Zoological Research最新文献

Neuronal intranuclear inclusion disease (NIID) is a rare autosomal dominant neurodegenerative disorder defined by the presence of eosinophilic intranuclear inclusions across both central and peripheral components of the nervous system, as well as multiple visceral organs, resulting in pronounced clinical heterogeneity. Following the discovery of pathogenic GGC repeat expansions in the NOTCH2NLC gene as the underlying genetic driver, a diverse array of experimental platforms has been established to probe NIID pathogenesis, including adeno-associated virus-mediated expression systems, transgenic animal models, and patient-derived cellular systems such as brain organoids. Collectively, these models recapitulate key histopathological and behavioral phenotypes observed in NIID and have elucidated multiple molecular and cellular pathways implicated in disease progression. This review systematically examines the current landscape of NIID model systems, highlighting their respective contributions to understanding disease pathogenesis, evaluating their experimental limitations, and identifying avenues for future refinement. Such integrative analysis is critical for advancing the development of more faithful disease models and facilitating the identification of therapeutic targets for NIID.

Ongoing climate change is driving high-altitude bird species to occupy even higher elevations, yet physiological and regulatory responses enabling these transitions remain poorly understood. This study investigated acute hypoxic responses in saker falcons ( Falco cherrug) inhabiting the Qinghai-Xizang Plateau by exposing individuals to simulated altitudes of 5 000-6 000 m above sea level (a.s.l.), exceeding their typical elevation range (approximately 4 300 m a.s.l.). GPS tracking data indicated that juvenile falcons maintained comparable activity levels across 4 000-5 000 m and 5 000-6 000 m a.s.l. ranges. However, pre-fledging individuals subjected to 6 000 m hypoxia for three days exhibited marked increases in hemoglobin concentration and blood glucose. Transcriptomic profiling revealed significant suppression of glycolytic activity, notably characterized by reduced expression of hexokinase 1 ( HK1), a key enzymatic gene involved in the glycolytic pathway. ATAC-seq further identified enhanced chromatin accessibility within the HK1 locus under hypoxia, revealing two conserved cis-regulatory elements recognized by the transcription factor NR3C1 in the hypoxia-treated group. NR3C1 expression was negatively correlated with HK1. Notably, both elements were unique and evolutionarily conserved in avian taxa, suggesting a potential role in hypoxia resilience among highland birds. These findings provide mechanistic insights into the molecular and physiological strategies employed by sakers to tolerate acute hypoxic stress and inform conservation efforts for high-altitude bird species on the Qinghai-Xizang Plateau and other alpine ecosystems facing accelerating climate change.

Oral ulcers (OUs) are among the most common lesions of the oral mucosa, typically associated with pain and burning sensations, and remain clinically challenging due to the scarcity of effective treatment options. Cy _RL-QN15, a novel ultra-short cyclic heptapeptide recently shown to promote skin repair, diabetic wound healing, and follicle neogenesis, was evaluated for its therapeutic potential in mucosal repair. Using a rat OU model and a primary oral epithelial cell inflammation model, Cy _RL-QN15 significantly accelerated wound closure through coordinated modulation of immune-epithelial crosstalk, including suppression of inflammatory cytokine release from macrophages and neutrophils, reduction of pro-inflammatory factor secretion by oral epithelial cells, and enhancement of their proliferation and migration. Mechanistic studies employing alanine scanning mutagenesis and microscale thermophoresis revealed that Cy _RL-QN15 directly interacted with Toll-like receptor 4 (TLR4) via a methionine-dependent binding interface (K _d=2.64 µmol/L), thereby inhibiting downstream MyD88/NF-κB signaling. As the first ultra-short cyclic heptapeptide identified to antagonize TLR4, Cy _RL-QN15 represents a mechanistically distinct immunomodulatory scaffold that restores mucosal homeostasis and offers a promising therapeutic candidate for TLR4-based OU intervention.

Teleost peripheral blood contains a remarkably high proportion of B cells, accounting for 15%-50% of circulating lymphocytes. However, their immune responses to bacterial infection are yet to be elucidated. In the present study, 10× Genomics single-cell RNA sequencing (scRNA-seq) was employed to characterize the transcriptomic landscape of peripheral blood IgM ⁺ B cells in grass carp ( Ctenopharyngodon idella) following challenge with Aeromonas hydrophila, a major aquatic pathogen. Six transcriptionally distinct IgM ⁺ B cell subpopulations were identified, including (im)mature B cells, innate B cells, proliferating B cells, IgD ^high B cells, and two infection-induced subsets denoted as infection Ⅰ and Ⅱ B cells. Bacterial infection altered the cellular heterogeneity of IgM ⁺ B cells, triggered metabolic reprogramming in (im)mature and innate B cell subpopulations, and enhanced the immunological activation of circulating B cells. Notably, infection Ⅰ B cells demonstrated robust induction of interferon φ1 ( IFNφ1), a type I IFN, following A. hydrophila exposure. This induction was further validated through in vitro bacterial stimulation, indicating that teleost B cells actively contribute to innate antibacterial responses through IFN signaling. Additionally, the IgD ^high B cell subpopulation remained consistently present in peripheral blood across both infected and uninfected states, pointing to a constitutive and likely mature phenotype. These findings significantly advance our understanding of the heterogeneity of peripheral blood IgM ⁺ B cells and provide new insights into IgM ⁺ B cell-mediated immune responses in teleost fish.

Oxidative stress arises from disruption of the balance between reactive oxygen species (ROS) production and detoxification and constitutes a fundamental driver of diverse pathological diseases. Skin photoaging is a well-recognized example, primarily driven by chronic ultraviolet (UV) exposure and marked by progressive structural and functional deterioration. UV-induced ROS accelerate macromolecular degradation and impair epidermal and dermal barrier integrity, highlighting the urgent need for effective antioxidant interventions. Antioxidant peptides (AOPs), whether naturally occurring or synthetically engineered, have shown considerable potential in mitigating ROS-induced cellular damage. Amphibians, which possess highly permeable skin and are continuously challenged by fluctuating environmental conditions, represent a rich source of bioactive peptides with potent antioxidant properties. In particular, AOPs isolated from amphibian skin secretions demonstrate notable efficacy in ROS scavenging and mitigation of oxidative damage, offering promising candidates for anti-photoaging therapies. This review provides an integrated overview of ROS generation and signaling, the molecular mechanisms linking oxidative stress to skin photoaging, and the emerging biomedical potential of amphibian-derived AOPs. Deeper mechanistic insight into their structure and function is expected to accelerate the development of novel peptide-based interventions for photoaging and other oxidative stress-associated dermatological disorders.

Lipid droplets (LDs) serve as dynamic organelles central to host immune response and bacterial infection resistance by recruiting multiple proteins and peptides with established antiviral and antibacterial properties. Although macrophage polarization is integral to both innate immunity and lipid homeostasis, the regulatory influence of LDs on this process remains unclear. In this study, augmentation of LDs via oleic acid (OA) treatment attenuated M1 polarization in RAW264.7 macrophages. Given that LD budding is mediated by fat storage-inducing transmembrane protein 2 (FIT2) encoded by FITM2, transcriptomic analysis following FITM2 knockdown revealed suppressed expression of fatty acid-binding protein 5 (FABP5), a lipid-binding protein that further modulated LD abundance. Both FIT2 and FABP5 were found to regulate LD content and collectively contributed to inhibition of M1 macrophage polarization. This shift impaired macrophage capacity to mount effective antibacterial responses. These findings identify a coordinated role for LDs and FABP5 in modulating M1 macrophage polarization, establishing a mechanistic link between lipid metabolism and innate host defense against bacterial infection.

Tauopathies represent a class of neurodegenerative diseases (NDs), including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), Pick's disease (PiD), and corticobasal degeneration (CBD), defined by intracellular accumulation of misfolded and hyperphosphorylated tau protein. The pathogenic cascade involves hyperphosphorylation, conformational changes, and aggregation into neurofibrillary tangles (NFTs), which are spatially and functionally linked to neuronal dysfunction, synaptic loss, and progressive cognitive and motor decline. To elucidate tau-mediated mechanisms, diverse transgenic rodent models expressing wild-type or mutant forms of human TAU have been generated. Although these models have advanced understanding of tau aggregation and propagation, tau-targeting therapies have failed to produce clinical benefits, raising concerns about the precise mechanism underlying tauopathies and the fidelity of animal models in evaluating therapeutic targets. This review systematically examines the neuropathological and behavioral phenotypes across established rodent and non-human primate (NHP) tauopathy models, highlighting mechanistic insights into tau-driven pathology. The advantages, limitations, and translational barriers of each model are critically evaluated to inform the development of more predictive preclinical platforms for therapeutic discovery.

Chromatin remodeling and transcriptional reprogramming play critical roles during mammalian meiotic prophase I; however, the precise mechanisms regulating these processes remain poorly understood. Our previous work demonstrated that deletion of heat shock factor 5 (HSF5), a member of the heat shock factor family, induces meiotic arrest and male infertility. However, the molecular pathways through which HSF5 governs meiotic progression have not yet been fully elucidated. In this study, a comprehensive multi-omics approach was applied to investigate the role of HSF5 in modulating chromatin dynamics and transcriptional reprogramming during pachynema progression. Analysis of ATAC-seq and single-cell RNA sequencing data revealed significant alterations in chromatin accessibility and disruption of the transcriptional regulatory network (TRN) in Hsf5 ^-/- spermatocytes. Additionally, HSF5 deficiency resulted in defective XY body formation and altered histone modifications. Notably, Hsf5 ^-/- spermatocytes also exhibited abnormal spermatoproteasome activity specifically on sex chromosomes, with evidence indicating that HSF5 may form a complex with USP7 in vivo to suppress H2AK119ub on meiotic sex chromosomes. These findings provide new insights into the complex, multifunctional role of HSF5 in regulating key meiotic events and advancing our understanding of its function during pachynema progression.

Red light therapy is a clinically validated, noninvasive approach for improving skin structure and stimulating collagen renewal. However, the molecular mechanisms by which light therapy reverses collagen-related skin degeneration remain unclear. Using a natural aging mouse model, this study investigated the effects of red light therapy on skin structure and regeneration. Unlike other wavelengths, red light rapidly increased dermal thickness and stimulated epidermal renewal by enhancing collagen synthesis in dermal fibroblasts and activating collagen/integrin-induced proliferation and differentiation of epidermal keratinocytes, resulting in significant improvements in skin morphology. Mechanistically, red light increased endogenous TGFβ expression in fibroblasts, which up-regulated type I collagen mRNA and protein expression via activation of SMAD2/3/4 nuclear translocation. Simultaneously, red light elevated intracellular cAMP, triggering AKT activation that inhibited matrix metalloproteinase expression via the NRF2/HO-1-dependent pathway, thereby reducing collagen degradation. The accumulation of type I collagen in dermal fibroblasts stimulated integrin signaling, promoting epidermal keratinocyte proliferation and differentiation. Red light-induced AKT activation also enhanced fibroblast proliferation, further amplifying collagen production and collagen-mediated epidermal renewal. These findings elucidate the mechanisms by which red light stimulates endogenous TGFβ and AKT signaling to regulate type I collagen production, driving coordinated dermis-epidermis remodeling. This pathway represents a potential therapeutic target for the prevention and treatment of age-related dermal degeneration.

Social hierarchies are central to the organizational structure of group-living species, shaping individual physiology, behavior, and social interactions. Dopaminergic (DA) systems, particularly within the ventral tegmental area (VTA) and dorsal raphe nucleus (DR), have been linked to motivation and competitive behaviors, yet their region-specific contributions to social dominance remain insufficiently defined. This study investigated the role of VTA and DR DA neurons in regulating social dominance in sexually naïve male C57BL/6J mice. Stable hierarchies were established using the tube test, after which both dominant and subordinate mice exhibited elevated c-Fos expression within the VTA and DR. Notably, dominant mice displayed significantly greater c-Fos activation in DR DA neurons compared to subordinates. Fiber photometry revealed that DA neurons in both regions were activated during proactive push behaviors and inhibited during passive retreats, with DR neurons showing stronger activation during dominance-related actions. Chemogenetic inhibition of DR DA neurons in dominant mice reduced their social rank, whereas activation in subordinates elevated their rank. In contrast, chemogenetic modulation of VTA DA neurons had no significant effect on social dominance. Manipulation of DA neurons in both regions produced rank-dependent changes in specific anxiety-like behavioral phenotypes. These findings highlight the distinct roles of DR and VTA DA neurons in social hierarchy regulation, identifying DR DA neurons as a critical component in the modulation of social dominance.