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Sep 2018
MicroRNAs are short sequences of non-coding RNAs crucial in regulation of cell development, proliferation and differentiation. Some of them showed to be related with the expression of osteogenic genes. Aim of the present review was to evaluate the biological effects of titanium implant surfaces activated with miRNAs or antimiRNAs. A bibliographical electronic research was carried out on PubMed/Medline. Articles investigating the influences of miRNA functionalized surfaces on human or animal cells were included. Reports were excluded if investigating surfaces modified with molecules different from miRNAs, if miRNAs were not loaded to titanium surfaces. Five articles met the inclusion criteria. Surfaces functionalized with miRNAs showed to up-regulate the expression of osteogenic genes like RUNX2, OPN, OCN, BMP, OSX, ALP, COL1 and COL3. Investigated surfaces additionally showed more bone-like mineralized tissues, bone lacunae, osteocytes and new blood vessels. MiRNAs loaded to titanium implant surfaces stimulate the expression of genes related to osteoblasts differentiation, osteogenesis, osseointegration and reparation of mineralized tissues. Vectors used to link titanium surfaces and miRNAs did not show cytotoxicity or interference with cells’ viability.
Mar 2024 DOI 10.14302/issn.2572-3030.jcgb-24-4970
Melanoma treatment has improved significantly with the development of immune checkpoint inhibition (ICI), which has greatly enhanced the survival rates of patients with metastatic melanoma. However, a significant number of patients do not respond well to ICI treatment and experience progression. This highlights the critical need for practical means to track melanoma patients' response to ICI. To address this issue, the patterns of circulating miRNAs were studied in liquid biopsies of melanoma patients. These miRNAs have the potential to provide essential information regarding the cancer stage, progression, and the presence of PD-L1 in tumor tissue. A sophisticated flow cytometric test was used to measure up to 63 different miRNAs at once. The study identified a combination of nine miRNAs that are capable of distinguishing between different stages of melanoma, particularly stage IV. Additionally, five miRNAs were pinpointed which are downregulated in patients who do not respond to ICI treatment. Furthermore, two miRNAs were found that correlate to the level of PD-L1 in tumor tissue, and low levels of miR-150-5p were linked to poorer overall survival. These findings suggest that circulating miRNAs could serve as valuable markers to predict the effectiveness of ICI, provide insights into the cancer's stage and PD-L1 status, and ultimately help physicians make better treatment decisions in the future. However, further research is needed to confirm these findings and establish their clinical usefulness.
Oct 2020 DOI 10.14302/issn.2379-7835.ijn-20-3418
Isolation methods that employ readily-available inexpensive supplies on the open market, which are reliable, as well as economical, such as nucleic acid amplification techniques (NAAT) based on microfluidic technology in low-resource research settings (LRRS) that meets the ASSURED guidelines are essential to develop a noninvasive diagnostic colon cancer screen in stool using micro(mi)RNA molecules. A combination of a microfluidic-based MiRNA stool test with a reliable rolling circle amplification/detection method applied to the quantification of miRNA molecules, result in an affordable sensitive and specific isothermal method for the noninvasive quantitative detection of miRNAs in LRRS. Scientists and engineers have become interested in miRNAs, and they have intensified their efforts to apply emerging simple detection tools to the important bioanalytical challenge of quantifying these small 18-26 nt long molecules. Some of the proposed approaches incorporate novel material, such as simple centrifuges and methods based on microfluidic technology, while others utilize the interesting biological properties of these molecules, such as forming branched RCA structures, allowing for the detection of these biomarker molecules at an attomolar "aM" concentration level, using low cost extraction and isothermal amplification methods in LRRS. We have been interested in studying colorectal cancer (CRC) because it is the 3rd most common malignancy worldwide, and stool can be obtained noninvasively from the patients. We have focused in this research on colon cancer (CC) because it is more common in the USA than rectal cancer (RC). The innovation of our approach lies in the exploratory use of an affordable, quantitative miRNA profiling in noninvasive stool samples in LRRS, whose extracted fragile total RNA is stabilized shortly after excretion from stool by commercially available kits, so it does not ever fragment, followed by quantitative standardized analytical tests that are neither labor intensive, nor require expensive instrumentation, in order to develop apanel of novel miRNA genes for the noninvasive diagnostic screening of early left and right sporadic colon cancers, more economically, and with higher sensitivity and specificity than any other colon cancer screening test currently available on the market. To show the clinical sensitivity and specificity of the proposed quantitative miRNA test using simple methodologies in LRRS,the miRNA results are to be correlated with FOBT, colonoscopy, and pathology data. Standardization establishes test’s performance criteria (sample selection, optimal sample running conditions, preservation and storage), in order to ensure that the assay will perform the same way in any laboratory, by any trained personnel, anywhere in low-resource laboratory settings worldwide.
Jun 2020 DOI 10.14302/issn.2379-7835.ijn-19-3123
Isolation methods that employ readily-available inexpensive supplies on the open market, which are reliable, as well as economical, such as nucleic acid amplification techniques (NAAT) based on microfluidic technology in low-resource research settings (LRRS) that meets the ASSURED guidelines are essential to develop a noninvasive diagnostic colon cancer screen in stool using micro(mi)RNA molecules. A combination of a microfluidic-based MiRNA stool test with a reliable rolling circle amplification/detection method applied to the quantification of miRNA molecules, result in an affordable sensitive and specific isothermal method for the noninvasive quantitative detection of miRNAs in LRRS. Scientists and engineers have become interested in miRNAs, and they have intensified their efforts to apply emerging simple detection tools to the important bioanalytical challenge of quantifying these small 18-26 nt long molecules. Some of the proposed approaches incorporate novel material, such as simple centrifuges and methods based on microfluidic technology, while others utilize the interesting biological properties of these molecules, such as forming branched RCA structures, allowing for the detection of these biomarker molecules at an attomolar "aM" concentration level, using low cost extraction and isothermal amplification methods in LRRS. We have been interested in studying colorectal cancer (CRC) because it is the 3rd most common malignancy worldwide, and stool can be obtained noninvasively from the patients. We have focused in this research on colon cancer (CC) because it is more common in the USA than rectal cancer (RC). The innovation of our approach lies in the exploratory use of an affordable, quantitative miRNA profiling in noninvasive stool samples in LRRS, whose extracted fragile total RNA is stabilized shortly after excretion from stool by commercially available kits, so it does not ever fragment, followed by quantitative standardized analytical tests that are neither labor intensive, nor require expensive instrumentation, in order to develop apanel of novel miRNA genes for the noninvasive diagnostic screening of early left and right sporadic colon cancers, more economically, and with higher sensitivity and specificity than any other colon cancer screening test currently available on the market. To show the clinical sensitivity and specificity of the proposed quantitative miRNA test using simple methodologies in LRRS,the miRNA results are to be correlated with FOBT, colonoscopy, and pathology data. Standardization establishes test’s performance criteria (sample selection, optimal sample running conditions, preservation and storage), in order to ensure that the assay will perform the same way in any laboratory, by any trained personnel, anywhere in low-resource laboratory settings worldwide.
Mar 2019 DOI 10.14302/issn.2379-7835.ijn-19-2578
We present below a mechanistic cellular and molecular approaches for the development of Anti-Inflammatory biomarkersof Probiotic Bacteria in Fermented Foods. Probiotics are live microorganisms that promote human health by counteracting the noxious toxic gut microflora in human intestine, by modulating of the tight junctions, and by increasing mucin production, enforcing intestinal epithelial cell barrier function, modifying microbial community within the gut intestinal disorders, and improving immune responses associated with chronic inflammation in experimental animal models, collectively enhancing human health. Cytokine secretion by intestinal epithelial cells and macrophages are regulated by probiotics through key signaling pathways such as nuclear factor-κB and mitogen-activated kinases, resulting in alleviation of several disorders such as allergies, diabetes, obesity, heart diseases and cancer. MicroRNAs are small non-coding RNA molecules involved in transcriptional and post-translational regulation of gene expression by inhibiting gene translation. Using in vitro and in vivo approaches in cell lines and mice models to study effects of probiotic conditional media and heat-killed bacterial strains with anti-inflammatory effect to elucidate the mechanisms by which probiotics affect signaling pathways, and by using global cytokine and microRNA gene expression analyses approaches to develop biomarkers for studying different pro- and anti-inflammatory activities, and using statistical approaches to analyse the data, we show that cytokines and miRNAs have an essential role in regulation of cancerous and inflammatory pathways. This mechanistic approach will result in developing specific disease biomarkers for the early diagnosis of certain pathogenic states, as well as evaluating the effect of different dietary components on developed biomarkers in health states that will promote and enhance human health. Comparing the concordance of the in vitro to the in vivo research findings will confirm the correspondence of both approaches to each other. Moreover, this study will have a major public health relevance in elucidating the role of miRNAs and their targets in inflammation, paving the way to diagnosing and treating of pathogenic human disease stages.
Feb 2019 DOI 10.14302/issn.2471-7061.jcrc-18-2526
There is currently no validated micro(mi)RNA diagnostic stool test to screen for colon cancer (CC) on the market because of the complexity of fecal density, vulnerability of stool to daily changes, and the presence of three sources of miRNAs in stool (cell-free from fecal homogenates, exsosomal miRNAs from fecal exosomes, and fecal colonocytes). To address these complexities, we have first carried out a microarray miRNA experiment, using Affymetrix GeneChip miRNA 2.0 Arrays, on immunocaptured and enriched stool colonocytes of 15 subjects (three healthy controls and twelve colon cancer patients [three TNM stage 0-1 (e.g., polyps◻ ³ 1 cm, villous or tubvillous, or with high grade dysplasia), three stage 2, three stage 3, and three stage 4 in triplicates to select a smaller panel of 14 preferentially expressed mature miRNAs associated with colon cancer (12 Up-Regulated, miR-19a, miR-20a, miR-21, miR-31, miR-34a, miR-96, miR-106a, miR-133a, miR-135b, miR-206, miR-224 and miR-302; and 2 Down-Regulated, miR-143 and miR-145). In a subsequent validation study carried out on total small RNA extracted by immunocapture, followed by RT that employed TaqMan® miRNA Reverse Transcription (RT) Kit and a Custom TaqMan RT Primer Pool, absolute quantification of miRNAs, in copies/µl, was measured using a chip-based Absolute QuantStudio 3D Digital PCR analysis. To ensure that we have chosen human and not bacterial small total RNA, we have carried out coextraction protocols with E. coli K1 strain RS18, compare Agilent electrophoretic patterns, and also sequenced random samples throughout this research using mRNA/miRNA sequencing. Our initial quantitative dPCR miRNA data presented herein showe that the quantitative changes in the expression of a few mature miRNA genes in stool, which are associated with right and left colon cancer, would provide for a more convenient, sensitive and specific diagnostic screening markers thatare more useful than those test markers currently available on the market, such as the low-sensitivity (<15%) fecal occult blood test (FOBT); result in better compliance; and is more economical than the invasive and expensive colonoscopy exam in colon cancer, which can be cured if that cancer is detected at the early TNM stages, and that becomes incurable and deadly if not diagnosed before metastasis. Initial test performance characteristics of the miRNA approach showed that the test has a high numerical predictive value in colon cancer. Moreover, underpinning of the miRNA markers as a function of total RNA showed that the test can numerically differentiate between control subjects and colon cancer patients, particularly at the early stages of that curable cancer. We propose to extend our initial research results to a larger prospective and randomized five-years nested case-control study, to validate the expression of the above 14 miRNAs, in stool of 180 individuals in an epidemiologically designed study, using (30 controls and 150 colon cancer patients (thirty precancerous polyps (stage 0-1), forty five stage 2, and seventy-five colon cancer stages 3 or 4). chosen randomly by an epidemiological method from 900 control and CC subjects to allow for an adequate time to collect the required 900 stool samples, as well as allowing for statistically valid analysis, standardized test conditions, and to provide a mean for determining the true sensitivity and specificity of a miRNA-screening approach in noninvasive human stool. Power-analysis has indicated that a total of 180 individuals, which will take us 5 years to enroll in testing, is an appropriate number of subjects to standardize and validate our proposed miRNA screening test. We may find out at the end of the proposed validation study in stool that fewer miRNAs, or even one miRNA, may suffice to serve as an efficient and a quantitative marker for the non-invasive diagnostic screening of colon cancer in human stool. The above approach when combined with bioinformatics analysis, to correlate miRNA seed data with our previously published messenger (m)RNA target data in stool, allows for a thorough mechanistic understanding of how miRNA genes regulate mRNA expression, and would offer a better comprehensive diagnostic screening test for the non-invasive early detection stage (0-1) of colon cancer. In order to show the clinical sensitivity and specificity of the proposed miRNA test, the absolute miRNA PCR values, in copies/µl, will be correlated with FOBT, colonoscopy, and pathology data. Standardization will establish test’s performance characteristics (sample selection, optimal sample running conditions, preservation and storage) to ensure that the assay will perform the same way in any laboratory, by any trained personnel, anywhere in the World. Ultimately, a smaller number of selected validated miRNAs (<10) showing increased and reduced expression could suffice to give quantitative miRNAs colon cancer expression values, useful for the early diagnostic screening of that curable cancer.
Jun 2017 DOI 10.14302/issn.2329-9487.jhc-17-1536
Over the last few decades, many research works highlighted the role of miRNAs on cardiac diseases. Ischaemic heart disease (IHD) or coronary heart disease is a condition that is mainly caused by atherosclerosis. It has been established that microribonucleic acids regulate many factors that are involved in the development and pathophysiology of IHD. As a result, there are great potential opportunities for miRNAs to be used as a biomarker for disease differentiation, as well as novel drug targets or therapeutics for the treatment and also as a diagnostic approach. As it is now evident that miRNAs play critical roles in the disease mechanisms, this review article tried to focus on the pathway, in which; the miRNAs stimulate the IHD to develop. By understanding the mechanisms, it will be possible to present a complete strategy of IHD treatment and also solving all the impediments that are highlighted in this article. Still, there are a number of limitations and obstacles on the way of developing a proper therapeutic approach that can be approved and well accepted. This review is mainly dependent on the potential of miRNAs as a promising arena on the field of cardiac treatment and the possible obstacles that are needed to be explored and overcome.
Oct 2015 DOI 10.14302/issn.2329-9487.jhc-15-677
The aim of this review is to compile our understanding of microRNA (miRNA) and its significance in Hypertension (HTN) pathophysiology. The wide spectrum of health disparity is one of the reasons for the dominance of HTN in humans for decades. We are striving hard to understand these variations, and we know to some extent that genetic susceptibilities do exist in HTN. Understanding miRNA will add to the current understanding of the disease process. In later parts, we discussed possible clinical implications of miRNAs in HTN as a biomarker of disease expression and its potential in prognostic and therapeutic applications in HTN.
May 2015 DOI 10.14302/issn.2572-3030.jcgb-14-495
Thyroid carcinomas encompass a wide spectrum ranging from differentiated thyroid carcinoma (DTC) to poorly differentiated (PDC) and anaplastic thyroid carcinoma (ATC). DTC of both follicular (FTC) and papillary (PTC) types can progress to PDC and AC. The aim of our study was to evaluate if there is differential microRNA (miRNA) expression in various tumor subtypes during this progression. The miRNA profile of differentiated carcinomas (Follicular and Papillary) and ATC were compared with that of PDCs either by itself or in a background of differentiated carcinomas and anaplastic carcinomas. Unsupervised hierarchical clustering analysis revealed that FTC and PDC tend to cluster together in the absence of ATC. Interestingly, in cases with presence of all components i.e. FTC, PDC and ATC, the miRNA profile of poorly differentiated component clusters with that of the Anaplastic carcinoma component. miR-494 and miR-125a-5p were found to be differentially regulated in tumors with an anaplastic component and even the well-differentiated component (FTC) of these tumors were found to be aligned with the anaplastic profile. In addition, we also discovered some differentially regulated miRNAs in follicular variant of papillary thyroid carcinoma as compared to follicular thyroid carcinoma (miR-486-5p and miR-31).
May 2015 DOI 10.14302/issn.2379-7835.ijn-14-603
Epigenetic mechanisms based on DNA methylation, histone modifications and RNA interference have recently showed important association to the development of a wide variety of diseases such as cancer, cardiovascular, metabolic, skin, autoimmune diseases and neurologic disorders. In the context of preventive aspects, the importance of nutrition on epigenetic function has been revealed. Therefore, drastic changes in dietary modifications may contribute to reduced disease risk. For instance, dietary intervention has been showed to affect DNA methylation in Alzheimer’s disease patients. Moreover, maternal high-fat diet can regulate gene expression through promoter histone modifications. Most importantly, RNA interference and particularly micro-RNA mediated regulation of gene expression has been linked to disease development. Remarkably, dietary intake has been demonstrated to significantly affect various miRNAs and their regulation on gene function. In this review, the relationship between epigenetics and disease and development of drugs based on epigenetic targets is presented as well as the influence of dietary intake on epigenetic mechanisms and its effect on disease prevention and therapy will be discussed.