Atherosclerosis is a major cardiovascular disease and in 2016, the World Health Organisation (WHO) estimated 17.5 million global deaths, corresponding to 31% of all global deaths, were driven by ...inflammation and deposition of lipids into the arterial wall. This leads to the development of plaques which narrow the vessel lumen, particularly in the coronary and carotid arteries. Atherosclerotic plaques can become unstable and rupture, leading to myocardial infarction or stroke. Extracellular vesicles (EVs) are a heterogeneous population of vesicles secreted from cells with a wide range of biological functions. EVs participate in cell-cell communication and signalling via transport of cargo including enzymes, DNA, RNA and microRNA in both physiological and patholophysiological settings. EVs are present in atherosclerotic plaques and have been implicated in cellular signalling processes in atherosclerosis development, including immune responses, inflammation, cell proliferation and migration, cell death and vascular remodeling during progression of the disease. In this review, we summarise the current knowledge regarding EV signalling in atherosclerosis progression and the potential of utilising EV signatures as biomarkers of disease.
•Extracellular vesicles are secreted under physiological and pathological conditions.•They participate in cellular signalling via transfer of their cargo.•They may contribute to all stages of atherosclerotic lesion progression.•Circulating extracellular vesicles could serve as biomarkers.•Extracellular vesicles could be used as therapeutic tools.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
RNA interference (RNAi) is a potent and specific post-transcriptional gene silencing process. Since its discovery, tremendous efforts have been made to translate RNAi technology into therapeutic ...applications for the treatment of different human diseases including respiratory diseases, by manipulating the expression of disease-associated gene(s). Similar to other nucleic acid-based therapeutics, the major hurdle of RNAi therapy is delivery. Pulmonary delivery is a promising approach of delivering RNAi therapeutics directly to the airways for treating local conditions and minimizing systemic side effects. It is a non-invasive route of administration that is generally well accepted by patients. However, pulmonary drug delivery is a challenge as the lungs pose a series of anatomical, physiological and immunological barriers to drug delivery. Understanding these barriers is essential for the development an effective RNA delivery system. In this review, the different barriers to pulmonary drug delivery are introduced. The potential of RNAi molecules as new class of therapeutics, and the latest preclinical and clinical studies of using RNAi therapeutics in different respiratory conditions are discussed in details. We hope this review can provide some useful insights for moving inhaled RNAi therapeutics from bench to bedside.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Osteoporosis is the consequence of altered bone metabolism resulting in the systemic reduction of bone strength and increased risk of fragility fractures. MicroRNAs (miRNAs) regulate gene ...expression on a post-transcriptional level and are known to take part in the control of bone formation and bone resorption. In addition, it is known that miRNAs are secreted by many cell types and can transfer “messages” to recipient cells. Thus, circulating miRNAs might not only be useful as surrogate biomarkers for the diagnosis or prognosis of pathological conditions, but could be actively modulating tissue physiology. Therefore, the aim of this study was to test whether circulating miRNAs that exhibit changes in recent osteoporotic fracture patients could be causally related to bone metabolism. In the first step we performed an explorative analysis of 175 miRNAs in serum samples obtained from 7 female patients with recent osteoporotic fractures at the femoral neck, and 7 age-matched female controls. Unsupervised cluster analysis revealed a high discriminatory power of the top 10 circulating miRNAs for patients with recent osteoporotic fractures. In total 6 miRNAs, miR-10a-5p, miR-10b-5p, miR-133b, miR-22-3p, miR-328-3p, and let-7g-5p exhibited significantly different serum levels in response to fracture (adjusted p-value < 0.05). These miRNAs were subsequently analyzed in a validation cohort of 23 patients (11 control, 12 fracture), which confirmed significant regulation for miR-22-3p, miR-328-3p, and let-7g-5p. A set of these and of other miRNAs known to change in the context of osteoporotic fractures were subsequently tested for their effects on osteogenic differentiation of human mesenchymal stem cells (MSCs) in vitro. The results show that 5 out of 7 tested miRNAs can modulate osteogenic differentiation of MSCs in vitro. Overall, these data suggest that levels of specific circulating miRNAs change in the context of recent osteoporotic fractures and that such perturbations of “normal” levels might affect bone metabolism or bone healing processes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Loss of functionality during aging of cells and organisms is caused and accompanied by altered cell-to-cell communication and signalling. One factor thereby is the chronic accumulation of senescent ...cells and the concomitant senescence-associated secretory phenotype (SASP) that contributes to microenvironment remodelling and a pro-inflammatory status. While protein based SASP factors have been well characterized, little is known about small extracellular vesicles (sEVs) and their miRNA cargo. Therefore, we analysed secretion of sEVs from senescent human dermal fibroblasts and catalogued the therein contained miRNAs. We observed a four-fold increase of sEVs, with a concomitant increase of >80% of all cargo miRNAs. The most abundantly secreted miRNAs were predicted to collectively target mRNAs of pro-apoptotic proteins, and indeed, senescent cell derived sEVs exerted anti-apoptotic activity. In addition, we identified senescence-specific differences in miRNA composition of sEVs, with an increase of miR-23a-5p and miR-137 and a decrease of miR-625-3p, miR-766-3p, miR-199b-5p, miR-381-3p, miR-17-3p. By correlating intracellular and sEV-miRNAs, we identified miRNAs selectively retained in senescent cells (miR-21-3p and miR-17-3p) or packaged specifically into senescent cell derived sEVs (miR-15b-5p and miR-30a-3p). Therefore, we suggest sEVs and their miRNA cargo to be novel, members of the SASP that are selectively secreted or retained in cellular senescence.
•Heat stress significantly induced unreduced pollen formation in Camellia nitidissima.•An overview of miRNAs presented in heated anther of Camellia nitidissima is provided.•MiRNAs involved in ...unreduced pollen formation induced by heat stress are screened.
Heat stress is often employed as a physical mutagenic agent to produce unreduced gametes because of its operational advantages and consistency of treatment. MicroRNAs (miRNAs) are critical for the control of gene expression through post-transcription in plants exposed to abiotic stresses. Here, the effect of heat stress on flower buds and pollen in Camellia nitidissima was investigated, and it was demonstrated that heat treatment significantly stimulated the formation of unreduced pollen. The highest frequency of unreduced pollen, 48.67 ± 2.10%, was obtained in the treatment at 42 °C for 4 hrs. Integrated analysis was conducted to identify and characterize the miRNAs and their targets involved in unreduced pollen formation induced by heat stress, through small RNA, degradome, and transcriptome sequencing. In all 268 known and 234 novel miRNAs were identified from heated anthers (AnT), untreated anthers (AnC), heated petals (PeT), and untreated petals (PeC) samples, of which 42 miRNAs were specifically regulated in the comparison of AnT vs AnC. The targets of miRNAs were predicted by degradome analysis, and the expression profiles of these targets were characterized based on transcriptome sequencing. A total of 150 negatively regulated DE miRNA-DEG pairs were found using the 42 specifically regulated DE miRNAs in AnT vs AnC as screening criteria. Among them, ten candidate miRNA-target pairs that were involved in unreduced pollen formation induced by heat stress were screened based on the GO annotation of the targets. One pair (Cni-miR535a-MUS81), two pairs (Cni-miR168b-TUBA1 and Cni-miR6478-TUBB), seven pairs (Cni-miR8674-STL1, Cni-miR159f-CSLG2, Cni-miR535b-SBT1.6, Cni-miRn37-TBL6, Cni-miRn112-BGAL2, Cni-miRn61-RHD3, and Cni-miR168b-TUBA1), and one pair (Cni-miR156k-GRV2) were associated with cross-overs, microtubule, cell wall, and vacuole, respectively. For the first time, our findings indicate the potential roles of miRNAs in unreduced pollen formation. It is also a fundamental resource for further study on miRNA-mediated regulation of unreduced pollen formation induced by heat stress in C. nitidissima.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Regulation of the PI-3 kinase (PI3K)/Akt signalling pathway is essential for maintaining the integrity of fundamental cellular processes, cell growth, survival, death and metabolism, and ...dysregulation of this pathway is implicated in the development and progression of cancers. Receptor tyrosine kinases (RTKs) are major upstream regulators of PI3K/Akt signalling. The phosphatase and tensin homologue (PTEN), a well characterised tumour suppressor, is a prime antagonist of PI3K and therefore a negative regulator of this pathway. Loss or inactivation of PTEN, which occurs in many tumour types, leads to overactivation of RTK/PI3K/Akt signalling driving tumourigenesis. Cellular PTEN levels are tightly regulated by a number of transcriptional, post-transcriptional and post-translational regulatory mechanisms. Of particular interest, transcription of the PTEN pseudogene, PTENP1, produces sense and antisense transcripts that exhibit post-transcriptional and transcriptional modulation of PTEN expression respectively. These additional levels of regulatory complexity governing PTEN expression add to the overall intricacies of the regulation of RTK/PI-3 K/Akt signalling. This review will discuss the regulation of oncogenic PI3K signalling by PTEN (the regulator) with a focus on the modulatory effects of the sense and antisense transcripts of PTENP1 on PTEN expression, and will further explore the potential for new therapeutic opportunities in cancer treatment.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
RNA interference (RNAi) is being extensively investigated as a potential therapeutic strategy for cancer treatment. However, RNAi-based therapeutics have not yet been used to treat cancer because of ...their instability and the difficulty of microRNA (miRNA) delivery. Plasmonic nanoparticle-based RNAi nanotherapeutics have been developed for accurate and sensitive diagnosis and a strong therapeutic effect on cancers by leveraging their ease-of-use and specific properties such as photothermal conversion. In this review, recent strategies and advances in plasmonic nanoparticle-based miRNA delivery are briefly presented to facilitate the detection and treatment of several cancers. The challenges and potential opportunities afforded by the RNAi-based theragnosis field are discussed. We expect that the RNAi-integrated plasmonic nanotherapeutics discussed in this review can provide insights for the early diagnosis and effective treatment of cancer.
RNA interference (RNAi) is a potential strategy for cancer diagnosis and treatment. Especially, plasmonic nanomaterial-based RNAi delivery systems have various advantages using its plasmonic property, such as optical imaging and photothermal effect. In this review, recently announced microRNA detection using plasmonic nanomaterials and small interfering RNA (siRNA)-based treatment techniques are briefly described for cancer therapy. Display omitted
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
MicroRNA (miRNA) is an important biomarker for early diagnosis or progression of a disease because the type and amount of its release can vary depending on the type or condition of the cell. However, ...since microRNAs exist at low concentrations in the body with several microRNAs released, it is necessary to develop a biosensor that can sensitively measure multiple miRNAs. In this study, a metal-enhanced fluorescence (MEF)-based highly sensitive nanobiosensor for measuring multiple miRNAs was developed. To extend the plasmonic-based MEF phenomenon to fluorescent materials with various emission wavelengths, porous gold (Au) nanorods with a wide absorption wavelength were synthesized. Using this, two different miRNAs were simultaneously measured sensitively and selectively. The proposed sensing method is a highly sensitive, rapid, simple, and one-step way for multiplex detection of miRNAs. It can be used for early diagnosis of cancer and other nucleic acid-related diseases.
•The multiplexed metal-enhanced fluorescence (MEF) nanobiosensor was developed.•Porous Au nanorod induced multiple MEF to measure multi-miRNAs simultaneously.•The limit of detection was around 0.1 pM with rapid (< 60 min) manner.•This sensor could be applied as a platform technology for multi miRNA detection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Crop domestication has a tremendous impact on socioeconomic conditions and human civilization. Modern cultivars were domesticated from their wild progenitors thousands of years ago by the ...selection of natural variation by humans. New cultivars are being developed by crossing two or more compatible individuals. But the limited genetic diversity in the cultivars severely affects the yield and renders the crop susceptible to many biotic and abiotic stresses. Crop wild relatives (CWRs) are the rich reservoir for many valuable agronomic traits. The incorporation of useful genes from CWR is one of the sustainable approaches for enriching the gene pool of cultivated crops. However, CWRs are not suited for urban and intensive cultivation because of several undesirable traits. Researchers have begun to study the domestication traits in the CWRs and modify them using genome-editing tools to make them suitable for extensive cultivation. Growing evidence has shown that modification in these genes is not sufficient to bring the desired change in the neodomesticated crop. However, the other dynamic genetic factors such as microRNAs (miRNAs), transposable elements, cis-regulatory elements and epigenetic changes have reshaped the domesticated crops. The creation of allelic series for many valuable domestication traits through genome editing holds great potential for the accelerated development of neodomesticated crops. The present review describes the current understanding of the genetics of domestication traits that are responsible for the agricultural revolution. The targeted mutagenesis in these domestication genes via clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 could be used for the rapid domestication of CWRs.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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