Animal Cells and Systems最新文献

Natural killer T (NKT) cells are innate-like T lymphocytes that express natural killer (NK) cell receptors (NKRs), which recognize glycolipid antigens presented by the MHC class I-like protein CD1d, linking innate and adaptive immunity. NKT cells include two main subsets, type I and type II, which differ in TCR usage and antigen specificity. In addition, NKT-like cells, which express NKRs but are CD1d-independent, have attracted growing interest in neuroimmunology. These NKR-expressing T cells play important roles in either promoting or suppressing pathological conditions within the brain. This review overviews recent advances in understanding NKT cells in immune disorders of the central nervous system (CNS), including neurodegenerative diseases, neuroinflammation, autoimmune diseases, brain injury, and CNS malignancies, such as glioblastoma. By interacting with CD1d on non-immune cells (e.g. astrocytes) and immune cells (e.g. microglia) through their TCR, type I NKT cells help maintain or disrupt immune homeostasis in the CNS. In addition, exogenous ligands, such as alpha-galactosylceramide, can modify type I and type II NKT cell phenotypes and promote regulatory functions in NKT-like cells, which may mitigate excessive inflammation. This review provides insights into how NKT cell subsets could serve as therapeutic targets for neuroinflammatory diseases.

The overall structure and development of the central nervous system (CNS) are highly conserved among vertebrates. Peak neurogenesis generally precedes the main wave of astrogliogenesis; exuberant synapses are formed and pruned during critical periods; and the neurotransmitter gamma-aminobutyric acid (GABA) shifts from depolarizing to hyperpolarizing as the brain matures. The sequence of these key developmental events is broadly similar across vertebrate model organisms, including mouse, Xenopus, and zebrafish. Despite this overall similarity, the relative duration of each event varies substantially, and key events such as live birth in mammals do not occur in fish or frogs. These differences must be considered when translating findings from one species to another. In this review, we compare several developmental events that are relevant to modeling human diseases in animal models, including microglial colonization and blood-brain barrier formation. We also present comparative developmental timelines as a resource for translational neuroscience research.

Parkinson's disease (PD) is characterized by nigrostriatal dopaminergic (DAergic) degeneration and motor dysfunction. Many PD patients also show circadian rhythm disturbances. Increasing evidence links circadian clock dysfunction to PD pathology. REV-ERBα is a circadian nuclear receptor that regulates DAergic genes under physiological conditions. However, its role in nigrostriatal dopamine (DA) homeostasis and motor function in PD remains unclear. In this study, we found elevated Rev-erbα mRNA expression in tyrosine hydroxylase (TH)-positive neurons of the substantia nigra (SN) in a 6-hydroxydopamine (6-OHDA) mouse model of PD. To test its functional role, we assessed the acute effects of local SN microinjection of the REV-ERBα antagonist SR8278. We found that SR8278 partially recovered motor performance and improved fine motor function. These effects occurred regardless of circadian timing. SR8278 administration did not restore TH expression or tissue DA levels in the striatum and SN. However, in vivo microdialysis showed enhanced extracellular DA turnover in the striatum. Specifically, while extracellular DA metabolites level increased, basal extracellular DA levels showed no change. Together, these findings identify REV-ERBα as a potential therapeutic target that modulates extracellular nigrostriatal DA dynamics and improves motor function in PD.

Visceral sensory neurons (VSNs) play an essential role in interoception, but it remains challenging to selectively access them using genetic tools due to their anatomical location and shared molecular markers with central autonomic circuits. Although transgenic models visualizing Phox2b-expressing neurons have been developed to genetically label VSNs, concurrent Phox2b expression in the hindbrain limits their selectivity. To overcome these limitations, we engineered several Phox2b promoter-driven adeno-associated virus (AAV) vectors and evaluated the effects of capsid serotype, delivery route, and injection timing. Using systemic delivery of AAV-PHP.S-Phox2b-Cre, we found that postnatal day 8 is an optimal time window for efficient and selective labeling of VSNs with a relatively low dose. The result contrasts with neonatal administration, which led to extensive ectopic labeling at the same dose. Unexpectedly, lingual submucosal delivery of AAV-retro-Phox2b-Cre, initially intended to label tongue-innervating sensory neurons, also labeled most vagal neurons. These labeled neurons were AAV-retro capsid-specific, because local delivery of AAV-PHP.S-Phox2b-Cre labeled cells only near the injection site. Altogether, this study provides practical parameters for selective genetic access to VSNs using AAV.

Zinc finger E-box binding homeobox 1 (ZEB1) is a key transcription factor that induces the epithelial-mesenchymal transition (EMT) and promotes lung cancer progression. While circular RNAs (circRNAs) are also involved in EMT, their connection with ZEB1 remains unclear. Here, using RNA sequencing coupled with CIRI-full analysis, we identified 25 circRNAs differentially expressed in ZEB1-overexpressing lung cancer cells. Among them, circDennd1b was significantly downregulated. circDennd1b knockdown promoted cell proliferation, migration, and invasion, and induced EMT. Conversely, circDennd1b overexpression inhibited cancer cell migration and invasion. We also found that circDennd1b inhibits cell migration by sponging the miR-181 family. These data indicate that the ZEB1/circDennd1b/miR-181 axis promotes lung cancer progression and could offer a new approach for treatment.

Caenorhabditis elegans, a nematode genetic model, is often synchronized in experiments to accurately observe its unbiased phenotypes. Chemical synchronization, simple bleaching of gravid worms, has been widely used to obtain eggs in bulk because the eggshell is extremely resistant to harsh conditions. While those eggs are considered to preserve their natural properties and are allowed to hatch to obtain synchronized worms, it has not been fully investigated whether chemical synchronization influences embryonic and post-embryonic traits. In this study, we compared some phenotypes observed in worms collected by picking laid eggs and by chemical synchronization. Chemical synchronization decreased hatching and developmental rates and, in some conditions, affected morphological traits, such as body length and head size, and brood size. In contrast, chemical synchronization did not affect the developmental potential of early- or later-stage eggs, or chemosensory behaviors. While the lifespan of wild-type worms did not change, the daf-16 loss-of-function mutant with an extremely short lifespan showed much variation when chemically synchronized. This study clarifies the impacts of chemical synchronization of worms and provides some critical considerations for its use.

Mitochondria-associated ER membranes (MAMs) are inter-organelle contact sites that mediate signaling between the ER and mitochondria. MAMs play crucial roles in Ca²⁺ transfer, lipid metabolism, mitochondrial respiration, protein homeostasis, autophagy, and ER stress. In the central nervous system (CNS), these functions are particularly important because neurons and glial cells require precise communication between ER and mitochondria to sustain various neuronal functions. Previous studies often interpreted the MAM dysfunction associated with disease as an alteration in ER-mitochondria coupling. More recently, however, MAMs are regarded as functionally specialized signaling platforms whose molecular composition is dynamic, cell type- and disease stage-dependent. Here, we discuss how MAM remodeling underlies a range of neurological diseases, including neurodegenerative and neurodevelopmental conditions, neuropsychiatric disorders, neuroinflammation, neuronal aging, and brain tumors.

Neurons do not always use a 'one neurotransmitter-one receptor' paradigm to communicate at synapses. Some neurons communicate using more than one neurotransmitter, a phenomenon termed co-transmission. Co-transmission can occur through a few distinct organizational modes at synapses, enabling the integration of excitatory, inhibitory, and modulatory signals in various combinations. Increasingly, evidence suggests that these organizational modes are particularly important in neural circuits functioning in stress response. In monoaminergic nuclei, the lateral habenula, and the hippocampus, stress exposure induces shifts in co-transmission via circuit-specific changes to neurotransmitter balance. Here, we review recent advances in our understanding of co-transmission in these circuits, with an emphasis on evidence that distinct modes of small-molecule co-transmission are employed in circuits that contribute to some of the multidimensional aspects of stress. We further discuss potential mechanisms that may recalibrate multi-transmitter signaling during stress-stimulated co-transmission. Currently, evidence suggests that stress affects not only single-transmitter systems but also multi-transmitter communication across neural circuits. Viewing co-transmission as a dynamic substrate of stress-induced neural plasticity, this review provides new insight into the neural basis of adaptive and maladaptive stress responses and may help identify novel therapeutic opportunities for affective disorders, such as major depressive disorder and bipolar disorder.

A deciduous tree belonging to the Combretaceae family, Terminalia chebula Retz. has a long history of traditional use in diabetes management. However, it is not fully understood how the extract of T. chebula exerts the antidiabetic effects. To identify the constituents responsible for this activity, we investigated the bark of T. chebula and determined the structures of compounds exhibiting antidiabetic potential. Using molecular networking, LC-MS, and NMR analysis, we identified five phytochemical compounds (1-5): arjunglucoside I (1), arjunetin (2), arjungenin (3), (-)-catechin (4), and (-)-epicatechin (5). We found that arjunglucoside I and arjunetin selectively inhibited α-glucosidase, but not α-amylase, suggesting that they may regulate postprandial glucose levels with few gastrointestinal side effects. Both compounds significantly increased the gene expression of insulin (ins) but decreased that of pck1, which encodes phosphoenolpyruvate carboxykinase (PEPCK), a key enzyme in gluconeogenesis. These effects were also observed under metabolic stress induced by cAMP/dexamethasone, indicating feedback regulation between insulin and gluconeogenesis pathways. Arjunglucoside I and arjunetin protected zebrafish from oxidative damage induced by alloxan, modulated calcium signaling-related gene expression under insulin-resistant conditions, and increased glucose uptake in insulin-resistant C2C12 myotubes. Collectively, these results provide insights into the use of arjunglucoside I and arjunetin for diabetes treatment and the development of novel antidiabetic agents derived from the promising phytochemicals.

Fibrosis is characterized by excessive extracellular matrix (ECM) deposition driven by sustained pro-fibrotic signaling and underlies a wide range of pathological conditions. Accordingly, strategies that broadly suppress ECM production are considered promising for the treatment of fibrosis. Although calcium hydroxyapatite (CaHA) is primarily used as a nanoparticle-based dermal filler, previous observations that it affects collagen production suggest its potential repurposing as a regulator of ECM-related programs. Here, we investigated the anti-fibrotic efficacy of CaHA and the signaling mechanisms underlying its effects. CaHA broadly suppressed ECM-related gene expression in fibroblasts, extending beyond collagen to multiple ECM components and associated regulatory factors. Mechanistically, CaHA attenuated Piezo1-associated Ca²⁺ signaling and was also associated with activation of the PKA pathway. Importantly, CaHA similarly reduced ECM-related gene expression in a fibrotic liver cell model, supporting the broader relevance of its anti-fibrotic activity. Together, these findings identify CaHA as a broad suppressor of ECM-related gene expression through modulation of Piezo1-associated Ca²⁺ signaling and PKA-associated pathways, and support its potential as an anti-fibrotic therapeutic strategy.