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1.
Sci Rep ; 14(1): 10539, 2024 05 08.
Article in English | MEDLINE | ID: mdl-38719941

ABSTRACT

Abnormal angiogenesis leads to tumor progression and metastasis in colorectal cancer (CRC). This study aimed to elucidate the association between angiogenesis-related genes, including VEGF-A, ANGPT-1, and ANGPT-2 with both metastatic and microsatellite alterations at selected tetranucleotide repeats (EMAST) subtypes of CRC. We conducted a thorough assessment of the ANGPT-1, ANGPT-2, and VEGF-A gene expression utilizing publicly available RNA sequencing and microarray datasets. Then, the experimental validation was performed in 122 CRC patients, considering their disease metastasis and EMAST+/- profile by using reverse transcription polymerase chain reaction (RT-PCR). Subsequently, a competing endogenous RNA (ceRNA) network associated with these angiogenesis-related genes was constructed and analyzed. The expression level of VEGF-A and ANGPT-2 genes were significantly higher in tumor tissues as compared with normal adjacent tissues (P-value < 0.001). Nevertheless, ANGPT-1 had a significantly lower expression in tumor samples than in normal colon tissue (P-value < 0.01). We identified a significantly increased VEGF-A (P-value = 0.002) and decreased ANGPT-1 (P-value = 0.04) expression in EMAST+ colorectal tumors. Regarding metastasis, a significantly increased VEGF-A and ANGPT-2 expression (P-value = 0.001) and decreased ANGPT-1 expression (P-value < 0.05) were established in metastatic CRC patients. Remarkably, co-expression analysis also showed a strong correlation between ANGPT-2 and VEGF-A gene expressions. The ceRNA network was constructed by ANGPT-1, ANGPT-2, VEGF-A, and experimentally validated miRNAs (hsa-miR-190a-3p, hsa-miR-374c-5p, hsa-miR-452-5p, and hsa-miR-889-3p), lncRNAs (AFAP1-AS1, KCNQ1OT1 and MALAT1), and TFs (Sp1, E2F1, and STAT3). Network analysis revealed that colorectal cancer is amongst the 82 significant pathways. We demonstrated a significant differential expression of VEGF-A and ANGPT-1 in colorectal cancer patients exhibiting the EMAST+ phenotype. This finding provides novel insights into the molecular pathogenesis of colorectal cancer, specifically in EMAST subtypes. Yet, the generalization of in silico findings to EMAST+ colorectal cancer warrants future experimental investigations. In the end, this study proposes that the EMAST biomarker could serve as an additional perspective on CMS4 biology which is well-defined by activated angiogenesis and worse overall survival.


Subject(s)
Angiopoietin-1 , Angiopoietin-2 , Colorectal Neoplasms , Gene Expression Regulation, Neoplastic , Neovascularization, Pathologic , Vascular Endothelial Growth Factor A , Humans , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Colorectal Neoplasms/metabolism , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/pathology , Angiopoietin-1/genetics , Angiopoietin-1/metabolism , Angiopoietin-2/genetics , Angiopoietin-2/metabolism , Male , Female , Middle Aged , Neoplasm Metastasis , Aged , Microsatellite Repeats/genetics , Gene Expression Profiling , Gene Regulatory Networks , Angiogenesis
2.
Heliyon ; 10(10): e31194, 2024 May 30.
Article in English | MEDLINE | ID: mdl-38803922

ABSTRACT

Background: Esophageal adenocarcinoma (EAC) is a common cancer with a poor prognosis in advanced stages. Therefore, early EAC diagnosis and treatment have gained attention in recent decades. It has been found that various pathological changes, particularly Barrett's Esophagus (BE), can occur in the esophageal tissue before the development of EAC. In this study, we aimed to identify the molecular contributor in BE to EAC progression by detecting the essential regulatory genes that are differentially expressed in both BE and EAC. Materials and methods: We conducted a comprehensive bioinformatics analysis to detect BE and EAC-associated genes. The common differentially expressed genes (DEGs) and common single nucleotide polymorphisms (SNPs) were detected using the GEO and DisGeNET databases, respectively. Then, hub genes and the top modules within the protein-protein interaction network were identified. Moreover, the co-expression network of the top module by the HIPPIE database was constructed. Additionally, the gene regulatory network was constructed based on miRNAs and circRNAs. Lastly, we inspected the DGIdb database for possible interacted drugs. Results: Our microarray dataset analysis identified 92 common DEGs between BE and EAC with significant enrichment in skin and epidermis development genes. The study also identified 22 common SNPs between BE and EAC. The top module of PPI network analysis included SCEL, KRT6A, SPRR1A, SPRR1B, SPRR3, PPL, SPRR2B, EVPL, and CSTA. We constructed a ceRNA network involving three specific mRNAs, 23 miRNAs, and 101 selected circRNAs. According to the results from the DGIdb database, TD101 was found to interact with the KRT6A gene. Conclusion: The present study provides novel potential candidate genes that may be involved in the molecular association between Esophageal adenocarcinoma and Barrett's Esophagus, resulting in developing the diagnostic tools and therapeutic targets to prevent progression of BE to EAC.

3.
Biomed Pharmacother ; 172: 116248, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38325262

ABSTRACT

Myocardial infarction (MI) is the leading cause of heart failure (HF), accounting for high mortality and morbidity worldwide. As a consequence of ischemia/reperfusion injury during MI, multiple cellular processes such as oxidative stress-induced damage, cardiomyocyte death, and inflammatory responses occur. In the next stage, the proliferation and activation of cardiac fibroblasts results in myocardial fibrosis and HF progression. Therefore, developing a novel therapeutic strategy is urgently warranted to restrict the progression of pathological cardiac remodeling. Recently, targeting long non-coding RNAs (lncRNAs) provided a novel insight into treating several disorders. In this regard, numerous investigations have indicated that several lncRNAs could participate in the pathogenesis of MI-induced cardiac remodeling, suggesting their potential therapeutic applications. In this review, we summarized lncRNAs displayed in the pathophysiology of cardiac remodeling after MI, emphasizing molecular mechanisms. Also, we highlighted the possible translational role of lncRNAs as therapeutic targets for this condition and discussed the potential role of exosomes in delivering the lncRNAs involved in post-MI cardiac remodeling.


Subject(s)
Heart Failure , Myocardial Infarction , RNA, Long Noncoding , Humans , RNA, Long Noncoding/genetics , Ventricular Remodeling/genetics , Myocardial Infarction/genetics , Heart Failure/genetics , Myocytes, Cardiac
4.
Eur J Med Res ; 29(1): 76, 2024 Jan 24.
Article in English | MEDLINE | ID: mdl-38268045

ABSTRACT

BACKGROUND: Acute kidney injury (AKI) is one of the preventable complications of percutaneous coronary intervention (PCI). This study aimed to develop machine learning (ML) models to predict AKI after PCI in patients with acute coronary syndrome (ACS). METHODS: This study was conducted at Tehran Heart Center from 2015 to 2020. Several variables were used to design five ML models: Naïve Bayes (NB), Logistic Regression (LR), CatBoost (CB), Multi-layer Perception (MLP), and Random Forest (RF). Feature importance was evaluated with the RF model, CB model, and LR coefficients while SHAP beeswarm plots based on the CB model were also used for deriving the importance of variables in the population using pre-procedural variables and all variables. Sensitivity, specificity, and the area under the receiver operating characteristics curve (ROC-AUC) were used as the evaluation measures. RESULTS: A total of 4592 patients were included, and 646 (14.1%) experienced AKI. The train data consisted of 3672 and the test data included 920 cases. The patient population had a mean age of 65.6 ± 11.2 years and 73.1% male predominance. Notably, left ventricular ejection fraction (LVEF) and fasting plasma glucose (FPG) had the highest feature importance when training the RF model on only pre-procedural features. SHAP plots for all features demonstrated LVEF and age as the top features. With pre-procedural variables only, CB had the highest AUC for the prediction of AKI (AUC 0.755, 95% CI 0.713 to 0.797), while RF had the highest sensitivity (75.9%) and MLP had the highest specificity (64.35%). However, when considering pre-procedural, procedural, and post-procedural features, RF outperformed other models (AUC: 0.775). In this analysis, CB achieved the highest sensitivity (82.95%) and NB had the highest specificity (82.93%). CONCLUSION: Our analyses showed that ML models can predict AKI with acceptable performance. This has potential clinical utility for assessing the individualized risk of AKI in ACS patients undergoing PCI. Additionally, the identified features in the models may aid in mitigating these risk factors.


Subject(s)
Acute Coronary Syndrome , Acute Kidney Injury , Percutaneous Coronary Intervention , Humans , Male , Middle Aged , Aged , Female , Acute Coronary Syndrome/surgery , Percutaneous Coronary Intervention/adverse effects , Bayes Theorem , Stroke Volume , Ventricular Function, Left , Iran , Acute Kidney Injury/epidemiology , Acute Kidney Injury/etiology , Machine Learning
5.
Biomater Adv ; 156: 213710, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38035639

ABSTRACT

As the only reliable treatment option for end-stage liver diseases, conventional liver transplantation confronts major supply limitations. Accordingly, the decellularization of discarded livers to produce bioscaffolds that support recellularization with progenitor/stem cells has emerged as a promising translational medicine approach. The success of this approach will substantially be determined by the extent of extracellular matrix (ECM) preservation during the decellularization process. Here, we assumed that the matrix metalloproteinase (MMP) inhibition could reduce the ECM damage during the whole liver decellularization of an animal model using a perfusion-based system. We demonstrated that the application of doxycycline as an MMP inhibitor led to significantly higher preservation of collagen, glycosaminoglycans, and hepatic growth factor (HGF) contents, as well as mechanical and structural features, including tensile strength, fiber integrity, and porosity. Notably, produced bioscaffolds were biocompatible and efficiently supported cell viability and proliferation in vitro. We also indicated that produced bioscaffolds efficiently supported HepG2 cell function upon seeding onto liver ECM discs using albumin and urea assay. Additionally, MMP inhibitor pretreated decellularized livers were more durable in contact with collagenase digestion compared to control bioscaffolds in vitro. Using zymography, we confirmed the underlying mechanism that results in these promising effects is through the inhibition of MMP2 and MMP9. Overall, we demonstrated a novel method based on MMP inhibition to ameliorate the ECM structure and composition preservation during liver decellularization as a critical step in fabricating transplantable bioengineered livers.


Subject(s)
Liver Transplantation , Tissue Scaffolds , Animals , Tissue Scaffolds/chemistry , Matrix Metalloproteinase Inhibitors/pharmacology , Matrix Metalloproteinase Inhibitors/analysis , Matrix Metalloproteinase Inhibitors/metabolism , Extracellular Matrix/chemistry , Liver
6.
EXCLI J ; 22: 645-669, 2023.
Article in English | MEDLINE | ID: mdl-37636026

ABSTRACT

Circular RNAs (CircRNAs) are a class of regulatory RNA transcripts, which are ubiquitously expressed in eukaryotes. CircRNA dysregulation has been shown to disrupt the interaction of the Wnt/ß-catenin pathway, which regulates several biological processes involved in tumorigenesis, thereby contributing to the development and progression of cancer. Interactions of tumor-derived circRNAs with the Wnt/ß-catenin signaling pathway provide both clinical diagnostic biomarkers and promising therapeutic targets. In this review, we outlined current evidence on the roles of circRNAs associated with the Wnt/ß-catenin pathway in regulating lung cancer formation and development. We believe that our findings will assist in the advancement or establishment of circRNA-based lung cancer therapeutic approaches.

7.
Front Cardiovasc Med ; 10: 1174816, 2023.
Article in English | MEDLINE | ID: mdl-37293283

ABSTRACT

Polyphenols are abundant in regular diets and possess antioxidant, anti-inflammatory, anti-cancer, neuroprotective, and cardioprotective effects. Regarding the inadequacy of the current treatments in preventing cardiac remodeling following cardiovascular diseases, attention has been focused on improving cardiac function with potential alternatives such as polyphenols. The following online databases were searched for relevant orginial published from 2000 to 2023: EMBASE, MEDLINE, and Web of Science databases. The search strategy aimed to assess the effects of polyphenols on heart failure and keywords were "heart failure" and "polyphenols" and "cardiac hypertrophy" and "molecular mechanisms". Our results indicated polyphenols are repeatedly indicated to regulate various heart failure-related vital molecules and signaling pathways, such as inactivating fibrotic and hypertrophic factors, preventing mitochondrial dysfunction and free radical production, the underlying causes of apoptosis, and also improving lipid profile and cellular metabolism. In the current study, we aimed to review the most recent literature and investigations on the underlying mechanism of actions of different polyphenols subclasses in cardiac hypertrophy and heart failure to provide deep insight into novel mechanistic treatments and direct future studies in this context. Moreover, due to polyphenols' low bioavailability from conventional oral and intravenous administration routes, in this study, we have also investigated the currently accessible nano-drug delivery methods to optimize the treatment outcomes by providing sufficient drug delivery, targeted therapy, and less off-target effects, as desired by precision medicine standards.

8.
Front Cell Dev Biol ; 10: 1082657, 2022.
Article in English | MEDLINE | ID: mdl-36704201

ABSTRACT

Assisted reproductive techniques as a new regenerative medicine approach have significantly contributed to solving infertility problems that affect approximately 15% of couples worldwide. However, the success rate of an in vitro fertilization (IVF) cycle remains only about 20%-30%, and 75% of these losses are due to implantation failure (the crucial rate-limiting step of gestation). Implantation failure and abnormal placenta formation are mainly caused by defective adhesion, invasion, and angiogenesis. Placental insufficiency endangers both the mother's and the fetus's health. Therefore, we suggested a novel treatment strategy to improve endometrial receptivity and implantation success rate. In this strategy, regulating mir-30d expression as an upstream transcriptomic modifier of the embryo implantation results in modified expression of the involved genes in embryonic adhesion, invasion, and angiogenesis and consequently impedes implantation failure. For this purpose, "scaffold/matrix attachment regions (S/MARs)" are employed as non-viral episomal vectors, transfecting into trophoblasts by exosome-liposome hybrid carriers. These vectors comprise CRISPR/dCas9 with a guide RNA to exclusively induce miR-30d gene expression in hypoxic stress conditions. In order to avoid concerns about the fetus's genetic manipulation, our vector would be transfected specifically into the trophoblast layer of the blastocyst via binding to trophoblast Erb-B4 receptors without entering the inner cell mass. Additionally, S/MAR episomal vectors do not integrate with the original cell DNA. As an on/off regulatory switch, a hypoxia-sensitive promoter (HRE) is localized upstream of dCas9. The miR-30d expression increases before and during the implantation and placental insufficiency conditions and is extinguished after hypoxia elimination. This hypothesis emphasizes that improving the adhesion, invasion, and angiogenesis in the uterine microenvironment during pregnancy will result in increased implantation success and reduced placental insufficiency, as a new insight in translational medicine.

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