Computational approaches for circRNAs prediction and in silico characterization.

Circular RNAs (circRNAs) are single-stranded and covalently closed non-coding RNA molecules originated from RNA splicing. Their functions include regulatory potential over other RNA species, such as microRNAs, messenger RNAs and RNA binding proteins. For circRNA identification, several algorithms are available and can be classified in two major types: pseudo-reference-based and split-alignment-based approaches. In general, the data generated from circRNA transcriptome initiatives is deposited on public specific databases, which provide a large amount of information on different species and functional annotations. In this review, we describe the main computational resources for the identification and characterization of circRNAs, covering the algorithms and predictive tools to evaluate its potential role in a particular transcriptomics project, including the public repositories containing relevant data and information for circRNAs, recapitulating their characteristics, reliability and amount of data reported.

Differences in Bacterial Small RNAs in Stool Samples from Hypercholesterolemic and Normocholesterolemic Subjects.

Cholesterol metabolism is important at the physiological level as well as in several diseases, with small RNA being an element to consider in terms of its epigenetic control. Thus, the aim of this study was to identify differences between bacterial small RNAs present at the gut level in hypercholesterolemic and normocholesterolemic individuals. Twenty stool samples were collected from hypercholesterolemic and normocholesterolemic subjects. RNA extraction and small RNA sequencing were performed, followed by bioinformatics analyses with BrumiR, Bowtie 2, BLASTn, DESeq2, and IntaRNA, after the filtering of the reads with fastp. In addition, the prediction of secondary structures was obtained with RNAfold WebServer. Most of the small RNAs were of bacterial origin and presented a greater number of readings in normocholesterolemic participants. The upregulation of small RNA ID 2909606 associated with Coprococcus eutactus (family Lachnospiraceae) was presented in hypercholesterolemic subjects. In addition, a positive correlation was established between small RNA ID 2149569 from the species Blautia wexlerae and hypercholesterolemic subjects. Other bacterial and archaeal small RNAs that interacted with the LDL receptor (LDLR) were identified. For these sequences, the prediction of secondary structures was also obtained. There were significant differences in bacterial small RNAs associated with cholesterol metabolism in hypercholesterolemic and normocholesterolemic participants.

Personal and household PM2.5 and black carbon exposure measures and respiratory symptoms in 8 low- and middle-income countries.

BACKGROUND: Household air pollution (HAP) from cooking with solid fuels has been associated with adverse respiratory effects, but most studies use surveys of fuel use to define HAP exposure, rather than on actual air pollution exposure measurements. OBJECTIVE: To examine associations between household and personal fine particulate matter (PM2.5) and black carbon (BC) measures and respiratory symptoms. METHODS: As part of the Prospective Urban and Rural Epidemiology Air Pollution study, we analyzed 48-h household and personal PM2.5 and BC measurements for 870 individuals using different cooking fuels from 62 communities in 8 countries (Bangladesh, Chile, China, Colombia, India, Pakistan, Tanzania, and Zimbabwe). Self-reported respiratory symptoms were collected after monitoring. Associations between PM2.5 and BC exposures and respiratory symptoms were examined using logistic regression models, controlling for individual, household, and community covariates. RESULTS: The median (interquartile range) of household and personal PM2.5 was 73.5 (119.1) and 65.3 (91.5) µg/m3, and for household and personal BC was 3.4 (8.3) and 2.5 (4.9) x10-5 m-1, respectively. We observed associations between household PM2.5 and wheeze (OR: 1.25; 95%CI: 1.07, 1.46), cough (OR: 1.22; 95%CI: 1.06, 1.39), and sputum (OR: 1.26; 95%CI: 1.10, 1.44), as well as exposure to household BC and wheeze (OR: 1.20; 95%CI: 1.03, 1.39) and sputum (OR: 1.20; 95%CI: 1.05, 1.36), per IQR increase. We observed associations between personal PM2.5 and wheeze (OR: 1.23; 95%CI: 1.00, 1.50) and sputum (OR: 1.19; 95%CI: 1.00, 1.41). For household PM2.5 and BC, associations were generally stronger for females compared to males. Models using an indicator variable of solid versus clean fuels resulted in larger OR estimates with less precision. CONCLUSIONS: We used measurements of household and personal air pollution for individuals using different cooking fuels and documented strong associations with respiratory symptoms.

MicroRNA-20a-5p Downregulation by Atorvastatin: A Potential Mechanism Involved in Lipid-Lowering Therapy.

The treatment of hypercholesterolemia is mainly based on statins. However, the response to pharmacological therapy shows high inter-individual variability, resulting in variable effects in both lipid lowering and risk reduction. Thus, a better understanding of the lipid-lowering mechanisms and response variability at the molecular level is required. Previously, we demonstrated a deregulation of the microRNA expression profile in HepG2 cells treated for 24 h with atorvastatin, using a microarray platform. In the present study, we evaluated the expression of hsa-miR-17-5p, hsa-miR-20a-5p and hsa-miR-106a-5p in hypercholesterolemic patients before and after atorvastatin treatment and in HepG2 cells treated for 24 h with atorvastatin The miRNA hsa-mir-20a-5p was repressed after atorvastatin treatment in hypercholesteremic subjects and in HepG2 cells in culture. Repression of hsa-mir-20a-5p increased LDLR gene and protein expression in HepG2 cells, while hsa-mir-20a-5p overexpression reduced LDLR gene and protein expression.

Dysregulated MicroRNAs as Biomarkers or Therapeutic Targets in Cisplatin-Induced Nephrotoxicity: A Systematic Review.

The purpose of this systematic review was to map out and summarize scientific evidence on dysregulated microRNAs (miRNAs) that can be possible biomarkers or therapeutic targets for cisplatin nephrotoxicity and have already been tested in humans, animals, or cells. In addition, an in silico analysis of the two miRNAs found to be dysregulated in the majority of studies was performed. A literature search was performed using eight databases for studies published up to 4 July 2021. Two independent reviewers selected the studies and extracted the data; disagreements were resolved by a third and fourth reviewers. A total of 1002 records were identified, of which 30 met the eligibility criteria. All studies were published in English and reported between 2010 and 2021. The main findings were as follows: (a) miR-34a and miR-21 were the main miRNAs identified by the studies as possible biomarkers and therapeutic targets of cisplatin nephrotoxicity; (b) the in silico analysis revealed 124 and 131 different strongly validated targets for miR-34a and miR-21, respectively; and (c) studies in humans remain scarce.

Histological Evaluation and Gene Expression Profiling of Autophagy-Related Genes for Cartilage of Young and Senescent Rats.

Autophagy is a cellular mechanism that protects cells from stress by digesting non-functional cellular components. In the cartilage, chondrocytes depend on autophagy as a principal mechanism to maintain cellular homeostasis. This protective role diminishes prior to the structural damage that normally occurs during aging. Considering that aging is the main risk factor for osteoarthritis, evaluating the expression of genes associated with autophagy in senescent cartilage might allow for the identification of potential therapeutic targets for treatment. Thus, we studied two groups of young and senescent rats. A histological analysis of cartilage and gene expression quantification for autophagy-related genes were performed. In aged cartilage, morphological changes were observed, such as an increase in cartilage degeneration as measured by the modified Mankin score, a decrease in the number of chondrocytes and collagen II (Col2a1), and an increase in matrix metalloproteinase 13 (Mmp13). Moreover, 84 genes associated with autophagy were evaluated by a PCR array analysis, and 15 of them were found to be significantly decreased with aging. Furthermore, an in silico analysis based on by two different bioinformatics software tools revealed that several processes including cellular homeostasis, autophagosome assembly, and aging-as well as several biological pathways such as autophagy, insulin-like growth factor 1 (IGF-1) signaling, PI3K (phosphoinositide 3-kinase)/AKT (serine/threonine kinase) signaling, and mammalian target of rapamycin (mTOR) signaling-were enriched. In conclusion, the analysis identified some potential targets for osteoarthritis treatment that would allow for the development of new therapeutic strategies for this chronic disease.

Prodigiosin Modulates the Immune Response and Could Promote a Stable Atherosclerotic Lession in C57bl/6 Ldlr-/- Mice.

Atherosclerosis is a chronic inflammatory disease, whose progression and stability are modulated, among other factors, by an innate and adaptive immune response. Prodiginines are bacterial secondary metabolites with antiproliferative and immunomodulatory activities; however, their effect on the progression or vulnerability of atheromatous plaque has not been evaluated. This study assessed the therapeutic potential of prodigiosin and undecylprodigiosin on inflammatory marker expression and atherosclerosis. An in vitro and in vivo study was carried out. Migration, low-density lipoprotein (LDL) uptake and angiogenesis assays were performed on cell types involved in the pathophysiology of atherosclerosis. In addition, male LDL receptor null (Ldlr-/-) C57BL/6J mice were treated with prodigiosin or undecylprodigiosin for 28 days. Morphometric analysis of atherosclerotic plaques, gene expression of atherogenic factors in the aortic sinus and serum cytokine quantification were performed. The treatments applied had slight effects on the in vitro tests performed, highlighting the inhibitory effect on the migration of SMCs (smooth muscle cells). On the other hand, although no significant difference in atherosclerotic plaque progression was observed, gene expression of IL-4 and chemokine (C-C motif) ligand 2 (Ccl2) was downregulated. In addition, 50 µg/Kg/day of both treatments was sufficient to inhibit circulating tumor necrosis factor alpha (TNF-α), interleukin-2 (IL-2) and interferon-gamma (IFN-γ) in serum. These results suggested that prodigiosin and undecylprodigiosin modulated inflammatory markers and could have an impact in reducing atherosclerotic plaque vulnerability.

Propolis Reduces the Expression of Autophagy-Related Proteins in Chondrocytes under Interleukin-1ß Stimulus.

BACKGROUND: Osteoarthritis (OA) is a progressive and multifactorial disease that is associated with aging. A number of changes occur in aged cartilage, such as increased oxidative stress, decreased markers of healthy cartilage, and alterations in the autophagy pathway. Propolis extracts contain a mixture of polyphenols and it has been proved that they have high antioxidant capacity and could regulate the autophagic pathway. Our objective was to evaluate the effect of ethanolic extract of propolis (EEP) on chondrocytes that were stimulated with IL-1ß. METHODS: Rabbit chondrocytes were isolated and stimulated with IL-1ß and treated with EEP. We evaluated cell viability, nitric oxide production, healthy cartilage, and OA markers, and the expression of three proteins associated with the autophagy pathway LC3, ATG5, and AKT1. RESULTS: The EEP treatment reduces the expression of LC3, ATG5, and AKT1, reduces the production of nitric oxide, increases the expression of healthy markers, and reduces OA markers. CONCLUSIONS: These results suggest that treatment with EEP in chondrocytes that were stimulated with IL-1ß has beneficial effects, such as a decrease in the expression of proteins associated with autophagy, MMP13, and production of nitric oxide, and also increased collagen II.

Epigenetic Modifications of Major Depressive Disorder.

Major depressive disorder (MDD) is a chronic disease whose neurological basis and pathophysiology remain poorly understood. Initially, it was proposed that genetic variations were responsible for the development of this disease. Nevertheless, several studies within the last decade have provided evidence suggesting that environmental factors play an important role in MDD pathophysiology. Alterations in epigenetics mechanism, such as DNA methylation, histone modification and microRNA expression could favor MDD advance in response to stressful experiences and environmental factors. The aim of this review is to describe genetic alterations, and particularly altered epigenetic mechanisms, that could be determinants for MDD progress, and how these alterations may arise as useful screening, diagnosis and treatment monitoring biomarkers of depressive disorders.

Frequency and specificity of red blood cell alloimmunization in chilean transfused patients.

BACKGROUND: Alloimmunization is an adverse effect of blood transfusions. In Chile, alloimmunization frequency is not established, and for this reason the aim of this study was to investigate the prevalence and specificity of red blood cell (RBC) alloantibodies in Chilean transfused subjects. METHODS: Records from 4,716 multi-transfused patients were analyzed. In these patients, antibody screening was carried out prior to cross-matching with a commercially available two-cell panel by the microcolum gel test, and samples with a positive screen were analyzed for the specificity of the alloantibody with a 16-cell identification panel. RESULTS: The incidence of RBC alloimmunization in transfused patients was 1.02% (48/4,716) with a higher prevalence in women (40/48). We detected 52 antibodies, the most frequent specificities identified were anti-E (30.8%), anti-K (26.9%), anti-D (7.7%), and anti-Fy(a) (5.8%). The highest incidence of alloantibodies was observed in cancer and gastroenterology patients. CONCLUSION: The data demonstrated a low alloimmunization frequency in Chilean transfused patients, principally associated with antibodies anti-E, anti-K, anti-D, and anti-Fy(a).

SLCO1B1 c.388A>G Polymorphism Is Associated with HDL-C Levels in Response to Atorvastatin in Chilean Individuals.

The use of statins as the preferred lipid-lowering therapy has clearly demonstrated its efficacy in the treatment of hypercholesterolemia, reducing also the risk of coronary events and cardiovascular disease mortality. In this study, we assessed single nucleotide polymorphisms (SNPs) in the SLCO1B1 gene and their effect on atorvastatin response. We included 129 Chilean hypercholesterolemic patients undergoing 10 mg/day of atorvastatin therapy during 4 weeks. Lipid profile was determined before and after drug administration. Genotyping of SLCO1B1 rs4149056 (c.521T>C) SNP was performed with allele-specific polymerase chain reaction, whilst polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for genotyping the SLCO1B1 rs2306283 (c.388A>G) variant. After statin therapy, concentrations of TC, LDL-C and TG had a decrease from baseline (p < 0.05). Also, HDL-C levels increased (p < 0.05). Minor allele frequencies for the rs2306283 and rs4149056 variants were 0.547 and 0.136, respectively. LDL-C response to atorvastatin was not associated with the SLCO1B1 rs4149056 nor the rs2306283 polymorphisms (p > 0.05). However, the latter SNP was associated with HDL-C variability after atorvastatin medication (p = 0.02). This study indicates that LDL-C reduction following atorvastatin therapy is not influenced by the SNPs evaluated. In addition, the polymorphism rs2306283 at the SLCO1B1 gene determines greater HDL-C concentrations in response to atorvastatin medication in Chilean hypercholesterolemic subjects.

Identification of microRNAs involved in the modulation of pro-angiogenic factors in atherosclerosis by a polyphenol-rich extract from propolis.

New vessel formation plays a critical role in the progression and vulnerability of atherosclerotic lesions. It has been shown that polyphenols from propolis attenuate the progression of atherosclerosis and also exert inhibitory effects on angiogenic factors. However, the mechanisms underlying these effects are not completely understood. Thus, this study aimed to identify microRNAs (miRNAs) involved in the modulation of pro-angiogenic factors in the atherosclerotic plaques of LDL receptor gene knockout mice treated with a polyphenol-rich extract of Chilean propolis. The progression of the atherosclerotic lesions was significantly attenuated in treated mice compared with control mice. Using microarray analysis and a bioinformatic approach, we identified 29 differentially expressed miRNAs. Many of these miRNAs were involved in biological processes associated with angiogenesis, such as the cell cycle, cell migration, cell growth and proliferation. Among them, three miRNAs (miR-181a, miR-106a and miR-20b) were over-expressed and inversely related to the expression of Vegfa (vascular endothelial growth factor A) and Hif1a (hypoxia inducible factor 1 alpha). In addition, VEGF-A protein expression was attenuated in histological sections obtained from the aortic sinuses of treated mice. VEGFA is a key pro-angiogenic factor in atherosclerotic plaques, and Hif1a, which is expressed in the necrotic nucleus of the atheroma, is its main inducer. We found a correlation between the over-expression of miR-181a, miR-106a and miR-20b and their target genes, Hif1a and Vegfa, which is consistent with attenuation of the atherosclerotic lesion. In conclusion, our data analysis provides evidence that the anti-angiogenic effects of polyphenols from Chilean propolis can be modulated by miRNAs, in particular miR-181a, miR-106a and miR-20b.

Hybrid Cardiac Rehabilitation Program in a Low-Resource Setting: A Randomized Clinical Trial.

Importance: While effective, cardiovascular rehabilitation (CR) as traditionally delivered is not well implemented in lower-resource settings. Objective: To test the noninferiority of hybrid CR compared with traditional CR in terms of cardiovascular events. Design, Setting, and Participants: This pragmatic, multicenter, parallel arm, open-label randomized clinical trial (the Hybrid Cardiac Rehabilitation Trial [HYCARET]) with blinded outcome assessment was conducted at 6 referral centers in Chile. Adults aged 18 years or older who had a cardiovascular event or procedure, no contraindications to exercise, and access to a mobile telephone were eligible and recruited between April 1, 2019, and March 15, 2020, with follow-up until July 29, 2021. Interventions: Participants were randomized 1:1 in permuted blocks to the experimental arm, which received 10 center-based supervised exercise sessions plus counseling in 4 to 6 weeks and then were supported at home via telephone calls and text messages through weeks 8 to 12, or the control arm, which received the standard CR of 18 to 22 sessions with exercises and education in 8 to 12 weeks. Main Outcomes and Measures: The primary outcome was cardiovascular events or mortality. Secondary outcomes were quality of life, return to work, and lifestyle behaviors measured with validated questionnaires; muscle strength and functional capacity, measured through physical tests; and program adherence and exercise-related adverse events, assessed using checklists. Results: A total of 191 participants were included (mean [SD] age, 58.74 [9.80] years; 145 [75.92%] male); 93 were assigned to hybrid CR and 98 to standard CR. At 1 year, events had occurred in 5 unique participants in the hybrid CR group (5.38%) and 9 in the standard CR group (9.18%). In the intention-to-treat analysis, the hybrid CR group had 3.80% (95% CI, -11.13% to 3.52%) fewer cardiovascular events than the standard CR group, and relative risk was 0.59 (95% CI, 0.20-1.68) for the primary outcome. In the per-protocol analysis at different levels of adherence to the intervention, all 95% CIs crossed the noninferiority boundary (eg, 20% adherence: absolute risk difference, -0.35% [95% CI, -7.56% to 6.85%]; 80% adherence: absolute risk difference, 3.30% [95% CI, -3.70% to 10.31%]). No between-group differences were found for secondary outcomes except adherence to supervised CR sessions (79.14% [736 of 930 supervised sessions] in the hybrid CR group vs 61.46% [1201 of 1954 sessions] in the standard CR group). Conclusions and Relevance: The results suggest that a hybrid CR program is noninferior to standard center-based CR in a low-resource setting, primarily in terms of recurrent cardiovascular events and potentially in terms of intermediate outcomes. Hybrid CR may induce superior adherence to supervised exercise. Clinical factors and patient preferences should inform CR model allocation. Trial Registration: ClinicalTrials.gov Identifier: NCT03881150.

Effect of intermediate-term firewood smoke air pollution on cardiometabolic risk factors and inflammatory markers.

Background: Temuco is a city in Southern Chile with elevated levels of air pollution (AP), mainly due to using wood as combustion throughout the cold season. The study aimed to assess the differences in cardiometabolic risk factors, estimated cardiovascular risk, and blood level of inflammatory markers between high AP (HAP) and low AP (LAP) periods. Methods: A prospective panel study was conducted between January to September 2018. Air pollution was assessed by PM2.5 concentration. Ninety individuals from the general population were included in the study. Measurements were performed in the HAP and LAP, including medical history and lifestyle, physical activity assessment, physical exam, and fasting blood samples for glucose, lipids, and circulatory inflammatory mediators. Results: In the high air pollution period, systolic blood pressure was 3 mmHg higher (p = 0.05). HDL-cholesterol was 14.2 mg/dl lower (p < 0.001), Framingham risk score increased from 14.5 to 18.0 (p < 0.001), and highly significant lower levels of interleukins, MCP1, MMP1, MMP2, sICAM, and svCAM were observed. Conclusions: HAP was associated with increased cardiometabolic risk factors and estimated cardiovascular risk. However, a lower level of circulating acute inflammatory molecules was observed. Inflammatory molecules blood levels were not associated with changes in cardiometabolic risk factors.

Modulation of the Cardiovascular Effects of Polycyclic Aromatic Hydrocarbons: Physical Exercise as a Protective Strategy.

Exposure to polycyclic aromatic hydrocarbons (PAHs) present in air pollution increases cardiovascular risk. On the contrary, physical exercise is a widely used therapeutic approach to mitigate cardiovascular risk, but its efficacy in an environment of air pollution, particularly with PAHs, remains unclear. This study investigates the effects of exercise on inflammation, endothelial dysfunction, and REDOX imbalance due to PAH exposure using a mouse model. Twenty male BALB/c mice were subjected to a mixture of PAHs (phenanthrene, fluoranthene, pyrene) in conjunction with aerobic exercise. The investigation evaluated serum levels of inflammatory cytokines, gene expression linked to inflammatory markers, endothelial dysfunction, and REDOX imbalance in aortic tissues. Furthermore, the study evaluated the expression of the ICAM-1 and VCAM-1 proteins. Exercise led to notable changes in serum inflammatory cytokines, as well as the modulation of genes associated with endothelial dysfunction and REDOX imbalance in aortic tissue. In turn, exercise produced a modulation in the protein expression of ICAM-1 and VCAM-1. The findings implicate the potential of exercise to counter PAH-induced damage, as demonstrated by changes in markers. In conclusion, exercise could mitigate the adverse effects related to exposure to PAHs present in air pollution, as evidenced by changes in inflammatory markers, endothelial dysfunction, and REDOX imbalance.

Genotype analysis to clarify RhD variants in discrepant samples of Chilean population.

Introduction: The D antigen variants are classified as weak, partial, and extremely weak (DEL) and can be differentiated using molecular tests. In Chile, the laboratories of local blood centers do not identify variants of the D antigen, referring them for study to the Reference Laboratory of the Public Health Institute of Chile. So, our aim was to talk about the results of the molecular analysis of variants of the D antigen in samples that had different results in the serological classification. Methods: In the D antigen classification of the Rh system, 479 samples with serological discrepant results were sent for molecular analysis. The Rh phenotype was performed with monoclonal anti-C, anti-c, anti-E, and anti-e antisera by direct agglutination. To find the D antigen, researchers used direct agglutination with monoclonal antisera and indirect antiglobulin testing with the column (gel) agglutination method. Molecular analysis was performed with a polymerase chain reaction with sequence-specific primers (SSP-PCR) and sequencing. Results and discussion: The presence of D antigen variants was confirmed in 332 samples (69.3%), with an initial discrepancy in serological classification. In this group of discrepant samples, the frequency of weak RhD variants was 66% (219/332), that of extremely weak RhD was 28% (93/332), and that of partial RhD was 6% (20/332). The weak variants type 2 (27.4%), type 3 (8.4%), type 48 (8.4%), and type 1 (8.1%) were the next most prevalent variants after RHD*DEL43 (28%). The ccEe (R2r) phenotype was the most frequently detected (38.4%) and is present in 87% of the RHD*DEL43 samples. The E antigen is associated with the presence of this variant. Our analyses give the first description of D antigen variants in Chile. The most common variants are DEL type (RHD*DEL43) and weak (weak type 2), which are linked to the ccDEe (R2r) phenotype. These findings allow us to characterize the variants of the D antigen in Chile and, according to the obtained data, to design strategies for the management of donors, patients, and pregnant women.

Polycyclic Aromatic Hydrocarbons (PAHs) Exposure Triggers Inflammation and Endothelial Dysfunction in BALB/c Mice: A Pilot Study.

The particulate matter present in air pollution is a complex mixture of solid and liquid particles that vary in size, origin, and composition, among which are polycyclic aromatic hydrocarbons (PAHs). Although exposure to PAHs has become an important risk factor for cardiovascular disease, the mechanisms by which these compounds contribute to increased cardiovascular risk have not been fully explored. The aim of the present study was to evaluate the effects of PAH exposure on systemic pro-inflammatory cytokines and markers of endothelial dysfunction. An intervention was designed using a murine model composed of twenty BALB/c male mice separated into controls and three groups exposed to a mixture of phenanthrene, fluoranthene, and pyrene using three different concentrations. The serum levels of the inflammatory cytokines and gene expression of adhesion molecules located on endothelial cells along with inflammatory markers related to PAH exposure in aortic tissue were determined. Furthermore, the expression of the ICAM-1 and VCAM-1 proteins was evaluated. The data showed significant differences in IL-6 and IFN-γ in the serum. In the gene expression, significant differences for ICAM-1, VCAM-1, and E-Selectin were observed. The results suggest that phenanthrene, fluoranthene, and pyrene, present in air pollution, stimulate the increase in serum inflammatory cytokines and the expression of markers of endothelial dysfunction in the murine model studied, both relevant characteristics associated with the onset of disease atherosclerosis and cardiovascular disease.

Contribution of MicroRNAs in Chemoresistance to Cisplatin in the Top Five Deadliest Cancer: An Updated Review.

Cisplatin (DDP) is a well-known anticancer drug used for the treatment of numerous human cancers in solid organs, including bladder, breast, cervical, head and neck squamous cell, ovarian, among others. Its most important mode of action is the DNA-platinum adducts formation, inducing DNA damage response, silencing or activating several genes to induce apoptosis; these mechanisms result in genetics and epigenetics modifications. The ability of DDP to induce tumor cell death is often challenged by the presence of anti-apoptotic regulators, leading to chemoresistance, wherein many patients who have or will develop DDP-resistance. Cancer cells resist the apoptotic effect of chemotherapy, being a problem that severely restricts the successful results of treatment for many human cancers. In the last 30 years, researchers have discovered there are several types of RNAs, and among the most important are non-coding RNAs (ncRNAs), a class of RNAs that are not involved in protein production, but they are implicated in gene expression regulation, and representing the 98% of the human genome non-translated. Some ncRNAs of great interest are long ncRNAs, circular RNAs, and microRNAs (miRs). Accumulating studies reveal that aberrant miRs expression can affect the development of chemotherapy drug resistance, by modulating the expression of relevant target proteins. Thus, identifying molecular mechanisms underlying chemoresistance development is fundamental for setting strategies to improve the prognosis of patients with different types of cancer. Therefore, this review aimed to identify and summarize miRs that modulate chemoresistance in DDP-resistant in the top five deadliest cancer, both in vitro and in vivo human models.

Anthocyanins Found in Pinot Noir Waste Induce Target Genes Related to the Nrf2 Signalling in Endothelial Cells.

Grape pomace is a source of anthocyanins, which can prevent cardiovascular diseases due to their antioxidant properties. Anthocyanin activity is associated with the ability to regulate oxidative stress through the transcription factor Nrf2. Thus, the present study aimed to evaluate if the anthocyanins found in Pinot noir pomace extract can affect the target genes related to the Nrf2 signalling pathway in endothelial cells. Our results highlight that the predominant anthocyanin in the Pinot noir pomace extract was malvidin-3-glucoside (3.7 ± 2.7 Eq. Malv-3-glu/kg). Molecular docking indicated that cyanidin-3-glucoside (-6.9 kcal/mol), malvidin-3-glucoside (-6.6 kcal/mol) and peonidin-3-glucoside (-6.6 kcal/mol) showed the highest affinities for the binding sites of the BTB domains in Keap1, suggesting that these components may modify the interaction of this protein with Nrf2. In addition, when HUVEC cells were exposed to different concentrations of Pinot noir pomace extract (100 µg/mL, 200 µg/mL, and 400 µg/mL), no changes in Nrf2 gene expression were observed. However, the gene expression of HO-1 and NQO1, which are in the signalling pathway of this transcription factor, increased according the concentrations of the extract (p = 0.0004 and p = 0.0084, respectively). In summary, our results show that anthocyanins play a very important role in Nrf2 activation and release, while at the same time not promoting its transcription. These preliminary results strongly suggest that the Pinot noir pomace extract can serve as a potent bioactive component source that protects cells against oxidative stress.

MicroRNAs Involved in Intrinsic Apoptotic Pathway during Cisplatin-Induced Nephrotoxicity: Potential Use of Natural Products against DDP-Induced Apoptosis.

Cisplatin (cis-diamminedichloroplatinum (II), DDP) is an antineoplastic agent widely used in the treatment of solid tumors because of its extensive cytotoxic activity. However, the main limiting side effect of DDP use is nephrotoxicity, a rapid deterioration in kidney function due to toxic chemicals. Several studies have shown that epigenetic processes are involved in DDP-induced nephrotoxicity. Noncoding RNAs (ncRNAs), a class of epigenetic processes, are molecules that regulate gene expression under physiological and pathological conditions. MicroRNAs (miRNAs) are the most characterized class of ncRNAs and are engaged in many cellular processes. In this review, we describe how different miRNAs regulate some pathways leading to cell death by apoptosis, specifically the intrinsic apoptosis pathway. Accordingly, many classes of natural products have been tested for their ability to prevent DDP-induced apoptosis. The study of epigenetic regulation for underlying cell death is still being studied, which will allow new strategies for the diagnosis and therapy of this unwanted disease, which is presented as a side effect of antineoplastic treatment.