Blood miRNAs miR-549a, miR-552, and miR-592 serve as potential disease-specific panels to diagnose colorectal cancer.

Introduction: miRNAs originating from colorectal cancer (CRC) tissue receive significant focus in the early diagnosis of CRC due to their stability in body fluids. However, if these miRNAs originated from alternative organs, their prognostic value will diminish. Thus, in this study, we aim to identify disease-specific miRNAs for colorectal cancer (CRC) by employing bioinformatics and experimental methodologies. Method: To identify CRC-specific miRNAs, we retrieved miRNA profiles of CRC and normal tissues from the Cancer Genome Atlas (TCGA) database. Subsequently, computational strategies were utilized to select potential candidate miRNAs. Following this, the expression levels of the potent miRNAs were assessed through RT-qPCR in both CRC tissue and serum samples from patients (N = 46), as well as healthy individuals (N = 46). Additionally, the associations between clinicopathological characteristics, survival outcomes, and diagnostic accuracy were evaluated. Results: A total of 8893 RNA-seq expression data were acquired from TCGA, comprising 8250 data from 19 distinct cancer types and 643 corresponding healthy samples. Based on the computational methodology, miR-549a, miR-552, and miR-592 were identified as the principal expressed miRNAs in colorectal cancer (CRC). Within these miRNAs, miR-552 displayed a substantial association with tumors at the N and T stages. miR-549a and miR-592 were observed to be linked exclusively to the invasion of tumor depth and tumor stage (TNM), respectively. The receiver operating characteristic (ROC) analysis conducted on the miRNA expression in serum samples revealed that all miRNAs exhibited an area under the ROC curve (AUC) of up to 0.86, thereby indicating their high diagnostic accuracy. Conclusion: Considering the strong associations of these three identified miRNAs with CRC, they can collectively serve as a panel for specific discrimination of CRC from other types of cancer within the body. Although this study focused solely on CRC, this approach can potentially be applied to other cancer types as well.

Vanillin serves as a potential substitute for chemical chelator desferal in iron-overloaded mice.

PURPOSE: Iron toxicity occurs under iron-overloaded settings, such as a high iron diet and blood transfusion, and damages important organs. Vanillin has been proven to have potential iron chelation capability. Given the negative effects of commonly used iron chelators like deferoxamine (DFO), we sought to examine the iron chelation potency of vanillin and evaluate its potential effect in the treatment of iron overload-related disorders. METHODS: 42 male NMRI mice were prepared for this purpose, and except for the negative control group, iron overload conditions were generated in them by injecting iron. Then normal saline (as a control), vanillin, and DFO (n = 7) were subsequently given to iron-overloaded mice. In the following, the activity of antioxidant enzymes catalase and superoxide dismutase were measured in the blood serum, brain, kidney, spleen, lung, and liver tissues of mice. Furthermore, the level of lipid peroxidation was determined by measuring the amount of malondialdehyde. Also, Perl's and H&E staining were used to examine the physiopathology changes of tissues. FINDINGS: Vanillin, a natural antioxidant compound, outperformed deferoxamine, a chemical iron chelator. Along with a decrease in iron content, the activity of catalase and superoxide dismutase enhanced in the iron-overloaded groups that were treated with vanillin. The level of lipid peroxidation was also declined in the iron-overloaded mice receiving vanillin. CONCLUSION: Vanillin can be used as a suitable substitute for chemical chelators with fewer side effects and equivalent efficiency. We encourage the use of this compound as a natural iron chelator following performing additional safety and efficacy studies.

Positive effect of miR-2392 on fibroblast to cardiomyocyte-like cell fate transition: An in silico and in vitro study.

INTRODUCTION: Somatic cell fate transition is now gained great importance in tissue regeneration. Currently, research is focused on heart tissue regeneration by reprogramming diverse cells into cardiomyocyte-like cells. Here, we examined the possible effect of miRNAs on the transdifferentiation of fibroblasts into cardiomyocyte-like cells. METHODS: First heart-specific miRNAs were identified by comparing the gene expression profiles of heart tissue to other body tissues using bioinformatic techniques. After identifying heart-specific miRNAs, their cellular and molecular functions were studied using the miRWalk and miRBase databases. Then the candidate miRNA was cloned into a lentiviral vector. Following, human dermal fibroblasts were cultured and treated with compounds forskolin, valproic acid, and CHIR99021. After 24 h, the lentivector harboring miRNA gene was transfected into the cells to initiate the transdifferentiation process. Finally, after a two-week treatment period, the efficiency of transdifferentiation was examined by inspecting the appearance of the cells and measuring the expression levels of cardiac genes and proteins using RT-qPCR and immunocytochemistry techniques. RESULTS: Nine miRNAs were identified with higher expression in the heart. The miR-2392 was nominated as the candidate miRNA due to its function and specific expression in the heart. This miRNA has a direct connection with genes involved in cell growth and differentiation; e.g., MAPK and Wnt signaling pathways. According to in vitro results cardiac genes and proteins demonstrated an increase in expression in the fibroblasts that simultaneously received the three chemicals and miR-2392. CONCLUSION: Considering the ability of miR-2392 to induce the expression of cardiac genes and proteins in fibroblast cells, it can induce fibroblasts to differentiate into cardiomyocyte-like cells. Therefore, miR-2392 could be further optimized for cardiomyocyte regeneration, tissue repair, and drug design studies.

The natural iron chelators' ferulic acid and caffeic acid rescue mice's brains from side effects of iron overload.

Studies have shown that iron accumulation in the brain leads to neurogenic disorders. Novel iron chelating agents such as natural remedies are useful to decrease the side effects of iron in the brain. In addition, flavones and polyphenols are capable of chelating metals. In the current study, we evaluated the iron chelating capacity of ferulic acid and caffeic acid in the brain tissues of iron-overloaded mice. The mice received iron dextran intraperitoneally four times a week for 6 weeks. Next, blood samples were taken from the mice. In addition, brain tissues were excised for tissue staining as well as total iron and catalase (CAT) activity assessment. Ferulic acid and caffeic acid significantly decreased iron content in both brain and serum samples. Ferulic acid decreased iron by 50 and 51% more than the iron dextran-treated mice and by 43 and 2% more than desferal (DFO)-treated mice in serum and brain, respectively. In addition, caffeic acid reduced iron 57% more than the iron-treated group and 49 and 2% more than the desferal-treated group in the serum and brain, respectively. The catalase activity decreased with the increase in iron. By administering natural compounds, the catalase activity was increased equal to that of the control group. Thus, ferulic acid and caffeic acid might be possible natural iron chelators for brain iron overload therapy.

Reduction of iron toxicity in the heart of iron-overloaded mice with natural compounds.

BACKGROUND: Iron-overload is one of the risk factors in susceptible individuals. Iron-overload causes complications such as diastolic dysfunction, arrhythmias, ventricular dilation, and systolic dysfunction in the heart. Therefore, particular care is needed for those who need blood transfusions or patients with underlying heart diseases. PURPOSE: In this study, we examined the ability of five compounds, hesperidin, coumarin, caffeic acid, ferulic acid, and vanillin, to reduce the effects of iron-overdose in the heart of iron-overloaded mice. METHODS: For this purpose, 84 mice were prepared and except for the control group, iron-overload conditions were created in them by injecting iron. The hearts of mice were then harvested and the activities of the antioxidant enzymes catalase and superoxide dismutase were evaluated. Additionally, the amount of lipid peroxidation was measured by assessing the quantity of malondialdehyde. The physiopathology of cardiac tissue was considered by Perl's and H&E staining. RESULTS: According to the results, almost all natural compounds showed better performance than desferal, as an iron chelator chemical. Meanwhile, hesperidin, vanillin, and ferulic acid were the best antioxidant compounds and were able to improve the activity of antioxidant enzymes by reducing the amount of deposited iron. CONCLUSION: We recommend the use of the above compounds as natural iron chelators after completing additional studies.

Naringin is a promising natural compound for therapy of iron-overload disorders

Abstract Naringin has been shown to exhibit satisfying iron chelation capacity. Considering the side effects of routinely-used iron chelator (desferrioxamine, DFO), we decided to evaluate the iron chelation potency of naringin to discover whether or not it can be a promising natural substitute for treatment of excessive iron-related diseases. 35 mice were classified into five groups of 7 and subjected to iron dextran administration to induce the iron-overload condition. Iron-overloaded mice were then treated with normal saline (as control), naringin or DFO Morphology changes, and iron deposition in liver tissues were studied using H&E and Perl's staining. The results revealed that naringin is more potent than DFO in removing excessive iron ions deposited in liver tissues, indicating that naringin is a promising natural compound for therapy of iron overload disorders

In silico drug repurposing for the treatment of heart diseases using gene expression data and molecular docking techniques.

Heart diseases are known as the most primary causes of mortality worldwide. Although many therapeutic approaches and medications are proposed for these diseases, the identification of novel therapeutics in fatal heart conditions is promptly demanded. Besides, the interplay between gene expression data and molecular docking provides several novel insights to discover more effective and specific drugs for the treatment of the diseases. This study aimed to discover potent therapeutic drugs in the heart diseases based on the expression profile of heart-specific genes exclusively. Initially, the heart-specific and highly expressed genes were identified by comparing the gene expression profile of different body tissues. Subsequently, the druggable-genes were identified using in silico techniques. The interaction between these druggable genes with more than 1600 FDA approved drugs was then investigated using the molecular docking simulation. By comprehensively analyzing RNA-sequencing data obtained from 949 normal tissue samples, 48 heart-specific genes were identified in both the heart development and function. Notably, of these, 24 heart-specific genes were capable to be considered as druggable genes, among which only MYBPC3, MYLK3, and SCN5A genes entered the molecular docking process due to their functions. Afterward, the pharmacokinetics properties of top 10 ligands with the highest binding affinity for these proteins were studied. Accordingly, methylergonovine, fosaprepitant, pralatrexate, daunorubicin, glecaprevir, digoxin, and venetoclax drugs were competent, in order to interact with the target proteins perfectly. It was shown that these medications can be used as specific drugs for the treatment of heart diseases after fulfilling further experiments in this regard.

Comparison Between Hesperidin, Coumarin, and Deferoxamine Iron Chelation and Antioxidant Activity Against Excessive Iron in the Iron Overloaded Mice.

OBJECTIVE: Iron accumulation in the brain leads to the development of Alzheimer's and Parkinson's diseases. Nowadays, iron chelation therapy is the best way to decrease the side effects of iron and amyloid plaques accumulation. Iron chelators are commonly used for the treatment of Alzheimer's disease. Previous studies have shown that natural products such as phenol and flavonoid compounds could chelate heavy metals. In the current study, we examined the iron chelation activity of hesperidin and coumarin on the brain tissue of iron-overloaded mice. METHODS: 48 NMRI male mice were divided into eight groups (n = 6). Six groups were treated with iron dextran (100 mg/kg/day) four times a week for 6 weeks. After stopping the injections for a month, five groups of iron-overloaded mice were treated with hesperidin, coumarin, and desferal four times a week subsequent for four subsequent weeks. Finally, the mice were anesthetized, and blood samples were collected from the ventricle of the heart for subsequent examination. The brain tissues were isolated and fixed in the 4% paraformaldehyde solution for Perl's staining. RESULTS: The results show that hesperidin and coumarin could strongly chelate excessive iron from the serum and deposit iron from the brain tissue compared to desferal group. Catalase and super oxidase activity were decreased in the iron-overloaded group, but in the treated group by hesperidin and coumarin, the enzyme's activity was increased significantly. CONCLUSION: Hesperidin and coumarin, as natural products, are powerful options to chelate iron ions and increase the activity of antioxidant enzymes.