Search Results (1,745)

Xyloglucan endotransglucosylase/hydrolases (XTHs) are a class of cell wall-associated enzymes involved in the construction and remodeling of cellulose/xyloglucan crosslinks. However, knowledge of this gene family in the model monocot Brachypodium distachyon is limited. A total of 29 BdXTH genes were identified from the whole genome, and these were further divided into three subgroups (Group I/II, Group III, and the Ancestral Group) through evolutionary analysis. Gene structure and protein motif analyses indicate that closely clustered BdXTH genes are relatively conserved within each group. A highly conserved amino acid domain (DEIDFEFLG) responsible for catalytic activity was identified in all BdXTH proteins. We detected three pairs of segmentally duplicated BdXTH genes and five groups of tandemly duplicated BdXTH genes, which played vital roles in the expansion of the BdXTH gene family. Cis-elements related to hormones, growth, and abiotic stress responses were identified in the promoters of each BdXTH gene, and when roots were treated with two abiotic stresses (salinity and drought) and four plant hormones (IAA, auxin; GA3, gibberellin; ABA, abscisic acid; and BR, brassinolide), the expression levels of many BdXTH genes changed significantly. Transcriptional analyses of the BdXTH genes in 38 tissue samples from the publicly available RNA-seq data indicated that most BdXTH genes have distinct expression patterns in different tissues and at different growth stages. Overexpressing the BdXTH27 gene in Brachypodium led to reduced root length in transgenic plants, which exhibited higher cellulose levels but lower hemicellulose levels compared to wild-type plants. Our results provide valuable information for further elucidation of the biological functions of BdXTH genes in the model grass B. distachyon. Full article

The transgenic animals have been yielding invaluable insights into amyloid pathology by replicating the key features of Alzheimer’s disease (AD). However, there is no clear relationship between senile plaques and memory deficits. Instead, cognitive impairment and synaptic dysfunction are particularly linked to a rise in Aβ_1-42 oligomer level. Thus, injection of Aβ_1-42 oligomers into a specific brain region is considered an alternative approach to investigate the effects of increased soluble Aβ species without any plaques, offering higher controllability, credibility and validity compared to the transgenic model. The hippocampal CA1 (cornu ammonis 1) region is selectively affected in the early stage of AD and specific targeting of CA1 region directly links Aβ oligomer-related pathology with memory impairment in early AD. Next, the inhibitory avoidance (IA) task, a learning paradigm to assess the synaptic basis of CA1-dependent contextual learning, triggers training-dependent synaptic plasticity similar to in vitro HFS (high-frequency stimulation). Given its reliability in assessing contextual memory and synaptic plasticity, this task provides an effective framework for studying early stage AD-related memory deficit. Therefore, in this review, we will focus on why Aβ_1-42 oligomer injection is a valid in vivo model to investigate the early stage of AD and why dorsal CA1 region serves as a target area to understand the adverse effects of Aβ_1-42 oligomers on contextual learning through the IA task. Full article

Cadmium (Cd) is a highly toxic heavy metal that disrupts development and reproduction, primarily through oxidative stress. In this context, sulforaphane (SFN), an antioxidant compound, may serve as a promising agent to counteract Cd-induced oxidative damage and prevent developmental and reproductive abnormalities. This study aimed to evaluate the effect of SFN on reproductive toxicity induced by cadmium chloride (CdCl₂) in the nematode Caenorhabditis elegans (C. elegans). Five experimental groups were established: (I) Control: no treatment, (II) dimethyl sulfoxide (DMSO): 48 h with 0.01% DMSO, (III) CdCl₂: 24 h with 4600 µM CdCl₂, (IV) SFN + CdCl₂: 24 h with 100 µM SFN followed by 24 h with both SFN and CdCl₂, and (V) SFN: 48 h with 100 µM SFN. Co-exposure to SFN and CdCl₂ prevented the reduction in the percentage of adult nematodes and increased egg-laying. It also significantly improved hatching rates, allowing more embryos to reach the larval stage, and prevented reductions in body size. However, no effects were observed on glutathione S-transferase-4 (GST-4) levels in the transgenic CL2166 strain. In conclusion, SFN substantially prevents Cd-induced reproductive toxicity in C. elegans. Future studies should investigate the molecular mechanisms by which SFN enhances egg-laying and offspring viability in this model. Full article

Objectives: To investigate the efficacy and underlying mechanisms of IBCar’s biological activity in breast cancer models, both in cell culture and in mice, and to compare its effects on cancer versus normal cells. Methods: The cytotoxicity of IBCar was evaluated using the MTS assay to assess metabolic activity and the clonogenic assay to determine reproductive integrity. The impact of IBCar on microtubule integrity, mitochondrial function, and multiple signaling pathways was analyzed using Western blotting, microarray analysis, and live cell imaging. The therapeutic effectiveness of orally administered IBCar was assessed in a transgenic mouse model of Luminal B breast cancer and in mice implanted with subcutaneous triple-negative breast cancer xenografts. Results: IBCar demonstrated potent cytotoxicity across a diverse panel of breast cancer cell lines, including those with mutant or wild-type TP53, and cell lines with short and long doubling times. Comparative analysis revealed distinct responses between normal and cancer cells, including differences in IBCar’s effects on the mitochondrial membrane potential, endoplasmic reticulum stress and activation of cell death pathways. In breast cancer cells, IBCar was cytotoxic at nanomolar concentrations, caused irreversible microtubule depolymerization leading to sustained mitochondrial dysfunction, endoplasmic reticulum stress, and induced apoptosis. In normal cells, protective mechanisms included reversible microtubule depolymerization and activation of pro-survival signaling via the caspase-8 and riptosome pathways. The therapeutic potential of IBCar was confirmed in mouse models of Luminal B and triple negative BC, where it exhibited strong antitumor activity without detectable toxicity. Conclusions: These findings collectively support IBCar as a promising, effective, and safe therapeutic candidate for breast cancer treatment. Full article

There is a growing body of research showing that Alzheimer’s disease (AD) is related to enteric dysbacteriosis. Exercise can be effective in alleviating AD, but the effects that exercise has on the gut microbiota in AD patients needs to be further studied. Through this study, we aimed to investigate the differences in the diversity of gut microorganisms between AD model mice and wild-type mice and the effect that treadmill exercise has on the composition of the gut microbiota in both types of mice. C57BL/6 wild-type mice were randomly divided into a sedentary control group (WTC) and an exercise group (WTE); APP/PS1 double transgenic mice were also randomly divided into a sedentary control group (ADC) and an exercise group (ADE). After the control group remained sedentary for 12 weeks and a 12-week treadmill exercise intervention was adopted for the exercise group, the rectal contents were collected so that they could undergo V3-V4 16S rDNA sequencing, and a comparative analysis of the microbial composition and diversity was also performed. The alpha diversity of the gut microbiota in AD mice was lower than that in wild-type mice, but exercise increased the gut microbial diversity in both types of mice. At the phylum level, the dominant microorganisms in all four groups of mice were Bacteroidetes and Firmicutes. There was an increase in the Bacteroidetes phylum in AD mice. Treadmill exercise reduced the abundance of Bacteroidetes in both groups of mice, whereas the abundance of Firmicutes increased. At the genus level, Muribaculaceae, the Lachnospiraceae_NK4A136_group, Alloprevotella, and Alistipes were in relatively high abundance. Muribaculaceae and Alloprevotella were in greater abundance in AD mice than in wild-type mice, but both decreased after treadmill exercise. Through performing linear discriminant analysis effect size (LEfSe), we found that the dominant strains in AD mice were Campilobacterota, Helicobacteraceae, Escherichia–Shigella, and other malignant bacteria, whereas exercise resulted in an increase in probiotics among the dominant strains in both types of mice. Although gut microbial diversity decreases and malignant bacteria increase in AD mice, treadmill exercise can increase gut microbial diversity and lead to the development of dominant strains of probiotics in both types of mice. These findings provide a basis for applying exercise as a treatment for AD. Full article

Investigating brain area functions requires advanced technologies, but meaningful insights depend on correlating neural signals with behavior. Traditional mice behavior annotation methods, including manual and semi-automated approaches, are limited by subjectivity and time constraints. To overcome these limitations, our study employs the YOLO neural network for precise mice tracking and composite RGB frames for behavioral scoring. Our model, trained on over 10,000 frames, accurately classifies sitting, running, and grooming behaviors. Additionally, we provide statistical metrics and data visualization tools. We further combined AI-powered behavior labeling to examine hippocampal neuronal activity using fluorescence microscopy. To analyze neuronal circuit dynamics, we utilized a manifold analysis approach, revealing distinct functional patterns corresponding to transgenic 5xFAD Alzheimer’s model mice. This open-source software enhances the accuracy and efficiency of behavioral and neural data interpretation, advancing neuroscience research. Full article

UDP-glycosyltransferases (UGTs) play essential roles in various biological processes, such as phytohormone homeostasis, abiotic stress adaptation, and secondary metabolite biosynthesis. Populus euphratica is a model species for investigating stress adaptation; however, the PeUGT gene family has yet to be systematically characterized. Here, we identified 134 UGT genes in P. euphratica. Phylogenetic analysis classified these genes into 16 major groups (A–P), and UGT genes within the same groups showed similar structural characteristics. Tandem duplication events were identified as the predominant mechanism driving the expansion of the PeUGT family. Cis-acting element analysis revealed an enrichment of motifs associated with developmental regulation, light response, phytohormone signaling, and abiotic stress in the promoters of PeUGT genes. Expression profiling demonstrated spatiotemporal regulation of the PeUGT genes under drought stress. Among them, PeUGT110 was significantly induced by PEG treatment in the leaf, root, and stem tissues of P. euphratica. Overexpression of PeUGT110 enhanced drought tolerance in transgenic Arabidopsis. Furthermore, the PeUGT110-OE lines exhibited reduced malonaldehyde accumulation, elevated proline content, higher superoxide dismutase activity, and upregulated expression of stress-related genes under drought stress. The results demonstrated that PeUGT110 plays a critical role in plant drought resistance. These findings establish a foundation for elucidating the function of PeUGT genes. Full article

Blood–brain barrier (BBB) dysfunction is a hallmark of cerebral small vessel disease (cSVD). This study aimed to identify a mouse model that replicates BBB impairment and shares key cSVD risk factors. Transgenic db/db and LDLr^−/−.Leiden mice, both prone to obesity and hypertension, were compared to C57BL/6J controls. BBB leakage was assessed using DCE-MRI and sodium fluorescein (NaFl); cerebral blood flow (CBF) by MRI. Dyslipidemia and vascular inflammation were measured by plasma tests. Tight junction integrity, endothelial dysfunction (glucose transporter 1, GLUT-1) and neuroinflammation were evaluated with immunohistochemistry and PCR. Both transgenic models developed an obese phenotype with hyperinsulinemia, but only LDLr^−/−.Leiden mice showed human-like dyslipidemia. When fed a high-fat diet (HFD) or HFD plus cholesterol, LDLr^−/−.Leiden mice showed reduced CBF, endothelial dysfunction (lowered GLUT-1), elevated vascular inflammation (ICAM-1, VCAM-1, S-selectin), and BBB leakage, as evidenced by DCE-MRI and NaFl, together with reduced ZO-1 and claudin-5 expression. Contrastingly, db/db mice showed endothelial dysfunction without BBB leakage. Neuroinflammation (IBA-1, GFAP) was observed only in LDLr^−/−.Leiden groups, consistent with BBB disruption. These findings indicate that LDLr^−/−.Leiden mice, but not db/db mice, are a promising translational model for studying BBB dysfunction in cSVD, offering insights into disease mechanisms and a platform for therapeutic development. Full article

Despite remarkable progress in cancer immunotherapy, many agents that show efficacy in murine or in vitro models fail to translate clinically. Zebrafish (Danio rerio) have emerged as a powerful complementary model that addresses several limitations of traditional systems. Their optical transparency, genetic tractability, and conserved immune and oncogenic signaling pathways enable high-resolution, real-time imaging of tumor–immune interactions in vivo. Importantly, zebrafish offer a unique opportunity to study the core mechanisms of health and sickness, complementing other models and expanding our understanding of fundamental processes in vivo. This review provides an overview of zebrafish immune system development, highlighting tools for tracking innate and adaptive responses. We discuss their application in modeling immune evasion, checkpoint molecule expression, and tumor microenvironment dynamics using transgenic and xenograft approaches. Platforms for high-throughput drug screening and personalized therapy assessment using patient-derived xenografts (“zAvatars”) are evaluated, alongside limitations, such as temperature sensitivity, immature adaptive immunity in larvae, and interspecies differences in immune responses, tumor complexity, and pharmacokinetics. Emerging frontiers include humanized zebrafish, testing of next-generation immunotherapies, such as CAR T/CAR NK and novel checkpoint inhibitors (LAG-3, TIM-3, and TIGIT). We conclude by outlining the key challenges and future opportunities for integrating zebrafish into the immuno-oncology pipeline to accelerate clinical translation. Full article

Background: Esophageal squamous cell carcinoma (ESCC) is a fatal malignant tumor. Several studies have demonstrated that immune checkpoint inhibitors can provide clinical benefits to patients with ESCC. However, the single-agent efficacy of these agents remains limited. Although combination therapies (e.g., radiotherapy, chemotherapy) can help to overcome immunotherapy resistance in ESCC, their severe side effects limit clinical application. This study aimed to explore new resistance mechanisms to immunotherapy in ESCC and identify novel molecular targets to overcome immunotherapy resistance. Methods: We employed immunohistochemistry staining to examine the p-FGFR1^Y654 in tumor samples obtained from 103 patients with ESCC, in addition to evaluating CD8+ T cell infiltration. In vitro expression, western blotting, CCK-8, 5-bromo-2′-deoxyuridine incorporation assays, and migration assays were used to confirm the impact of AZD4547 on p-FGFR1^Y654 expression and the proliferation and migration in ESCC cell lines. Through RNA sequencing analysis, databases such as the Cancer Genome Atlas (TCGA) and Gene Set Cancer Analysis (GSCA), and the reconstruction of transgenic mice using the humanized immune system, we validated the correlation between the expression of p-FGFR1^Y654 and CD8+ T cell infiltration. We also explored how p-FGFR1^Y654 recruits myeloid-derived suppressor cells (MDSCs) through the CXCL8–CXCR2 axis to suppress the therapeutic efficacy of immunotherapy in ESCC. Finally, the tumor-suppressive effects of AZD4547 combined with immunotherapy were confirmed in vivo in tumor-bearing mice with a humanized immune system. Results: We found that the inhibition of p-FGFR1^Y654 expression in ESCC can enhance CD8+ T cell infiltration by suppressing the CXCL8-–XCR2 recruitment of MDSCs. AZD4547, combined with immunotherapy, further promotes immunotherapeutic efficacy in ESCC. Conclusions: In conclusion, our study presents a promising model for combination therapy in ESCC immunotherapy. Full article

We aimed to examine the effect of zonulin and zonulin inhibition on gastrointestinal (GI) motility and the mRNA expression of zonulin and the protease-activated receptor 2 (par2), the primary receptor for zonulin, under conditions of inflammation by lipopolysaccharide (LPS) injection. The experimental models included zonulin transgenic mice (ztm), par2 knockout ztm (ztm-par2 −/−), ztm exposed to the zonulin inhibitor AT1001 (ztm-AT1001), and wildtype mouse controls. GI transit was measured by fluorescein isothiocyanate-dextran and mRNA expression by real-time quantitative polymerase chain reaction in whole, and in epithelial and non-epithelial tissues of all GI segments. There were no differences in the GI transit between mouse groups at baseline. After the LPS injection, ztm mice had an attenuated slowing of the GI transit compared to wildtype mice. The zonulin-inhibited mice had motility patterns similar to wildtype mice. zonulin upregulation was noted in GI segments of the ztm, ztm-par2 −/−, and ztm-AT1001 after the LPS injection. Differences in motility patterns between ztm and zonulin inhibition models despite zonulin expression in GI segments of all mouse groups supports that PAR2 is key for zonulin’s effect on motility under conditions of inflammation. However, the findings from the epithelial and non-epithelial compartments suggest that the pathway of activity is complex and likely indirect. Full article

Pathological aggregation of α-synuclein (αS) is implicated in the pathogenesis of Parkinson’s disease (PD) and other α-synucleinopathies. The current view is that neuron-to-neuron spreading of αS pathology contributes to the progression of α-synucleinopathy. We used an A53T mutant human αS transgenic mouse model (TgA53T) to examine whether the site of pathogenic αS inoculation affects the pattern of neuropathology and whether soluble and insoluble fractions derived from crude pathogenic tissue lysates exhibit differential capacities to initiate αS pathology. To test whether the inoculation site impacts the ultimate spatial/temporal patterns of αS pathology, αS preformed fibrils (PFFs), or brain homogenates from TgA53T mice with α-synucleinopathy, were injected into the cortex/striatum, brainstem, or skeletal muscle. In all cases, inoculation of pathogenic αS induced end-stage motor dysfunction within ~100 days post-inoculation (dpi). Significantly, irrespective of the inoculation sites, the ultimate distribution of the αS pathology was like that seen in normally aged TgA53T mice at end-stage, indicating that the intrinsic neuronal vulnerability is a significant determinant in the induction of αS pathology, even when initiated by inoculation of pathogenic αS. Temporal analysis of brainstem-injected TgA53T mice show that initial αS pathology was seen by 30 days post-inoculation and inflammatory changes occur at later stages. In addition, we show that both highly soluble (S150) and insoluble (P150) fractions from end-stage TgA53T mice can seed de novo αS pathology in vivo. Moreover, the endoplasmic reticulum (ER)-enriched fraction from the TgA53T mice were highly pathogenic as the ER fraction induced αS pathology faster than other fractions when injected unilaterally into TgA53T mice. Our results suggest that multiple αS species from the brain can initiate the development of progressive αS pathology. Full article

Among the molecules implicated in inflammation-associated tumorigenesis, Chitinase 3-like 1 (CHI3L1/YKL-40/Brp-39) has emerged as a particularly compelling target due to its multifaced roles in immune regulation, tissue remodeling, and cancer progression. Elevated CHI3L1 expression is observed in various human cancers and corresponding animal models. CHI3L1 directly promotes tumor cell proliferation and angiogenesis and also contributes to immune evasion by establishing an immunosuppressive environment in inflamed tissues. Mechanistically, CHI3L1 exerts its effects through the modulation of STAT3, MAPK, and PI3K/Akt signaling pathways and by interacting with cell surface receptors, such as IL-13Rα2 and RAGE. Studies using transgenic and knockout mouse models have revealed a strong association between CHI3L1 expression and cancer progression. In models of colon and lung cancer, CHI3L1 overexpression correlates with increased tumor size and number, whereas CHI3L1 deficiency markedly suppresses tumor formation. However, its involvement appears to be context-dependent and varies among different epithelial tumor types. These findings suggest that CHI3L1 is a potential therapeutic target and diagnostic biomarker for inflammation-associated cancers. Animal studies provide valuable insights into the immunological mechanisms of CHI3L1-mediated tumorigenesis but also highlight the need for cautious interpretation due to inherent technical limitations. Full article

Zebrafish is a well-recognized model for studying human genetic disorders. Recently, we proposed the homozygous cdkl5^sa21938 mutant zebrafish as a model of CDKL5 deficiency disorder (CDD), a developmental epileptic encephalopathy with diverse symptoms. This study aimed to explore Cdkl5-associated molecular mechanisms in zebrafish and assess their similarity to those in mammals. We conducted RNA sequencing on whole cdkl5^−/− zebrafish and wild-type siblings at 5 and 35 days post-fertilization (dpf) to compare their gene expression profiles. Most significant differentially expressed genes (DEGs) were related to muscle, neuronal, and visual systems which are affected in CDD. Gene Ontology analysis revealed downregulated DEGs enriched in muscle development, extracellular matrix, and actin cytoskeleton functions at both stages, while upregulated DEGs were enriched in eye development functions at 35 dpf. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed enrichment of downregulated DEGs in focal adhesion and extracellular matrix (ECM)-receptor interaction pathways at both stages. Neuronal development DEGs were mainly downregulated at both stages, while synaptic signaling DEGs were upregulated at 35 dpf. Crossing cdkl5^−/− mutants with the Hb9:GFP transgenic line showed fewer motor neuron cells with shorter axons compared to the wild type, which may explain the impaired motor phenotype observed in zebrafish and CDD patients. Moreover, we identified key downregulated DEGs related to cartilage development at both stages and bone development at 35 dpf, potentially explaining the skeletal defects seen in zebrafish and CDD individuals. In conclusion, Cdkl5 loss in zebrafish leads to dysregulation of genes involved in CDKL5-associated functions in mammals, providing new insights into its less studied functions and phenotypes. Full article

This review critically examines the evolving landscape of genetic animal models for investigating cardiovascular diseases (CVDs). We analyze established models, including spontaneously hypertensive rats, Watanabe hyperlipidemic rabbits, etc., and transgenic models that have advanced our understanding of essential and secondary hypertension, atherosclerosis, and non-ischemic diseases of the heart. This review systematically evaluates the translational strengths and physiological limitations of these approaches across species barriers. Particular attention is paid to emerging technologies—AAV-mediated gene delivery, CRISPR-Cas9 editing, and chemogenetic tools—that enable unprecedented precision in manipulating cardiac-specific gene expression to study pathophysiological mechanisms. We address persistent challenges including off-target effects and transgene expression variability, while highlighting innovations in synthetic vectors and tissue-specific targeting strategies. This synthesis underscores how evolving genetic technologies are revolutionizing cardiovascular research paradigms, offering refined disease models and optimized therapeutic interventions that pave the way toward personalized medicine approaches for the world’s leading cause of mortality. Full article