PubMed

Cell Biosci. 2025 Jan 22;15(1):6. doi: 10.1186/s13578-024-01340-3.ABSTRACTBACKGROUND: Japanese encephalitis (JE) induced by Japanese encephalitis virus (JEV) infection is the most prevalent diagnosed epidemic viral encephalitis globally. The underlying pathological mechanisms remain largely unknown. Given that viruses are obligate intracellular parasites, cellular metabolic reprogramming triggered by viral infection is intricately related to the establishment of infection and progression of disease. Therefore, uncovering and manipulating the metabolic reprogramming that underlies viral infection will help elucidate the pathogenic mechanisms and develop novel therapeutic strategies.METHODS: Metabolomics analysis was performed to comprehensively delineate the metabolic profiles in JEV-infected mice brains and neurons. Metabolic flux analysis, quantitative real-time PCR, western blotting and fluorescence immunohistochemistry were utilized to describe detailed glutamine-glutamate metabolic profiles during JEV infection. Exogenous addition of metabolites and associated compounds and RNA interference were employed to manipulate glutamine-glutamate metabolism to clarify its effects on viral replication. The survival rate, severity of neuroinflammation, and levels of viral replication were assessed to determine the efficacy of glutamine supplementation in JEV-challenged mice.RESULTS: Here, we have delineated a novel perspective on the pathogenesis of JE by identifying an aberrant low flux in glutamine-glutamate metabolism both in vivo and in vitro, which was critical in the establishment of JEV infection and progression of JE. The perturbed glutamine-glutamate metabolism induced neurotransmitter imbalance and created an immune-inhibitory state with increased gamma-aminobutyric acid/glutamate ratio, thus facilitating efficient viral replication both in JEV-infected neurons and the brain of JEV-infected mice. In addition, viral infection restrained the utilization of glutamine via the glutamate-α-ketoglutaric acid axis in neurons, thus avoiding the adverse effects of glutamine oxidation on viral propagation. As the conversion of glutamine to glutamate was inhibited after JEV infection, the metabolism of glutathione (GSH) was simultaneously impaired, exacerbating oxidative stress in JEV-infected neurons and mice brains and promoting the progression of JE. Importantly, the supplementation of glutamine in vivo alleviated the intracranial inflammation and enhanced the survival of JEV-challenged mice.CONCLUSION: Altogether, our study highlights an aberrant glutamine-glutamate metabolism during JEV infection and unveils how this facilitates viral replication and promotes JE progression. Manipulation of these metabolic alterations may potentially be exploited to develop therapeutic approaches for JEV infection.PMID:39844330 | DOI:10.1186/s13578-024-01340-3

J Anim Sci Biotechnol. 2025 Jan 23;16(1):12. doi: 10.1186/s40104-024-01142-0.ABSTRACTBACKGROUND: The synchronized absorption of amino acids (AAs) and glucose in the gut is crucial for effective AA utilization and protein synthesis in the body. The study investigated how the starch digestion rate and AA levels impact intestinal AA digestion, transport and metabolism, breast muscle protein metabolism, and growth in grower broilers. A total of 720 21-day-old healthy male Arbor Acres Plus broilers were randomly assigned to 12 treatments, each with 6 replicates of 10 birds. The treatments comprised 3 different starch [corn: control, cassava: rapidly digestible starch (RDS), and pea: slowly digestible starch (SDS)] with 4 different AA levels [based on standardized ileal digestible lysine (SID Lys), 0.92%, 1.02% (as the standard), 1.12% and 1.22%].RESULTS: An interaction between dietary starch sources and SID Lys levels significantly affected breast muscle yield (P = 0.033). RDS and SDS diets, or SID Lys levels of 0.92%, 1.02%, or 1.22%, significantly decreased the breast muscle yield of broilers in contrast to the corn starch diet with 1.12% SID Lys (P = 0.033). The SID Lys levels of 1.12% and 1.22% markedly improved body weight (BW), body weight gain (BWG) from 22 to 42 days of age, and mRNA expression of y+LAT1 and mTOR while reducing feed intake (FI) and feed/gain ratio (F/G) compared to the 0.92% SID Lys level (P < 0.05). The SDS diet significantly decreased BW and BWG of broilers from 22 to 42 days of age, distal ileal starch digestibility, jejunal amylase and chymotrypsin activities, and mRNA expression of GLUT2 and y+LAT1 compared to the corn starch diet (P < 0.05). The RDS diet suppressed the breast muscle mass by down-regulating expression of mTOR, S6K1, and eIF4E and up-regulating expression of MuRF, CathepsinB, Atrogin-1, and M-calpain compared to the corn starch diet (P < 0.05). Targeted metabolomics analysis revealed that the SDS diet significantly increased acetyl-CoA and α-ketoglutaric acid levels in the tricarboxylic acid (TCA) cycle (P < 0.05) but decreased the ileal digestibility of Lys, Tyr, Leu, Asp, Ser, Gly, Pro, Arg, Ile, and Val compared to the corn starch group (P < 0.05).CONCLUSION: The SDS diet impaired broiler growth by reducing intestinal starch digestibility, which inhibited intestinal AA and glucose absorption and utilization, increased AA oxidation for energy supply, and lowered the efficiency of protein synthesis. Although the RDS diet resulted in growth performance similar to the corn starch diet, it reduced breast muscle mass by inhibiting protein synthesis and promoting degradation.PMID:39844287 | DOI:10.1186/s40104-024-01142-0

J Transl Med. 2025 Jan 22;23(1):105. doi: 10.1186/s12967-024-06028-3.ABSTRACTChimeric antigen receptor (CAR) T-cell therapy plays a critical role in the treatment of B-cell hematologic malignancies. The combination of PD-1 inhibitors and CAR-T has shown encouraging results in treating patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, there are still cases where treatment is ineffective. This study aimed to investigate the role of IL4I1 in the poor efficacy of CD19 CAR-T combined with PD-1 inhibitors in R/R DLBCL and to explore potential mechanisms. Transcriptomic and metabolomic correlation analyses were performed on tumor tissue from DLBCL patients. We employed an in vitro co-culture system consisting of Pfeiffer cells, CD19 CAR-T and macrophages to investigate the underlying mechanisms. It was found that IL4I1 levels were significantly increased in the tumor tissues of R/R DLBCL patients compared to responders. Correlation analysis revealed a positive association between IL4I1 and tryptophan (Trp)-kynurenic acid (Kyn) related metabolites. In the in vitro co-culture model, the presence of IL4I1 inhibited the cytotoxicity of CAR-T cells. Depletion of IL4I1 disrupted the IDO-AHR-Kyn signaling pathway, thereby enhancing the effectiveness of PD-1 inhibitors in combination with CD19 CAR-T for DLBCL treatment. CAR-T-mediated cytotoxicity was significantly inhibited when IL4I1 was present in the in vitro co-culture model. These findings suggest that IL4I1 may be a contributing factor to poor prognosis in R/R DLBCL patients. IL4I1 expression enhances immunosuppression via the IDO-AHR-Kyn pathway, inhibiting the effectiveness of PD-1 inhibitors combined with CD19 CAR-T. Therefore, suppression of IL4I1 may represent a potential target for combination therapy in DLBCL.PMID:39844281 | DOI:10.1186/s12967-024-06028-3

Cardiovasc Diabetol. 2025 Jan 22;24(1):36. doi: 10.1186/s12933-025-02586-y.ABSTRACTAtherosclerosis, a chronic inflammatory condition characterized by plaque formation, often leads to instability, particularly under Type 2 diabetes mellitus (T2DM) conditions, which exacerbate cardiovascular risks. However, the molecular mechanisms underlying this process remain incompletely understood. In this study, we investigated the correlation between acute coronary syndrome (ACS) and serum levels of Nε-carboxyethyl-lysin (CEL), a prominent advanced glycation end product (AGE) elevated in T2DM, in a cohort of 225 patients with coronary artery disease. Using a murine model of atherosclerosis complicated by T2DM, we examined the effects of CEL on plaque stability and macrophage autophagy. Our findings revealed that elevated serum CEL levels are independently associated with increased ACS incidence. Metabolomic profiling identified CEL as a key AGE contributing to plaque instability in diabetic conditions. Mechanistically, CEL disrupted macrophage autophagy and plaque stability by perturbing the Receptor for Advanced Glycation End products (RAGE)/Liver Kinase B1 (LKB1)/AMP-activated Protein Kinase 1 (AMPK1)/Sirtuin 1 (SIRT1) signaling cascade. This pathway further regulated autophagic activity through SIRT1-mediated acetylation of Zinc Finger with KRAB and SCAN Domains 3 (ZKSCAN3). These findings highlight CEL's critical role in promoting plaque instability in T2DM by impairing key molecular pathways that regulate autophagy, offering potential therapeutic targets for managing atherosclerosis in diabetic patients.PMID:39844245 | DOI:10.1186/s12933-025-02586-y

Cell Commun Signal. 2025 Jan 22;23(1):40. doi: 10.1186/s12964-025-02041-1.ABSTRACTAutophagic activation in immune cells, gut microbiota dysbiosis, and metabolic abnormalities have been reported separately as characteristics of systemic lupus erythematosus (SLE). Elucidating the crosstalk among the immune system, commensal microbiota, and metabolites is crucial to understanding the pathogenesis of autoimmune diseases. Emerging evidence shows that basophil activation plays a critical role in the pathogenesis of SLE; however, the underlying mechanisms remain largely unknown. Here, we investigated the effects of autophagic inhibition on the pathogenesis of basophils in SLE using Autophagy-related gene 5 (Atg5) knockout (Atg5-/-) as an autophagic inhibitor. Specifically, we knocked out basophilic Atg5 in vivo to investigate its impact on lupus metabolism. Furthermore, Atg5-/- basophils were transferred to basophil-depleted MRL/MpJ-Faslpr (MRL/lpr) mice to study their effect on disease metabolism. Metagenomic and targeted metabolomic sequencing results indicated considerable reduction in the levels of plasma autoantibodies and inflammatory cytokines in the Atg5-/- basophil transfer group compared with that in the control group. Transplanting Atg5-/- basophils improved the gut microbiota balance in MRL/lpr mice, increasing the abundance of beneficial bacteria, such as Ligilactobacillus murinus and Faecalitalea rodentium, and reducing that of potentially pathogenic bacteria such as Phocaeicola salanitronis. The transplantation of Atg5-deficient basophils improved lupus symptoms by modulating lipid and amino acid metabolism. This improvement was linked to changes in the gut microbiota, particularly an increase in Ligilactobacillus murinus and Faecalitalea rodentium populations. These microbial shifts are believed to promote the production of beneficial metabolites, such as γ-linolenic acid and oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine, while reducing the levels of harmful metabolites such as arginine. These alterations in the metabolic profile contribute to the alleviation of lupus symptoms. Collectively, these findings reveal a novel role of basophil autophagy in SLE, highlighting its potential as a therapeutic target.PMID:39844180 | DOI:10.1186/s12964-025-02041-1

Mol Med. 2025 Jan 22;31(1):19. doi: 10.1186/s10020-025-01067-y.ABSTRACTBACKGROUND: Uremia (UR) is caused by increased UR-related toxins in the bloodstream. We explored the mechanism of enterogenous toxin methylmalonic acid (MMA) in calcium-phosphorus metabolic disorder in UR rats via the Wnt/β-catenin pathway.METHODS: The UR rat model was established by 5/6 nephrectomy. The fecal bacteria of UR rats were transplanted into Sham rats. Sham rats were injected with exogenous MMA or Salinomycin (SAL). Pathological changes in renal/colon tissues were analyzed. MMA concentration, levels of renal function indicators, serum inflammatory factors, Ca2+/P3+, and parathyroid hormone, intestinal flora structure, fecal metabolic profile, intestinal permeability, and glomerular filtration rate (GFR) were assessed. Additionally, rat glomerular podocytes were cultured, with cell viability and apoptosis measured.RESULTS: Intestinal flora richness and diversity in UR rats were decreased, along with unbalanced flora structure. Among the screened 133 secondary differential metabolites, the MMA concentration rose, showing the most significant difference. UR rat fecal transplantation caused elevated MMA concentration in the serum and renal tissues of Sham rats. The intestinal flora metabolite MMA or exogenous MMA promoted intestinal barrier impairment, increased intestinal permeability, induced glomerular podocyte loss, and reduced GFR, causing calcium-phosphorus metabolic disorder. The intestinal flora metabolite MMA or exogenous MMA induced inflammatory responses and facilitated glomerular podocyte apoptosis by activating the Wnt/β-catenin pathway, which could be counteracted by repressing the Wnt/β-catenin pathway.CONCLUSIONS: Enterogenous toxin MMA impelled intestinal barrier impairment in UR rats, enhanced intestinal permeability, and activated the Wnt/β-catenin pathway to induce glomerular podocyte loss and reduce GFR, thus aggravating calcium-phosphorus metabolic disorder.PMID:39844078 | DOI:10.1186/s10020-025-01067-y

BMC Plant Biol. 2025 Jan 23;25(1):97. doi: 10.1186/s12870-025-06113-9.ABSTRACTBACKGROUND: Torreya grandis, a prominent tree species of the autochthonous subtropical region of China, possesses a drupe-like fruit containing a nut that is rich in nutrients and bioactive compounds. However, the effect of calcium (Ca2+) sugar alcohol (CSA), a newly developed chelated Ca2+-fertilizer, on the secondary metabolism of phenolics in T. grandis nuts is largely unknown, for which transcriptomic and metabolomic analysis was carried out.RESULTS: Transcriptome sequencing detected 47,064 transcripts, and several phenolic acid biosynthesis pathway-related genes were identified. Correlation analysis showed that the four transcription factors, TgWRKY1, TgAP2-1, TgAP2-3, and TgAP2-4, were positively associated with the accumulation of phenolic acids. Furthermore, the binding of TgAP2-1 to the TgHCT promoter was confirmed using yeast one hybrid and dual-luciferase assays. Furthermore, the expression of TgHCT in Nicotiana enhanced the total flavonoid content.CONCLUSIONS: Our results indicated that a new regulatory module, Ca2+-AP2-HCT, involved in the regulation of phenolic acid biosynthesis was revealed, expanding the understanding of the role of Ca2+ fertilizers in plant secondary metabolism.PMID:39844048 | DOI:10.1186/s12870-025-06113-9

BMC Plant Biol. 2025 Jan 23;25(1):94. doi: 10.1186/s12870-025-06123-7.ABSTRACTBACKGROUND: Potassium plays a crucial role in determining the quality of flue-cured tobacco leaves. Our prior investigations have demonstrated that using potassium-efficient rootstocks through grafting offers a viable solution to the prevalent issue of low potassium levels in Chinese flue-cured tobacco leaves. Nevertheless, the specific molecular mechanisms responsible for the increase in potassium content following grafting in tobacco leaves have yet to be elucidated. This study revealing for the first time how grafting improves potassium utilization efficiency through combined transcriptome and metabolome analysis.RESULTS: This study selected Wufeng NO. 2, a potassium-efficient variety, and Yunyan 87, a main cultivar, as the research subjects to investigate the underlying reasons for differential potassium utilization efficiency among different tobacco rootstocks through transcriptome and metabolic data analysis of grafted tobacco. The results showed a considerable increment of 90.1% in the potassium content of the grafted tobacco leaves. Overall, 2044 differentially expressed genes were identified through transcriptome analysis, with the majority being enriched in plant hormone signal transduction and the MAPK pathway. Metabolome analysis revealed 175 metabolites with significant differences, primarily involving primary metabolites such as amino acids and carbohydrates. Among these, there was an increase in the metabolites levels related to glycolysis, amino acid metabolism, and the TCA cycle pathway in grafted tobacco leaves. The key metabolites and genes in the above pathways were selected for Mantel-Pearson correlation analysis, leading to the identification of 2 genes and 3 metabolites, including IAA, CIP1, D-fructose, Fumaric acid and Oxoglutaric acid, that were significantly associated with the increased potassium content in grafted tobacco.CONCLUSIONS: This study uncovers the intricate molecular mechanism behind grafting tobacco to enhance potassium utilization efficiency, thereby offering theoretical support for enhancing crop nutrient utilization efficiency through grafting technology.PMID:39844046 | DOI:10.1186/s12870-025-06123-7

BMC Microbiol. 2025 Jan 22;25(1):38. doi: 10.1186/s12866-025-03764-4.ABSTRACTBACKGROUND: Depression is a common mental disorder accompanied by gut microbiota dysbiosis, which disturbs the metabolism of the host. While diurnal oscillation of the intestinal microbiota is involved in regulating host metabolism, the characteristics of the intestinal microbial circadian rhythm in depression remain unknown. Our aim was to investigate the microbial circadian oscillation signature and related metabolic pathways in a mouse model with depression-like behaviours.METHODS: Chronic restraint stress (CRS) was used to induce depressive-like behaviours in C57BL/6J mice. The open field test (OFT) and forced swimming test (FST) were used to evaluate anxiety- and depressive-like behaviours in the control and CRS groups. Afterwards, faecal samples from the two groups were collected every four hours from ZT2 (9:00 am) to ZT22 (5:00 am). Faecal 16 S rRNA gene sequencing and metabolomics analysis were performed, and the microbial circadian rhythm was analysed via the MetaCycle package in R/RStudio.RESULTS: CRS mice exhibited depressive-like behaviours after 4 weeks of restriction. Alpha- and beta-diversity analyses revealed that the microbial composition in control and CRS mice oscillated throughout the day. The circadian rhythm analyses revealed that at the phylum level, Bacteroidota, Firmicutes, Cyanobacteria and Patescibacteria showed circadian rhythmicity in the CRS group. At the genus level, Dubosiella and Romboutsia showed circadian rhythmicity in the control group, and Dubosiella abundance was correlated with tryptophan and galactose metabolism. In the CRS group, Bacteroides, Parabacteroides, and Rikenellaceae_RC9_gut_group showed circadian rhythmicity; among these genera, Parabacteroides was related to tryptophan metabolism, axon regeneration, phenylalanine metabolism and tyrosine metabolism.CONCLUSION: Our data highlight the importance of observing the diurnal oscillation of the microbiome in host with depressive-like states. Rhythmicity in the microbiome may affect the host by regulating distinct metabolic pathways during the light and dark phases. A better combination of microbiota composition and oscillation would help to offer novel insight into key genera and their potential effects on depression.PMID:39844033 | DOI:10.1186/s12866-025-03764-4

BMC Genomics. 2025 Jan 22;26(1):63. doi: 10.1186/s12864-025-11258-w.ABSTRACTBACKGROUND: The cryoinjury of semen during cryopreservation reduces sperm motility, constraining the application of artificial insemination (AI) in bovine reproduction. Some fertility markers, related to sperm motility before and after freezing have been identified. However, little is known about the biological mechanism through which freezing reduces sperm motility. This study investigated the selective effects of cryoinjury on high-motility sperm (HMS) and low-motility sperm (LMS) in frozen-thawed from the perspectives of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and ATP levels. The molecular mechanism of decreased sperm motility caused by cryoinjury was explored through a joint analysis of 4D-label free quantitative proteomics and non-targeted metabolomics.RESULTS: The results indicate that low levels of ROS and high degrees of MMP and ATP play a critical role in the survival of HMS during the freezing process. The sperm samples from the frozen-thawed HMS and LMS were analysed for proteomics and metabolomics, 2,465 proteins and 4,135 metabolites were detected in bovine sperm samples. In contrast to LMS, HMS have 106 proteins and 106 metabolites with high abundance expression, and 79 proteins and 223 metabolites with low abundance expression. Proteomics and metabolomics data exhibit that highly expressed antioxidant enzymes and metabolites in HMS can maintain sperm motility by regulating the ROS produced during freezing to prevent sperm from oxidative stress and apoptosis. Furthermore, the KEGG analysis of differential proteins and metabolites during the freezing process implies that the significant enrichment of glycolysis and cAMP in HMS can guarantee energy supply.CONCLUSIONS: The results provided that during the process of bovine sperm freezing, highly expressed antioxidant enzymes can regulate the reactive oxygen species levels to avoid oxidative stress and the glycolysis signalling pathway ensures ATP production can sustain frozen-thawed sperm motility.PMID:39844026 | DOI:10.1186/s12864-025-11258-w

Nature. 2025 Jan 22. doi: 10.1038/s41586-024-08439-0. Online ahead of print.ABSTRACTCancer cells in the tumour microenvironment use various mechanisms to evade the immune system, particularly T cell attack1. For example, metabolic reprogramming in the tumour microenvironment and mitochondrial dysfunction in tumour-infiltrating lymphocytes (TILs) impair antitumour immune responses2-4. However, detailed mechanisms of such processes remain unclear. Here we analyse clinical specimens and identify mitochondrial DNA (mtDNA) mutations in TILs that are shared with cancer cells. Moreover, mitochondria with mtDNA mutations from cancer cells are able to transfer to TILs. Typically, mitochondria in TILs readily undergo mitophagy through reactive oxygen species. However, mitochondria transferred from cancer cells do not undergo mitophagy, which we find is due to mitophagy-inhibitory molecules. These molecules attach to mitochondria and together are transferred to TILs, which results in homoplasmic replacement. T cells that acquire mtDNA mutations from cancer cells exhibit metabolic abnormalities and senescence, with defects in effector functions and memory formation. This in turn leads to impaired antitumour immunity both in vitro and in vivo. Accordingly, the presence of an mtDNA mutation in tumour tissue is a poor prognostic factor for immune checkpoint inhibitors in patients with melanoma or non-small-cell lung cancer. These findings reveal a previously unknown mechanism of cancer immune evasion through mitochondrial transfer and can contribute to the development of future cancer immunotherapies.PMID:39843734 | DOI:10.1038/s41586-024-08439-0

Nat Commun. 2025 Jan 22;16(1):924. doi: 10.1038/s41467-025-56210-4.ABSTRACTPolymeric nanoparticles (NPs) are promising tools used for immunomodulation and drug delivery in various disease contexts. The interaction between NP surfaces and plasma-resident biomolecules results in the formation of a biomolecular corona, which varies patient-to-patient and as a function of disease state. This study investigates how the progression of acute systemic inflammatory disease influences NP corona compositions and the corresponding effects on innate immune cell interactions, phenotypes, and cytokine responses. NP coronas alter cell associations in a disease-dependent manner, induce differential co-stimulatory and co-inhibitory molecule expression, and influence cytokine release. Integrated multi-omics analysis of proteomics, lipidomics, metabolomics, and cytokine datasets highlight a set of differentially enriched TLR4 ligands that correlate with dynamic NP corona-mediated immune activation. Pharmacological inhibition and genetic knockout studies validate that NP coronas mediate this response through TLR4/MyD88/NF-κB signaling. Our findings illuminate the personalized nature of corona formation under a dynamic inflammatory condition and its impact on NP-mediated immune activation profiles and inflammation, suggesting that disease progression-related alterations in plasma composition can manifest in the corona to cause unintended toxicity and altered therapeutic efficacy.PMID:39843415 | DOI:10.1038/s41467-025-56210-4

J Periodontal Res. 2025 Jan 22. doi: 10.1111/jre.13380. Online ahead of print.ABSTRACTAIM: The correlation between periodontitis and colorectal cancer (CRC) has drawn widespread attention. However, how periodontitis affects CRC progression remains unclear.METHODS: C57BL/6 mice were used to establish experimental periodontitis and CRC model. Histological alterations of periodontium and colon were observed by hematoxylin and eosin staining. Micro-computed tomography (micro-CT) was applied to evaluate alveolar bone loss (ABL). Tumor growth was detected by immunofluorescence. Gut bacteria were analyzed using 16S rRNA sequencing. Gas chromatography-mass spectrometry (GC-MS) was performed to observe the alterations of gut microbial metabolites. The detection of associated pathways was carried out using quantitative real-time PCR (qRT-PCR).RESULTS: Experimental periodontitis significantly induced increases in tumor number in mice with CRC. Double immunofluorescence for Ki67 and β-catenin, as well as Cyclin D1 and β-catenin, indicated that experimental periodontitis observably promoted tumor growth. 16S rRNA sequencing and untargeted metabolomics analysis displayed that experimental periodontitis altered gut microbial community and metabolite profiles in CRC mice. Notably, we found that experimental periodontitis dramatically increased the level of three oncometabolites (serotonin, adenosine, and spermine) in mice with CRC.CONCLUSION: Alterations of gut microbial community and metabolites might be relevant in experimental periodontitis deteriorating CRC.PMID:39843386 | DOI:10.1111/jre.13380

Plant Physiol. 2025 Jan 23:kiaf030. doi: 10.1093/plphys/kiaf030. Online ahead of print.ABSTRACTProteins with Toll/interleukin-1 receptor (TIR) domains are widely distributed in both prokaryotes and eukaryotes, serving as essential components of immune signaling. Although monocots lack the major TIR-nucleotide-binding (NB)-leucine-rich repeat (LRR)-type (TNL) immune receptors, they possess a small number of TIR-only proteins, the function of which remains largely unknown. In the monocot maize (Zea mays), there are three conserved TIR-only genes in the reference genome, namely ZmTIR1 to ZmTIR3. A genome-wide scan for TIR genes and comparative analysis revealed that these genes exhibit low sequence diversity and do not show copy number variation among 26 diverse inbred lines. ZmTIR1 and ZmTIR3, but not ZmTIR2, specifically trigger cell death and defense gene expression when overexpressed in Nicotiana benthamiana leaves. These responses depend on the critical glutamic acid and cysteine residues predicted to be essential for TIR-mediated NADase and 2',3'-cAMP/cGMP synthetase activity, respectively, as well as the key TIR downstream regulator Enhanced Disease Susceptibility 1 (EDS1). Overexpression of ZmTIR3 in N. benthamiana produces signaling molecules, including 2'cADPR, 2',3'-cAMP and 2',3'-cGMP, a process that requires the enzymatic glutamic acid and cysteine residues of ZmTIR3. ZmTIR expression in maize is barely detectable under normal conditions, but is substantially induced by different pathogens. Importantly, the maize Zmtir3 knockout mutant exhibits enhanced susceptibility to the fungal pathogen Cochliobolus heterostrophus, highlighting the role of ZmTIR3 in maize immunity. Overall, our results unveil the function of the maize ZmTIRs. We propose that the pathogen-inducible ZmTIRs play an important role in maize immunity, likely through their enzymatic activity and via EDS1-mediated signaling.PMID:39843224 | DOI:10.1093/plphys/kiaf030

Carbohydr Polym. 2025 Mar 15;352:123223. doi: 10.1016/j.carbpol.2025.123223. Epub 2025 Jan 3.ABSTRACTThe extraction of polysaccharides from wood by-products is recognized as a green re-utilization approach to shape a recycling-oriented society. In this research, we identified the structural properties of arabinogalactan (AG) extracted from Larix sibirica Ledeb wood chips and verified its efficacy as an additive in broiler framing. Results showed that the molecular weight of AG is 19.805 KDa. Methylation analysis and NMR spectra indicate that AG has a 1,6-linked Galp backbone, side residues mainly branched at C-1,3,6 on β-D-Galp. The Ara residues were substituted at C-3 of 1,6-linked Galp consisting of α-L-Araf-(1→3)-α-L-Araf-(1 → 3)-α-L-Araf (1→ and α-L-Araf-(1 → 4) β-D-Galp-(1 → 3)-β-D-Galp-(1→. As a dietary supplement in broiler model, AG treatment improved the body weight of broilers especially breast and leg muscle weight. Furthermore, AG could regulate host immune response, gut microbiota composition, and metabolic activity, especially promoting lipid metabolism. By means of serum non-targeted metabolomics analysis, enrichment of pantothenate and CoA biosynthesis and beta-alanine metabolism pathways could be determined. AG treatment led to a rise in bacteria that produce SCFAs, with elevated concentrations of acetic and butyric acids. In conclusion, AG can be considered as a potential dietary supplement to beneficially affect host's health status.PMID:39843118 | DOI:10.1016/j.carbpol.2025.123223

Adv Nutr. 2025 Jan 20:100378. doi: 10.1016/j.advnut.2025.100378. Online ahead of print.ABSTRACTManaging diabetes in patients on peritoneal dialysis (PD) is challenging due to the combined effects of dietary glucose, glucose from dialysate, and other medical complications. Advances in technology that enable continuous biological data collection are transforming traditional management approaches. This review explores how multi-omics technologies and artificial intelligence (AI) are enhancing glucose management in this patient population. Continuous glucose monitoring (CGM) offers significant advantages over traditional markers like hemoglobin A1c (HbA1c). Unlike HbA1c, which reflects an average glucose level, CGM provides real-time, dynamic glucose data that allow clinicians to make timely adjustments, leading to better glycemic control and outcomes. Multi-omics approaches are valuable for understanding genetic factors that influence susceptibility to diabetic complications, particularly those related to advanced glycation end-products (AGEs). Identifying genetic polymorphisms that modify a patient's response to AGEs allows for personalized treatments, potentially reducing the severity of diabetes-related pathologies. Metabolomic analyses of peritoneal dialysis effluent are also promising, as they help identify early biomarkers of metabolic dysregulation. Early detection can lead to timely interventions and more tailored treatment strategies, improving long-term patient care. AI integration is revolutionizing diabetes management for PD patients by processing vast datasets from CGM, genetic, metabolic and microbiome profiles. AI can identify patterns and predict outcomes that may be difficult for humans to detect, enabling highly personalized recommendations for diet, medication, and dialysis management. Furthermore, AI can assist clinicians by automating data interpretation, improving treatment plans and enhancing patient education. Despite the promise of these technologies, there are limitations. CGM, multi-omics and AI require significant investment in infrastructure, training and validation studies. Additionally, integrating these approaches into clinical practice presents logistical and financial challenges. Nevertheless, personalized, data-driven strategies offer great potential for improving outcomes in diabetes management for PD patients.PMID:39842720 | DOI:10.1016/j.advnut.2025.100378

Fish Shellfish Immunol. 2025 Jan 20:110150. doi: 10.1016/j.fsi.2025.110150. Online ahead of print.ABSTRACTSexual dimorphism is well-documented in aquaculture, particularly regarding growth differences, wherein one sex often grows faster than the other. However, despite the phenomenon being so widely documented, its underlying molecular mechanisms remain poorly understood. As an important digestive and immune organ, the gut plays key roles in the regulation of fish growth. In this study, we conducted RNA-seq and metabolomic analysis on the gut of female and male common carp. We discovered that growth-related pathways, such as "Glycolysis/Gluconeogenesis" and "Riboflavin metabolism" are significantly enriched in the gut of female carp. Conversely, pathways linked to disease resistance, such as "Th17 cell differentiation" and "Autophagy-animal" are predominantly enriched in male carp. Following intraperitoneal injection of spring viraemia of carp virus (SVCV) into both male and female carp, quantitative reverse transcription polymerase chain reaction (RT-qPCR) analysis and histopathological staining confirmed that male carp exhibit greater disease resistance compared to females. This study identified the disease resistance dimorphism in common carp and specific mechanisms underlying growth differences. Our findings offer valuable insights for the application of growth dimorphism and disease-resistant breeding in fish.PMID:39842680 | DOI:10.1016/j.fsi.2025.110150

Cell Signal. 2025 Jan 20:111620. doi: 10.1016/j.cellsig.2025.111620. Online ahead of print.ABSTRACTCetuximab resistance is a significant challenge in the treatment of head and neck squamous cell carcinoma (HNSCC). In this study, cetuximab-resistant HNSCC cell lines were established, and untargeted metabolomics was used to detect differences in metabolite profiles between sensitive and resistant cell lines. It was found that glutathione metabolism significantly differed between the sensitive and resistant lines. Combining these findings with transcriptome data, correlation analysis of metabolites revealed that IDH2 regulated glutathione metabolism and contributed to cetuximab resistance in FaDu cells. In vitro experiments showed that IDH2 was highly expressed in FaDu-CR cells, and IDH2 knockdown significantly enhanced the sensitivity of FaDu and FaDu-CR cells to cetuximab. IDH2 knockdown reduced GSH levels and GPX4 expression in FaDu and FaDu-CR cells under cetuximab treatment, while increasing lipid ROS levels. In vivo experiments demonstrated that IDH2 knockdown decreased the tumorigenic ability of FaDu-CR cells in nude mice treated with cetuximab, as well as reduced GPX4 and Ki67 levels in tumor tissues. In conclusion, IDH2 regulated glutathione metabolism and contributed to cetuximab resistance in HNSCC. This study explores strategies to ameliorate cetuximab resistance in HNSCC preclinical models, providing new insights for reversing cetuximab resistance in HNSCC.PMID:39842530 | DOI:10.1016/j.cellsig.2025.111620

Biochim Biophys Acta Mol Cell Biol Lipids. 2025 Jan 20:159595. doi: 10.1016/j.bbalip.2025.159595. Online ahead of print.ABSTRACTTerahertz (THz) radiation has gained attention due to technological advancements, but its biological effects remain unclear. We investigated the impact of 2.3 THz radiation on SK-MEL-28 cells using metabolomic and gene network analysis. Forty metabolites, primarily related to purine, pyrimidine synthesis and breakdown pathways, were significantly altered post-irradiation. Lipids, such as ceramides and phosphatidylcholines, were also affected. Gene network reconstruction and analysis identified key regulators of the enzymes involved in biosynthesis and degradation of significantly altered metabolites. Mitochondrial membrane components, such as the respiratory chain complex, the proton-transporting ATP synthase complex, and components of lipid rafts, reacted to THz radiation. We propose that THz radiation induces reversible disruption of the lipid raft macromolecular structure, thereby altering mitochondrial molecule transport while maintaining protein integrity, which explains the high cell survival rate. Our findings enhance the understanding of THz biological effects and emphasize the role of membrane components in the cellular response to THz radiation.PMID:39842507 | DOI:10.1016/j.bbalip.2025.159595

Toxicology. 2025 Jan 21;511:154063. doi: 10.1016/j.tox.2025.154063. Online ahead of print.ABSTRACTImidacloprid (IMI) and cadmium (Cd) have been shown to be harmful to mammals separately, but their combined toxicity to mammals remains largely unknown. In this study, biochemical analysis (oxidative stress and serum indicators of liver and kidney function), pathological sections and multiomics (metabolomics and transcriptomics) methods were used to investigate the changes and mechanisms of liver and kidney in mice coexposed to IMI and Cd. Biochemical analysis and pathological section results showed that oxidative stress, organ function, and cell damage were aggravated after the combination of the two methods. Omics results revealed the following mechanism: When mouse liver and kidney cells were threatened by the external environment, mitochondrial DNA was inhibited, which leads to changes in energy metabolism. In this process, lipid metabolism and amino acid metabolism were disordered, resulting in the inhibition of substances related to lipid metabolism and amino acid metabolism that protect the body from oxidative damage, and then showed more serious liver and kidney oxidative stress and liver and kidney function and cell damage. This research offers novel insights for the assessment of the safety profile associated with the concurrent exposure of the two chemicals in mammalian species.PMID:39842396 | DOI:10.1016/j.tox.2025.154063