Animal Cells and Systems最新文献

Peroxiredoxin6 (Prdx6) is a bifunctional antioxidant enzyme with both peroxidase and phospholipase A₂ activities. Although its molecular roles are well established, the developmental role of Prdx6 remains poorly understood. To address this gap in the literature, this study aimed to examine the in vivo function of Prdx6 in primitive myelopoiesis using Xenopus laevis embryos. We found that prdx6 is specifically expressed in myeloid progenitors originating from the anterior ventral blood island during early embryogenesis. Knockdown of prdx6 significantly reduced the number of myeloid cells, without affecting their migration ability. Embryos depleted of prdx6 exhibited elevated levels of reactive oxygen species (ROS) and decreased cellular proliferation. Co-injection of morpholino (MO)-resistant prdx6 mRNA or treatment with N-acetylcysteine (NAC) successfully restored both ROS levels and myeloid cell numbers, suggesting that Prdx6 supports primitive myeloid cell development by maintaining redox homeostasis. These findings reveal a novel role of Prdx6 in ROS-dependent proliferation of myeloid progenitors during early vertebrate development.

Endothelial cells regulate diverse vascular functions by perceiving and reacting to laminar shear stress. In this study, a novel shear-sensing receptor was identified through the use of a pro-inflammatory protein, lysyl-tRNA synthetase (KARS), which is known to be secreted from endothelial cells via autophagy. Binding assays demonstrated that cytokeratin-1 (CK1) interacts with KARS at the endothelial cell surface. Additionally, CK1 was shown to be critical for ECM-cell adhesion and endothelial sensing of shear stress by mediating interactions with laminin and integrin α6. Overexpression of CK1 results in hyperactivation of endothelial nitric oxide synthase (eNOS) in response to laminar shear stress (LSS), potentially reducing the risk of atherosclerosis. Furthermore, elevated CK1 expression significantly decreases leukocyte adhesion to endothelial cells by modulating nitric oxide production stimulated by LSS. Conversely, CK1 knockdown leads to the formation of actin fibers and diminishes LSS-induced activation of several cell signaling components. These findings indicate that CK1 is a shear-sensing receptor, providing new perspectives on the close relationship between cell-to-matrix adhesion and mechanosensing.

Holoprosencephaly (HPE) is the most frequent developmental disorder of the forebrain. In HPE, the early single anlage of the forebrain, the anterior neural plate (ANP) which encompasses the future telencephalon and eye field, fails to divide. BMP signaling and antagonism are overall important for nervous system development. The focus of this study was on the role of the ligand bmp7b and the receptor bmpr1ba during forebrain development. The zebrafish loci of bmp7b and bmpr1ba were targeted transiently with CRISPR/Ca9. Crispants for both bmp7b and bmpr1ba presented HPE and cyclopia, one central eye. Subsequently, the ANP was addressed in bmp7b Crispants. The morphology of the eye field was affected, with important markers, rx3, six3b and cxcr4a expressed condensed at the midline. Induced expression of bmp4 is also known to result in HPE. Such bmp4 induction altered the expression of bmpr1ba. Zebrafish Crispants for bmp7b and bmpr1ba can be used as a novel HPE model. A challenge in future analyses will be the penetrance of phenotypes in Crispants. The advantages are, however, that analyses can be conducted anywhere, without the need of mutant lines. One important aspect for future analysis will be the role of individual bmp ligands, receptors and antagonists in forebrain development.

Bavachin, a bioactive phytoestrogen from Psoralea corylifolia, has shown promising therapeutic potential in various cancers, but its effects on ovarian cancer remain unexplored. In this study, we investigate the anti-cancer mechanisms of bavachin in ES2 and OV90 ovarian cancer cells and its potential to enhance paclitaxel sensitivity. Bavachin significantly inhibited cell proliferation and spheroid formation while inducing caspase-dependent apoptosis through modulation of Bcl-2 family proteins. Mechanistically, bavachin disrupted mitochondrial function by inducing membrane depolarization and calcium dysregulation, leading to comprehensive impairment of cellular bioenergetics including both oxidative phosphorylation and glycolysis. Furthermore, bavachin activated the endoplasmic reticulum stress pathway as evidenced by upregulation of GRP78, ATF4, PERK, and CHOP, and notably inhibited phosphorylation of ERK1/2 and p38 MAPK signaling pathways essential for tumor cells survival. Combination treatment with bavachin enhanced the cytotoxic effects of paclitaxel, showing synergistic anti-cancer activity in both cell lines. These findings demonstrate that bavachin effectively suppresses ovarian cancer growth through multiple mechanisms and may serve as a promising therapeutic agent, particularly in combination with conventional chemotherapy.

Messenger ribonucleic acid (mRNA) vaccines have become a prevalent immunization method, even as the coronavirus disease 2019 (COVID-19) pandemic recedes. However, the potential adverse effects using mRNA vaccines need to be explored in this evolving landscape. In this study, 60 participants were randomly assigned to receive either an mRNA vaccine, specifically for COVID-19, or a conventional vaccine for meningococcal disease. Symptom records and blood samples were collected on Days 0, 3, and 7 after vaccination. Results showed that recipients of mRNA vaccines exhibited elevated levels of serum acute-phase proteins, such as haptoglobin and C-reactive protein, alongside decreased white blood cell counts compared to those receiving conventional vaccines. Proteomic analysis identified significant changes in nine proteins, including interactions involving complement component C9, haptoglobin, and alpha-1-acid glycoprotein, suggesting implications for complement activation and inflammatory responses. Furthermore, variability in anti-polyethylene glycol antibody levels was noted among mRNA vaccine recipients compared to conventional vaccine recipients. This research aims to provide useful information to help develop future vaccination strategies and shape research directions to mitigate individual adverse effects.

In recent years, the intricate relationship between the immune system and neurological disorders has garnered significant attention. While the central nervous system had long been perceived as immunologically privileged, emerging research has revealed complex interactions among immune cells, inflammatory mediators, and neural components that collectively influence the pathogenesis and progression of various neurological disorders. This comprehensive review explores the crucial role of the cytokine interleukin-17(IL-17) in neurological diseases. It examines the complex contributions of IL-17 to both neurodevelopmental and neurodegenerative disorders, highlighting its diverse mechanisms and its impact on neuro-immune crosstalk. Moreover, we assess the evidence supporting the potential therapeutic role of modulating IL-17, considering its beneficial and detrimental effects. Through a comprehensive analysis of current research, we aim to provide insights into the modulatory role of IL-17 in neurological disorders.

Scutellaria baicalensis extracts (SBE) have demonstrated potential therapeutic effects against gastrointestinal disorders. This study evaluated the effects of SBE on zymosan-induced irritable bowel syndrome (IBS) symptoms and the underlying mechanisms involved. The major components of SBE, baicalin and baicalein, were quantified using high-performance liquid chromatography. SBE inhibited pacemaker potentials in interstitial cells of Cajal in vitro, with an IC₅₀ value of 27.48 μg/mL. In an animal model of IBS, SBE administration restored colonic length, weight, and stool consistency. Furthermore, SBE reduced tumor necrosis factor-α expression and alleviated pain-associated behaviors. Histological analysis revealed that SBE treatment restored normal colon tissue structure and significantly reduced inflammation. Electrophysiological recordings demonstrated that SBE inhibited the activity of transient receptor potential (TRP) channels, including TRPV1, TRPV4 and TRPA1, as well as voltage-gated sodium channels (NaV1.5), which are associated with visceral pain hypersensitivity. These findings suggest that SBE has therapeutic potential, making it a promising candidate for the management of IBS.

Loranthus tanakae Franch. and Sav. is a traditional herbal remedy with anti-inflammatory and antioxidative properties, used to treat joint and respiratory inflammation. In this study, we investigated the therapeutic effects of L. tanakae ethanol extract (LTE) on atopic dermatitis (AD). An ovalbumin (OVA)-induced AD animal model and a human keratinocyte cell line, HaCaT, were used to assess LTE treatment effects on AD. An in vitro experiment showed that LTE treatment significantly decreased the production of regulated upon activation, normal T cell expressed and secreted (RANTES) cytokines and macrophage-derived chemokines (MDC) in tumor necrosis factor-alpha (TNF-α)/interferon-gamma (IFN-γ) (TNF-α/IFN-γ)-stimulated HaCaT cells in a concentration-dependent manner. In addition, treatment with LTE markedly reduced the translocation of signal transducer and activator transcription 1 (STAT1) protein to the nucleus and the phosphorylation of Janus kinase 2 (JAK2) in TNF-α/IFN-γ-stimulated HaCaT cells. In the in vivo experiment, administration of LTE significantly decreased the levels of immunoglobulin E (IgE) and interleukin-13 (IL-13) of OVA-induced AD mice, which was supported by histological evidence. Moreover, LTE treatment markedly reduced inflammatory cell infiltration and edema in the OVA-induced AD mice's damaged lesions. In addition, applying LTE notably inhibited the phosphorylation of JAK2 and STAT1 in the OVA-induced AD mice, supported by in vitro results. In conclusion, LTE effectively alleviated the AD-induced skin inflammation in the OVA-induced AD animal model and TNF-α/IFN-γ-stimulated HaCaT cells; this was related to the suppression of JAK2 and STAT1 phosphorylation. These findings suggest that LTE has potential as a therapeutic agent for AD management.

Xenopus embryo is a useful model for evaluating the adverse effects of any compounds on the cellular processes essential for early development and adult tissue homeostasis. Our chemical library screening with frog embryos identified artesunate (ART) as an inhibitor of the BMP signaling pathway to interfere with the specification of embryonic germ layers. Exposure to ART led to reduction of the anterior-posterior body axis, malformed tail structures and loss of pigment cells in the trunk region of embryos. The severely defective embryos exhibited truncation of posterior structures, resembling the phenotypes of tadpoles depleted of BMPs. Consistent with these morphological deformities, ART exposure inhibited the BMP-dependent transcriptions of target genes and specification of ventral mesoderm. In contrast, the expression of an organizer-specific gene induced by Activin/Nodal signaling remained unchanged in ART-treated cells. ART also enhanced anterior neural differentiation at the expense of epidermal and neural crest cell fates. Unexpectedly, we observed that ART exposure accelerates proteasomal degradation of a BMP transducer Smad1, leading to upregulation of MAP kinase activity. Taken together, these results suggest that ART acts as an inhibitor of BMP signaling pathway, exerting severe adverse effects on the specification of germ layers in vertebrate early development.

Yes-associated protein (YAP), a key co-transcription factor of the Hippo pathway, is a promising drug target for cancer therapy due to its critical role in promoting cell proliferation, survival, and tumor progression when dysregulated. While most Hippo pathway-targeting drugs focus on disrupting TEAD-YAP interactions or modulating the MST or LATS kinase cascade, new approaches are needed to identify small molecules that regulate YAP activity. In this study, we conducted high-throughput screening of FDA-approved drugs to discover potential YAP modulators. Using a NanoBiT-based system, which enables real-time and quantitative measurement of protein interactions, combined with phenotype-based assays in EGFP-YAP-expressing cells, we identified compounds that activate or inhibit YAP function. Among the identified YAP regulators, the microtubule destabilizer vinorelbine promoted YAP nuclear localization and transcriptional activation, while the antipsychotic drug thioridazine enhanced YAP phosphorylation at Ser127, resulting in its cytoplasmic retention and reduced transcriptional activity, effectively suppressing cancer cell growth. These findings demonstrate the potential of FDA-approved drugs in modulating YAP activity and present a novel screening strategy for developing YAP-targeting therapeutics. Furthermore, this approach can be extended to identify modulators of other signaling pathways, advancing drug discovery for a wide range of diseases.