Frataxin Loss Promotes Angiotensin II-Induced Endothelial-to-Mesenchymal Transition.

BACKGROUND: The metabolic flexibility of endothelial cells is linked to their phenotypic plasticity. Frataxin is critical in determining the iron metabolism and fate of endothelial cells. This study aimed to investigate frataxin-mediated metabolic remodeling during the endothelial-to-mesenchymal transition (EndoMT). METHODS AND RESULTS: Endothelial cell-specific frataxin knockout and frataxin mutation mice were subjected to angiotensin II to induce hypertension. EndoMT and cardiac fibrosis were assessed using histological and protein expression analyses. Fatty acid oxidation (FAO) in microvascular endothelial cells was measured using a Seahorse XF96 analyzer. We showed that inhibition of FAO accompanies angiotensin II-induced EndoMT. Frataxin knockout mice promote EndoMT, associated with increased cardiac fibrosis following angiotensin II infusion. Angiotensin II reduces frataxin expression, which leads to mitochondrial iron overload and subsequent carbonylation of sirtuin 3. In turn, carbonylated sirtuin 3 contributes to the acetylated frataxin at lysine 189, making it more prone to degradation. The frataxin/sirtuin 3 feedback loop reduces hydroxyl-CoA dehydrogenase α subunit-mediated FAO. Additionally, silymarin is a scavenger of free radicals, restoring angiotensin II-induced reduction of FAO activity and sirtuin 3 and frataxin expression, improving EndoMT both in vitro and in vivo. Furthermore, frataxin mutation mice showed suppressed EndoMT and improved cardiac fibrosis. CONCLUSIONS: The frataxin/sirtuin 3 feedback loop has the potential to attenuate angiotensin II-induced EndoMT by improving FAO.

Large-scale foundation model on single-cell transcriptomics.

Large pretrained models have become foundation models leading to breakthroughs in natural language processing and related fields. Developing foundation models for deciphering the 'languages' of cells and facilitating biomedical research is promising yet challenging. Here we developed a large pretrained model scFoundation, also named 'xTrimoscFoundationα', with 100 million parameters covering about 20,000 genes, pretrained on over 50 million human single-cell transcriptomic profiles. scFoundation is a large-scale model in terms of the size of trainable parameters, dimensionality of genes and volume of training data. Its asymmetric transformer-like architecture and pretraining task design empower effectively capturing complex context relations among genes in a variety of cell types and states. Experiments showed its merit as a foundation model that achieved state-of-the-art performances in a diverse array of single-cell analysis tasks such as gene expression enhancement, tissue drug response prediction, single-cell drug response classification, single-cell perturbation prediction, cell type annotation and gene module inference.

Nutritional Programming of the Lifespan of Male Drosophila by Activating FOXO on Larval Low-Nutrient Diet.

Nutrition during the developmental stages has long-term effects on adult physiology, disease and lifespan, and is termed nutritional programming. However, the underlying molecular mechanisms of nutritional programming are not yet well understood. In this study, we showed that developmental diets could regulate the lifespan of adult Drosophila in a way that interacts with various adult diets during development and adulthood. Importantly, we demonstrated that a developmental low-yeast diet (0.2SY) extended both the health span and lifespan of male flies under nutrient-replete conditions in adulthood through nutritional programming. Males with a low-yeast diets during developmental stages had a better resistance to starvation and lessened decline of climbing ability with age in adulthood. Critically, we revealed that the activity of the Drosophila transcription factor FOXO (dFOXO) was upregulated in adult males under developmental low-nutrient conditions. The knockdown of dFOXO, with both ubiquitous and fat-body-specific patterns, can completely abolish the lifespan-extending effect from the larval low-yeast diet. Ultimately, we identify that the developmental diet achieved the nutritional programming of the lifespan of adult males by modulating the activity of dFOXO in Drosophila. Together, these results provide molecular evidence that the nutrition in the early life of animals could program the health of their later life and their longevity.

Inhibitor GSK690693 extends Drosophila lifespan via reduce AKT signaling pathway.

Aging is a process involving physiological changes that lead to the decline of biological functions of various tissues and organs of the body. Therefore, it is crucial to find anti-aging drugs that can intervene with the changes induced because of aging and slow down the degeneration of the biological functions. Among many signaling pathways linked with aging and aging-related diseases, PI3K-AKT signaling pathway has attracted major attention in aging biology. In this research paper, we have demonstrated that AKT inhibitor GSK690693 can extend lifespan in Drosophila irrespective of start of the treatment from the beginning of life or the mid-life. Effect of GSK690693 for lifespan extension has been primarily related to the improvements in oxidative resistance, intestinal integrity and increased autophagy, but not in physical activity or starvation resistance. Furthermore, GSK690693 treatment reduced the activation of AKT and ERK, consequently activating FOXO, GSK-3ß and apoptosis to modulate longevity of flies. Remarkably, GSK690693 did not induce hyperglycemia after treatment. The results indicate that GSK690693 may become an effective compound for anti-aging intervention.

Comparative proteomics analysis of dietary restriction in Drosophila.

To explore the underlying mechanism of dietary restriction (DR) induced lifespan extension in fruit flies at protein level, we performed proteome sequencing in Drosophila at day 7 (young) and day 42 (old) under DR and ad libitum (AL) conditions. A total of 18629 unique peptides were identified in Uniprot, corresponding to 3,662 proteins. Among them, 383 and 409 differentially expressed proteins (DEPs) were identified from comparison between DR vs AL at day 7 and 42, respectively. Bioinformatics analysis revealed that membrane-related processes, post-transcriptional processes, spliceosome and reproduction related processes, were highlighted significantly. In addition, expression of proteins involved in pathways such as spliceosomes, oxidative phosphorylation, lysosomes, ubiquitination, and riboflavin metabolism was relatively higher during DR. A relatively large number of DEPs were found to participate in longevity and age-related disease pathways. We identified 20 proteins that were consistently regulated during DR and some of which are known to be involved in ageing, such as mTORC1, antioxidant, DNA damage repair and autophagy. In the integration analysis, we found 15 genes that were stably regulated by DR at both transcriptional as well as translational levels. Our results provided a useful dataset for further investigations on the mechanism of DR and aging.

A workflow for exploring ligand dissociation from a macromolecule: Efficient random acceleration molecular dynamics simulation and interaction fingerprint analysis of ligand trajectories.

The dissociation of ligands from proteins and other biomacromolecules occurs over a wide range of timescales. For most pharmaceutically relevant inhibitors, these timescales are far beyond those that are accessible by conventional molecular dynamics (MD) simulation. Consequently, to explore ligand egress mechanisms and compute dissociation rates, it is necessary to enhance the sampling of ligand unbinding. Random Acceleration MD (RAMD) is a simple method to enhance ligand egress from a macromolecular binding site, which enables the exploration of ligand egress routes without prior knowledge of the reaction coordinates. Furthermore, the τRAMD procedure can be used to compute the relative residence times of ligands. When combined with a machine-learning analysis of protein-ligand interaction fingerprints (IFPs), molecular features that affect ligand unbinding kinetics can be identified. Here, we describe the implementation of RAMD in GROMACS 2020, which provides significantly improved computational performance, with scaling to large molecular systems. For the automated analysis of RAMD results, we developed MD-IFP, a set of tools for the generation of IFPs along unbinding trajectories and for their use in the exploration of ligand dynamics. We demonstrate that the analysis of ligand dissociation trajectories by mapping them onto the IFP space enables the characterization of ligand dissociation routes and metastable states. The combined implementation of RAMD and MD-IFP provides a computationally efficient and freely available workflow that can be applied to hundreds of compounds in a reasonable computational time and will facilitate the use of τRAMD in drug design.

Pharmacological Treatment of Alzheimer's Disease: Insights from Drosophila melanogaster.

Aging is an ineluctable law of life. During the process of aging, the occurrence of neurodegenerative disorders is prevalent in the elderly population and the predominant type of dementia is Alzheimer's disease (AD). The clinical symptoms of AD include progressive memory loss and impairment of cognitive functions that interfere with daily life activities. The predominant neuropathological features in AD are extracellular ß-amyloid (Aß) plaque deposition and intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated Tau. Because of its complex pathobiology, some tangible treatment can only ameliorate the symptoms, but not prevent the disease altogether. Numerous drugs during pre-clinical or clinical studies have shown no positive effect on the disease outcome. Therefore, understanding the basic pathophysiological mechanism of AD is imperative for the rational design of drugs that can be used to prevent this disease. Drosophila melanogaster has emerged as a highly efficient model system to explore the pathogenesis and treatment of AD. In this review we have summarized recent advancements in the pharmacological research on AD using Drosophila as a model species, discussed feasible treatment strategies and provided further reference for the mechanistic study and treatment of age-related AD.

Sexual dimorphism in the nutritional requirement for adult lifespan in Drosophila melanogaster.

The nutritional requirements of Drosophila have mostly been studied for development and reproduction, but the minimal requirements for adult male and female flies for lifespan have not been established. Following development on a complete diet, we find substantial sex difference in the basic nutritional requirement of adult flies for full length of life. Relative to females, males require less of each nutrient, and for some nutrients that are essential for development, adult males have no requirement at all for lifespan. The most extreme (and surprising) sex differences were that chronic cholesterol and vitamin deficiencies had no effect on the lifespan of adult males, but they greatly decreased lifespan in females. Female oogenesis rather than chromosomal karyotype and mating status is the key cause of this gender difference in life-sustaining nutritional requirements. These data are important to the way we understand the mechanisms by which diet modifies lifespan.

Gene expression patterns determine the differential numbers of dorsocentral macrochaetes between Musca domestica and Drosophila melanogaster.

The evolutionary differences in sensory bristle patterns on the thorax of dipterans are an excellent model for studying the patterns of evolutionary development. We observed that Drosophila melanogaster has two pairs of the large bristles, called macrochaetes, in the dorsocentral (DC) region of the notum, while Musca domestica retains six DC macrochaetes. To explore possible mechanism by which these two dipteran species have different numbers of DC bristles, we compared the corresponding protein sequences, the gene expression levels and the spatial expression patterns of five genes (scute, pnr, ush, hairy, and emc) for bristle development between two species. We also checked the overexpression of scute and emc in transgenic flies. The results demonstrated a strong conservation of five protein sequences between these two species. The mRNA expression of the five genes differed significantly between D. melanogaster and M. domestica. The gene expression patterns exhibited a species-specific pattern during the larval development stage. It suggests that the function of these genes has been conserved in regulating the development of macrocheates between housefly and fruit fly, whereas the gene expression levels, especially spatial expression patterns lead to species-specificity in DC bristles.