Search

Triple-negative breast cancer (TNBC), characterized by high invasiveness, is associated with poor prognosis and elevated mortality rates. Despite the development of effective therapeutic targets for TNBC, systemic chemotherapy and radiotherapy (RdT) remain prevalent treatment modalities. One notable challenge of RdT is the acquisition of radioresistance, which poses a significant obstacle in achieving optimal treatment response. Compelling evidence implicates non-coding RNAs (ncRNAs), gene expression regulators, in the development of radioresistance. This systematic review focuses on describing the role, association, and/or involvement of ncRNAs in modulating radioresponse in TNBC. In adhrence to the PRISMA guidelines, an extensive and comprehensive search was conducted across four databases using carefully selected entry terms. Following the evaluation of the studies based on predefined inclusion and exclusion criteria, a refined selection of 37 original research articles published up to October 2023 was obtained. In total, 33 different ncRNAs, including lncRNAs, miRNAs, and circRNAs, were identified to be associated with radiation response impacting diverse molecular mechanisms, primarily the regulation of cell death and DNA damage repair. The findings highlighted in this review demonstrate the critical roles and the intricate network of ncRNAs that significantly modulates TNBC's responsiveness to radiation. The understanding of these underlying mechanisms offers potential for the early identification of non-responders and patients prone to radioresistance during RdT, ultimately improving TNBC survival outcomes., (© 2024. The Author(s).)

MiRNAs, a class of non-coding RNA molecules, have emerged as critical modulators of telomere length and telomerase activity by finely tuning the expression of target genes (and not gene targets) within signaling pathways involved in telomere homeostasis. The primary objective of this systematic review was to compile and synthesize the existing body of knowledge on the role, association, and involvement of miRNAs in telomere length. Additionally, the review explored the regulation, function, and activation mechanism of the human telomerase reverse transcriptase (hTERT) gene and telomerase activity in tumor cells. A comprehensive analysis of 47 selected articles revealed 40 distinct miRNAs involved in these processes. These miRNAs were shown to exert their function, in both clinical cases and cell line models, either directly or indirectly, regulating hTERT and telomerase activity through distinct molecular mechanisms. The regulatory roles of these miRNAs significantly affected major cancer phenotypes, with outcomes largely dependent on the tissue type and the cellular actions within the tumor cells, whereby they functioned as oncogenes or tumor suppressors. These findings strongly support the pivotal role of miRNAs in modulating telomere length and telomerase activity, thereby contributing to the intricate and complex regulation of telomere homeostasis in tumor cells. Moreover, they emphasize the potential of targeting miRNAs and key regulatory genes as therapeutic strategies to disrupt cancer cell growth and promote senescence, offering promising avenues for novel cancer treatments., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Synthetic 10-methoxy-canthin-6-one (Mtx-C), an alkaloid derivative, exhibits cytotoxic effects against acute myeloid cells (AMLs) and leukemic stem cells (LSCs) at a concentration of approximately 60 μM. However, the antitumor mechanism of Mtx-C in AMLs and LSCs remains elusive. Using Mtx-C at concentrations with low cytotoxicity (2-4 μM) for 72 h, we observed cell arrest with the accumulation of cells in the G 2 /M phase of the cell cycle. This effect was controlled by cyclin B1 expression and induction of the DNA damage cascade characterized by ATM, ATR, Chk1/2, p53, and H2A.X phosphorylation. Molecular docking analysis confirmed Mtx-C as a DNA intercalator. Moreover, the expression of inhibitors of cyclin-dependent kinases, including p21 (Cip1) and p27 (Kip1), increased. In addition, several miRNAs that are considered oncosuppressors were regulated by Mtx-C in Kasumi-1 cells. Finally, concomitant with cell cycle arrest, the underlying molecular mechanisms of Mtx-C in AML cells include myeloid differentiation, as evidenced by the increased expression of PU.1, myeloperoxidase, CD15, CD11b, and CD14 in the AML and LSC populations with the participation of p38 mitogen-activated protein kinase. Thus, we showed that Mtx-C simultaneously induced cell cycle arrest and myeloid differentiation in AML lineages and in the LSC population, providing insights into new therapeutic alternatives for the treatment of AML based on naturally occurring molecules., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Breast cancer (BC), a heterogeneous group of diseases, is the most frequent type and the leading cause of cancer-related death among women worldwide. Tumor heterogeneity directly impacts cancer progression and treatment, as evidenced by the patients´ diverse prognosis and treatment responses across the distinct molecular subtypes. Triple-negative breast cancer (TNBC), which accounts for 10-20% of all diagnosed BC cases, is an aggressive BC subtype with a challenging prognosis. Current treatment options include systemic chemotherapy and/or target therapies based on PARP and PD-L1 inhibitors for eligible patients. MicroRNAs (miRNAs) are important regulatory non-coding RNAs (ncRNAs) in TNBC tumorigenesis. These molecules are present both intracellularly and released into biofluids, packaged into extracellular vesicles (EVs). Emerging evidence indicates that EVs-associated miRNAs (EVs-miRNAs), transferred from parental to recipient cells, are key mediators of cell-to-cell communication. Considering their stability and abundance in several biofluids, these molecules may reflect the epigenomic composition of their tumors of origin and contribute to mediate tumorigenesis, similar to their intracellular counterparts. This review provides the current knowledge on EVs-miRNAs in the TNBC subtype, focusing on their role in regulating mRNA targets involved in tumor phenotypes and their clinical relevance as promising biomarkers in liquid biopsies., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

MicroRNAs (miRNAs) are involved in the regulation of mitochondrial function and homeostasis, and in the modulation of cell metabolism, by targeting known oncogenes and tumor suppressor genes of metabolic-related signaling pathways involved in the hallmarks of cancer. This systematic review focuses on articles describing the role, association, and/or involvement of miRNAs in regulating the mitochondrial function and metabolic reprogramming of cancer cells. Following the PRISMA guidelines, the articles reviewed were published from January 2010 to September 2022, with the search terms "mitochondrial microRNA" and its synonyms (mitochondrial microRNA, mitochondrial miRNA, mito microRNA, or mitomiR), "reprogramming metabolism," and "cancer" in the title or abstract). Thirty-six original research articles were selected, revealing 51 miRNAs with altered expression in 12 cancers: bladder, breast, cervical, colon, colorectal, liver, lung, melanoma, osteosarcoma, pancreatic, prostate, and tongue. The actions of miRNAs and their corresponding target genes have been reported mainly in cell metabolic processes, mitochondrial dynamics, mitophagy, apoptosis, redox signaling, and resistance to chemotherapeutic agents. Altogether, these studies support the role of miRNAs in the metabolic reprogramming hallmark of cancer cells and highlight their potential as predictive molecular markers of treatment response and/or targets that can be used for therapeutic intervention.

MicroRNA (miRNAs) are small non-coding RNA molecules involved in a wide range of biological processes through the post-transcriptional regulation of gene expression. Most studies evaluated microRNA expression in human, and despite fewer studies in veterinary medicine, this topic is one of the most exciting areas of modern veterinary medicine. miRNAs showed to be part of the pathogenesis of diseases and reproduction physiology in animals, making them biomarkers candidates. This review provides an overview of the current knowledge regarding miRNAs' role in reproduction and animal diseases, diagnostic and therapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Prostate cancer-related deaths are mostly caused by metastasis, which indicates the importance of identifying clinical prognostic biomarkers. In this study, we evaluated the expression profile of exosomal microRNAs (miRNAs) derived from metastatic prostate cancer (mPCa) cell lines (LNCaP and PC-3). miRNA signatures in exosomes and cells were evaluated by miRNA microarray analysis. Fourteen miRNAs were identified as candidates for specific noninvasive biomarkers. The expression of five miRNAs was validated using RT-qPCR, which confirmed that miR-205-5p, miR-148a-3p, miR-125b-5p, miR-183-5p, and miR-425-5p were differentially expressed in mPCa exosomes. Bioinformatic analyses showed that miR-425-5p was associated with residual tumor, pathologic T and N stages, and TP53 status in PCa samples. Gene ontology analysis of negatively correlated and predicted targeted genes showed enrichment of genes related to bone development pathways. The LinkedOmics database indicated that the potential target HSPB8 has a significant negative correlation with miR-425-5p. In conclusion, this study identified a panel of exosomal miRNAs with potential value as prognostic biomarkers for prostate cancer., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Acute-on-chronic liver failure (ACLF) is a condition characterized by acute decompensation of cirrhosis, associated with organ failure(s), and high short-term mortality. The microRNAs or miRNAs are small non-coding RNA molecules, stable in circulating samples such as biological fluids, and the difference in expression levels may indicate the presence, absence and/or stage of the disease. We analyzed here the miRNA profiling to identify potential diagnostic or prognostic biomarkers for ACLF. The major miRNAs discovered were validated in a cohort of patients with acute decompensation of cirrhosis grouped in no ACLF or ACLF according to EASL-CLIF definition. Relationship between serum miRNAs and variables associated with liver-damage and survival outcomes were verified to identify possible prognostic markers. Our results showed twenty altered miRNAs between no ACLF and ACLF patients, and twenty-seven in patients who died in 30 days compared with who survived. In validation phase, miR-223-3p and miR-25-3p were significantly altered in ACLF patients and in those who died in 30 days. miR-223-3p and miR-25-3p expression were associated with the lowest survival in 30 days. The decrease in miR-223-3p and miR-25-3p expression was associated with the presence of ACLF and poor prognosis. Of these, miR-25-3p was independently related to ACLF and 30-day mortality.

In light of the evidence that in contrast to most healthy tissues, several neoplasms overexpress fatty acid synthase (FASN) upon their dependence on increased lipogenesis; targeting of this protein is being considered as a valuable strategy in anticancer drug development. This can be particularly relevant for aggressive tumors such as melanoma in which FASN overexpression has been associated with increased depth of invasion and worse prognosis. We have previously shown that a sub-class of cyclic imides, the N-phenylmaleimides, presented antitumor activity against L1210 leukemia and B16F10 melanoma with evidences of interference in the energetic metabolism. Here, we aimed to investigate if some selected N-phenylmaleimides (M1 and M5) interfere with fatty acids metabolism and its relation with cancer. For that, a model of pre-adipocytes differentiation (3T3-L1 cells) and also human melanoma cells (SK-Mel-147) were used. As results, when 3T3-L1 cells were exposed to non-cytotoxic concentrations of M1 and M5 in the presence of an adipogenic cocktail, intracellular lipid content decreased by 26-36%, marking the inhibition of adipocyte differentiation. High selectivity indexes were obtained for both compounds for tumoral cells. Cell cycle phases analysis revealed a remarkable proportion of cells with DNA fragmentation after their exposure to M1 and M5. This was correlated to both apoptosis and necrosis, showed by Annexin-V/PI assay. Furthermore, M1 and M5 reduced FASN expression by 19-39%, respectively. In conclusion, M1 and M5 presented antiadipogenic and antitumoral activities. The antitumoral activity that was associated to apoptosis and necrosis is a possible consequence of the FASN reduction, which in turn, might result in a fuel decrease to cell proliferation. As it happens with antiangiogenic activity, reduction of fatty acid synthesis might be a potential target for cancer treatment in a strategy of hunger-strike, which valorizes these N-phenylmaleimides as candidates for drug development., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Maleimides consist of an important class of compounds easily synthesized with multiple functional group modification that provides expressive pharmacological properties including, antitumoral activity, mediated mainly by oxidative stress. For this reason, the present study was designed to evaluate the cytotoxicity and the role of reactive oxygen species (ROS) in maleimide-induced cell death. Cell viability assays were performed to determine the cell death type in leukemia cell line induced by the compounds. The oxidative stress in maleimidetreated cells was characterized by antioxidant enzymes activities, intracellular ROS generation, and lipid peroxidation. In addition, we evaluated mitochondrial membrane potential and ATP level. Maleimide derivatives exhibited cytotoxic effects in leukemia cells with significantly increased ROS generation. However, cell viability was partly restored by catalase-treated cells. Caspases activities and caspase-independent key genes related to apoptosis were not altered by maleimides, suggesting necrosis as the main cell death process. Maleimide-induced necrosis was associated with oxidative stress, as an imbalance between ROS levels and glutathione reductase (GR) activity. This damage was also demonstrated by loss of mitochondrial membrane potential (MMP) and ATP depletion in cells treated with maleimide derivatives. These findings strongly confirmed that maleimide derivatives promoted cell death in leukemia cells triggered by oxidative stress, indicating that these compounds might be promising antitumor agents or lead molecules.

This study evaluated the effects of curcumin and/or insulin on antioxidant enzyme activity in blood, liver, and kidney, as well as on lipid peroxidation and delta aminolevulinic dehydratase (δ-ALA-D) activity, and a histopathological analysis of streptozotocin-induced diabetic rats. The animals were divided into six groups (n = 6): control/saline (C); control/curcumin (CCur); diabetic/saline (D); diabetic/insulin (DIns); diabetic/curcumin (DCur); and diabetic/insulin/curcumin (DInsCur). After 30 days of treatment with curcumin and/or insulin, the animals were sacrificed and the liver, kidney, and serum were used for experimental determinations. Results of histopathological analysis showed that the treatment with insulin ameliorate renal and hepatic lesions from both DIns and DInsCur groups. TBARS levels were significantly increased in serum, liver, and kidney in D group and the administration of curcumin and insulin prevented this increase in DIns and DCur groups. The activities of catalase (CAT), superoxide dismutase, and δ-ALA-D presented a significant decrease in the liver and kidney D group when compared to C group (P < 0.05). The animals treated with curcumin and insulin presented an increase of CAT activity, revealing a positive interaction between both substances. The treatments with curcumin or insulin prevented oxidative stress in blood, through modulation of enzymatic antioxidant defenses. These findings contributed to the comprehension that antioxidants from medicinal plants could be used as adjuvant in the treatment of this endocrinopathy and not as single therapy.