± 4.32 nm, successfully encapsulated these antibiotics with an encapsulation efficiency of 37.73 ± 3.19%. Compared to non-PEGylated liposomes (L-Ab), Mal-PL-Ab exhibited reduced toxicity in human dermal cells, emphasizing the importance of PEGylation in minimizing adverse effects. Mal-PL-Ab significantly decreased the minimum inhibitory concentration (MIC) values against both E. coli and K. pneumoniae by 9.33-fold and eightfold reduction (compared to non-PEGylated liposomes with 2.33-fold and 2.33fold reduction), respectively, indicating enhanced efficacy against MDR strains. Furthermore, in vitro scratch assay and gene expression analysis of human dermal fibroblast revealed that Mal-PL-Ab promoted cell proliferation, migration, and wound healing through upregulation of cell cycle, DNA repair, and angiogenesis-related genes. Harnessing the power of encapsulation, Mal-PL-Ab presents a novel avenue for enhanced antibiotic delivery and wound healing, potentially transcending the limitations of traditional options.

MAML3-fusions modulate vascular and immune tumour microenvironment and confer high metastatic risk in pheochromocytoma and paraganglioma

Pheochromocytomas and paragangliomas are rare neuroendocrine tumours. Around 20-25% of patients develop metastases, for which there is an urgent need of prognostic markers and therapeutic stratification strategies. The presence of a MAML3-fusion is associated with increased metastatic risk, but neither the processes underlying disease progression, nor targetable vulnerabilities have been addressed. We have compiled a cohort of 850 patients, which has shown a 3.65% fusion prevalence and represents the largest MAML3-positive series reported to date. While MAML3-fusions mainly cause single pheochromocytomas, we also observed somatic post-zygotic events, resulting in multiple tumours in the same patient. MAML3-tumours show increased expression of neuroendocrine-to-mesenchymal transition markers, MYC-targets, and angiogenesis-related genes, leading to a distinct tumour microenvironment with unique vascular and immune profiles. Importantly, our findings have identified MAML3-tumours specific vulnerabilities beyond Wnt-pathway dysregulation, such as a rich vascular network, and overexpression of PD-L1 and CD40, suggesting potential therapeutic targets.

HIF-1α–dependent regulation of angiogenic factor expression in Müller cells by mechanical stimulation

Mechanical stress regulates various biological processes in cells, tissues, and organs as well as contributes to the pathogenesis of various diseases. The retina is subjected to mechanical stress imposed by intraocular pressure as well as by retinal hemorrhage and edema. Responses to mechanical stress have been studied in retinal pigment epithelial cells and Müller cells of the retina, with the former cells having been found to undergo a stress-induced increase in the expression of vascular endothelial growth factor (VEGF), which plays a key role in physiological and pathological angiogenesis in the retina. We here examined the effects of stretch stimulation on the expression of angiogenic factors in cultured human Müller cells. Reverse transcription and quantitative PCR analysis revealed that expression of the VEGF-A gene was increased by such stimulation in Müller cells, whereas that of the angiopoietin 1 gene was decreased. An enzyme-linked immunosorbent assay showed that stretch stimulation also increased VEGF secretion from these cells. Expression of the transcription factor HIF-1α (hypoxia-inducible factor–1α) was increased at both mRNA and protein levels by stretch stimulation, and the HIF-1α inhibitor CAY10585 prevented the effects of mechanical stress on VEGF-A gene expression and VEGF secretion. Furthermore, RNA-sequencing analysis showed that the expression of angiogenesis-related pathway genes was upregulated by stretch stimulation. Our results thus suggest that mechanical stress induces VEGF production in Müller cells in a manner dependent on HIF-1α, and that HIF-1α is therefore a potential therapeutic target for conditions such as diabetic retinopathy, age-related macular degeneration, and retinal vein occlusion.

Identifying and validating angiogenesis-related genes remodeling tumor microenvironment and suppressing immunotherapy response in gastric cancer

Angiogenesis significantly correlates with tumor microenvironment remodeling and immunotherapy response. Our study aimed to construct a prognostic angiogenesis-related model for gastric cancer. Using public database, a angiogenetic related five-gene (FGF1, GRB14, PAK3, PDGFRA, and PRKD1) model was identified. The top 25 % of patients were defined as high-risk, and the remaining as low-risk. The area under the curve for 1-, 3-, and 5-year overall survival (OS) were 0.646, 0.711, and 0.793, respectively. Survival analysis showed a better 10-year OS in low-risk patients in the construction (HR = 0.57, p = 0.002) and validation cohorts. GO and GSEA revealed that DEGs were enriched in extracellular matrix receptor interactions, dendritic cell antigen processing/presentation regulation, and angiogenesis pathways. CIBERSORT analysis revealed abundant naïve B cells, resting mast cells, resting CD4+ memory T cells, M2 macrophages, and monocytes in high-risk subgroups. The TIMER database showed strong positive correlations between PAK3, FGF1, PRKD1, and PDGFRA expression levels and the infiltration of CD4+ T cells and macrophages. The IOBR analysis revealed an immunosuppressive environment in the high-risk subgroup. Low-risk patients show a higher response rate to anti-PD1 treatment. TMA showed that FGF1 overexpression was associated with poor prognosis and CD4+ T cells and macrophage infiltration. In vivo study based on the 615 mice indicated that inhibiting FGF1 function could suppress tumor growth and enhance anti-PD1 therapeutic efficacy. In summary, we established a five-angiogenesis-related gene model to predict survival outcomes and immunotherapy responses in patients with gastric cancer and identified FGF1 as a prognostic gene and potential target for improving immune treatment.

The molecular mechanism responsible for HbSC retinopathy may depend on the action of the angiogenesis-related genes ROBO1 and SLC38A5.

HbSC disease, a less severe form of sickle cell disease, affects the retina more frequently and patients have higher rates of proliferative retinopathy that can progress to vision loss. This study aimed to identify differences in the expression of endothelial cell-derived molecules associated with the pathophysiology of proliferative sickle cell retinopathy (PSCR). RNAseq was used to compare the gene expression profile of circulating endothelial colony-forming cells from patients with SC hemoglobinopathy and proliferative retinopathy (n = 5), versus SC patients without retinopathy (n = 3). Real-time polymerase chain reaction (qRT-PCR) was used to validate the RNAseq results. A total of 134 differentially expressed genes (DEGs) were found. DEGs were mainly associated with vasodilatation, type I interferon signaling, innate immunity and angiogenesis. Among the DEGs identified, we highlight the most up-regulated genes ROBO1 (log2FoldChange = 4.32, FDR = 1.35E-11) and SLC38A5 (log2FoldChange = 3.36 FDR = 1.59E-07). ROBO1, an axon-guided receptor, promotes endothelial cell migration and contributes to the development of retinal angiogenesis and pathological ocular neovascularization. Endothelial SLC38A5, an amino acid (AA) transporter, regulates developmental and pathological retinal angiogenesis by controlling the uptake of AA nutrient, which may serve as metabolic fuel for the proliferation of endothelial cells (ECs) and consequent promotion of angiogenesis. Our data provide an important step towards elucidating the molecular pathophysiology of PSCR that may explain the differences in ocular manifestations between individuals with hemoglobinopathies and afford insights for new alternative strategies to inhibit pathological angiogenesis.

Angiogenesis related genes based prognostic model of glioma patients developed by multi-omics approach

IntroductionGlioma, particularly glioblastoma (GBM), is a highly malignant brain tumor with poor prognosis despite current therapeutic approaches. The tumor microenvironment (TME), plays a crucial role in glioma progression by promoting invasion and drug resistance. Angiogenesis, the formation of new blood vessels, is a tightly regulated process involving endothelial cell activation, proliferation, and migration. In cancer, angiogenesis becomes dysregulated, leading to excessive blood vessel formation.MethodsWe enrolled bulk data of TCGA-LGG/GBM, CGGA-693, and CGGA-325 cohorts, scRNA data of GSE162631, GSE84465, and GSE138794 cohorts. Identification of malignant cells was conducted by “copycat” R package. The “AUCell” R package scored the activity of target gene set of each single cell. Consensus clustering was applied using the “ConsensusClusterPlus” R package, while tumor-infiltrating immune cells were determined using “IOBR” R package. To construct a prognostic model, we used LASSO and multiCOX algorithms based on the expression levels of the 15 hub genes, the efficacy of which was verified by KM and ROC analysis.ResultsWe identified 4 different malignant cell subclusters in glioma and disclosed their distinct gene expression patterns and interactions within TME. We identified differentially expressed immune-related genes (DE-ARGs) in glioma and found 15 genes that were specifically expressed in the malignant glioma cell populations. Glioma cells with higher expression of these DE-ARGs were associated with gliogenesis, glial cell development, and vasculature development. We found that tumor-infiltrating monocytes were the main interacting cell type within glioma TME. Using the expression patterns of the 15 screened DE-ARGs, we categorized glioma samples into 2 molecular clusters with distinct immune features, suggesting a possible relationship between angiogenesis and immune activation and recruitment. We constructed a prognostic model based on the expression levels of the 15 DE-ARGs and evaluated its predictive ability for glioma patient outcomes, which displayed exceedingly high efficacy.ConclusionWe characterized different malignant cell subclusters in glioma and investigate their gene expression patterns and interactions within TME. We constructed a prognostic model based on the expression levels of the 15 DE-ARGs and evaluated its predictive ability for glioma patient outcomes, which displayed exceedingly high efficacy.

Purification and characterization of the produced hyaluronidase by Brucella Intermedia MEFS for antioxidant and anticancer applications

Hyaluronidase (hyase) is an endoglycosidase enzyme that degrades hyaluronic acid (HA) and is mostly known to be found in the extracellular matrix of connective tissues. In the current study, eleven bacteria isolates and one actinomycete were isolated from a roaster comb and screened for hyase production. Seven isolates were positive for hyase, and the most potent isolate was selected based on the diameter of the transparent zone. Based on the morphological, physiological, and 16 S rRNA characteristics, the most potent isolate was identified as Brucella intermedia MEFS with accession number OR794010. The environmental conditions supporting the maximum production of hyase were optimized to be incubation at 30 ºC for 48 h and pH 7, which caused a 1.17-fold increase in hyase production with an activity of 84 U/mL. Hyase was purified using a standard protocol, including precipitation with ammonium sulphate, DEAE as ion exchange chromatography, and size exclusion chromatography using Sephacryle S100, with a specific activity of 9.3-fold compared with the crude enzyme. The results revealed that the molecular weight of hyase was 65 KDa, and the optimum conditions for hyase activity were at pH 7.0 and 37 °C for 30 min. The purified hyase showed potent anticancer activities against colon, lung, skin, and breast cancer cell lines with low toxicity against normal somatic cells. The cell viability of hyase-treated cancer cells was found to be in a dose dependent manner. Hyase also controlled the growth factor-induced cell cycle progression of breast cancer cells and caused relative changes in angiogenesis-related genes as well as suppressed many pro-inflammatory proteins in MDA cells compared with 5-fluorouracil, indicating the significant role of hyase as an anticancer agent. In addition, hyase recorded the highest DPPH scavenging activity of 65.49% and total antioxidant activity of 71.84% at a concentration of 200 µg/mL.