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PubMed2026

Integrative computational analysis combining network pharmacology, regulatory network modeling, and molecular dynamics reveals the mechanisms of Quanshen compound in ITP.

UNLABELLED: Immune thrombocytopenia (ITP) is a hemorrhagic disorder caused by immune dysfunction. Quanshen Compound (QSC) is an in-house preparation developed by the Uyghur Hospital in Hotan Prefecture. This study primarily investigates and validates the potential pharmacological basis and mechanism of action of QSC in modulating immune thrombopoiesis. Based on the multi-database screening of the QSC and the related targets of ITP, the intersection was obtained to construct a protein-protein interaction (PPI) network and screen the core targets; the intersection targets were analyzed for gene ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using R packages; a component-target-pathway network was constructed to screen the key active components and their mechanisms of action. At the same time, the TF-mRNA-miRNA regulatory network of the core targets was constructed, and chromosome localization and subcellular localization analysis were performed; further, the binding stability of key components and core targets was verified through molecular docking and molecular dynamics simulation. A total of 227 potential target sites were screened out, among which TNF, IL6, AKT1, TP53 and IL1B were the core targets. The enrichment results indicated that these intersecting target sites mainly participated in inflammatory responses, immune regulation and hemostasis-related biological processes, and were significantly enriched in the PI3K-Akt signaling pathway, Toll-like receptor signaling pathway, Th17 cell differentiation and PD-1/PD-L1 signaling pathway. The core target TF-mRNA-miRNA regulatory network contained 184 nodes and 200 edges, suggesting that the core targets were subject to multi-level regulation. Molecular docking results showed that the main active components had good binding activity with the core targets, and molecular dynamics simulation further verified the stability of the complex. QSC may improve ITP through a multi-component, multi-target, and multi-pathway synergistic mechanism involving key targets such as TNF, IL6, AKT1, TP53, and IL1B, as well as the PI3K-Akt signaling pathway. These findings provide new insights into the potential therapeutic mechanisms of QSC against ITP and warrant further experimental validation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00718-0.

Immune thrombocytopenia↗

PubMed2026

Firemaster 550 differentially alters gene expression underlying synaptic function in amygdala of prairie voles after gestational or lactational exposure.

Neurodevelopmental disorders often share similar behavioral diagnostic criteria including socioemotional and cognitive deficits. The prairie vole is a uniquely suitable model to study these deficits because they demonstrate strong social affiliation, bi-parental care, and partner attachment. Previously, we have shown that developmental exposure to the flame-retardant mixture Firemaster 550 (FM 550) impairs socioemotional behavior in the prairie vole and alters underlying neuroanatomy and function. However, the mechanisms for impaired pair bonding in males and increased anxiety in females remain unknown, along with the specific critical window(s) of vulnerability. Herein, we exposed prairie vole dams to FM 550 during gestation or lactation, and performed bulk RNA-seq on the amygdala, a hub of socioemotional processing, in their adult offspring. Two mathematically orthogonal methods were utilized for analysis, a linear statistical method and an ensemble machine learning method, incorporating sex as a biological variable. Gene ontology (GO) pathway analysis was performed following both and results compared to identify potential mechanisms of toxicity. GO results indicated consistent expression changes in the Synapse cellular component in all conditions, and implicated glutamatergic signaling specifically. Additionally, gestational exposure (GE) altered genes underlying modulation of synaptic transmission and neural development, while lactational exposure (LE) impacted genes underlying synaptic plasticity, axon guidance, and mitophagy. Machine learning identified disruption of endocrine system development, regulation of biosynthetic processes in GE animals, and suppression of various neuroinflammatory genes across multiple groups. Finally, we performed RNA expression analysis using Nanostring and demonstrated stronger correlation with the differentially expressed genes (DEG) of interest in females than males. Overall, this study demonstrates both the intersecting and distinct impacts of FM 550 exposure on amygdalar gene expression depending on sex and timing of exposure.

Animals↗

PubMed1984

Mechanisms in the development of retinotectal projections in the chick embryo studied by surgical deflection of the retinal pathway.

Retinotopic analysis of the pathways of normal and aberrant retinal axons within the tectum of developing chick embryos was performed by selective labeling of retinal axons with a fluorescent dye, rhodamine-B isothiocyanate. To produce aberrant retinal axons, the presumptive optic chiasma was surgically disorganized at the 3rd day of incubation. At the 11th and 13th days of incubation, more than half of the operated embryos exhibited several aberrant retinal axons which reached ectopic parts of the tectum. The pathways of these aberrant axons within the tectum depended on the position of their initial invasion into the tectum at the diencephalotectal junction, and not on their position of origin within the retina. The aberrant retinal axons did not show any sign of correction of their pathways toward their normal sites of innervation within the tectum. As development proceeded, elimination of the aberrant retinal axons occurred. By the 16th day of incubation, almost all operated embryos lacked aberrant retinal axons and although the total number of axons often appeared reduced, a nearly normal topography of retinotectal projections was established. These findings indicate that the initial invasion of the retinal axons into the tectum is conducted predominantly by nonspecific mechanisms and, thereafter, a selective maintenance of appropriate retinal axons occurs.

Animals↗

PubMed2024

A lipidomic study on the lens epithelial cells of patients with age related cataracts.

Age related cataracts (ARC) represent the main reason for blindness globally. The lens epithelial cells (LECs) participate not only in the metabolism of many substances in the lens but also in maintaining lens transparency. This study used lipidomics to investigate the metabolic differences in LECs of ARC patients with different severity, aiming at identifying potential metabolic biomarkers of ARC. Patients diagnosed with ARC and underwent cataract surgery at Shanghai Tongren Hospital were selected to participate in this study, which were classified as mild ARC group and severe ARC group. During their cataract surgery, anterior lens capsules(LCs) containing LECs were obtained. The lipidomics of LECs were analyzed using the liquid chromatography‑mass spectrometry (LC-MS). Potential pathways of lipids were searched for using databases such as the Kyoto Encyclopedia of Genes and Genomes (KEGG) and MetaboAnalyst platform. In LEC lipids, 26 lipids have been identified as potential biomarkers between mild ARC and severe ARC, with AUC values of 0.67-0.94. The pathway analysis results revealed that the Glycerophospholipid (GPL) metabolism was significantly influenced, indicating that these metabolic markers contribute significantly to regulating this pathway. The LEC metabolic spectrum demonstrates a proficient ability to differentiate between patients with varying levels of cataracts. Herein, we have successfully identified potential metabolic biomarkers and pathways that have proven to be valuable in enhancing our understanding of ARC pathogenesis. The finding has translational value for developing new cataract treatment methods in the future.

Humans↗

PubMed1986

Characterization of retrograde conduction by direct endocardial recording from an accessory atrioventricular pathway.

Accessory pathway electrograms are rarely recorded in patients with Wolff-Parkinson-White syndrome. In one patient, during electrophysiologic study, simultaneous local ventricular (V) accessory pathway (AP) and atrial (A) deflections were recorded during bipolar catheter endocardial mapping over the pathway. Analysis of changes in electrographic intervals during performance of the ventricular extrastimulus technique allowed characterization of the retrograde conduction properties of the pathway. As coupling intervals were decreased, an initial increase was seen in the AP2A2 interval with subsequent ventriculoatrial block between the accessory pathway and atrium. When coupling intervals were further decreased, the V2AP2 interval lengthened with ultimate block between the ventricle and accessory pathway. These findings support the concept of impedance mismatch as the cause of conduction block in accessory pathways with the distal junction of the accessory pathway being the most vulnerable.

Adult↗

PubMed1999

Vertebrate homologs of Drosophila suppressor of fused interact with the gli family of transcriptional regulators.

The hedgehog (Hh) signaling pathway is crucial for pattern formation during metazoan development. Although originially characterized in Drosophila, vertebrate homologs have been identified for several, but not all, genes in the pathway. Analysis of mutants in Drosophila demonstrates that Suppressor of fused [Su(fu)] interacts genetically with genes encoding proteins in the Hh signal transduction pathway, and its protein product physically interacts with two of the proteins in the Hh pathway. We report here the molecular cloning and characterization of chicken and mouse homologs of Su(fu). The chick and mouse proteins are 27% identical and 53% similar at the amino acid level to the Drosophila melanogaster and Drosophila virilis proteins. Vertebrate Su(fu) is widely expressed in the developing embryo with higher levels in tissues that are known to be patterned by Hh signaling. The chick Su(fu) protein can physically interact with factors known to function in Hh signal transduction including the Drosophila serine/threonine kinase, Fused, and the vertebrate transcriptional regulators Gli1 and Gli3. This interaction may be significant for transcriptional regulation, as recombinant Su(fu) enhances the ability of Gli proteins to bind DNA in electrophoretic mobility shift assays.

Amino Acid Sequence↗

PubMed2000

Regulators of cell death in disease resistance.

Cell death and disease resistance are intimately connected in plants. Plant disease resistance genes (R genes) are key components in pathogen perception and have a potential to activate cell death pathways. Analysis of R proteins suggests common molecular mechanisms for pathogen recognition and signal emission whereas the subsequent signalling unexpectedly involves a network of pathways of parallel, branching and converging action. Disease resistance signalling mutants have revealed novel types of regulatory proteins whose biochemical functions are still unknown. Accumulation of small molecules such as salicylic acid, reactive oxygen intermediates, and nitric oxide amplifies resistance responses and directs cells to initiate cell death programs. Genetic analyses of lesion mimic mutants provide a glimpse of how cell death thresholds are set via an interplay of positive and negative regulatory components.

Apoptosis↗

PubMed2026

Proteomics profiling of serum and liver in GSD Ia and Ib patients: insights into complication mechanisms and circulation biomarkers.

BACKGROUND: Glycogen Storage Disease (GSD) Types Ia and Ib are rare metabolic diseases caused by gene variants in G6PC1 and SLC37A4, respectively. Although life-threatening fasting hypoglycemia can be controlled by a strict diet, patients often suffer from multiple metabolic abnormalities and severe long-term complications. However, the underlying mechanisms remain incompletely understood, and there is a lack of effective monitoring biomarkers. Therefore, the aims of this study are to investigate the pathological mechanisms of the disease and disease complications in GSD I and identify potential protein biomarkers. METHODS: Comprehensive untargeted proteomics was performed on 18 GSD Ia and 8 GSD Ib sera samples from patients with 21 matched control sera, complemented by liver 3 GSD Ia samples and 1 GSD Ib sample from patient liver tissues, compared to 10 donor liver samples. RESULTS: We identified 415 proteins in total. Significantly changed (FDR < 0.05) were observed in 158 (38%) proteins for GSD Ia vs Control, 116 (28%) for GSD Ib vs. Control, and 151 (36%) for GSD Ia vs. Ib. Pathway analysis revealed distinct alterations in serum/plasma, with 58, 32, and 29 significantly changed biological processes (FDR < 0.05) in these three comparisons, respectively. The coagulation pathway was the most significantly changed one in the GSD Ia patients. Immune response-associated proteins, especially immunoglobulins, were increased in GSD Ib specifically. Proteins related to liver injury, cholesterol, and amyloidosis were altered in two subtypes, though more pronounced in GSD Ia. Potential biomarkers with significant alterations both in the circulation and in the liver tissue were identified specifically for monitoring GSD I subtypes and prognosing liver deterioration, namely APOC1 and CD5L to distinguish between GSD Ia and Ib and ALDOB for the presence of hepatocellular carcinoma (HCC) in GSD Ia patients. CONCLUSIONS: These findings provide new insights into the differences between the two GSD I subtypes and the pathogenesis of GSD I-related complications, as well as highlighting the potential of protein circulating biomarkers for monitoring complication progression in GSD I and assessing HCC risk in GSD Ia patients.

Humans↗

PubMed2014

Persistent inflammation, immunosuppression, and catabolism syndrome after severe blunt trauma.

BACKGROUND: We recently proffered that a new syndrome persistent inflammation, immunosuppression, and catabolism syndrome (PICS) has replaced late multiple-organ failure as a predominant phenotype of chronic critical illness. Our goal was to validate this by determining whether severely injured trauma patients with complicated outcomes have evidence of PICS at the genomic level. METHODS: We performed a secondary analysis of the Inflammation and Host Response to Injury database of adults with severe blunt trauma. Patients were classified into complicated, intermediate, and uncomplicated clinical trajectories. Existing genomic microarray data were compared between cohorts using Ingenuity Pathways Analysis. Epidemiologic data and outcomes were also analyzed between cohorts on admission, Day 7, and Day 14. RESULTS: Complicated patients were older, were sicker, and required increased ventilator days compared with the intermediate/uncomplicated patients. They also had persistent leukocytosis as well as low lymphocyte and albumin levels compared with uncomplicated patients. Total white blood cell leukocyte analysis in complicated patients showed that overall genome-wide expression patterns and those patterns on Days 7 and 14 were more aberrant from control subjects than were patterns from uncomplicated patients. Complicated patients also had significant down-regulation of adaptive immunity and up-regulation of inflammatory genes on Days 7 and 14 (vs. magnitude in fold change compared with control and in magnitude compared with uncomplicated patients). On Day 7, complicated patients had significant changes in functional pathways involved in the suppression of myeloid cell differentiation, increased inflammation, decreased chemotaxis, and defective innate immunity compared with uncomplicated patients and controls. Subset analysis of monocyte, neutrophil, and T-cells supported these findings. CONCLUSION: Genomic analysis of patients with complicated clinical outcomes exhibit persistent genomic expression changes consistent with defects in the adaptive immune response and increased inflammation. Clinical data showed persistent inflammation, immunosuppression, and protein depletion. Overall, the data support the hypothesis that patients with complicated clinical outcomes are exhibiting PICS. LEVEL OF EVIDENCE: Epidemiologic study, level III.

Adolescent↗

PubMed2026

Integrative multi-omics analysis unravels the metabolic landscape and reveals serum biomarkers for early diagnosis of hyperuricemia.

BACKGROUND: Hyperuricemia (HUA) is a major risk factor for gout and multiple metabolic disorders. Although serum uric acid (UA) is the gold standard for HUA diagnosis, it fails to reflect early metabolic disturbances and shows limited predictive value for asymptomatic HUA. This study sought to elucidate the pathological mechanisms underlying HUA and identify novel diagnostic biomarkers beyond UA. METHODS: This study enrolled 195 patients with HUA and 98 healthy controls. Global metabolomics and proteomics profiling were performed to characterize molecular alterations underlying HUA. Based on the biological relevance of the shared dysregulated pathways, a pathway correlation network was constructed to elucidate the pathological mechanisms driving HUA initiation and progression. Furthermore, diagnostic biomarkers for HUA were identified using machine learning algorithms, and were validated with an external cohort. RESULTS: HUA patients exhibited distinct metabolic and proteomic profiles compared with healthy controls. Integrated multi-omics pathway analysis revealed that peroxisome proliferators-activated receptor signaling pathway, arachidonic acid metabolism, purine metabolism, pyrimidine metabolism and sphingolipid signaling pathway were significantly dysregulated in HUA. Among them, arachidonic acid metabolism was identified as a hub pathway involved in HUA progression. Furthermore, a metabolite panel consisting of cysteine-S-sulfate, glycerophosphocholine and 4-hydroxyphenylpyruvic acid was screened by machine learning and validated in an independent cohort, which showed slightly higher diagnostic performance for HUA than UA. CONCLUSIONS: This study reveals the core metabolic and protein regulatory networks of HUA, and identifies a novel serum metabolite panel for the diagnosis of HUA. These findings provide new insights for improved clinical diagnosis and management.

Humans↗

PubMed2026

Parallel single-cell host immune profiling and pathogen genomic characterization in Klebsiella-associated sepsis: a pilot study.

OBJECTIVES: Sepsis is a life-threatening syndrome characterized by profound immune dysregulation and substantial biological heterogeneity. Here, we conducted a pilot study to explore host immune remodeling in Klebsiella-associated sepsis by combining single-cell RNA sequencing of peripheral blood mononuclear cells with whole-genome sequencing of the corresponding bloodstream isolates. METHODS: In this prospective observational pilot study, we analyzed peripheral blood mononuclear cells (PBMCs) from two patients with Klebsiella-associated sepsis and two healthy controls (HC) using single-cell RNA sequencing. PBMC composition, differential transcriptional responses, and pathway analysis were assessed across immune subsets. The corresponding bloodstream isolates were characterized by phenotypic antimicrobial susceptibility testing and whole-genome sequencing. RESULTS: Compared to HC, septic patients showed expansion of the myeloid compartment and contraction of the NK/T compartment. High-resolution analysis suggested shifts within lymphoid populations. At the transcriptional level, sepsis was associated with compartment-specific enrichment of interferon-related and host-defence pathways, as well as oxidative phosphorylation, ATP synthesis, and mitochondrial electron transport signatures across multiple PBMC subsets. Classical monocytes exhibited a coordinated decrease in MHC class II-related transcripts. The sepsis-associated isolates were identified as Klebsiella pneumoniae and Klebsiella variicola and were notable for overall antimicrobial susceptibility, limited resistomes, and absence of canonical hypervirulence determinants. CONCLUSION: Our data provide a preliminary description of immune remodeling during Klebsiella-associated sepsis and suggest that severe clinical disease may be associated with isolates lacking classical multidrug-resistance or hypervirulence features. These findings should be interpreted as preliminary and hypothesis-generating and require validation in larger cohorts with detailed clinical severity assessment.

Female↗

PubMed2025

Sex differences in cerebrospinal fluid proteomics of patients with restless legs syndrome.

STUDY OBJECTIVES: The pathobiology of restless legs syndrome (RLS) remains poorly understood, complicating effective treatment. This observational cross-sectional study aimed to identify a cerebrospinal fluid proteomic signature of RLS and to explore sex-specific differences in cerebrospinal fluid proteomics. METHODS: Cerebrospinal fluid samples were collected from 22 untreated RLS patients and 18 controls, matched for age, body mass index, and sex. Proteomic analysis was conducted using the SOMAscan platform, assessing over 7000 peptides. RESULTS: Eight proteins were differentially abundant between patients and controls, with CRP and JAML increased, and TAPBPL and IL1RL1 decreased. Pathway analysis highlighted significant involvement in immune response, coagulation, and cytoskeletal regulation. Analyses were then carried out using sex stratification, comparing men and women separately. Sex-specific analyses revealed more pronounced proteomic alterations in males (68 differentially abundant proteins vs. control males) than in females (17 proteins). Gene enrichment analysis revealed that men with RLS had more involvement in gene regulation and epigenetic factors than control males and women with restless legs syndrome had greater involvement in systemic inflammatory and vascular processes than control females. CONCLUSIONS: This study identified a cerebrospinal fluid proteomic signature in RLS, implicating immune and inflammatory pathways in the disease's pathophysiology. Significant sex differences in protein level suggest potential sex-specific mechanisms in RLS, warranting further investigation. These findings contribute to the current understanding of RLS and could inform future therapeutic strategies.

Humans↗

PubMed2000

Mosaicism in the alpha-like protein genes of group B streptococci.

Members of a family of repeat-containing surface proteins of group B streptococci (GBS) defined by the alpha C and Rib proteins exhibit size variability and cross-reactivity and have been studied as potential vaccine components. We report evidence of horizontal DNA transfer with subsequent recombination as a mechanism generating diversity within this antigen family. Alp2 and Alp3 are additional members of the alpha C protein family identified in strains of the emerging GBS serotypes V and VIII. Each contains an overall genetic organization highly similar to that of the alpha C and Rib proteins, including a tandem repeat region and conserved N- and C-terminal regions. Among different strains, protein size varies according to the number of tandem repeats within the corresponding gene. Unlike the alpha C and Rib proteins, however, the newly described alpha-like proteins contain other regions, including one similar to the IgA-binding region of the GBS beta C protein, a nontandem repeat region, and an isolated repeat highly homologous to the alpha C repeat. Sequence analysis of the regions flanking the alpha C protein gene on a 13.7-kb insert reveals several ORFs that are likely to be involved in basic metabolic pathways. Analysis of corresponding flanking regions in other GBS strains, including the parent strains of the newly described alpha-like proteins, shows striking conservation among all strains studied. These findings indicate that the alpha-like proteins are encoded by mosaic variants at a single genomic locus and suggest that recombination after horizontal DNA transfer is a means of generating diversity within this protein family.

Amino Acid Sequence↗

PubMed2026

Admission whole-blood transcriptomic characterization of a neutrophil-predominant systemic immune response in patients with acute traumatic brain injury.

BACKGROUND: Acute traumatic brain injury (TBI) is accompanied by systemic immune responses, but their whole-blood transcriptomic features at hospital arrival remain incompletely characterized. We aimed to characterize these features in patients with acute TBI compared with healthy controls. METHODS: In this single-center prospective observational study, we performed whole-blood RNA sequencing on hospital-arrival samples from 42 patients with acute TBI and 21 healthy controls. Analyses included differential expression (limma-voom; FDR < 0.05, |log2FC| > 0.7), functional enrichment, Ingenuity Pathway Analysis, CIBERSORTx LM22 deconvolution, and per-sample neutrophil degranulation signature scoring. RESULTS: Differential expression analysis identified 996 upregulated and 863 downregulated genes, with marked upregulation of inflammation-, innate immunity-, and neutrophil-related genes including DUSP1, HMGB2, MMP9, and S100A8. Canonical pathways with positive IPA z-scores included Neutrophil degranulation, Neutrophil Extracellular Trap Signaling Pathway, and Toll-like Receptor Signaling; upstream regulators included TNF, IL1B, IFNG, and STAT3. Deconvolution identified 7 of 22 differing subsets (q < 0.05), with relatively higher myeloid and lower lymphoid fractions in TBI. The Neutrophil degranulation signature score correlated with Injury Severity Score within TBI (Spearman ρ = +0.55; q < 0.001). CONCLUSIONS: Admission whole-blood transcriptomics characterized a neutrophil-predominant systemic transcriptional response in patients with acute TBI. This response was also evident among patients without major extracranial injury and was associated with total ISS. However, because the study lacked an appropriately matched non-TBI trauma comparator, the findings should be interpreted as a descriptive characterization of a systemic injury response accompanying TBI and do not establish a TBI-specific molecular signature or mechanism.

gene expression↗

PubMed2024

S100A9 induces tissue remodeling of human nasal epithelium in chronic rhinosinusitis with nasal polyp.

BACKGROUND: Chronic inflammation triggers tissue remodeling in human nasal epithelial (HNE) cells. S100A9, a protein secreted by inflammatory cells, exhibits potent proinflammatory activity. However, its effect on HNE cell remodeling, such as squamous metaplasia, remains unclear. Therefore, this study aimed to determine the effects and underlying pathways of S100A9 on HNE cell remodeling and investigate its clinical implications in chronic rhinosinusitis (CRS). METHODS: Cultured HNE cells were treated with S100A9. Bulk RNA sequencing was performed to analyze gene ontology (GO). Ingenuity pathway analysis (IPA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were also analyzed. Additionally, immunohistochemistry and multiplex immunofluorescence were performed on tissue samples obtained from 60 patients, whose clinical informations were also reviewed. RESULTS: GO enrichment analysis indicated that S100A9 induced tissue remodeling in HNE cells toward squamous metaplasia. IPA and KEGG commonly showed that S100A9 affected HNE cells associated with the IL-17 signaling pathway, including target molecules such as matrix metalloproteinase 1 (MMP1) and small proline-rich protein 2A (SPRR2A). Squamous metaplasia with a marked expression of S100A9 was observed in 50% of CRS with nasal polyps (CRSwNPs). In addition, in multiplex immunofluorescence, the S100A9 in sub-epithelium was co-expressed with myeloperoxidase, a neutrophil marker, and MMP1 and SPRR2A were strongly expressed in epithelial remodeling. Clinically, the expression of S100A9 correlated with sino-nasal outcome test-22 (r = 0.294, p = 0.022) and Lund-Mackay scores (r = 0.348, p = 0.006). CONCLUSION: S100A9 induces tissue remodeling in HNE cells. Its increased expression in CRSwNP, particularly squamous epithelium, correlates with disease severity. This suggests the clinical potential of S100A9 as a biomarker for CRS severity.

Humans↗

PubMed2026

11-O-galloylbergenin alleviates LPS-stimulated inflammation in RAW 264.7 macrophages by targeting Grb2, RhoA, and Cdc42 in the RAS signaling pathway.

OBJECTIVE: This study aimed to explore the anti-inflammatory mechanism of 11-O-galloylbergenin in macrophages. METHODS: Lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages were treated with 11-O-galloylbergenin. Cytotoxicity was assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and cytokine secretion was measured by enzyme-linked immunosorbent (ELISA) assay. Data-independent acquisition (DIA)-based proteomics, Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, western blotting, and molecular docking were also performed. RESULTS: 11-O-Galloylbergenin (≤50 μg/mL) was non-cytotoxic and significantly suppressed tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) secretion. Proteomics analysis identified 209 differentially expressed proteins (DEPs) that showed opposite expression trends before and after 11-O-galloylbergenin treatment. Seven of these DEPs were enriched in the RAS pathway: RhoA, Cdc42, Grb2, RalB, Calm3, Gnb2, and Pla2g4a. Western blotting confirmed that 11-O-galloylbergenin downregulated RhoA, Cdc42, and Grb2 expression. Molecular docking revealed good binding affinity of 11-O-galloylbergenin to RhoA, Cdc42, and Grb2. CONCLUSION: 11-O-Galloylbergenin alleviates LPS-stimulated inflammation in RAW 264.7 macrophages by inhibiting the RAS signaling pathway.

Animals↗

PubMed2025

PhIP-Seq uncovers marked heterogeneity in acute rheumatic fever autoantibodies.

Acute rheumatic fever (ARF) and associated rheumatic heart disease are serious sequelae after infection with group A Streptococcus (Strep A). Autoantibodies are thought to contribute to pathogenesis, with deeper exploration of the autoantibody repertoire needed to improve mechanistic understanding and identify new biomarkers. Phage immunoprecipitation sequencing (PhIP-Seq) with the HuScan library (>250,000 overlapping 90-mer peptides spanning the human proteome) was utilized to analyze autoreactivity in sera from children with ARF, uncomplicated Strep A pharyngitis, and matched healthy controls. A global proteome-wide increase in autoantigen reactivity was observed in ARF, as was marked heterogeneity between patients. Public epitopes, common between individuals with ARF were rare, and comprised less than 1% of all enriched peptides. Differential analysis identified both unknown and previously identified ARF autoantigens, including PPP1R12B, a myosin phosphatase complex regulatory subunit expressed in cardiac muscle, and members of the collagen protein family, respectively. Pathway analysis found antigens from the disease-relevant processes encompassing sarcomere and heart morphogenesis were targeted. In sum, PhIP-Seq has substantially expanded the spectrum of autoantigens in ARF, and reveals the rarity of public epitopes in the disease. It provides further support for the role of epitope spreading in pathogenesis and has identified PPP1R12B as an enriched autoantigen.

Humans↗

PubMed2026

Multi-omics revealed the effects of rumen to blood path on early lactation performance in transition dairy cows.

BACKGROUND: The transition period is vitally important to the life cycle of dairy cows. However, the function of the microbiota during both pre- and post-partum and their relationship with ruminal, plasma, and milk metabolites still require systematic investigation. To address this, the 7 highest- and 7 lowest-performing animals among a cohort of 100 dairy cows were selected based on their postpartum energy-corrected milk yield. Rumen fluid and plasma samples were collected during both pre- and post-partum periods, whereas milk samples were obtained postpartum. Shotgun metagenomics of rumen contents in addition to metabolomics of rumen, plasma, and milk samples were performed to evaluate the associations between ruminal microbes and early lactation performance in transition dairy cows. RESULTS: Compared with prepartum cows, postpartum high-yield cows had greater concentrations of ruminal volatile fatty acids and plasma total bile acid. Moreover, plasma urea nitrogen and most amino acids, peptides, and their derivatives in plasma and milk were increased in postpartum high-yield cows, relative to postpartum low-yield cows. Metagenomic analysis revealed that the relative abundances of several species within the Prevotella, Succinimonas, Succinatimonas, and Methanosphaera increased, while other bacteria belong to Alistipes and Bacteroides, and archaeal Methanobrevibacter species decreased in postpartum cows, particularly in postpartum high-yield cows. Co-occurrence network and correlation analysis suggested that Prevotella and Succinatimonas were negatively correlated to Alistipes, Bacteroides, and Methanobrevibacter, potentially contributing to the nutritionally efficient phenotype of postpartum high-yield cows. A metabolic pathway analysis of our metagenomic data revealed that postpartum high-yield cows possessed more microbial genes involved in starch utilization and amino acid synthesis, while a wide range of microbial genes involved in cellulose utilization, acetogenesis, and amino acid degradation were found in prepartum cows with low-yield in postpartum. A structural equation model analysis showed that the increased relative abundances of Prevotella tf.2-5 and Succinatimonas CAG_777 were related to greater concentrations of plasma chenodeoxycholic acid glycine conjugate, milk 5-Methoxytryptophan, and energy-corrected milk yield. Finally, pan-genomic analysis confirmed that Alistipes, Bacteroides, and Methanobrevibacter possess genetic conservation of both hydrogenases and dehydrogenases, which may contribute to energy loss in the rumen via hydrogen dissipation. CONCLUSION: In summary, our findings provide a fundamental understanding of how microbiome-dependent mechanisms contribute to early lactation performance in dairy cows during the transition period. The increased abundance of Prevotella, Succinimonas, and Succinatimonas in postpartum cows suggest that they are important microbes during the transition period and may help in coping with metabolic challenges, while improving nutrient utilization efficiency during this period. Our study underscores the importance of the ruminal microbiome during the transition period and highlights the need for rumen-based nutritional intervention strategies to improve production efficiency in ruminants. Video Abstract.

Animals↗