Pre-clinical and clinical importance of miR-21 in human cancers: Tumorigenesis, therapy response, delivery approaches and targeting agents.

The field of non-coding RNA (ncRNA) has made significant progress in understanding the pathogenesis of diseases and has broadened our knowledge towards their targeting, especially in cancer therapy. ncRNAs are a large family of RNAs with microRNAs (miRNAs) being one kind of endogenous RNA which lack encoded proteins. By now, miRNAs have been well-coined in pathogenesis and development of cancer. The current review focuses on the role of miR-21 in cancers and its association with tumor progression. miR-21 has both oncogenic and onco-suppressor functions and most of the experiments are in agreement with the tumor-promoting function of this miRNA. miR-21 primarily decreases PTEN expression to induce PI3K/Akt signaling in cancer progression. Overexpression of miR-21 inhibits apoptosis and is vital for inducing pro-survival autophagy. miR-21 is vital for metabolic reprogramming and can induce glycolysis to enhance tumor progression. miR-21 stimulates EMT mechanisms and increases expression of MMP-2 and MMP-9 thereby elevating tumor metastasis. miR-21 is a target of anti-cancer agents such as curcumin and curcumol and its down-regulation impairs tumor progression. Upregulation of miR-21 results in cancer resistance to chemotherapy and radiotherapy. Increasing evidence has revealed the role of miR-21 as a biomarker as it is present in both the serum and exosomes making them beneficial biomarkers for non-invasive diagnosis of cancer.

Harmful effects of true-to-life nanoplastics derived from PET water bottles in human alveolar macrophages.

The increasing presence of secondary micro/nanoplastics (MNPLs) in the environment requires knowing if they represent a real health concern. To such end, an important point is to test representative MNPLs such as the denominated true-to-life MNPLs, resulting from the degradation of plastic goods in lab conditions. In this study, we have used polyethylene terephthalate (PET) NPLs resulting from the degradation of PET water bottles. Since inhalation is an important exposure route to environmental MNPLS, we have used mouse alveolar macrophages (MH-S) as a target cell, and the study focused only on the cells that have internalized them. This type of approach is novel as it may capture the realistic adverse effects of PETNPLs only in the internalized cells, thereby mitigating any biases while assessing the risk of these MNPLs. Furthermore, the study utilized a set of biomarkers including intracellular reactive oxygen species (ROS) levels, variations on the mitochondrial membrane potential values, and the macrophage polarization to M1 (pro-inflammatory response) and M2 (anti-proinflammatory response) as possible cellular effects due to PETNPLs in only the cells that internalized PETNPLs. After exposures lasting for 3 and 24 h to a range of concentrations (0, 25, 50, and 100 µg/mL) the results indicate that no toxicity was induced despite the 100% internalization observed at the highest concentration. Significant intracellular levels of ROS were observed, mainly at exposures lasting for 24 h, in an indirect concentration-effect relationship. Interestingly, a reduction in the mitochondrial membrane potential was observed, but only at exposures lasting for 24 h, but without a clear concentration-effect relationship. Finally, PETNPL exposure shows a significant polarization from M0 to M1 and M2 subtypes. Polarization to M1 (pro-inflammatory stage) was more marked and occurred at both exposure times. Polarization to M2 (anti-inflammatory stage) was only observed after exposures lasting for 24 h. Due to the relevance of the described biomarkers, our results underscore the need for further research, to better understand the health implications associated with MNPL exposure.

Hazard assessment of nanoplastics is driven by their surface-functionalization. Effects in human-derived primary endothelial cells.

During plastic waste degradation into micro/nanoplastics (MNPLs) their physicochemical characteristics including surface properties (charge, functionalization, biocorona, etc.) can change, potentially affecting their biological effects. This paper focuses on the surface functionalization of MNPLs to determine if it has a direct impact on the toxicokinetic and toxicodynamic interactions in human umbilical vein endothelial cells (HUVECs), at different exposure times. Pristine polystyrene nanoplastics (PS-NPLs), as well as their carboxylated (PS-C-NPLs) and aminated (PS-A-NPLs) forms, all around 50 nm, were used in a wide battery of toxicological assays. These assays encompassed evaluations on cell viability, cell internalization, induction of intracellular reactive oxygen species (iROS), and genotoxicity. The experiments were conducted at a concentration of 100 µg/mL, chosen to ensure a high internalization rate across all treatments while maintaining a sub-toxic concentration. Our results show that all PS-NPLs are internalized by HUVECs, but the internalization dynamic depends on the particle's functionalization. PS-NPLs and PS-C-NPLs internalization modify the morphology of the cell increasing its inner complexity/granularity. Regarding cell toxicity, only PS-A-NPLs reduced cell viability. Intracellular ROS was induced by the three different PS-NPLs but at different time points. Genotoxic damage was induced by the three PS-NPLs at short exposures (2 h), but not for PS-C-NPLs at 24 h. Overall, this study suggests that the toxicological effects of PSNPLs on HUVEC cells are surface-dependent, highlighting the relevance of using human-derived primary cells as a target.

The release of polylactic acid nanoplastics (PLA-NPLs) from commercial teabags. Obtention, characterization, and hazard effects of true-to-life PLA-NPLs.

This study investigates MNPLs release from commercially available teabags and their effects on both undifferentiated monocultures of Caco-2 and HT29 and in the in vitro model of the intestinal Caco-2/HT29 barrier. Teabags were subjected to mechanical and thermodynamic forces simulating the preparation of a cup of tea. The obtained dispersions were characterized using TEM, SEM, DLS, LDV, NTA, and FTIR. Results confirmed that particles were in the nano-range, constituted by polylactic acid (PLA-NPLs), and about one million of PLA-NPLs per teabag were quantified. PLA-NPLs internalization, cytotoxicity, intracellular reactive oxygen species induction, as well as structural and functional changes in the barrier were assessed. Results show that PLA-NPLs present high uptake rates, especially in mucus-secretor cells, and bio-persisted in the tissue after 72 h of exposure. Although no significant cytotoxicity was observed after the exposure to 100 µg/mL PLA-NPLs during 48 h, a slight barrier disruption could be detected at short-time periods. The present work reveals new insights into the safety of polymer-based teabags, the behavior of true-to-life MNPLs in the human body, as well as new questions on how repeated and prolonged exposures could affect the structure and function of the human intestinal epithelium.

Hazard assessment of different-sized polystyrene nanoplastics in hematopoietic human cell lines.

The environmental presence of micro/nanoplastics (MNPLs) is an environmental and human health concern. Such MNPLs can result from the physicochemical/biological degradation of plastic goods (secondary MNPLs) or can result from industrial production at that size, for different commercial purposes (primary MNPLs). Independently of their origin, the toxicological profile of MNPLs can be modulated by their size, as well as by the ability of cells/organisms to internalize them. To get more information on these topics we have determined the ability of three different sizes of polystyrene MNPLs (50, 200, and 500 nm) to produce different biological effects in three different human hematopoietic cell lines (Raji-B, THP-1, and TK6). Results show that none of the three sizes was able to induce toxicity (growth ability) in any of the tested cell types. Although transmission electron microscopy and confocal images showed cell internalization in all the cases, their quantification by flow cytometry demonstrated an important uptake by Raji-B and THP-1 cells, in comparison with TK6 cells. For the first ones, the uptake was negatively associated with the size. Interestingly, when the loss of mitochondrial membrane potential was determined, dose-related effects were observed for Raji-B and THP-1 cells, but not for TK6 cells. These effects were observed for the three different sizes. Finally, when oxidative stress induction was evaluated, no clear effects were observed for the different tested combinations. Our conclusion is that size, biological endpoint, and cell type are aspects modulating the toxicological profile of MNPLs.

Expression Patterns of miR181a and miR30d in Patients with Breast Cancer.

Background: One of the important molecular pathways in breast cancer is the PTEN-PI3K-AKT pathway. Any change in the activity of the PTEN gene can alter the PI3K-AKT pathway. Moreover, there are subsets of genes and pathways their expression changes by post-transcriptional regulations. For instance, gene regulation alters by non-coding RNAs such as micro-RNAs as post-transcriptional regulators that prevent the expression of the target transcript. Therefore, it is essential to assess the related alterations in micro-RNA expression patterns to find out the possible causes of conversions in related transcripts and pathways such as the PTENPI3K-AKT pathway in breast cancer. Methods: To determine the expression level of miR-181a and miR-30d in 30 breast tumor samples and 30 adjacent normal samples, the RNA extraction, and cDNA synthesis was performed by RiboEx (GeneAll, Korea). Finally, the Real-Time PCR method was used for quantitative analysis of the expression levels of these miRNAs. all the experimental part of the project in done at Islamic Azad University in 2017. Results: After analyzing comparisons in the expression level of miR-181a and miR-30d in tumor and normal tissues, there was a significant increase in the expression level of miR-181a in tumor samples compared with normal samples. Moreover, the expression level of miR-30d in tumor samples reported a significant decrease in comparison with normal samples (P<0.05). Conclusion: Upregulation of miR-181a may affect the transcription of the PTEN gene resulting in the cell progress to cancer. The Downregulation of miR-30d may also lead to cancer cell growth, due to a reduction in the affecting on the CREB gene transcript.