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PubMed2026

tRF-3021a, a tRNA-Ala-TGC derived 3' fragment, promotes glioblastoma cell invasion, suppresses apoptosis, and is required for normal levels of protein synthesis.

UNLABELLED: tRNA-derived fragments (tRFs) are relatively recently discovered class of small RNAs implicated in gene-regulatory processes in diverse biological contexts but there have been very few reports of a clear phenotypic role of these small RNAs in cancer progression. By analyzing small RNA-seq data from The Cancer Genome Atlas (TCGA), we found that high expression of three 3' tRFs (tRF-3a), tRF-3009a, tRF-3021a or tRF-3030a, is significantly associated with poor overall survival in low-grade glioma (LGG). In glioblastoma cells, tRF-3009a, tRF-3021a and tRF-3030a enhance cell invasion and migration but tRF-3021a was uniquely required for cell proliferation and suppression of apoptosis. Interestingly, tRF-3021a knockdown decreases global protein synthesis prior to and independent of apoptosis. These data indicate that tRF-3021a supports glioma cell survival and particularly protein synthesis while promoting cellular invasion and migration. Given its association with poor outcome in LGG patients, tRF-3021a represents a promising biomarker and potential therapeutic target in gliomas and these results provide a foundation for future studies to define its molecular interactors and downstream pathways controlling protein synthesis and apoptosis in cancer cells. IMPLICATION: tRF-3021a promotes malignant glioma phenotypes, sustains global protein synthesis and prevents spontaneous apoptosis, motivating efforts to evaluate it as a biomarker and therapeutic target.

Journal Article↗

PubMed2026

Immunomodulatory effects of palm-derived tocotrienol-rich fraction in healthy volunteers following influenza vaccination: A randomised clinical trial.

Most studies on vitamin E and immunity have focused on tocopherols, but the tocotrienol-rich fraction (TRF) from palm oil may exert stronger immunomodulatory effects. This study investigated the effect of various TRF doses on the immune response to influenza immunisation in healthy adults. We hypothesized daily supplementation with lower doses of TRF can boost immune response to the influenza vaccine in healthy Individuals. In a double-blind placebo-controlled trial, 150 participants (≥18 years) were randomised to receive placebo or TRF (50, 100, 200, or 400 mg) daily for 2 months, with vaccination on day 28. Blood samples collected on days 0, 28, and 56 were analyzed for humoral and cellular immunity, antioxidant status, and plasma concentrations of vitamin E. TRF significantly augmented anti-influenza antibody production across all doses, with the 400 mg group exhibiting the highest titers. A selective Th1-type immune response was observed, characterized by significant IFN-γ production upon restimulation in all TRF-supplemented groups compared with placebo. Plasma IL-12 was elevated in the highest dose, whereas the amount of EBI3 produced increased across a broader range of doses compared to placebo. TRF supplementation was associated with increased antioxidant enzyme activities and stable malondialdehyde activity. Elevated α-tocopherol concentrations observed, primarily at higher doses. Supplementation with TRF can enhance immune response to influenza immunisation by modulating humoral, Th1 responses and improving antioxidant status. Critically, antibody production increased similarly across all TRF doses, suggesting that lower doses may offer a cost-effective strategy for supporting humoral immunity, while higher doses provide broader immunomodulatory benefits.

Humans↗

PubMed2026

Changes in weight and metabolic health during and after cessation of a time-restricted feeding plus aerobic training in Swiss mice fed a high-fat diet.

Obesity is a chronic disease, representing a significant health problem worldwide. Unhealthy eating habits and sedentarism are key contributors to the development of obesity. Dietary and exercise strategies are the first-line therapies for weight loss or maintenance and have proven effective in controlling weight. However, long-term adherence is challenging, and rapid weight regain often follows intervention cessation. In mice, time-restricted feeding (TRF) and exercise (EXE) independently prevent weight gain and maintain metabolic health, yet weight regain is observed upon cessation. Whether combining TRF and EXE provides longer-lasting benefits remains unclear. Here, we assessed weight and metabolic parameters in Swiss male mice fed with a high-fat diet (HFD) during an 8-wk intervention of TRF (8-h food access in the active phase) or TRF combined with EXE (60-min treadmill running daily) and after cessation and transfer to ad libitum feeding. TRF and EXE interventions successfully mitigate weight gain, improve glycemic homeostasis, and attenuate lipid accumulation in the liver and adipose tissue hypertrophy compared to mice fed HFD ad libitum. However, cessation of both strategies led to rapid weight regain, impaired glycemic control, and increased circulating lipid levels. Although the combination of TRF and EXE led to the lowest body weight and best metabolic health, this group showed no protection against the metabolic impairments observed after TRF cessation alone. In conclusion, TRF and EXE are complementary strategies for managing metabolic health, but cessation of these interventions leads to rapid weight regain and metabolic deterioration, with only partial preservation of select metabolic adaptations. These findings underscore the critical need for sustained adherence to lifestyle interventions in obesity management.NEW & NOTEWORTHY This study demonstrates that combining time-restricted feeding with aerobic training improves weight and metabolic health in Swiss mice fed a high-fat diet. Importantly, we show that most metabolic benefits are lost after intervention cessation. However, insulin sensitivity and aspects of hepatic lipid metabolism are partially maintained after cessation of the intervention. These findings provide new insight into the durability of metabolic improvements induced by lifestyle interventions and highlight the potential of combined dietary and exercise strategies to counteract diet-induced obesity and metabolic dysfunction.

Animals↗

PubMed2026

Hepatic ketogenic insufficiency blunts exercise-induced energy expenditure and alters mitochondrial proteins in skeletal muscle.

Ketone body (KB) utilization increases during fasting and exercise due to enhanced hepatic fatty acid oxidation and KB production via the rate-limiting mitochondrial enzyme hydroxymethylglutaryl-CoA synthase (HMGCS2). Since KB metabolism intersects with multiple metabolic pathways and skeletal muscle KB catabolism rises during exercise, we tested the hypothesis that liver-specific HMGCS2 knockouts (KO) would have reduced energy expenditure (EE) and changes in the mitochondrial proteome of skeletal muscle with chronic exercise through voluntary wheel running (VWR), time-restricted feeding (TRF), or both combined to boost hepatic KB production and utilization. Control (CON) and HMGCS2 knockout (KO) mice (n = 6-8 per group) underwent sedentary ad libitum feeding (SED + AL), SED + TRF, VWR + AL, and VWR + TRF for 16 wk, with whole body EE measured using indirect calorimetry. In CON mice, VWR increased total EE by 19.5% and nonresting EE by 50% under AL conditions, and total EE by 16% and nonresting EE by 47.9% under TRF conditions. However, the EE increases seen with VWR did not occur in KO mice. Proteomic analysis revealed that the loss of liver HMGCS2 significantly impacted proteins involved in metabolic processes within skeletal muscle, including reduced oxidative phosphorylation (OXPHOS) protein expression in SED KO mice compared with sedentary CON. Notably, VWR restored OXPHOS protein expression in the muscle of the liver HMGCS2 KO but did not alter it in the CON. Furthermore, muscle from liver HMGCS2 KO mice had elevated expression of glycolytic pathways in sedentary and VWR conditions. These results indicate that hepatic ketogenic deficiency (HMGCS2 KO) diminishes exercise-induced increases in EE and uniquely impacts baseline and exercise-related adaptations in the metabolic and mitochondrial proteome of skeletal muscle.

Hydroxymethylglutaryl-CoA Synthase↗

PubMed2025

A general framework to over-express tRNA-derived fragments from their parental tRNAs in mammalian cells.

tRNA-derived fragments (tRFs), generated from the cleavage of mature or precursor tRNAs are a category of regulatory noncoding RNAs with diverse functions in physiological or pathophysiological conditions. Here we describe a framework for the over-expression of tRFs from their parental tRNAs in mammalian cells. The process involves bioinformatics analysis to identify specific tRNAs that produce the tRF, PCR amplification of corresponding tRNA genes, and insertion into expression vectors. Transfection is carried out in HEK293T cells and detection of tRFs is achieved through northern blotting and dual luciferase reporter assays. In the latter, a complementary sequence to the tRF of interest is inserted into the luciferase reporter. By observing the reduction in luciferase activity, we can validate the expression of tRFs. This method enables precise study of tRF functions and their roles in cellular processes.

Humans↗

PubMed2026

Improvement the accuracy and reproducibility of telomere length measurement utilizing qPCR.

Telomere length serves as a well-established molecular biomarker for evaluating aging and age-associated diseases. Among various methods, quantitative PCR for telomere length detection is convenient, rapid, cost-effective, and capable of high-throughput analysis in large epidemiological cohorts. However, numerous studies have indicated that issues related to differences in DNA quality caused by DNA extraction process significantly affect the accuracy and reproducibility of qPCR-based telomere length quantification. Initially, we established a model of DNA integrity variation, by utilizing nucleic acid endonucleases of serial activity units to cleave genomic DNA, generating DNA with varying degrees of degradation. The integrity of DNA templates decreases, the reduction of long fragments and the increase of short fragments in the mixed telomere products are the causes of the disruption in Ct values. Moreover, compared with longer reference gene amplicons, the short-segment internal gene reference can reduce the impact of genomic integrity on its amplification. Subsequently, we utilized additional gel excision purification to reduce degradation products. It was found that gel excision processing provides the best stability for telomere length detection with the lowest coefficient of variation. Additionally, the introduce of another calibrator sample, which is used for to adjust the T/S value of the test sample, narrows the deviation between qPCR-derived telomere length and gold-standard Terminal Restriction Fragment (TRF) measurements. Collectively, these results reveal that gel excision purification supports stable telomere detection. Calculating the correction coefficient incorporating the short internal reference and calibrator minimizes measurement deviations relative to sample TRF values.

Telomere↗

PubMed2025

The suprachiasmatic nucleus regulates brown fat thermogenesis in male mice through an adrenergic receptor ADRB3-S100B signaling pathway.

The suprachiasmatic nucleus (SCN), the central circadian pacemaker, orchestrates daily metabolic rhythms, yet its role in substrate selection and thermogenic adaptation under stress remains insufficiently understood. Here, we show that SCN lesioning abolishes the adaptive suppression of brown adipose tissue (BAT) thermogenesis typically observed during time-restricted feeding in subthermoneutral environments (TRF-STE), a paradigm that imposes concurrent nutrient and thermal stress. Contrary to wild-type responses, SCN-lesioned mice maintain elevated BAT thermogenic activity, despite impaired lipolysis, instead shifting toward glucose-driven heat production. This phenotype is accompanied by sustained sympathetic tone and β3-adrenergic receptor (ADRB3) signaling in BAT. Mechanistically, we identify a SCN-regulated ADRB3-S100B signaling axis underlying this metabolic reprogramming. S100B, a nutrient-sensitive calcium-binding protein, is upregulated in BAT following SCN disruption, where it promotes thermogenesis by stimulating brown adipocyte proliferation and suppressing senescence. Functional studies reveal that S100B is both necessary and sufficient for sustaining BAT thermogenesis under TRF-STE. Furthermore, diverse SCN disruption models, including light-induced circadian arrhythmia, N-Methyl-D-aspartic acid (NMDA) excitotoxicity, and Caspase-3-mediated ablation, consistently elevate S100B expression in BAT, reinforcing its role as a convergent effector of SCN-regulated metabolic adaptation. Thus, in intact animal, the SCN restrains the ADRB3-S100B module, gating BAT thermogenic output in accordance with energetic availability. Disruption of SCN output lifts this restraint, unmasking a latent ADRB3-S100B program that preserves thermogenesis when lipid fuel is limited. These findings reveal a previously unrecognized role of the SCN in governing thermogenic flexibility and fuel partitioning, and position the ADRB3-S100B axis as a potential target for mitigating circadian misalignment and metabolic disease.

Animals↗

PubMed2025

Fins as a reliable surrogate tissue for age-related changes of telomeres and DNA methylation in gonads of a short-lived fish.

Senescence is a multifactorial and individualised process of age-related physiological decline. Cellular markers, such as telomere length and DNA methylation, can reveal subtle changes associated with chronological age or expected lifespan. In this study, we evaluated the utility of fin tissue as a surrogate for assessing telomere length and proportion of DNA methylation in the gonads of a small, short-lived laboratory fish, the turquoise killifish (Nothobranchius furzeri). We collected fin and gonadal tissues from both females and males at three different ages. We extracted DNA to measure telomere length via terminal restriction fragment (TRF) analysis and global DNA methylation levels using double-digest restriction-associated DNA sequencing (ddRADseq). Our results show a notable correspondence between telomere length and DNA methylation patterns in fin and gonadal tissues. These findings support the use of fin biopsies as a non-lethal method for assessing ageing biomarkers in the gonads of small freshwater fish.

Animals↗

PubMed2025

Methods for purification and characterization of nicked tRNAs.

While tRNA-derived fragments (tDRs) play important roles in gene expression regulation, it is technically challenging to distinguish bona fide tDRs from nicked tRNAs. This is because analytical techniques used to study RNA, such as northern blot, RT-qPCR or sequencing involve the use of denaturing reagents (e.g., phenol, formamide, urea) or physical procedures (e.g., heat) that convert nicked tRNAs into tRNA halves or other tDRs. In this chapter, we describe a protocol that enables the purification of nicked tRNAs under non-denaturing conditions that preserve their 3D structure. Purified nicked tRNAs can then be either enzymatically repaired into almost full-length tRNAs, or chromatographically separated from single-stranded tDRs before detection. These protocols will allow researchers to distinguish between structurally distinct but sequence identical tDRs and nicked tRNAs, disentangling their biological functions.

RNA, Transfer↗

PubMed2024

Detection of mitochondrial tDRs in killifish embryos and other non-model organisms.

In recent years a diversity of small noncoding RNAs have been identified that originate from the mitochondrial genome. These mitosRNAs are often dominated by tRNA-derived small RNAs (mito-tDRs). Differential expression of mito-tDRs is associated with responses to stress. They also appear to be expressed differentially during development and their expression may be enriched in stress-tolerant animals. Very little is currently known about roles or modes of action of these sequences, although they are implicated in a diversity of processes such as cell cycle regulation, mRNA stability, regulation of ROS production, and import of proteins into the mitochondrion. To better understand the various roles these sequences may play, it is critical that we understand their diversity, cellular location, and the context for their expression. This protocol outlines the methodologies used to detect mitosRNAs, including mito-tDRs, in embryos and cells of the annual killifish Austrofundulus limnaeus. We highlight critical steps in the isolation of RNA, creation of sequencing libraries, bioinformatics processing of sequence data, and methods for validation of expression that support a robust discovery pipeline for mitosRNAs even from species with incomplete reference genome sequences.

Animals↗

PubMed2025

Short-term diet intervention comprising of olive oil, vitamin D, and omega-3 fatty acids alters the small non-coding RNA (sncRNA) landscape of human sperm.

Offspring health outcomes are often linked with epigenetic alterations triggered by maternal nutrition and intrauterine environment. Strong experimental data also link paternal preconception nutrition with pathophysiology in the offspring, but the mechanism(s) routing effects of paternal exposures remain elusive. Animal experimental models have highlighted small non-coding RNAs (sncRNAs) as potential regulators of paternal effects. Here, we characterised the baseline sncRNA landscape of human sperm and the effect of a 6-week dietary intervention on their expression profile. This study involves sncRNAseq profiling, that was performed on a subset (n = 17) of the participants enrolled in the PREPARE trial: 9 from the control group and 8 from the intervention group. 5'tRFs, miRNAs and piRNAs were the most abundant sncRNA subtypes identified; their expression was associated with age, BMI, and sperm quality. Nutritional intervention with olive oil, vitamin D and omega-3 fatty acids altered expression of 3 tRFs, 15 miRNAs and 112 piRNAs, targeting genes involved in fatty acid metabolism and transposable elements in the sperm genome. PREPARE Trial registration number: ISRCTN50956936, Trial registration date: 10/02/2014.

Humans↗