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Nanocurcumin supplementation ameliorates Behcet's disease by modulating regulatory T cells: A randomized, double-blind, placebo-controlled trial.
Abbasian, S, Soltani-Zangbar, MS, Khabbazi, A, Farzaneh, R, Malek Mahdavi, A, Motavalli, R, Hajialilo, M, Yousefi, M
International immunopharmacology. 2021;(Pt B):108237
Abstract
Current research was designed to assess the effects of nanocurcumin supplementation on regulatory T (Treg) cells frequency and function in Behçet's disease (BD). In this randomized double-masked, placebo-controlled trial, 36 BD subjects were randomly put into two groups to take one 80 mg nanocurcumin capsule or placebo daily for 8 weeks. Before and after trial, disease activity, Treg cells frequency and expression of related immunologic parameters including forkhead box protein P3 (Foxp3) transcription factor messenger RNA (mRNA) and microRNAs (miRNAs) such as miRNA-25 and miRNA-106b as well as cytokines including transforming growth factor (TGF)-β and interleukin (IL)-10 were studied. Thirty-two patients (17 in the nanocurcumin and 15 in the placebo groups) completed the trial. Treg cells frequency increased significantly in the nanocurcumin group compared with baseline (P < 0.001) and placebo group (P < 0.001). Moreover, FoxP3, TGF-β, IL-10, miRNA-25, and miRNA-106b mRNA expression levels increased considerably in the nanocurcumin group compared to baseline (P < 0.001) and placebo group (P < 0.001, P < 0.001, P = 0.025, P = 0.011, and P < 0.001, respectively). Significant increases in serum TGF-β and IL-10 were seen in nanocurcumin group compared with baseline (P < 0.001) and placebo group (P = 0.001 and P < 0.001, respectively). Significant decrease in disease activity was found in nanocurcumin group compared with placebo group (P = 0.044). Our study provided a promising view for desirable effects of nanocurcumin supplementation in improving immunological parameters and disease activity in BD.
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Atrial Fibrillation in Heart Failure Is Associated with High Levels of Circulating microRNA-199a-5p and 22-5p and a Defective Regulation of Intracellular Calcium and Cell-to-Cell Communication.
Garcia-Elias, A, Tajes, M, Yañez-Bisbe, L, Enjuanes, C, Comín-Colet, J, Serra, SA, Fernández-Fernández, JM, Aguilar-Agon, KW, Reilly, S, Martí-Almor, J, et al
International journal of molecular sciences. 2021;(19)
Abstract
MicroRNAs (miRNAs) participate in atrial remodeling and atrial fibrillation (AF) promotion. We determined the circulating miRNA profile in patients with AF and heart failure with reduced ejection fraction (HFrEF), and its potential role in promoting the arrhythmia. In plasma of 98 patients with HFrEF (49 with AF and 49 in sinus rhythm, SR), differential miRNA expression was determined by high-throughput microarray analysis followed by replication of selected candidates. Validated miRNAs were determined in human atrial samples, and potential arrhythmogenic mechanisms studied in HL-1 cells. Circulating miR-199a-5p and miR-22-5p were significantly increased in HFrEF patients with AF versus those with HFrEF in SR. Both miRNAs, but particularly miR-199a-5p, were increased in atrial samples of patients with AF. Overexpression of both miRNAs in HL-1 cells resulted in decreased protein levels of L-type Ca2+ channel, NCX and connexin-40, leading to lower basal intracellular Ca2+ levels, fewer inward currents, a moderate reduction in Ca2+ buffering post-caffeine exposure, and a deficient cell-to-cell communication. In conclusion, circulating miR-199a-5p and miR-22-5p are higher in HFrEF patients with AF, with similar findings in human atrial samples of AF patients. Cells exposed to both miRNAs exhibited altered Ca2+ handling and defective cell-to-cell communication, both findings being potential arrhythmogenic mechanisms.
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Small in Size, but Large in Action: microRNAs as Potential Modulators of PTEN in Breast and Lung Cancers.
Abadi, AJ, Zarrabi, A, Gholami, MH, Mirzaei, S, Hashemi, F, Zabolian, A, Entezari, M, Hushmandi, K, Ashrafizadeh, M, Khan, H, et al
Biomolecules. 2021;(2)
Abstract
MicroRNAs (miRNAs) are well-known regulators of biological mechanisms with a small size of 19-24 nucleotides and a single-stranded structure. miRNA dysregulation occurs in cancer progression. miRNAs can function as tumor-suppressing or tumor-promoting factors in cancer via regulating molecular pathways. Breast and lung cancers are two malignant thoracic tumors in which the abnormal expression of miRNAs plays a significant role in their development. Phosphatase and tensin homolog (PTEN) is a tumor-suppressor factor that is capable of suppressing the growth, viability, and metastasis of cancer cells via downregulating phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling. PTEN downregulation occurs in lung and breast cancers to promote PI3K/Akt expression, leading to uncontrolled proliferation, metastasis, and their resistance to chemotherapy and radiotherapy. miRNAs as upstream mediators of PTEN can dually induce/inhibit PTEN signaling in affecting the malignant behavior of lung and breast cancer cells. Furthermore, long non-coding RNAs and circular RNAs can regulate the miRNA/PTEN axis in lung and breast cancer cells. It seems that anti-tumor compounds such as baicalein, propofol, and curcumin can induce PTEN upregulation by affecting miRNAs in suppressing breast and lung cancer progression. These topics are discussed in the current review with a focus on molecular pathways.
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Identification and molecular characterization of miRNAs and their target genes associated with seed development through small RNA sequencing in chickpea.
Pradhan, S, Verma, S, Chakraborty, A, Bhatia, S
Functional & integrative genomics. 2021;(2):283-298
Abstract
Multiple studies have attempted to dissect the molecular mechanism underlying seed development in chickpea (Cicer arietinum L.). These studies highlight the need to focus on the role of miRNAs in regulating storage protein accumulation in seeds. Therefore, a total of 8,856,691 short-read sequences were generated from a small RNA library of developing chickpea seeds and were analyzed using miRDeep-P to identify 74 known and 26 novel miRNA sequences. Known miRNAs were classified into 22 miRNA families with miRNA156 family being most abundant. Of the 26 putative novel miRNAs identified, only 22 could be experimentally validated using stem loop end point PCR. Differential expression analyses led to the identification of known as well as novel miRNAs that could regulate various stages of chickpea seed development. In silico target prediction revealed several important target genes and transcription factors like SPL, mediator of RNA Polymerase II transcription subunit 12, aspartic proteinase and NACs, which were further validated by real-time PCR analysis. A comparative expression analysis in chickpea genotypes with contrasting seed protein content revealed one known (Car-miR156h) and two novel miRNA (Car-novmiR7 and Car-novmiR23) candidates to be highly expressed in the LPC (low protein content) chickpea genotypes, targets of which are known to regulate seed storage protein accumulation. Therefore, this study provides a useful resource in the form of miRNA and their targets which can be further utilized to understand and manipulate various regulatory mechanisms involved in seed development with the overall aim of improving yield and nutrition attributes in chickpea.
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miR-125a-5p impairs the metastatic potential in breast cancer via IP6K1 targeting.
Minini, M, Senni, A, He, X, Proietti, S, Liguoro, D, Catizone, A, Giuliani, A, Mancini, R, Fuso, A, Cucina, A, et al
Cancer letters. 2021;:48-56
Abstract
The deregulation of PI3K/Akt signaling is among the most causes in inducing the acquisition of a metastatic phenotype in breast cancer cells, leading to Epithelial-Mesenchymal Transition (EMT). Inhibition of the PI3K/Akt pathway is known to be beneficial in the clinical setting. However, the activation of secondary pathways and toxicity profiles of available inhibitors, hindering optimal therapeutic results. Preliminary studies showed that myo-Inositol inhibits the PI3K/Akt pathway by exerting a pleiotropic anti-tumor action. Herein, we demonstrate that myo-Inositol triggers a prompt and profound remodeling of delineated expression pattern in triple-negative breast cancer cells (MDA-MB-231). Consequently, it inhibits metastasis and tumor progression through miR-125a-5p transcription and the subsequent inhibition of IP6K1. In contrast, hormone-responsive breast cancer cells (MCF-7) are insensitive to myo-Inositol. This is due to the persistence of MDM2 synthesis promoted by estrogen-dependent pathways. Conversely, the counteraction of estrogen effects recovered the sensitivity to myo-Inositol in the hormone-responsive model. Overall, these results identify a novel axis primed by miR-125a-5p to downregulate IP6K1 gene that inhibits metastasis. Thus, administration of myo-Inositol can activate this axis as a molecular target therapy in breast cancer.
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Plasma miRNA Biomarkers in Limited Volume Samples for Detection of Early-stage Pancreatic Cancer.
Dittmar, RL, Liu, S, Tai, MC, Rajapakshe, K, Huang, Y, Longton, G, DeCapite, C, Hurd, MW, Paris, PL, Kirkwood, KS, et al
Cancer prevention research (Philadelphia, Pa.). 2021;(7):729-740
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Abstract
Early detection of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcomes; however, PDAC is usually diagnosed late. Therefore, blood-based minimally invasive biomarker assays for limited volume clinical samples are urgently needed. A novel miRNA profiling platform (Abcam Fireplex-Oncology Panel) was used to investigate the feasibility of developing early detection miRNA biomarkers with 20 μL plasma from a training set (58 stage II PDAC cases and 30 controls) and two validation sets (34 stage II PDAC cases and 25 controls; 44 stage II PDAC cases and 18 controls). miR-34a-5p [AUC = 0.77; 95% confidence interval (CI), 0.66-0.87], miR-130a-3p (AUC = 0.74; 95% CI, 0.63-0.84), and miR-222-3p (AUC = 0.70; 95% CI, 0.58-0.81) were identified as significantly differentially abundant in plasma from stage II PDAC versus controls. Although none of the miRNAs individually outperformed the currently used serologic biomarker for PDAC, carbohydrate antigen 19-9 (CA19-9), combining the miRNAs with CA 19-9 improved AUCs from 0.89 (95% CI, 0.81-0.95) for CA 19-9 alone to 0.92 (95% CI, 0.86-0.97), 0.94 (95% CI, 0.89-0.98), and 0.92 (95% CI, 0.87-0.97), respectively. Gene set enrichment analyses of transcripts correlated with high and low expression of the three miRNAs in The Cancer Genome Atlas PDAC sample set. These miRNA biomarkers, assayed in limited volume plasma together with CA19-9, discriminate stage II PDAC from controls with good sensitivity and specificity. Unbiased profiling of larger cohorts should help develop an informative early detection biomarker assay for diagnostic settings. PREVENTION RELEVANCE Development of minimally invasive biomarker assays for detection of premalignant disease and early-stage pancreatic cancer is key to improving patient survival. This study describes a limited volume plasma miRNA biomarker assay that can detect early-stage resectable pancreatic cancer in clinical samples necessary for effective prevention and clinical intervention.
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Negative Regulation of ULK1 by microRNA-106a in Autophagy Induced by a Triple Drug Combination in Colorectal Cancer Cells In Vitro.
Salgado-García, R, Coronel-Hernández, J, Delgado-Waldo, I, Cantú de León, D, García-Castillo, V, López-Urrutia, E, Gutiérrez-Ruiz, MC, Pérez-Plasencia, C, Jacobo-Herrera, N
Genes. 2021;(2)
Abstract
Colorectal cancer (CRC) is among the top three most deadly cancers worldwide. The survival rate for this disease has not been reduced despite the treatments, the reason why the search for therapeutic alternatives continues to be a priority issue in oncology. In this research work, we tested our successful pharmacological combination of three drugs, metformin, doxorubicin, and sodium oxamate (triple therapy, or TT), as an autophagy inducer. Firstly, we employed western blot (WB) assays, where we observed that after 8 h of stimulation with TT, the proteins Unc-51 like autophagy activating kinase 1(ULK1), becline-1, autophagy related 1 protein (Atg4), and LC3 increased in the CRC cell lines HCT116 and SW480 in contrast to monotherapy with doxorubicin. The overexpression of these proteins indicated the beginning of autophagy flow through the activation of ULK1 and the hyperlipidation of LC3 at the beginning of this process. Moreover, we confirm that ULK1 is a bona fide target of hsa-miR-106a-5p (referred to from here on as miR-106a) in HCT116. We also observed through the GFP-LC3 fusion protein that in the presence of miR-106a, the accumulation of autophagy vesicles in cells stimulated with TT is inhibited. These results show that the TT triggered autophagy to modulate miR-106a/ULK1 expression, probably affecting different cellular pathways involved in cellular proliferation, survivance, metabolic maintenance, and cell death. Therefore, considering the importance of autophagy in cancer biology, the study of miRNAs that regulate autophagy in cancer will allow a better understanding of malignant tumors and lead to the development of new disease markers and therapeutic strategies.
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MicroRNA regulation of cholesterol metabolism.
Citrin, KM, Fernández-Hernando, C, Suárez, Y
Annals of the New York Academy of Sciences. 2021;(1):55-77
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Abstract
MicroRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level. Since many microRNAs have multiple mRNA targets, they are uniquely positioned to regulate the expression of several molecules and pathways simultaneously. For example, the multiple stages of cholesterol metabolism are heavily influenced by microRNA activity. Understanding the scope of microRNAs that control this pathway is highly relevant to diseases of perturbed cholesterol metabolism, most notably cardiovascular disease (CVD). Atherosclerosis is a common cause of CVD that involves inflammation and the accumulation of cholesterol-laden cells in the arterial wall. However, several different cell types participate in atherosclerosis, and perturbations in cholesterol homeostasis may have unique effects on the specialized functions of these various cell types. Therefore, our review discusses the current knowledge of microRNA-mediated control of cholesterol homeostasis, followed by speculation as to how these microRNA-mRNA target interactions might have distinctive effects on different cell types that participate in atherosclerosis.
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TFEB Signalling-Related MicroRNAs and Autophagy.
Corà, D, Bussolino, F, Doronzo, G
Biomolecules. 2021;(7)
Abstract
The oncogenic Transcription Factor EB (TFEB), a member of MITF-TFE family, is known to be the most important regulator of the transcription of genes responsible for the control of lysosomal biogenesis and functions, autophagy, and vesicles flux. TFEB activation occurs in response to stress factors such as nutrient and growth factor deficiency, hypoxia, lysosomal stress, and mitochondrial damage. To reach the final functional status, TFEB is regulated in multimodal ways, including transcriptional rate, post-transcriptional regulation, and post-translational modifications. Post-transcriptional regulation is in part mediated by miRNAs. miRNAs have been linked to many cellular processes involved both in physiology and pathology, such as cell migration, proliferation, differentiation, and apoptosis. miRNAs also play a significant role in autophagy, which exerts a crucial role in cell behaviour during stress or survival responses. In particular, several miRNAs directly recognise TFEB transcript or indirectly regulate its function by targeting accessory molecules or enzymes involved in its post-translational modifications. Moreover, the transcriptional programs triggered by TFEB may be influenced by the miRNA-mediated regulation of TFEB targets. Finally, recent important studies indicate that the transcription of many miRNAs is regulated by TFEB itself. In this review, we describe the interplay between miRNAs with TFEB and focus on how these types of crosstalk affect TFEB activation and cellular functions.
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The prognostic impact of circulating miRNAs in patients with advanced esophagogastric cancer during palliative chemotherapy.
van Zweeden, AA, Opperman, RCM, Honeywell, RJ, Peters, GJ, Verheul, HMW, van der Vliet, HJ, Poel, D
Cancer treatment and research communications. 2021;:100371
Abstract
The prognosis of patients with advanced oesophageal cancer (EC) and gastric cancer (GC) is poor. Circulating microRNAs (ci-miRNAs) may have prognostic and predictive value to improve patient selection for palliative treatment. The purpose of this study is to assess the prognostic and predictive value of specific ci-miRNAs in plasma of patients with EC and GC treated with first-line palliative gemcitabine and cisplatin. Droplet digital PCR (ddPCR) was used to quantify miR-200c-3p, miR-375, miR-21-5p, miR-148a-3p, miR-146a-5p, miR-141-3p and miR-218-5p in plasma from 68 patients. ci-miRNA expression was analyzed in relation to overall survival (OS), progression-free survival (PFS), and response to chemotherapy. ci-miRNA levels were detectable in 36 baseline (71%) samples and in 14 (47%) follow-up samples. Increased circulating miR-200c-3p in GC showed a trend (p = 0.06) towards a shorter OS. High circulating miR-375 was associated with a longer OS (p = 0.02) in patients with esophageal adenocarcinoma (EAC). No significant difference was observed in ci-miRNA expression between paired pre- and on-treatment samples. ci-miRNA expression was not associated with response to chemotherapy. ci-miRNAs can be measured in plasma samples of patients treated with first-line palliative chemotherapy using ddPCR despite prolonged storage in heparin. Elevated circulating miR-375 might be a prognostic marker for patients with EAC.