Animal Cells and Systems最新文献

Human periodontal ligament stem cells (hPDLSCs) are candidate seed cells for periodontal tissue regeneration. Enhancing the stemness maintenance and osteogenic differentiation potential of hPDLSCs is conducive to their role in periodontal tissue regeneration. The combination of dasatinib and quercetin, a type of senolytic, has been reported to affect cell senescence. However, whether it can regulate the osteogenic differentiation and stemness maintenance of hPDLSCs, and the related mechanisms, remain unknown. The present study analyzed the optimal concentrations of dasatinib and quercetin in combination for hPDLSCs and found that the combination of dasatinib and quercetin enhanced osteogenic differentiation and promoted the expression of stemness-related markers in hPDLSCs. The expression levels of TAZ and YAP were improved when hPDLSCs were incubated with dasatinib and quercetin. However, the osteogenesis-promoting effects of dasatinib plus quercetin were partly attenuated when TAZ was knocked down, and their effects on stemness-related markers were suppressed when YAP was inhibited. Taken together, the combination of dasatinib and quercetin promotes the osteogenic differentiation and stemness maintenance of hPDLSCs, and YAP/TAZ may be involved in this process. This combination may hold promise for improving hPDLSCs function in periodontal tissue regeneration.

Gene co-expression network inference from bulk tissue samples often misses cell-type-specific interactions, which can be detected through single-cell gene expression data. However, the noise and sparsity of single-cell data challenge the inference of these networks. We developed scNET, a framework for integrative cell-type-specific co-expression network inference from single-cell transcriptome data, demonstrating its utility in augmenting the human interactome for more accurate disease gene prediction. We address the limitations of de novo network inference from single-cell expression data through dropout imputation, metacell formation, and data transformation. Employing this data preprocessing pipeline, we inferred cell-type-specific co-expression links from single-cell atlas data, covering various cell types and tissues, and integrated over 850K of these inferred links into a preexisting human interactome, HumanNet, resulting in HumanNet-plus. This integration notably enhanced the accuracy of network-based disease gene prediction. These findings suggest that with proper data preprocessing, network inference from single-cell gene expression data can be highly effective, potentially enriching the human interactome and advancing the field of network medicine.

The Changbai Mountain Range is generally perceived as a barrier to amphibian distribution, but it might not be playing this role anymore. Rana coreana was first described as a Korean endemic species, split from Rana amurensis, which ranges at more northern latitude. The species was then found on the Shandong peninsula in China, where it was first described as Rana kunyuensis, before being synonymised with R. coreana. So far, the contact zone with R. amurensis was expected to be in the vicinity of Pyongyang in DPR Korea, west of the Baekdu Mountain Range. However, the species is known from a population further north, and during surveys in Dalian in Liaoning Province, China, we found R. coreana on the southern slopes of the Laoling Mountain Range facing the Yellow Sea. Our phylogenetic analyses based on mitochondrial ribosomal markers showed the individual to cluster with R. coreana samples from the Korean Peninsula. In addition, our ecological niche models showed the presence of suitable habitats outside of the known range of the species, deserving further investigation. The habitat of the species at this new locality is similar to the one known in the three range nations, and highlights the need for more surveys in northeast China as the barrier formed by the Changbai Range is more porous than originally expected.

Electro-hyperthermia therapy (EHT) has been known to cause temperature-dependent cell death and enhance the effects of conventional antitumor treatments, such as chemotherapy and radiotherapy. Furthermore, EHT modulates the innate and adaptive immune systems. Mistletoe is one of the most broadly studied complementary and alternative therapeutic agents for cancer treatment due to its ability to stimulate the immune systems. This study aimed to investigate the effects of EHT and mistletoe therapy combination on immune responses. Tumors induced by B16-BL6 melanoma cells were treated twice with modulated EHT (mEHT) (43°C for 10 or 20 min) and with intravenous injection of a Korean mistletoe extract (KME). We examined the level of interferon (IFN)-γ, granzyme, interleukin (IL)-2, IL-10, and tumor-specific antibodies using enzyme-linked immunosorbent assay methods to further study the immunological responses in the combination of mEHT and KME. Additionally, cytotoxic T lymphocyte (CTL) activity is investigated. In this study, we revealed a significant anti-tumor immunological activity elevation in tumor-bearing mice by combined mEHT and KME therapy. Specifically, the combination of mEHT and KME treatment was effective in inhibiting tumor growth in mice. The combination treatment elicited CTL immune response and increased IFN-γ and granzyme secretion. Particularly, the co-treatment appeared to efficiently suppress the immune signal related to tumor-associated macrophage differentiation. Importantly, tumor cell-specific antibodies could be induced in mice after mEHT-treated tumor cell immunization, which represent a promising cancer vaccine strategy. Thus, our results indicate the therapeutic actions of KME as a feasible partner of mEHT, suggesting its potential candidate for cancer immunotherapy. Abbreviations: APC, Antigen-presenting cell; CTL, Cytotoxic T lymphocyte; EHT, Electro-hyperthermia therapy; ELISA, Enzyme-linked immunosorbent assay; HSP, Heat shock protein; KME, Korean mistletoe extract; NK, Natural killer; PBS, Phosphate-buffered saline; QOL, Quality of life; RF, Radio-frequency; TAM, Tumor-associated macrophage.

Lamin B1, a crucial component of the nuclear lamina, plays a pivotal role in chromatin organization and transcriptional regulation in eukaryotic cells. While recent studies have highlighted the connection between Lamin B1 and RNA splicing regulation, the precise molecular mechanisms remain elusive. In this study, we demonstrate that Lamin B1 depletion leads to a global reduction in splicing factor expression, as evidenced by analysis of multiple RNA-seq datasets. Motif analysis suggests that members of the ETS transcription factor family likely bind to the promoter regions of these splicing factors. Further analysis using transcription factor databases and ChIP-seq data identified ETS1 as a key regulator of splicing factor expression. Hi-C sequencing revealed that the loss of Lamin B1 disrupts inter-LAD chromatin interactions near the ETS1 gene locus, resulting in its downregulation. These findings suggest that Lamin B1 indirectly regulates RNA splicing by sustaining proper ETS1 expression, uncovering a novel link between nuclear architecture, gene regulation, and RNA splicing.

Circadian rhythms are 24-hour cycles in various biological processes, such as sleep, wake, and hormone secretion, controlled by an internal clock. Disruption of circadian rhythms has been related to various human diseases. Abnormal expression of circadian rhythm-related genes, such as CLOCK, BMAL1, PER1, PER2, CRY1, CRY2, RORα, NPAS2, REV-ERBα and TIMELESS has also been reported to be associated with cancer. CLOCK, CRY1, NPAS2 and TIMELESS are related to cancer development. In contrast, BMAL1, PER1, PER2, CRY2, RORα and REV-ERBα related to inhibit cancer development and progression. Furthermore, studies suggest that circadian genes related to cancer can be regulated by ncRNAs such as miRNAs, lncRNAs and circRNAs and that dysregulation of these ncRNAs contributes to cancer development. Here, we summarize the mechanisms whereby ncRNA dysregulation leads to the abnormal expression of circadian genes in several cancers and the ncRNA and circadian gene-associated regulatory mechanisms that contribute to resistance to chemo - and radiotherapy. This review provides insights into the mechanistic involvements of the regulatory network of circadian genes and ncRNAs in cancer development.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by cognitive decline, anxiety-like behavior, β-amyloid (Aβ) accumulation, and tau hyperphosphorylation. BACE1, the enzyme critical for Aβ production, has been a major therapeutic target; however, direct BACE1 inhibition has been associated with adverse side effects. This study investigates the therapeutic potential of RA-PR058, a novel ramalin derivative, as a multi-targeted modulator of AD-related pathologies. The effects of RA-PR058 were evaluated in vitro and in vivo. In vitro studies used SH-SY5Y cells under oxidative stress conditions to assess BACE1 expression, while in vivo effects were studied in 3xTg-AD mice following one month of oral RA-PR058 treatment. Behavioral assessments, biochemical analyses, transcriptomic profiling, and pharmacokinetic evaluations were performed to determine the efficacy of RA-PR058. RA-PR058 significantly reduced oxidative stress-induced BACE1 expression in vitro and decreased cortical BACE1 expression in 3xTg-AD mice. In vivo treatment alleviated anxiety-like behavior and reduced tau phosphorylation at disease-relevant sites (Ser202/Thr205, Thr231, and Ser396). Transcriptomic analysis revealed RA-PR058-mediated gene expression changes related to central nervous system development, response to hypoxia, and neuroactive ligand-receptor interactions, suggesting broader regulatory effects on AD-related pathways. Pharmacokinetic analysis demonstrated that RA-PR058 exhibits high metabolic stability, minimal cytochrome P450 interactions, and moderate blood-brain barrier penetration. RA-PR058 demonstrates potential as a multi-target AD therapeutic by reducing BACE1 expression, tau hyperphosphorylation, and anxiety-like behavior, coupled with favorable pharmacokinetics. Additional studies are needed to assess cognitive effects and clarify molecular mechanisms, but RA-PR058 may represent a promising advancement in addressing AD's complex pathology.

Invasive species can be unpredictable in their ability to adapt and spread across novel landscapes. American bullfrogs (Lithobates catesbeianus) and red-eared sliders (Trachemys scripta elegans) have become invasive in South Korea since their introduction in the 1970s through the food and pet trades. One of the first steps to their population regulations is to determine each species' distribution in the country, which will allow for the identification of at-risk areas. In this study, we used a combination of kernel density and habitat suitability modeling to identify regions of current invasion and future spread for both species. We additionally modeled habitat suitability under a variety of climate scenarios, spanning 2021-2100 in order to determine possible climate change-based spread. For L. catesbeianus we found the total possible invasible area to be 46.2% of the country under current climate conditions, with 26.5% of the country currently invaded. For T. scripta, we found the total possible invasible area to be 38.5% of the country under current climate conditions, with 2.1% currently invaded. Finally, based on climate change predictions, both species are expected to have a decreased range of suitable area in the coming decades. The variations between the two invasive species pertain to their different breeding ecology.

Inflammatory bowel disease is a chronic condition characterized by inflammation of the gastrointestinal tract, resulting from an abnormal immune response to normal stimuli, such as food and intestinal flora. Since the etiology of this disease remains largely unknown, murine models induced by the consumption of dextran-sodium sulfate serve as a pivotal tool for studying colon inflammation. In this study, we employed both acute and chronic colitis mouse models induced by varying durations of dextran-sodium sulfate consumption to investigate the pathological and immunologic characteristics throughout the disease course. During the acute phase, activated innate inflammation marked by M1 macrophage infiltration was prominent. In contrast, the chronic phase was characterized by tissue remodeling, with a significant increase in M2 macrophages and lymphocytes. RNA-sequencing revealed genetic changes in acute and chronic colitis, marked by the maintenance of genomic integrity in the acute phase and extracellular matrix dynamics in the chronic phase. These phase-specific alterations reflect the multifaceted physiological processes involved in the initiation and progression of inflammation in the large intestine, underscoring the necessity for distinct experimental approaches for each phase. The findings demonstrate that the factors shaping the large intestinal immune microenvironment change specifically during the acute and chronic phases of experimental inflammatory bowel disease, highlighting the importance of developing therapeutic strategies that align with the disease course.

Osmoregulation is essential for the survival of aquatic organisms, particularly teleost fish facing osmotic challenges in environments characterized by variable salinity. While the gills are known for ion exchange, the intestine's role in water and salt absorption is gaining attention. Here, we investigated the adaptive responses of the intestine to salinity stress in guppies (Poecilia reticulata), observing significant morphological and transcriptomic alterations. Guppies showed superior salt tolerance compared to zebrafish (Danio rerio). Increasing salinity reduced villus length and intestinal diameter in guppies, while zebrafish exhibited damage to villus structure and loss of goblet cells. Transcriptomic analysis identified key genes involved in osmoregulation, tissue remodeling, and immune modulation. Upregulated genes included the solute carrier transporters slc2al and slc3al, which facilitate ion and water transport, as well as a transcription factor AP-1 subunit and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta, both of which participate in tissue repair and growth responses. In contrast, many genes related to the innate immune system (such as Tnfaip6) were downregulated, suggesting a shift toward the prioritization of osmoregulatory functions over immune responses. Interestingly, the differential expression of adaptation genes was linked to variations in epigenetic modifications and transcription factor activity. Transcription factors crucial for adapting to salt stress, such as bhlhe40, cebpd, and gata6, were progressively upregulated in guppies but remained downregulated in zebrafish. Our findings highlight the intricate mechanisms of adaptation to salinity stress in P. reticulata, providing insights into osmoregulatory mechanisms involving the intestine in aquatic organisms.