Molecules and Cells最新文献

The main cause of death in lung cancer patients is metastasis. Thus, efforts to suppress micrometastasis or distant metastasis in lung cancer, identify therapeutic targets and develop related drugs are ongoing. In this study, we identified SET and MYND domain-containing protein 5 (SMYD5) as a novel metastasis regulator in lung cancer and found that SMYD5 was overexpressed in lung cancer based on both RNA-sequencing analysis results derived from the TCGA portal and immunohistochemical analysis results; knockdown of SMYD5 inhibited cell migration and invasion by changing epithelial-mesenchymal transition markers and MMP9 expression in NCI-H1299 and H1703 cell lines. Additionally, SMYD5 knockdown increased Src homology 2-b3 expression by decreasing the level of H4K20 trimethylation. Furthermore, in an in vitro epithelial-mesenchymal transition system using TGF-β treatment, SMYD5 knockdown resulted in reduced cell migration and invasion in the highly invasive NCI-H1299 and H1703 cell lines. Based on these findings, we propose that SMYD5 could serve as a potential therapeutic target for lung cancer treatment and that cotreatment with an SMYD5 inhibitor and chemotherapy may enhance the therapeutic effect of lung cancer treatment.

Transcriptome analysis is widely used for current biological research but remains challenging for many experimental scientists. Here, we present a brief but broad guideline for transcriptome analysis, focusing on RNA sequencing, by providing the list of publicly available datasets, tools, and R packages for practical transcriptome analysis. This work will be useful for biologists to perform key transcriptomic analysis with minimum expertise in bioinformatics.

Environmental pollutants, including endocrine disruptors, heavy metals, nanomaterials, and pesticides, have been detected in various ecosystems and are of growing global concern. The potential for toxicity to non-target organisms has consistently been raised and is being studied using various animal models. In this review, we focus on pesticides frequently detected in the environment and investigate their potential exposure to livestock. Owing to the reproductive similarities between humans and pigs, various in vitro porcine models, such as porcine oocytes, trophectoderm cells, and luminal epithelial cells, are used to verify reproductive toxicity. These cell lines are being used to study the toxic mechanisms induced by various environmental toxicants, including organophosphate insecticides, pyrethroid insecticides, dinitroaniline herbicides, and diphenyl ether herbicides, which persist in the environment and threaten livestock health. Collectively, these results indicate that these pesticides can induce female reproductive toxicity in pigs and suggest the possibility of adverse effects on other livestock species. These results also indicate possible reproductive toxicity in humans, which requires further investigation.

Periodontitis (PD) is an inflammatory disease with alveolar bone destruction by osteoclasts (OCs). In PD, both inflammation and OC activation are significantly influenced by periodontal ligament fibroblasts (PDL-Fib). Yet, whether PDL-Fib has heterogeneity and whether distinct PDL-Fib subsets have specific functions have not been investigated. In this study, we discovered the complexity of PDL-Fib in PD, utilizing single-cell RNA sequencing data from human PD patients. We identified distinct subpopulations of PDL-Fib: one expressing interleukin-1 beta (IL-1β) and another expressing the receptor activator of nuclear factor-kappa B ligand (RANKL), both crucial in OC differentiation and bone resorption. In periodontal tissues of mice with PD, active IL-1β, cleaved caspase 1, and nucleotide-binding oligomerization domain-like receptor 3 (NLPR3) were significantly elevated, implicating the NLRP3 inflammasome in IL-1β production. Upon stimulation of PDL-Fib with LPS from Porphyromonas gingivalis (pg), the most well-characterized periodontal bacteria, a more rapid increase in IL-1β, followed by RANKL induction, was observed. IL-1β and tumor necrosis factor alpha (TNF-α), another LPS-responsive cytokine, effectively increased RANKL in PDL-Fib, suggesting an indirect effect of pgLPS through IL-1β and TNF-α on RANKL induction. Immunohistological analyses of mouse periodontal tissues also showed markedly elevated levels of IL-1β and RANKL upon PD induction and displayed separate locations of IL-1β-expressing PDL-Fib and RANKL-expressing PDL-Fib in PD. The heterogenic feature of fibroblasts expressing IL-1β and RANKL was also mirrored in our combined cross-tissue single-cell RNA sequencing datasets analysis. In summary, our study elucidates the heterogeneity of PDL-Fib, highlighting distinct functional groups for producing RANKL and IL-1β, which collectively promote OC generation and bone destruction in PD.

Aging is accompanied by the gradual deregulation of the transcriptome. However, whether age-dependent changes in the transcriptome are evolutionarily conserved or diverged remains largely unexplored. Here, we performed a meta-analysis examining the age-dependent changes in the transcriptome using publicly available datasets of 11 representative metazoans, ranging from Caenorhabditis elegans to humans. To identify the transcriptomic changes associated with aging, we analyzed various aspects of the transcriptome, including genome composition, RNA processing, and functional consequences. The use of introns and novel splice sites tended to increase with age, particularly in the brain. In addition, our analysis suggests that the age-dependent accumulation of premature termination codon-containing transcripts is a common feature of aging across multiple animal species. Using C. elegans as a test model, we showed that several splicing factors that are evolutionarily conserved and age-dependently downregulated were required to maintain a normal lifespan. Thus, aberrant RNA processing appears to be associated with aging and a short lifespan in various species.

MicroRNAs play a crucial role in directly reprogramming (converting) human fibroblasts into neurons. Specifically, miR-9/9* and miR-124 (miR-9/9*-124) display neurogenic and cell fate-switching activities when ectopically expressed in human fibroblasts by erasing fibroblast identity and inducing a pan-neuronal state. These converted neurons maintain the biological age of the starting fibroblasts and thus provide a human neuron-based platform to study cellular properties in aged neurons and model adult-onset neurodegenerative disorders using patient-derived cells. Furthermore, the expression of striatal-enriched transcription factors in conjunction with miR-9/9*-124 guides the identity of medium spiny neurons (MSNs), the primary targets in Huntington's disease (HD). Converted MSNs from HD patient-derived fibroblasts (HD-MSNs) can replicate HD-related phenotypes including neurodegeneration associated with age-related declines in critical cellular functions such as autophagy. Here, we review the role of microRNAs in the direct conversion of patient-derived fibroblasts into MSNs and the practical application of converted HD-MSNs as a model for studying adult-onset neuropathology in HD. We provide valuable insights into age-related, cell-intrinsic changes contributing to neurodegeneration in HD-MSNs. Ultimately, we address a comprehensive understanding of the complex molecular landscape underlying HD pathology, offering potential avenues for therapeutic application.

Translation of messenger ribonucleic acids (mRNAs) encoding integral membrane proteins or secreted proteins occurs on the surface of the endoplasmic reticulum (ER). When a nascent signal peptide is synthesized from the mRNAs, the ribosome-nascent chain complex (RNC) is recognized by the signal recognition particle (SRP) and then transported to the surface of the ER. The appropriate targeting of the RNC-SRP complex to the ER is monitored by a quality control pathway, a nuclear cap-binding complex (CBC)-ensured translational repression of RNC-SRP (CENTRE). In this study, using ribosome profiling of CBC-associated and eukaryotic translation initiation factor 4E-associated mRNAs, we reveal that, at the transcriptomic level, CENTRE is in charge of the translational repression of the CBC-RNC-SRP until the complex is specifically transported to the ER. We also find that CENTRE inhibits the nonsense-mediated mRNA decay (NMD) of mRNAs within the CBC-RNC-SRP. The NMD occurs only after the CBC-RNC-SRP is targeted to the ER and after eukaryotic translation initiation factor 4E replaces CBC. Our data indicate dual surveillance for properly targeting mRNAs encoding integral membrane or secretory proteins to the ER. CENTRE blocks gene expression at the translation level before the CBC-RNC-SRP delivery to the ER, and NMD monitors mRNA quality after its delivery to the ER.

Observing the activity of neural networks is critical for the identification of learning and memory processes, as well as abnormal activities of neural circuits in disease, particularly for the purpose of tracking disease progression. Methodologies for describing the activity history of neural networks using molecular biology techniques first utilized genes expressed by active neurons, followed by the application of recently developed techniques including optogenetics and incorporation of insights garnered from other disciplines, including chemistry and physics. In this review, we will discuss ways in which molecular biological techniques used to describe the activity of neural networks have evolved along with the potential for future development.