Search Results (213)

Colitis is a chronic relapsing inflammatory disorder characterized by persistent mucosal inflammation, epithelial barrier disruption, oxidative stress, immune dysregulation, and gut microbiota imbalance. Although current therapies have improved disease management, their long-term use is still limited by incomplete response, relapse, adverse effects, and high cost. Natural products have attracted increasing attention as promising candidates for colitis intervention because of their structural diversity, broad bioactivity, and multitarget regulatory potential. In veterinary medicine, colitis and colitis-related intestinal inflammatory disorders are also clinically relevant in companion animals, horses, and food-producing animals, where they contribute to diarrhea, impaired intestinal barrier function, reduced performance, treatment costs, and antimicrobial-use concerns. Therefore, natural products may have additional value as adjunctive, nutritional, or microbiota-modulating strategies in veterinary and comparative gastroenterology. This review summarizes the major categories of natural products investigated for colitis, including flavonoids, polyphenols, alkaloids, terpenoids, saponins, polysaccharides, plant extracts, and traditional herbal formulas, and discusses their principal mechanisms of action, such as anti-inflammatory activity, attenuation of oxidative stress, restoration of intestinal barrier integrity, modulation of immune responses, regulation of gut microbiota, and control of programmed cell death. We also highlight the major limitations of current research, including overreliance on preclinical models, insufficient target validation, poor bioavailability, and limited clinical evidence. Overall, natural products represent an important source of therapeutic candidates for colitis, but their clinical translation will require deeper mechanistic studies, standardized evaluation, and well-designed clinical investigations. Importantly, future studies should distinguish phenotype-associated changes from causal mechanisms by integrating direct target engagement, functional rescue experiments, microbiota-causality validation, and standardized pharmacokinetic and safety assessment. Full article

L-asparaginase (ASNase) is a paradigmatic amino-acid depletion therapy that induces systemic asparagine starvation and remains foundational in acute lymphoblastic leukemia (ALL). Amino-acid metabolism constitutes a fundamental therapeutic vulnerability in hematologic malignancies, yet the determinants of response to systemic asparagine depletion remain incompletely defined. Asparagine synthetase (ASNS) regulates intracellular asparagine biosynthesis and functions as a stress-responsive metabolic node embedded within adaptive nutrient-sensing pathways. Emerging transcriptomic and proteomic evidence demonstrates that reduced ASNS expression is enriched in biologically distinct subsets of acute myeloid leukemia (AML), particularly those characterized by immature differentiation states and cytogenetic features associated with metabolic fragility, including inv(16) and chromosome 7-associated disease. Clinical experience in natural killer/T-cell (NK/T-cell) neoplasms provides proof-of-principle that enzymatic asparagine depletion can achieve durable therapeutic efficacy in tumors intrinsically dependent on extracellular amino-acid supply, establishing extranodal NK/T-cell lymphoma (ENKTL) as a mechanistically aligned anchor indication beyond acute lymphoblastic leukemia. Integrative molecular analyses further indicate that ASNS deficiency functions as a permissive rather than deterministic biomarker, with therapeutic response modulated by lineage-specific metabolic wiring, adaptive stress signaling, and microenvironmental nutrient buffering. Advances in protein-anchored diagnostic platforms, including intracellular flow cytometry and quantitative proteomics, now enable operationalization of ASNS as a clinically actionable stratification marker. Mechanistic studies also suggest that amino-acid depletion may interact with apoptotic signaling networks, supporting rational combination strategies with targeted agents such as BCL-2 inhibitors. Collectively, these findings support a conceptual framework in which ASNS-low defines a context-dependent metabolic vulnerability rather than a uniform disease-wide predictor, underscoring the need for prospective biomarker-enriched clinical trials to establish ASNS-guided amino-acid depletion as a precision oncology strategy across heterogeneous myeloid and lymphoid malignancies. Full article

The genus Burkholderia encompasses both plant pathogenic and beneficial species, yet the genomic determinants underlying this lifestyle divergence remain poorly understood. Using 16S rRNA sequencing of 100 rice cultivars, our companion study demonstrated that resistant varieties are enriched in beneficial Burkholderiaceae, leading to the isolation of three phenotypically contrasting strains. Here, we present comparative genomic analyses of non-pathogenic biocontrol strain Burkholderia vietnamiensis J14EpLeaf2 and pathogenic strains Burkholderia gladioli A1EpSeed5 and Burkholderia cepacia J14Eple. Pathogenic strains possess significantly larger genomes (8.36–8.46 Mb) enriched in mobile genetic elements compared to the streamlined 6.95 Mb genome of B. vietnamiensis. CAZyme analysis revealed broader repertoires of glycoside hydrolases and polysaccharide lyases in pathogens, consistent with enhanced plant cell wall degradation. B. gladioli possesses a complete T3SS and expanded T6SS with 301 predicted effectors, while B. cepacia lacks structural T3SS genes but harbors 271 candidate effectors predicted to be secreted via alternative secretion pathways, compared to 180 in B. vietnamiensis. Notably, B. cepacia harbors cystic fibrosis-associated markers (cable pili, ZmpA/ZmpB), raising significant biosafety concerns that preclude its agricultural application. LC-MS validated IAA, ornibactin, and AHL production in B. vietnamiensis, supporting its plant growth-promoting and biocontrol functions. Computational PPI networks predicted distinct interaction landscapes requiring experimental validation. This study provides a genomic framework for distinguishing pathogenic from beneficial Burkholderia and supports B. vietnamiensis as a safe biocontrol agent while cautioning against B. cepacia J14Eple. Full article

Bacillus velezensis-based probiotics are increasingly recognized for their potential to enhance intestinal health in companion animals, yet their mechanisms of action in canine epithelial systems remain incompletely defined. This study aimed to evaluate whether a live Bacillus velezensis probiotic consortia (BC) modulates epithelial barrier integrity, immune signaling, apoptosis-renewal pathways, and metabolic activity in canine-relevant intestinal and macrophage cell models. MCA-B1 proximal gastrointestinal epithelial cells and DH82 macrophage-like cells were exposed to BC cultures, followed by quantification of tight-junction expression, permeability (FITC-Dextran), cytokine responses, phagocytic activity, apoptosis-related markers, and metabolomic profiles. BC treatment significantly strengthened the epithelial barrier, inducing a marked upregulation of Claudin 1 (CLDN1) (11.3 fold), CLDN4 (2.4 fold), Occludin (OCLN, 1.7 fold), and increasing key proteins including ZO-2 and cingulin while reducing LPS-induced FITC-Dextran permeability to 94.5%. BC concurrently modulated innate immune signaling, increasing MyD88 (33.2%), IL-8 (14.6 fold), IL-18 (2.6 fold), and IFNB1 protein levels, while enhancing anti-inflammatory regulation, including a robust rise in DH82-derived IL-10. Apoptosis-renewal markers shifted toward physiological turnover, with increased BCL2 (1.9 fold) and reduced BAK1. Metabolomic profiling of BC activity revealed elevated AMP, abundant Peptide Transporter 1 (PEPT1)-transportable peptides, increased γ-glutamyl metabolites, and lower Glutathione disulfide (GSSG), consistent with AMPK-linked tight-junction assembly and glutathione-supported redox buffering. Together, these data indicate that Bacillus velezensis-derived metabolites positively influence barrier-related, immunological, and metabolic responses in a canine proximal intestinal epithelial system and modulate functional responses in macrophage-like cells. These in vitro findings contribute to the mechanistic understanding of host cellular responses to Bacillus-associated metabolites. Full article

Seed initiation in Arabidopsis depends on regulatory transitions that begin before fertilization, yet these events are often treated as separate developmental episodes rather than as a connected sequence. Here, we synthesize evidence from megaspore mother cell (MMC) specification to endosperm cellularization and ask whether particular stage boundaries meet a narrow definition of developmental handover: a shift between dominant control logics, with detectable first-order consequences in the ensuing interval and acknowledged overlap across the boundary. This framework goes beyond canonical staging by distinguishing chronological succession from shifts in regulatory control, thereby clarifying where earlier states are expected to constrain later outcomes, which developmental boundaries are mechanistically well supported, and where further mechanistic resolution is most needed. We first examine how MMC singleness (restriction to a single reproductive founder cell per ovule primordium) emerges through coupled sporophytic restriction and local competence. We then consider how meiosis and female gametophyte maturation establish regulatory poise (an actively restrained and asymmetric mature female-gametophytic state), including cell-cycle restraint, companion-cell-restricted demethylation, and unequal gametic chromatin states that condition subsequent embryo and endosperm behavior. After fertilization, release of central-cell restraint, activation of an endosperm auxin program, and recruitment of maternal tissues together mark the onset of seed initiation. In this view, syncytial endosperm is an actively maintained developmental state shaped by parental dosage, epigenetic control, hormone signaling, and maternal interaction, whereas endosperm cellularization represents a regulated switch with seed-wide consequences. In Arabidopsis, the clearest handover is the mature female gametophyte-to-fertilization boundary, whereas the boundaries linking MMC specification to female gametophyte maturation and syncytial endosperm to cellularization remain provisional. Full article

Background/Objectives: Traditional histopathologic grading of renal cell carcinoma (RCC) is subjective, is poorly reproducible, and fails to predict responses to modern targeted agents or immunotherapies. In the era of precision oncology, molecular pathology offers objective tools for individualized management. We aimed to characterize genomic alterations in clear-cell RCC (ccRCC) with venous tumor thrombus and to develop pathology-driven panels for personalized prognostic stratification, with exploratory assessment of their potential to predict therapeutic response. Methods: Formalin-fixed paraffin-embedded pT1 ccRCC samples with and without thrombus underwent whole-exome sequencing. Distinct somatic mutations and copy number variations were incorporated into multigene panels. External assessment was performed in TCGA and PAWG cohorts, assessing survival outcomes and therapeutic biomarkers including homologous recombination deficiency (HRD), tumor mutational burden (TMB), and microsatellite instability (MSI). Results: Thrombus cases showed unique genomic heterogeneity compared with matched controls. Three multigene panels were constructed. Across external datasets, including a 354-patient TCGA-KIRC ccRCC cohort, the panels provided consistent molecular stratification signals for overall, disease-specific, and progression-free survival, complementing established pathological risk factors. They were significantly associated with established therapy-related genomic biomarkers, including HRD, TMB, and MSI, showing high sensitivity and negative predictive value in identifying patients unlikely to harbor these biomarker-positive profiles. These findings support the panels’ prognostic utility, with exploratory evidence for their potential in therapy response prediction. Conclusions: Small ccRCC with thrombus harbors distinct molecular pathological features. The proposed pathology-driven panels, compatible with FFPE tissue, represent pathology-compatible genomic tools that may support modern precision pathology by improving molecular risk stratification and informing exploratory therapeutic biomarker assessment. Full article

Food allergy is an exaggerated immune response, mediated by Immunoglobulin E (IgE) or by cells, to food antigens. Dogs and cats may present with both dermatological and gastrointestinal manifestations, although non-seasonal pruritus is the most common clinical sign. Despite advances in understanding the immunopathogenesis of this condition, the elimination–provocation test remains the gold standard for diagnosis. However, new diagnostic approaches, like molecular allergen macroarrays and lymphocyte proliferation assays, may complement traditional strategies, opening new perspectives for accurate diagnosis. For long-term management, strict avoidance of offending allergens is essential, but emerging therapeutic interventions, including immunotherapy using food components and targeted modulation of the gut–skin axis, are promising for improving clinical outcomes. This review summarizes current knowledge and highlights innovative approaches that can transform the diagnosis and management of food allergy in companion animals. Full article

Background/Objectives: We performed a systematic review of preclinical literature on the use of high-LET particle therapy, DDRi, and/or immunotherapy specifically in pMMR colorectal cancer. Methods: A systematic review of the literature published between 2014 and 2025 was conducted across major databases. Studies were included if they examined particle radiotherapy (e.g., proton, alpha, and carbon) or X-ray radiation either alone or in combination with DDRi and/or immune checkpoint inhibitors (ICIs) in pMMR colorectal cancer models. Results: In total, 131 studies met the inclusion criteria, including 70 preclinical studies. These studies consistently demonstrate that high-LET radiation amplifies immunogenic cell death, increases cGAS-STING pathway activation, and enhances tumor antigen presentation, thereby fostering greater immune infiltration and systemic antitumor responses. Concurrent irradiation with DDRi enhances persistent DNA damage and cytosolic DNA accumulation. In murine models, high-LET therapies show excellent local control, with manageable toxicity profiles. Combination regimens with ICIs exhibit improved local control and elicit systemic antitumor immune responses. Conclusions: High-LET particle radiation and/or the use of concurrent DDRi with ICI have significant preclinical evidence of immunostimulatory effects in pMMR rectal adenocarcinoma and increased response rates to immunotherapy. The clinical evidence will be reviewed in the companion manuscript. Full article

Domestic cats are among the most popular companion animals worldwide, with steadily increasing ownership and life expectancy. Paradoxically, despite their high prevalence and shared environmental exposures with humans, cats remain markedly underrepresented in molecular oncology research. Cancer is a leading cause of feline mortality, and alimentary lymphoma (AL) has emerged as one of the most common feline malignancies, yet its molecular landscape remains poorly characterized. This review summarizes current knowledge on feline AL, including epidemiology, risk factors, classification schemes, diagnostic challenges, treatment outcomes, and survival, with particular emphasis on low-grade alimentary lymphoma (LGAL), the most prevalent subtype. We discuss the complex relationship between chronic inflammatory enteropathies and lymphoma, highlighting diagnostic ambiguities and the inflammatory–neoplastic continuum. Importantly, we provide a critical overview of existing genomic, transcriptomic, epigenomic, proteomic, and metabolomic studies in feline AL, revealing a striking paucity of high-throughput, multi-omics analyses based on clinical material. Recent advances in feline genome assembly and annotation offer new opportunities to address these gaps. Furthermore, we compare feline AL with its human gastrointestinal T-cell lymphoma counterparts, demonstrating substantial molecular homology across key oncogenic pathways, including JAK/STAT signaling. This comparative perspective underscores the potential of feline AL as a naturally occurring model for the human disease. We conclude that comprehensive molecular characterization of feline AL is urgently needed to improve diagnostics, prognostication, and targeted therapies, with likely translational benefits for both veterinary and human oncology. Aim: The goal of this review is to summarize the current knowledge on feline alimentary lymphoma, including its origin, risk, classification, treatment approaches, and especially molecular landscape, which still remains poorly investigated with modern high-throughput techniques. Full article

Xylem and phloem are the defining features of vascular plants and are central to their evolutionary success. The origin and development of phloem and xylem within the vascular cylinder of rice primary roots (Oryza sativa L.) were investigated using serial sectioning and three-dimensional (3D) image processing techniques improved and developed by the authors. Protophloem mother cells and metaphloem sieve tube members were derived from vascular initials at about 20 μm from the apex of the vascular cylinder (AVC). Protophloem tissue and companion cells were generated through two successive divisions of protophloem mother cells 60–95 μm from the AVC of a 20 mm-long primary root. Metaxylem and late-metaxylem were initiated by the division of vascular initials at about 20 μm from the AVC of a 20 mm long root. Protoxylem was formed basipetally from secondary initials produced through periclinal division of pericycle cells at distances ranging 175–560 μm from the AVC. Protoxylem vessels could be clearly identified with a thickened cell wall preceding the thickening of metaxylem cell walls. Around 15 mm from the AVC of the 20 mm-long root, three kinds of xylem vessels (protoxylem, metaxylem and late metaxylem) were confirmed. The histogenesis of protophloem and protoxylem in rice primary roots was carefully analyzed and discussed in this study. In particular, the view has been confirmed regarding the pericycle origin of protoxylem in rice. Full article

The heart’s performance relies on its contractile and rhythmic properties, which are modulated not only by extrinsic autonomic inputs but also by the intrinsic cardiac nervous system (ICNS), a distributed network of intracardiac ganglia and neurons that integrates local sensory, autonomic, and inflammatory signals. Growing evidence indicates that cardiac fibrosis and neuronal remodeling are intertwined processes within this network. This review synthesizes current knowledge on molecular, structural, and functional remodeling of the ICNS to drive neurofibrosis, autonomic imbalance, and arrhythmogenesis. We outline ICNS anatomy and neurochemical diversity, then summarize core fibrotic mechanisms, fibroblast activation, extracellular matrix dynamics, and inflammatory signaling, and map these onto intracardiac ganglia. Across diabetes, myocardial infarction, heart failure, and neuroinflammatory states, shared pathways (e.g., IL-6/STAT3, TGF-β/SMAD, PI3K/AKT, MAPK/ERK, oxidative stress) suppress neuronal excitability, promote neuron–glia–fibroblast coupling, and culminate in neurofibrotic remodeling. We integrate functional data linking these changes to autonomic dysregulation and arrhythmia vulnerability. Future priorities involve constructing detailed human ICNS atlases and applying single-cell and spatial multi-omics to better characterize intracardiac neurons, their circuitry, and their interactions with fibroblasts and immune cells. These insights will be essential to inform targeted neuromodulation and anti-fibrotic interventions. The ICNS is a dynamic regulatory hub whose cells and circuits participate directly in cardiac fibrosis and electrical instability. Recognizing neurofibrosis as a companion process to myocardial fibrosis reframes therapeutic strategy toward preserving both neural and myocardial integrity. Full article

In vitro models for animal experiments serve as a crucial bridge connecting basic research and clinical translation, and their developmental history profoundly reflects the paradigm shifts in life science research. This article’s narrative reviews the evolutionary path from traditional two-dimensional (2D) cell culture to advanced three-dimensional (3D) organoid technology, focusing on how organoid technology overcomes the limitations of traditional models in terms of physiological relevance, species specificity, and ethical constraints. The review article elaborates on the current state of organoid research in veterinary science, including the construction of models for organs such as the intestine, liver, and reproductive system in livestock and companion animals. Addressing existing technical bottlenecks—such as insufficient model complexity, lack of standardization, and difficulties in simulating vascularization and the immune microenvironment—future development directions are proposed, including multi-organ chips, AI-assisted analysis, and the integration of gene editing. Research indicates that with the deep integration of cutting-edge technologies such as biomaterials, microfluidics, 3D printing, and AI, organoid technology is progressively becoming a core driver for advancing veterinary precision medicine, holding broad application prospects. Full article

Escherichia coli O157:H7 is a pathogenic bacterium that causes severe intestinal infections characterized by inflammation and disruption of the intestinal barrier. Probiotic lactic acid bacteria (LAB) from milk can support intestinal health and combat enteric pathogens; however, the potential of feline milk-derived LAB against E. coli O157:H7 infection remains unclear. In this study, Pediococcus acidilactici (P. acidilactici) M22, isolated from feline milk, was evaluated for probiotic activity in vitro and in vivo in a C57BL/6 mouse model of Escherichia coli O157:H7 infection. In vitro assays demonstrated that M22 significantly inhibited the adhesion of Escherichia coli O157:H7 to intestinal epithelial cells. For in vivo assessment, C57BL/6 mice were orally administered M22 prior to infection with E. coli O157:H7. Protective effects were evaluated by monitoring body weight loss, colon length, disease activity index (DAI), myeloperoxidase (MPO) activity, cytokine levels, tight junction protein expression, oxidative stress markers, and gut microbiota composition. M22-treated mice exhibited significantly less body weight loss and lower DAI scores than infected controls. M22 also prevented colon shortening, indicating reduced colonic damage. Probiotic treatment attenuated neutrophil infiltration and mucosal inflammation, as evidenced by decreased colonic MPO activity, reduced levels of pro-inflammatory cytokines, and elevated anti-inflammatory IL-10. Additionally, M22 preserved intestinal barrier function by upregulating tight junction proteins and mitigating infection-induced histopathological changes. M22 supplementation enhanced antioxidant defenses in colonic tissue (lower malondialdehyde, higher superoxide dismutase and glutathione), indicating reduced oxidative stress. Furthermore, gut microbiota analysis (16S rRNA sequencing) revealed that M22 counteracted infection-induced dysbiosis, restoring microbial diversity and a healthy composition (enrichment of beneficial commensals and suppression of harmful bacteria). By safeguarding intestinal integrity and homeostasis, M22 emerges as a promising next-generation probiotic for improving intestinal health in companion animals. Full article

This study investigated whether Whole blood viscosity (WBV) varies with age in clinically healthy Beagle dogs and Korean Shorthair cats and examined the hematologic and biochemical variables associated with WBV. WBV was measured across multiple shear rates using a scanning capillary viscometry; complete blood count (CBC) and serum chemistry profiles were also evaluated. Both species demonstrated characteristic shear-thinning behavior. WBV showed a strong association with red blood cell count (RBC), hematocrit (HCT), and hemoglobin (Hb) in both species, with additional association with serum proteins and cholesterol in dogs. No significant relationship between WBV and age was identified at any shear rate, and principal component analysis (PCA) revealed no age-related clustering in the viscosity profiles. These findings indicated that WBV does not exhibit meaningful age-dependent trends in healthy companion animals. This suggests that, in a clinical setting, deviations in normal WBV are more likely to influence underlying physiological or pathological factors than normal aging. Full article

Gammaretroviruses are ubiquitous pathogens, often associated with the induction of neoplasia, especially leukemia, lymphoma, and sarcoma, and with a propensity to target the germline. The latter trait has left extensive evidence of their infectious competence in vertebrate genomes, the human genome being no exception. Despite the continuing activity of gammaretroviruses in mammals, including Old World monkeys, apes, and gibbons, humans have apparently evaded novel infections by the virus class for the past 30 million years or so. Nevertheless, from the 1970s onward, cell culture studies repeatedly discovered gammaretroviral components and/or virus replication in human samples. The last novel ‘human’ gammaretrovirus, identified in prostate cancer tissue, culminated in the XMRV frenzy of the 2000s. In the end, that discovery was shown to be due to lab contamination with a murine gammaretrovirus. Contamination is also the likely source of the earlier findings. Complementation between genes of partially defective endogenous proviruses could have been another source of the virions observed. However, the capacity of many gammaretroviruses to replicate in human cell lines, as well as the presence of diverse infectious gammaretroviral species in our animal companions, for instance in mice, cats, pigs, monkeys, chickens, and bats, does not make a transmission to humans an improbable scenario. This review will summarize evidence for, or the lack of, gammaretrovirus infections in humans in the past, present, and near future. Aspects linked to the probabilities of novel gammaretrovirus infections in humans, regarding exposure risk in connection to modern lifestyle, geography, diet, and habitat, together with genetic and immune factors, will also be part of the review, as will be the estimated consequences of such novel infections. Full article