Advanced biology最新文献

Cardiac Aging

A combination of endurance and resistance exercises can mitigate age-related pathological changes in the heart in late life, such as cardiac remodeling and dysfunction. These beneficial effects on the heart are likely attributed to the activation of the anti-aging factor, Usf 2. More details can be found in article number 2400137 by Wanling Xuan and co-workers.

In eukaryotic cell nuclei, chromatin exhibits a high degree of structural and functional dynamics. Recent findings suggest that chromatin has the ability to reorganize in response to changes within the cellular microenvironment. Such changes include oxidative stress found in hyperoxia. While hyperoxia is recognized for causing DNA damage and disrupting cellular functions, the effects it has on chromatin structure and the implications thereof remain poorly understood. In this work, an imaging-based technique is developed to visualize and characterize nanoscale chromatin remodeling under hyperoxia in mesenchymal stromal cells, created via hydrogen peroxide treatment. High spatiotemporal variability of remodeling in different chromatin domains is found. Chromatin remodeling is hindered by the GSK126-mediated inhibition of methyltransferase EZH2, which regulates the chromatin compaction. Independent assays such as ATAC seq further revealed that chromatin is compacted by hyperoxia, which is mitigated by GSK126 pretreatment. Epigenetic modifications and DNA damage under hyperoxia is investigated, which is also found to be affected by the pretreatment of GSK126. The techniques and discoveries provide mechanistic insights into chromatin remodeling, potentially paving the way for novel therapeutic strategies to combat genotoxic oxidative stress—commonly associated with degenerative diseases and aging—and to enhance cell-based therapies in regenerative medicine.

Apolipoprotein A-I binding protein (AIBP) interacts with both apolipoprotein A-I and high-density lipoprotein. It modulates lipid raft-related signaling pathways and affects mitochondrial function, oxidative stress, and inflammatory responses, thereby playing an important role in atherosclerosis, neuroinflammation, and neurological disorders. The role of AIBP in cardiovascular diseases has been intensively studied. Nevertheless, recent studies have uncovered correlations between NAD(P)HX differential isomerase variants and various neurological disorders, further highlighting their substantial role in neurological diseases. This review outlines the current investigations on AIBP in neurometabolic diseases, neurodegenerative diseases, and neuropathic pain. The present advances are also updated in the function and regulation of AIBP in cholesterol metabolic and inflammatory signaling and explored the potential of AIBP as a promising strategy and target for neurological disorders.

Hirschsprung-associated enterocolitis (HAEC) is the most common and severe complication in patients with Hirschsprung's disease (HSCR) and is characterized by high morbidity, frequent recurrence and substantial mortality. The formation of macrophage extracellular traps (METs), a novel inflammatory mode of cell death, plays a significant role in the progression of various inflammatory diseases. However, the mechanisms underlying METs formation and their role in the progression of HAEC remain unclear. Here, the findings indicate that METs formation induced by the pyroptotic microenvironment enhances inflammatory responses and induces colonic epithelial cells (CECs) injury in HAEC. Mechanistically, high mobility group box 1 protein (HMGB1), derived from this pyroptotic environment, mediates METs formation through toll-like receptor 4 (TLR4)-p38 MAPK/p65 NF-kB signaling pathways. Furthermore, incubation of CECs with METs induces suppression of cell viability, more production of reactive oxygen species (ROS) and pyroptosis. In conclusion, HMGB1 mediates the communication between pyroptotic microenvironment and METs formation, triggering enhanced inflammatory responses and damage to CECs. Targeting HMGB1 presents a potential therapeutic strategy for HAEC.

Protoplast regeneration into plant cells and further into plants is an ongoing challenge in agricultural biotechnology. Inspired by mammalian tissue engineering, a strategic shift is proposed in plant tissue engineering to steer protoplast culture using fully synthetic materials-based culture platforms. Here a supramolecular materials method to engineer modular culture methods for protoplasts is chosen to use. Supramolecular monomers as modular building blocks allow to make various hydrogel formulations and to study different protoplast cultures; including 2D cultures on top of supramolecular hydrogels, 2.5D cultures using supramolecular fibers in solution, and 3D cultures when encapsulated in bulk hydrogels or microgels. Importantly, the need is shown for bioactive functionalization of the supramolecular hydrogels with a peptide additive in 2D protoplast cultures. After 11 days, the bioactive hydrogel induced protoplast enlargement, which is absent on pristine hydrogels. The opposite effect is present for protoplasts cultured in 3D, showing plasmolysis as a result of the bioactive additive. Interestingly, in 2.5D lower bioactive additive concentrations in supramolecular fibers stimulated protoplast enlargement, demonstrated by similar morphological changes as in 2D. Finally, protoplast encapsulation in supramolecular microgels is showcased. This work demonstrates the potential to modularly engineer various synthetic platforms to facilitate cellular agriculture.

Head and neck squamous cell carcinoma (HNSCC) is characterized by a high recurrence rate and poor prognosis. Ferroptosis, a regulated cell death, plays a significant role in inhibiting tumor progression. However, its role and regulatory mechanisms in HNSCC remain unclear. In this study, the expression of ferroptosis-related molecules in HNSCC is analysed and NCOA4 and FTH1 are identified as prognostic markers. TU177 and TU686 cells are transfected with plasmids for the overexpression or knockdown of NCOA4 and FTH1. MTT assays demonstrated reduced cell viability following either NCOA4 overexpression or FTH1 knockdown alone. Concurrently, ferroptosis hallmarks such as iron overload and ROS overproduction are upregulated in these conditions. Conversely, NCOA4 knockdown or FTH1 overexpression has the opposite effects. Furthermore, miR-182-5p is found to be significantly upregulated in HNSCC tissues. Mechanistic studies revealed that miR-182-5p directly binding to the NCOA4 3′ UTR, leading to the downregulation of NCOA4 expression and suppression of NCOA4/FTH1-mediated ferroptosis. In conclusion, the finding elucidate the role of miR-182-5p/NCOA4/FTH1 signaling axis in regulating ferroptosis in HNSCC and provide insights into the molecular mechanism underlying ferroptosis in HNSCC cells.

The axolotl (Ambystoma mexicanum) has a great capacity to regenerate its tissues; however, the fidelity and success of its regenerative process diminish with age. Retrotransposons make up the largest portion of the axolotl genome, and their expression may be involved in this age-related decline. Through an integrative analysis of repetitive element expression using RNA sequencing, it is shown that Ty3 retrotransposons are highly upregulated in the axolotl as an effect of chronological aging. Other non-long-terminal-repeat transposons, including long interspersed nuclear element 1, function as hubs of gene coexpression networks involved in muscle development and regulation of apoptosis and connective tissue replacement, which are also suppressed in adulthood. By contrast, it is found that during regeneration of the limb, these pathways and the expression of Ty3 retrotransposons are distinctly downregulated. Although the blastema can readjust most of the transposon differential expression in adulthood, several elements remain affected and may have an impact in the immune response during regeneration. This analysis provides a profile of retrotransposon expression through chronological aging and during limb regeneration in the axolotl and indicates that transposons are responsive to physiological changes in a tissue-specific way and may participate in the gene coregulatory networks underlying the regenerative process.

IFN-γ and TNF-α are two vital inflammatory factors elevated aberrantly in many diseases. Such an inflammatory microenvironment is detrimental to residual cells such as mesenchymal stem cells (MSCs), yet the precise mechanisms are not fully understood. IFN-γ and TNF-α have distinct effects on the immunoregulatory properties of MSCs, and they have been proposed as optimal priming factors to enhance the immunosuppressive capacity of engineered MSCs. Thus, the overall effects of IFN-γ and/or TNF-α exposure on MSCs needs to be elucidated. Here, it is found that IFN-γ and TNF-α synergistically induce cell death of MSCs via necroptosis. When MSCs are exposed to both IFN-γ and TNF-α, their morphological features and biological functions are impaired. Mechanistically revealed by RNA-Sequencing, the injured MSCs undergo a unique cell death process, namely necroptosis. Compared with controls, IFN-γ synergized with TNF-α to increase the expression of RIPK1, RIPK3, MLKL, and all other genes associated with necroptosis. Rescue experiments further demonstrate that this process can be reversed by RIPK3 and MLKL inhibitors but not by the RIPK1 inhibitor, suggesting a RIPK1-independent pathway. Collectively, this study discloses an inflammatory injury mechanism of MSCs, which may shed new light on revealing the MSCs deficits in many inflammatory diseases with expectations to inspire potential targeted therapies. In addition, inflammatory impairment should be taken into consideration when delivering cell therapy based on MSCs primed with IFN-γ and TNF-α.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling driven by endothelial cell injury. This study investigates the role of ferroptosis in PAH development and its underlying molecular mechanisms. Ferroptosis-related gene expression is analyzed using transcriptomic and single-cell RNA sequencing data. A PAH mouse model is induced by combined hypoxia and Semaxanib (SU5416) treatment. The impact of ferroptosis on pulmonary vascular remodeling is evaluated by measuring right ventricular systolic pressure (RVSP), the Fulton index, vascular wall thickness, and histological changes in pulmonary arteries. Transcriptomic analysis reveals downregulation of SLC7A11 and upregulation of ACSL1 and ACSL4 in PAH patients. Endothelial cells are identified as key mediators of ferroptosis, and inhibiting ferroptosis alleviates endothelial damage and vascular remodeling. Additionally, HIF1α signaling plays a crucial role in ferroptosis induction in PAH. These findings highlight ferroptosis as a critical mechanism of endothelial injury and a key contributor to PAH pathogenesis. Targeting ferroptosis offers promising new strategies for early intervention and targeted therapy in PAH.