Search Results (9)

MicroRNAs (miRNAs) are small non-coding RNAs that play pivotal roles in post-transcriptional gene regulation, influencing development, differentiation, and disease pathogenesis. Since their discovery in 1993, miRNAs have been recognized for their evolutionary conservation and pleiotropic effects, with the 2024 Nobel Prize underscoring their significance in post-transcriptional regulation via the RNA interference (RNAi) pathway. This review synthesizes the complete life cycle of miRNAs—from transcription and processing to function and decay—emphasizing regulatory mechanisms and their implications in human diseases, particularly cancer. We discuss how epitranscriptomic modifications influence miRNA biogenesis and activity, explore their nuclear and mitochondrial functions, and address emerging challenges in miRNA-based therapeutics, including the expanding small RNA landscape such as tRNA-derived small RNAs (tsRNAs), and Argonaute (AGO)-independent activities. Despite hurdles such as modest multi-target effects, off-target interactions, and delivery challenges, miRNAs remain promising as both biomarkers and therapeutic agents, underscoring the need for sustained research to bridge preclinical insights with clinical applications. Full article

MicroRNAs (miRNAs), as an integral component of gene regulatory networks, play a critical role in post-transcriptional regulation, maintaining a dynamic balance between miRNA biogenesis and turnover essential for maintaining cellular homeostasis. The regulation of miRNA turnover, particularly through target-directed microRNA degradation (TDMD), is emerging as a key mechanism in gene expression control in response to physiological, developmental, and environmental changes. This process is mediated by the ubiquitin–proteasome system (UPS), where the E3 ligase ZSWIM8 functions as an adaptor to facilitate the recognition and degradation of Argonaute (AGO) proteins, essential components of the miRNA-induced silencing complex (miRISC), thus negatively regulating gene expression. The ZSWIM8–UPS axis contributes to the precise modulation of miRNA levels by targeting AGO proteins for degradation, thereby influencing miRNA stability and function. This review summarizes the mechanisms underlying ZSWIM8-mediated TDMD, its molecular interactions, and the potential therapeutic applications of targeting miRNA turnover pathways. By understanding the regulation of miRNA degradation, we aim to inform future strategies for the clinical manipulation of miRNA-based therapeutics. Full article

MicroRNAs (miRNAs) are ~22-nucleotide small non-coding RNAs that play critical roles in gene regulation. The discovery of miRNAs in Caenorhabditis elegans in 1993 by the research groups of Victor Ambros and Gary Ruvkun opened a new era in RNA research. Typically, miRNAs act as negative regulators of gene expression by binding to complementary sequences within the 3′ untranslated regions of their target mRNAs. This interaction results in translational repression and/or target destabilization. The expression levels and activities of miRNAs are fine-tuned by multiple factors, including the miRNA biogenesis pathway, variability in target recognition, super-enhancers, post-transcriptional modifications, and target-directed miRNA degradation. Together, these factors form complex mechanisms that govern gene regulation and underlie several pathological conditions, including Argonaute syndrome, genetic diseases driven by super-enhancer-associated miRNAs, and miRNA-deadenylation-associated bone marrow failure syndromes. In addition, as miRNA genes have evolved rapidly in vertebrates, miRNA regulation in the brain is characterized by several unique features. In this review, we summarize recent insights into the role of miRNAs in human diseases, focusing on miRNA biogenesis; regulatory mechanisms, such as super-enhancers; and the impact of post-transcriptional modifications. By exploring these mechanisms, we highlight the intricate and multifaceted roles of miRNAs in health and disease. Full article

Including dietary fat can increase the energy density of diets fed to ruminants, reducing dry matter intake (DMI). Effects of different fat sources on nutrient digestion and fermentation can vary depending on dietary fat concentration and the forage-to-concentrate ratio (F:C). Therefore, this study’s objective was to screen the effects of fat sources supplemented at different concentrations to high- and low-forage diets on in vitro digestibility and fermentation. Treatments included either low forage (LF; 35%) or high forage (HF; 70%) with two fat levels (6 or 9% DM) using six different fat sources, plus control. The control diet (CON) had a basal level of fat in the diet (3% fat; 0% fat inclusion), and fat sources were added to attain 6% or 9% dietary fat and consisted of the following: Coconut oil, CO; Poultry fat, PF; Palm oil, PO; Palm kernel oil, PKO; Soybean oil, SOY; and Ca Salts, MEG. In vitro Gas Production (GP) modules were randomly assigned to treatments in a 2 × 2 × 7 factorial design and were incubated for four 24 h runs. The CO-fed module had the highest dry matter (DM) apparent digestibility (AD) (p < 0.01), followed by SOY and PF. The true DM digestibility (TDMD) and organic matter (OM) AD were the highest in CO (p < 0.01) than the other fat types. The AD for DM, OM, neutral detergent fiber (NDF), and acid detergent fiber (ADF) was higher in LF (p < 0.01). The 6% fat inclusion had a higher GP (109 vs. 103 mL ± 2.09; p < 0.03). Total volatile fatty acid (VFA) concentration was lower in different fat types than the CON and the acetate molar proportion (p > 0.01). The propionate was the lowest for the CON, which increased the acetate to propionate (A:P) ratio (p < 0.01). These results suggest that LF diets with high fat concentrations can be utilized, and different fat sources may improve DM and fiber digestibility. Full article

The epigenetic regulation of gene expression is a complex and tightly regulated process that defines cellular identity and is associated with health and disease processes. Oxidative stress is capable of inducing epigenetic modifications. The transcription factor NRF2 (nuclear factor erythroid-derived 2-like 2) is a master regulator of cellular homeostasis, regulating genes bearing antioxidant response elements (AREs) in their promoters. Here, we report the identification of ARE sequences in the promoter regions of genes encoding several epigenetic regulatory factors, such as histone deacetylases (HDACs), DNA methyltransferases (DNMTs), and proteins involved in microRNA biogenesis. In this research, we study this possibility by integrating bioinformatic, genetic, pharmacological, and molecular approaches. We found ARE sequences in the promoter regions of genes encoding several HDACs, DNMTs, and proteins involved in miRNA biogenesis. We confirmed that NRF2 regulates the production of these genes by studying NRF2-deficient cells and cells treated with dimethyl fumarate (DMF), an inducer of the NRF2 signaling pathway. In addition, we found that NRF2 could be involved in the target RNA-dependent microRNA degradation (TDMD) of miR-155-5p through its interaction with Nfe2l2 mRNA. Our data indicate that NRF2 has an epigenetic regulatory function, complementing its traditional function and expanding the regulatory dimensions that should be considered when developing NRF2-centered therapeutic strategies. Full article

MicroRNAs (miRNAs) are versatile, post-transcriptional regulators of gene expression. Canonical miRNAs are generated through the two-step DROSHA- and DICER-mediated processing of primary miRNA (pri-miRNA) transcripts with optimal or suboptimal features for DROSHA and DICER cleavage and loading into Argonaute (AGO) proteins, whereas multiple hairpin-structured RNAs are encoded in the genome and could be a source of non-canonical miRNAs. Recent advances in miRNA biogenesis research have revealed details of the structural basis of miRNA processing and cluster assistance mechanisms that facilitate the processing of suboptimal hairpins encoded together with optimal hairpins in polycistronic pri-miRNAs. In addition, a deeper investigation of miRNA–target interaction has provided insights into the complexity of target recognition with distinct outcomes, including target-mediated miRNA degradation (TDMD) and cooperation in target regulation by multiple miRNAs. Therefore, the coordinated or network regulation of both miRNA biogenesis and miRNA–target interaction is prevalent in miRNA biology. Alongside recent advances in the mechanistic investigation of miRNA functions, this review summarizes recent findings regarding the ordered regulation of miRNA biogenesis and miRNA–target interaction. Full article

In vitro methods have been standardized and tested to correctly simulate the rumen environment and fermentation process. A few studies have verified that the feed degradability achieved as a result of stirring the samples is higher when the samples are incubated under continuous stirring than when they are only stirred twice daily. The objective of this study has been to verify the effect of the speed of stirring on feed degradability during In vitro incubation. For this purpose, the apparent and true dry matter degradability (ADMD and TDMD) of grass hay, pelleted alfalfa, corn silage, barley meal, straw, and a total mixed ration (TMR) were measured after 48 h of incubation in jars under different rotation speeds. The same types of feed were placed in the four jars of each instrument, and the rotation system of the machine was modified to ensure the simultaneous rotation of a pair of original jars (which sometimes stopped and/or rotated slowly and irregularly) together with a pair of modified jars under regular and continuous rotation. A rev counter data logger was mounted onto the jars, and the rotation speeds of the original and modified jars were measured and compared under different conditions (empty jars, jars with liquid, jars with rumen fluid, and sample bags). The modifications to the instruments stabilized the rotation of the jars, thereby making the stirring more regular during incubation. The degradability was partly influenced by the regular stirring, albeit with just one instrument, and for grass hay, barley meal, corn silage, and TMR. In short, it has been found that the regular stirring of sample bags is not essential to obtain reliable degradability measurement during incubation, although it is better to maintain a constant rotation to ensure a regular and standardized In vitro incubation process and therefore to allow reproducibility and comparisons of the results on feed degradability. Full article

This research was undertaken with the aim of determining the effect of sodium hydroxide (NaOH) treatment on the chemical composition, in vitro gas production, neutral detergent fiber digestibility (NDFD) and true dry matter digestibility (TDMD), dry matter intake (DMI), and relative feed value (RFV) of common reed (Phragmites australis) straw. Reed straw was treated with 0% (control), 1%, 2%, and 3% NaOH and stored in 1.5-L glass jars in triplicate for 21 days. NaOH treatment had a significant effect on the chemical composition, in vitro gas production, NDFD and TDMD, DMI, and RFV of the reed straw. While it decreased the cell wall content of the reed straw, it significantly increased the NDFD, TDMD, DMI, and RFV. The neutral detergent fiber content of the reed straw decreased with NaOH treatment in a dose-dependent manner and ranged from 56.03% to 65.05%, whereas the NDFD increased and ranged from 53.10% to 59.99%. Metabolizable energy, organic matter digestibility, and TDMD values were improved, ranging from 9.15 to 10.19 MJ/kg DM, 58.46% to 65.05%, and 55.29% to 62.33%, respectively. The estimated RFV and DMI also improved, ranging from 84.70% to 95.58% and from 1.87% to 2.14% of body weight, respectively. The most effective treatment dose of NaOH was 3%. Therefore, it can be suggested that NaOH treatment has the potential to improve the nutritive value of reed straw. However, before large applications, further in vivo investigations are required to determine the effects of NaOH treatment on the feed intake and production of ruminant animals. Full article

The objective of this study was to evaluate the associative effects of rice straw with timothy hay and corn grain. Using an automated gas production system, in vitro ruminal fermentation was studied for six substrates: 100% rice straw, 100% timothy hay, 100% corn grain, 50% rice straw and 50% timothy hay, 50% rice straw and 50% corn grain, and 50% rice straw, 25% timothy hay, and 25% corn grain. Incubation was performed in three batches with different rumen fluids to assess the in vitro ruminal gas production kinetics and rumen parameters (pH, NH₃-N, volatile fatty acid (VFA), and true dry matter digestibility (TDMD)). The associated effects were tested by comparing the observed values of the composited feeds and the weighted means of individual feeds. There was a significant increase in NH₃-N when rice straw was fermented with timothy hay, corn grain, or both (p < 0.05). TDMD increased when corn grain was co-fermented, and the total gas and VFA production increased when all three feeds were co-fermented. We conclude that the feed value of rice straw increases when fed to animals along with timothy hay and corn grain. Full article