Animal Cells and Systems最新文献

Extracellular vesicles (EVs), transporting diverse cellular components, play a crucial role in intercellular communication in numerous physiological and pathological processes. EVs have also been recognized as a drug delivery platform for therapeutic purposes and cell-free regenerative medicine. While various approaches have focused on increasing EV production for efficient use therapeutic use of EVs, enhancing the quality of EVs, such as ensuring efficient uptake by their target cells, has not been widely explored. In this study, we linked a negative membrane curvature-forming inverse BAR (IBAR) domain with an integrin β tail-binding talin F3 domain to create the IBAR-F3 fusion protein. We observed that IBAR-F3 can trigger filopodia-like membrane protrusions and attract integrins to those protrusion-rich regions, when expressed in Chinese hamster ovary cells expressing integrin αIIbβ3. Surprisingly, the expression of IBAR-F3 also induced a robust production of EVs, which were then efficiently taken up by nearby cells in an integrin-dependent manner. Moreover, IBAR triggered integrin activation, presumably by inducing negative membrane curvature that likely disrupts the interaction between the integrin α and β transmembrane domain. Therefore, we suggest that IBAR-F3 should be utilized to promote both EV production and efficient uptake mediated by integrins. Furthermore, the negative curvature-inducing integrin activation suggests that integrins on EVs can be activated by the nanoscale change in the curvature of the EV without the need for conventional machinery to activate integrin inside the EVs.

Tyrosine kinase inhibitors (TKIs) have emerged as a potential treatment strategy for glioblastoma multiforme (GBM). However, their efficacy is limited by various drug resistance mechanisms. To devise more effective treatments for GBM, genetic characteristics must be considered in addition to pre-existing treatments. We performed an integrative analysis with heterogeneous GBM datasets of genomic, transcriptomic, and proteomic data from DepMap, TCGA and CPTAC. We found that poor prognosis was induced by co-upregulation of heat shock protein family A member 5 (HSPA5) and fibroblast growth factor receptor 1 (FGFR1). Co-up regulation of these two genes could regulate the PI3K/AKT pathway. GBM cell lines with co-upregulation of these two genes showed higher drug sensitivity to PI3K inhibitors. In the mesenchymal subtype, the co-upregulation of FGFR1 and HSPA5 resulted in the most malignant subtype of GBM. Furthermore, we found this newly discovered subtype was correlated with homologous recombination deficiency (HRD) In conclusion, we discovered novel druggable candidates within the group exhibiting co-upregulation of these two genes in GBM, suggest potential strategies for combination therapy.

Unlike vertebrates, the number of toothed taxa in invertebrates is very few, with leeches being the only tooth-bearing organisms in the phylum Annelida. Copious studies have been conducted regarding vertebrate teeth; however, studies regarding the structure and function of invertebrate teeth are limited. In this study, the tooth structure of leeches, specifically Hirudo nipponia and Haemadipsa rjukjuana, was revealed, which showed sharp and pointed teeth along the apex of three jaws. Understanding conserved signaling regulations among analogous organs is crucial for uncovering the underlying mechanisms during organogenesis. Therefore, to shed light on the evolutionary perspective of odontogenesis to some extent, we conducted de novo transcriptome analyses using embryonic mouse tooth germs, Hirudo teeth, and Helobdella proboscises to identify conserved signaling molecules involved in tooth development. The selection criteria were particularly based on the presence of tooth-related genes in mice, Hirudo teeth, and Helobdella proboscis, wherein 4113 genes were commonly expressed in all three specimens. Furthermore, the chemical nature of leech teeth was also examined via TEM-EDS to compare the chemical composition with vertebrate teeth. The examination of tissue-specific genetic information and chemical nature between leeches and mice revealed chemical similarities between leech and mice teeth, as well as conserved signaling molecules involved in tooth formation, including Ptpro, Prickle2, and Wnt16. Based on our findings, we propose that leech teeth express signaling molecules conserved in mice and these conserved tooth-specific signaling for dental hard tissue formation in mice would corresponds to the structural formation of the toothed jaw in leeches.

The ring finger protein 113A (RNF113A) serves as an E3 ubiquitin ligase and a subunit of the spliceosome. Mutations in the RNF113A gene are associated with X-linked trichothiodystrophy (TTD). However, the cellular roles of RNF113A remain largely unknown. In this study, we performed transcriptome profiling of RNF113A knockout (KO) HeLa cells using RNA sequencing and revealed the upregulation of NRF2 pathway-associated genes. Further analysis confirmed that the KO of RNF113A promotes nuclear localization of the NRF2 protein and elevates the mRNA levels of NRF2 target genes. RNF113A KO cells showed high levels of intracellular reactive oxygen species (ROS) and decreased resistance to cell death following H₂O₂ treatment. Additionally, RNF113A KO cells more sensitively formed stress granules (SGs) under arsenite-induced oxidative stress. Moreover, RNF113A KO cells exhibited a decrease in glutathione levels, which could be attributed to a reduction in GLUT1 expression levels, leading to decreased glucose uptake reactions and lower intracellular glucose levels. These alterations potentially caused a reduction in ROS scavenging activity. Taken together, our findings suggest that the loss of RNF113A promotes oxidative stress-mediated activation of the NRF2 pathway, providing novel insights into RNF113A-associated human diseases.

The role of ferroptosis-associated gene SLC7A11 in esophageal cancer progression is largely unknown, therefore, the effects of blocking SLC7A11 on esophageal squamous cell carcinoma (ESCC) cells are evaluated. Results showed that SLC7A11 was overexpressed in ESCC tissues both in mRNA and protein levels. Blocking SLC7A11 using Erastin suppressed the proliferation and colony formation of ESCC cells, decreased cellular ATP levels, and improved ROS production. Sixty-three SLC7A11-binding proteins were identified using the IP-MS method, and these proteins were enriched in four signaling pathways, including spliceosome, ribosome, huntington disease, and diabetic cardiomyopathy. The deubiquitinase inhibitors PR-619, GRL0617, and P 22077 could reduce at least 40% protein expression level of SLC7A11 in ESCC cells, and PR-619 and GRL0617 exhibited suppressive effects on the cell viability and colony formation ability of KYSE30 cells, respectively. Erastin downregulated GPX4 and DHODH and also reduced the levels of β-catenin, p-STAT3, and IL-6 in ESCC cells. In conclusion, SLC7A11 was overexpressed in ESCC, and blocking SLC7A11 using Erastin mitigated malignant phenotypes of ESCC cells and downregulated key ferroptosis-associated molecules GPX4 and DHODH. The therapeutic potential of targeting SLC7A11 should be further evaluated in the future.

The COVID-19 pandemic has significantly impacted human life, posing serious physical and psychological threats, particularly to the elderly. While individuals of all ages are susceptible to contracting COVID-19, older people face a heightened risk of developing various diseases due to age-related immunophysiological changes and preexisting health conditions. The interplay between immune health and physical activity is believed to hold even greater significance during a pandemic. Recent findings from our research indicate that the intervention of square stepping exercise (SSE), characterized by a rhythmic and controlled stepping pattern, resulted in increased levels of Brain-Derived Neurotrophic Factor (BDNF) in the elderly. BDNF, known to influence not only nerve cells but also immune cells, suggests a potential link between SSE and immune system modulation. Consequently, this exercise regimen holds promise in counteracting age-related immunophysiological changes, fine-tuning immune responses, and mitigating the severity of potential new virus outcomes, such as 'Disease X.' This review aims to underscore the significance of integrating SSE as a home-based program, serving as a potent tool to enhance immune resilience, prepare for future potential pandemics, and empower older individuals during challenging times. Through the practice of SSE, older adults may strengthen their ability to navigate the challenges posed by pandemics and maintain a sense of control over their well-being.

Parkinson's disease (PD) often results in hippocampal dysfunction, which leads to cognitive and emotional challenges and synaptic irregularities. This study attempted to assess behavioral anomalies and identify differentially expressed genes (DEGs) within the hippocampus of a hemiparkinsonian rat model to potentially uncover novel genetic candidates linked to hippocampal dysfunction. Striatal 6-hydroxydopamine (6-OHDA) infusions were performed unilaterally in the brains of adult SD rats, while dopaminergic impairments were verified in rats with 6-OHDA-lesioned striata. RNA sequencing and gene expression analysis unveiled 1018 DEGs in the ipsilateral rat hippocampus following 6-OHDA infusion: 631 genes exhibited upregulation, while 387 genes were downregulated (with FDR-adjusted p-value < 0.05 and absolute fold-change > 1.5). Gene ontology analysis of DEGs indicated that alterations in the hippocampi of 6-OHDA-lesioned rats were primarily associated with synaptic signaling, axon development, behavior, postsynaptic membrane, synaptic membrane, neurotransmitter receptor activity, and peptide receptor activity. The Kyoto Encyclopedia of Genes and Genomes analysis of DEGs demonstrated significant enrichment of the neuroactive ligand-receptor interaction, calcium signaling pathway, cAMP signaling pathway, axon guidance, and notch signaling pathway in rat hippocampi that had been subjected to striatal 6-OHDA infusion. STRING analysis confirmed a notable upregulation of eight hub genes (Notch3, Gng4, Itga3, Grin2d, Hgf, Fgf11, Htr3a, and Col6a2), along with a significant downregulation of two hub genes (Itga11 and Plp1), as validated by reverse transcription-quantitative polymerase chain reaction. This study provides a comprehensive transcriptomic profile of the hippocampi in a hemiparkinsonian rat model, thereby offering insights into the signaling pathways underlying hippocampal dysfunction.