生物学最新文献

Lactoferrin (LTF) has gained attention as a potential anti-cancer biomarker, but its role in left-sided colon cancer (LCC) remains poorly understood. This study explores the function of LTF in LCC and its underlying mechanisms. LTF expression was significantly elevated in tumor tissues compared to normal tissues (59.67-fold increase, p < .001). LTF overexpression significantly enhanced LCC cell proliferation, migration, and invasion (p < .01), while suppressing apoptosis (p < .05). In contrast, LTF knockdown markedly inhibited these oncogenic behaviors. Western blot analysis demonstrated that LTF overexpression led to increased phosphorylation of PI3K and Akt proteins (p < .01), suggesting activation of the PI3K/AKT signaling pathway, while LTF knockdown resulted in decreased phosphorylation levels (p < .01). This study identifies LTF as a promoter of LCC development via activation of the PI3K/AKT pathway, suggesting LTF as a promising therapeutic target. Further research is warranted to evaluate its clinical potential in LCC treatment.

Brown and beige adipose tissue represent evolutionary adaptations in mammals, functioning as specialized thermogenic organs to maintain body temperature. Over the past two decades, researches have demonstrated that white adipose tissue (WAT) browning is an effective strategy to enhance energy expenditure. However, a growing body of evidence indicates that the browning process frequently occurs in a variety of chronic disease states, though its pathophysiological significance remains unclear. This review summarized evidence of pathological browning observed in human diseases and animal models, including breast cancer, colorectal cancer (CRC), clear cell renal cell carcinoma (ccRCC), kidney health, burn injury, atherosclerotic, SARS-CoV-2 and sepsis. Despite distinct pathological contexts, adipose tissue browning is consistently observed. This suggests that browning may not simply serve its classical metabolically protective role, but instead reflect an atypical response to pathological stress. It is currently unclear whether this is a compensatory mechanism by the organism in a diseased state or merely a byproduct of the disease process. Whether this response is adaptive or a cause of disease progression remains unresolved. Future research should therefore focus on identifying the triggers and functional outcomes of pathological browning to better understand adipocyte plasticity and its role in disease progression.

Haemophilus parainfluenzae (Hpar) is a common colonizer found in the upper respiratory tract, although recently urogenital colonization has emerged as a clinical concern. Urogenital Hpar has been associated with increased antibiotic resistance and virulence compared to respiratory Hpar. We analyzed the genome of 270 Hpar isolates, including all sequencing data found in the NCBI sequence read archive database. The pangenome of respiratory and urogenital isolates were compared in order to find potential metabolic or pathogenic adaptations to different host environments. The pangenome-wide association study found significant genomic differences. Specifically, the two-component signal transduction system was significantly enriched in urogenital samples, which could explain the adaptations of Hpar to the unique physico-chemical conditions of the urethra. Additionally, the two-component system could work as a new target for antimicrobials against pathogenic Hpar. The polysaccharide capsule, the main virulence factor in Haemophilus spp. was present in 26/65 of the urogenital samples from our facility, an increase from previous studies. In summary, the data presented suggest that respiratory and urogenital isolates of Hpar belong to different genetic lineages, and therefore it is possible that unprotected oral sex is not the route of transmission of Hpar from the respiratory tract to the urethra. Given the limited amount of available sequences, future studies collecting more isolates from different spatiotemporal locations would shed more light on this issue.

Salmonella enteritidis is a globally prevalent zoonotic pathogen with a broad host range and high pathogenicity, ranking among the most common serotypes within the Salmonella genus. The widespread and often indiscriminate use of antibiotics has driven a continual rise in antimicrobial resistance among S. Enteritidis strains, posing a significant threat to public health. In this study, we employed a quantitative proteomics approach to investigate differential protein expression between meropenem-sensitive and -resistant S. Enteritidis strains. Bioinformatic analyses revealed significant downregulation of all the genes associated with the bacterial chemotaxis pathway in the resistant strain. To further explore the functional relevance of this pathway, we generated deletion mutants of 15 chemotaxis-related genes and assessed their susceptibility to meropenem. Notably, deletion of the mglB gene was associated with increased resistance. Given the known role of mglB in galactose transport, we hypothesized and subsequently confirmed that exogenous galactose supplementation enhances the bactericidal activity of meropenem against resistant strains. This synergistic effect was further validated in animal infection models. Collectively, these findings provide novel insights into the molecular basis of meropenem resistance in S. Enteritidis and highlight the potential of metabolic modulation as a strategy to restore antibiotic efficacy.

Adipose omeostasishomoeostasis is maintained through the precise coordination of lipogenesis, lipolysis, and adipocyte differentiation, with microenvironmental components dynamically regulating lipid metabolism. Even though the classical cAMP-PKA pathway has been well-characterized for its function in lipid metabolism by phosphorylating transcription factors and lipolytic enzymes, little is known about how it collaborates with elements of the adipose tissue microenvironment, such as immune cells and the vascular endothelium, especially in pathological situations like obesity. EPAC, a newly discovered cAMP effector, has shown new signalingsignallingsignalling signalling pathways in the immune and cardiovascular systems by activating small G proteins. However, there are important understanding gaps regarding its roles in adipose metabolism, namely adipocyte development, microenvironmental interaction, and the pathophysiology of metabolic diseases. By bringing together disparate studies on PKA and EPAC, this review provides the first comprehensive synthesis of the cAMP-PKA/EPAC dual signaling signalling signallingcins signalling network, filling in knowledge gaps. The reciprocal regulation between this signaling signalling signalling signalling network and the adipose microenvironment establishes a novel 'signaling-microenvironment-systemic metabolism' framework for understanding metabolic disorders, including obesity, diabetes, and hepatic steatosis. Pharmacological modulation of the PKA/EPAC signalingsignalling signalling signalling pathways may therefore represent a viable therapeutic approach for restoring adipose tissue homeostasis homoeostasis.

Avian infectious bronchitis virus (IBV) belongs to the genus Gammacoronavirus (family Coronaviridae), causes severe multi-system disease in chickens, inflicting major global economic losses. The molecular interplay between IBV and host metabolic networks remains poorly understood. Through integrated transcriptomic, metabolomic, and lipidomic profiling of oviduct tissues from specific-pathogen-free (SPF) chickens infected with the IBV QXL strain, we demonstrate tripartite metabolic reprogramming: 1) redirected glucose flux through the pentose phosphate pathway (PPP) to fuel nucleotide synthesis, 2) rewired lipid metabolism to prioritize de novo membrane biogenesis over fatty acid β-oxidation, and 3) orchestrated glycerophospholipid remodeling. This integrated analysis revealed a coordinated upregulation of fatty-acid biosynthesis genes and accumulation of specific glycerophospholipids and eicosanoids. Mechanistically, IBV co-opts the Warburg effect and PPP activation while uniquely suppressing fatty acid β-oxidation to channel fatty acids toward lipid droplets (LDs) biogenesis. Phosphatidylserine (PS) overproduction (e.g. 2.55-fold increase in PS(22:0/22:6)) and phospholipase A₂ (PLA₂)-mediated lysophospholipids (Lyso-PLs) and eicosanoids generation (e.g. 7.09-fold increase in prostaglandin E₂ (PGE₂)) emerged as critical regulators of membrane dynamics and inflammatory signaling. This process was centrally coordinated by the significant activation of peroxisome proliferator-activated receptor (PPAR) (e.g. 1.74-fold increase in ACSL1) and transforming growth factor-beta (TGF-β) (e.g. significant increase in p-SMAD2) signaling pathways, directly linking lipid remodeling to immunomodulation. Functionally, targeting acetyl-CoA carboxylase (ACC) or glucose-6-phosphate dehydrogenase (G6PD), alongside TGF-β pathway modulation, synergistically curtailed viral replication in vitro. Our findings delineate a critical PPAR-TGF-β cross-talk that governs lipid remodeling during infection and identify host metabolic nodes that are potentially targetable for antiviral intervention.

DNA methylation (DNAm) signatures are highly cell type-specific, yet most epigenome-wide association studies (EWAS) are performed on bulk tissue, potentially obscuring critical cell type-specific patterns. Existing computational tools for detecting cell type-specific DNAm changes are often limited by the accuracy of cell type deconvolution algorithms. Here, we introduce CEAM (Cell-type Enrichment Analysis for Methylation), a robust and interpretable framework for cell type enrichment analysis in DNA methylation data. CEAM applies over-representation analysis with cell type-specific CpG panels from Illumina EPIC arrays derived from nuclei-sorted cortical post-mortem brains from neurologically healthy aged individuals. The constructed CpG panels were systematically evaluated using both simulated datasets and published EWAS results from Alzheimer's disease, Lewy body disease, and multiple sclerosis. CEAM demonstrated resilience to shifts in cell type composition, a common confounder in EWAS, and remained robust across a wide range of differentially methylated positions, when upstream modeling of cell type composition was modeled with sufficient accuracy. Application to existing EWAS findings generated in neurodegenerative diseases revealed enrichment patterns concordant with established disease biology, confirming CEAM's biological relevance. The workflow is publicly available as an interactive Shiny app (https://um-dementia-systems-biology.shinyapps.io/CEAM/) enabling rapid, interpretable analysis of cell type-specific DNAm changes from bulk EWAS.

Infections with Streptococcus pyogenes are among the most important diseases caused by bacteria and are responsible for around 500,000 deaths every year. In 2024, macrolide-resistant S. pyogenes was added to the WHO's list of priority pathogens. The non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase GapN has been identified as a potential drug target in S. pyogenes. SpyGapN is the major NADP-reducing enzyme in these bacteria as they lack the oxidative part of the pentose phosphate pathway. In this study, in silico docking of compound libraries to the glyceraldehyde 3-phosphate binding pocket of SpyGapN was used to screen for potential competitive inhibitors. Among the candidates identified with this approach, 1,2-dihydroxyethane-1,2-disulfonate (glyoxal bisulfite) showed the strongest inhibition of SpyGapN activity in vitro. In a complementary approach, crystallographic fragment screening was conducted, which identified the ultra-low-molecular-weight compounds pyrimidine-5-amine and 4-hydroxypyridazine targeting the cofactor-binding pocket of SpyGapN. Both low-molecular-weight compounds were experimentally confirmed to inhibit the activity of purified SpyGapN. Combinations of glyoxal bisulfite with either pyrimidine-5-amine or 4-hydroxypyridazine enhanced the inhibitory effect of SpyGapN. Glyoxal bisulfite was able to kill S. pyogenes. This effect was accelerated by combining glyoxal bisulfite with 4-hydroxypyridazine. While these findings suggest that inhibition of SpyGapN probably contributes to the observed antibacterial activity, the exact mechanism of action remains to be confirmed, as the compounds also affect other G3P-converting enzymes. Nevertheless, these compounds provide a promising starting point for the development of more specific SpyGapN inhibitors.

Giardia duodenalis is an intestinal protozoan parasite responsible for giardiasis, a disease primarily characterized by diarrhea and associated with long-term complications such as malnutrition and growth impairment in children. The presence of Giardiavirus (GLV) has been shown to attenuate pathological damage in G. duodenalis-infected murine models and modulate distinct pro-inflammatory responses in host cells stimulated by Giardia. However, the understanding of the impact of the GLV on the G. duodenalis itself remains limited. Here, we found that GLV infection interfered with the host protein expression system by reducing both mRNA and protein levels of Giardia genes, while paradoxically enhancing mRNA translation efficiency. Additionally, GLV infection induced energy metabolic reprogramming in Giardia, as evidenced by the identification of 21 significantly altered energy metabolites. KEGG enrichment analysis revealed glycolysis/gluconeogenesis as the most prominently enriched metabolic pathway in GLV-infected Giardia. Notably, glycolysis continued to be upregulated with successive passages of GLV infection, even after the GLV load plateaued. The glycolytic enzyme enolase was found to be closely associated with GLV infection within Giardia, and morpholino-mediated knockdown of enolase expression resulted in a significant reduction in GLV replication. Overall, these findings demonstrate that GLV infection manipulates host translation and energy metabolic pathways to facilitate its persistence in G. duodenalis, and reveal both GLV and host metabolic targets as promising research subjects for developing drugs and vaccines for the prevention and treatment of giardiasis.

The diverse mycelial networks of fungi are generated through polar growth, cell division, and cell fusion. Most of the genes are well characterized as crucial for cellular communication and fusion processes in filamentous fungi, but their functions and molecular mechanisms remain poorly understood. Here, we functionally characterized the hyphal anastamosis protein 4 (AoHam4), hyphal anastamosis-8 protein (AoHam8) and serine/threonine protein phosphatase 2A (AoPP2A) in the model nematode-trapping fungus Arthrobotrys oligospora. Our results indicate that Aoham4, Aoham8 and Aopp2a genes are essential for hyphal fusion and trap morphogenesis, and modulate mycelial growth, conidial production, and pathogenicity in A. oligospora. Staining, RT-qPCR and transmission electron microscopy (TEM) results indicated that all three genes are involved in regulating reactive oxygen species (ROS) accumulation, lipid metabolism and autophagy processes. Moreover, RNA-Seq and liquid chromatography-mass spectrometry (LC-MS) experiments further confirmed that deletion of Aoham4, Aoham8 and Aopp2a genes affects transcription and metabolic levels. Yeast-two-hybrid (Y2H) analysis showed that AoPP2A can interact with AoSO (Soft, a fungus-specific scaffolding protein, is involved in signaling and secretion with the MAK-2 cascade). Since the ΔAoham8 mutant strain was more sensitive to cell wall-disrupting reagents, speculating that Aoham8 may regulate the mitogen-activated protein (MAP) kinase cascade response by activating the cell wall integrity pathway. Collectively, our studies illuminate the crucial roles of the fungal cell-fusion genes Aoham4, Aoham8 and Aopp2a in A. oligospora, as well as laying the groundwork for clarifying the mechanisms of mycelial development and trap morphogenesis of nematode-trapping fungi.