Jianpi-huayu Decotion regulates TREM1/DAP12 pathway to improve the immunosuppressive tumor microenvironment and enhance the anti-hepatocellular carcinoma effect of PD-1 inhibitors.

This study evaluated the effects of dietary supplementation with different levels of Spirulina platensis (SP) on laying performance, immune response, serum fatty acid profile of laying hens and SP's in vitro antioxidant capacity. About 160 hens were assigned to four dietary treatments: control (0) and SP-supplemented diets (1.5, 3, and 4.5g/kg diet). Supplementation with SP showed notable, significant positive effects on laying rate (92.9-94.5%), egg weight (62.2-67.1g), egg mass, yolk color, shell quality traits, and feed conversion ratio compared to the control group (P < 0.05). SP supplementation also enhanced the humoral immune response, as shown by increased Newcastle disease antibody titers, particularly at 1.5 and 3g/kg during the first 60 days. Gas Chromatography-Mass Spectrometry (GC-MS) analysis of serum fatty acid profile revealed a dose- and time-dependent increase in beneficial unsaturated fatty acids and a marked reduction in cholesterol levels in SP-fed hens. In vitro evaluations showed that SP extract had potent antioxidant activity with 2, 2-azino-bis-3 ethylbenzothiazoline-6-sulfonic acid (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity comparable to vitamins C and E, particularly at high concentrations (3 and 4.5g/kg). These results highlight the promising potential of Spirulina platensis as a functional, natural feed additive to improve the laying performance, egg quality, immune response, yolk fat and provide potent antioxidant protection in poultry production systems.

Pancreatic ductal adenocarcinoma (PDAC) is driven by genetic alterations in the pancreatic epithelium (e.g., KRAS) coupled with dysregulated innate immunity that triggers tumor-promoting chronic inflammation. However, the identity of innate immune molecular regulators as therapeutic targets in PDAC is ill-defined. Here, we show in PDAC patients that elevated tumoral expression of the inflammasome adaptor protein ASC and its downstream effector Caspase-1 is primarily colocalized to the pancreatic ductal epithelium and prognostic for poor survival. In the mutant Kras-driven KPC PDAC mouse model, global and conditional (pancreatic epithelial) ablation of ASC, or nanobody-mediated targeting of extracellular ASC, suppresses pancreatic tumorigenesis. Whole transcriptome profiling and multiplex immunofluorescence reveal that the tumor-promoting activities of epithelial-derived ASC align with molecular pathways for mitochondrial respiration, metabolism (glycolysis), and immune responses. Our discovery that ASC-containing inflammasomes promote PDAC by acting as a molecular bridge between innate immunity, mitochondrial dysfunction and metabolic reprogramming provides the rationale to therapeutically target ASC in cancers.

Glioblastoma (GBM) is one of the most aggressive malignancies of the central nervous system. Gemcitabine (GEM), a pyrimidine analogue with broad-spectrum anticancer activity, can activate the cGAS-STING pathway and alleviate the immunosuppressive microenvironment of GBM. However, its clinical application is hampered by the formidable challenge of crossing the blood-brain barrier (BBB) and accumulating at the tumor lesion. Herein, a dual-responsive biomimetic nanoprodrug (RMM@GEM NPs) was exploited to enhance the efficient BBB penetration and target cargo delivery by functionalization of glioblastoma cell membranes (MM) camouflaging and further targeting peptide RAP modification. After its selective accumulation at glioma lesion, RMM@GEM NPs accelerates GEM release under the tumor pathological stimuli of reactive oxygen species (ROS) and acidic microenvironment to robustly activate the STING signaling cascades (increased p-STING, p-TBK1, p-IRF3, and p-NF-κB). Simultaneously, cyclodextrin-mediated cholesterol depletion further suppresses PD-L1 expression and alleviates T-cell exhaustion. These findings highlight RMM@GEM NPs as a promising strategy to enhance immune responses in "cold" tumor, providing a potential candidate for efficient and safe immunotherapy in GBM.

Inhibitor development remains one of the most serious complications of replacement therapy in patients with hemophilia. Tumour necrosis factor-alpha (TNF-α) is a key pro-inflammatory cytokine, and its genetic variants have been implicated in immune-related conditions. The association between TNF-α gene polymorphisms and inhibitor formation in hemophilia has been explored. To systematically review and quantitatively synthesize available evidence on the association between TNF-α gene polymorphisms and the development of inhibitors in patients with hemophilia. A comprehensive literature search was conducted in PubMed and SciELO from inception to 11 February 2025. Eligible studies evaluated TNF-α polymorphisms in patients with hemophilia and reported data on inhibitor status. Data extraction and quality assessment (using the Q-Genie tool) were performed independently by two reviewers. Meta-analyses were conducted using the Mantel-Haenszel method, where pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Nineteen studies met the inclusion criteria for the systematic review, and ten were included in the meta-analysis. A significant association was observed between the rs1800629 (-308G>A) polymorphism and inhibitor development under the A-recessive model (OR = 2.00; 95% CI: 1.13-3.54). No significant associations were found for other TNF-α polymorphisms. This meta-analysis suggests that the TNF-α rs1800629 polymorphism may be associated with an increased risk of inhibitor development in patients with hemophilia. These findings highlight the potential role of inflammatory genetic variants in modulating the immune response to replacement therapy. Further large-scale, multi-ethnic studies are needed to confirm these results and better understand the underlying mechanisms.

CD4 + T cells are major reactive subpopulation for cellular and humoral immune responses following sepsis. The apoptosis of CD4 + T cells may contribute to sepsis-induced immunosuppression, and preventing the induction of endoplasmic reticulum stress (ERS) can ameliorate apoptosis of CD4 + T cells in sepsis. The mechanistic target of rapamycin (mTOR) pathway performs an essential regulatory role on ERS-apoptosis of CD4 + T cells. This study aims to elucidate the underlying mechanisms of mTOR regulation of ERS-apoptosis of CD4 + T cells. In this study, based on the cecal ligation and puncture (CLP) model, 4-phenylbutyric acid (4-PBA), we firstly detected the percentage of ERS-apoptosis of CD4 + T cells with flow cytometry, Western blotting. Next, we observed the autophagy process and related makers with transmission electron microscopy (TEM) and Western blotting. Furthermore, we created CLP models with T cell-specific mTOR and TSC1 genetic knockout mice, and bafilomycin A1(Baf-A1), a selective inhibitor of autophagy to explore the regulatory role and underlying mechanism of mTOR on ERS-apoptosis of CD4 + T cells. With rapamycin, we proved the clinical potential of mTOR. Here we observed a considerably higher percentage of apoptotic CD4 + T cells in sepsis, and 4-PBA (an inhibitor of ERS) could alleviate not only ERS, but also the apoptosis of CD4 + T cells. As our previous work proved, deletion of mTOR decreased ERS-apoptosis of CD4 + T cells in sepsis. Furthermore, deficient autophagy, especially impaired autophagic flux was observed in sepsis. Mechanistically, we found knockdown of mTOR erased impaired autophagic flux, decreased ER stress-induced apoptosis, which could be reversed by Baf-A1. More importantly, rapamycin (inhibitor of mTOR) showed great clinical potential. we proved that mTOR deletion could alleviate CD4 + T cells ERS-apoptosis by rescuing autophagy involving autophagosome -lysosome fusion. For the first time, we demonstrate the mTOR-autophagy-ERS-apoptosis axis in sepsis, enriching the targets for future discovery of new sepsis therapies.

The NF-κB pathway plays a critical role in mediating the innate immune response downstream of activated immune receptors such as the TNFαR. Activation of this pathway is induced by several ubiquitin ligases (e.g., cIAP, TRAFs, NEMO, β-TrCP, KPC1), including Nedd4-1. Nedd4-1 comprises a C2-WW(4)-HECT domain architecture. We recently characterized a primate-specific splice isoform of Nedd4-1, Nedd4-1(NE), in which the C2 domain is replaced by a large N-terminally Extended (NE) region. Using miniTurbo BioID, we identified here several components of the NF-κB pathway in complex with Nedd4-1(NE) (but not with the canonical Nedd4-1), including IKKα/β and p105-NF-κB1. We further show that (i) Nedd4-1(NE) ubiquitinates and promotes degradation of IKKβ, therefore inhibiting phosphorylation and promoting stability of its substrate, the inhibitory IκBα; (ii) active Nedd4-1(NE) binds and destabilizes NF-κB1, an interaction that is dependent upon Nedd4-1(NE)-mediated KPC1 ubiquitination. Furthermore, KPC1 promotes translocation of NF-κB1 to late endosomal membranes, where Nedd4-1(NE) resides, to facilitate the Nedd4-1(NE): NF-κB1 interaction. Consequently, Nedd4-1(NE)-mediated regulation of both IKKβ and NF-κB1 suppresses NF-κB1 nuclear translocation and activation of its target genes; and (iii) Nedd4-1(NE) (but not canonical Nedd4-1) mRNA expression is increased upon prolonged TNFα treatment of cells. This work uncovered an E3 ubiquitin ligase that suppresses the NF-κB1 pathway to ensure termination of this pro-inflammatory signaling pathway in primates via a negative feedback mechanism; Such an additional layer of immune regulation has important implications for understanding inflammatory homeostasis and its dysregulation in human disease.

The enzymes acetyl-CoA acetyltransferase (ACATs) are membrane-bound enzymes that play critical roles in the regulation of cellular cholesterol homeostasis in various tissues. Here, we aim to assess the effect of ACAT2 on lipid accumulation in cervical cancer (CC). ACAT2 expression is enhanced in CC and is closely associated with the immune evasion and clinical progression of CC. Knockdown of ACAT2 expression in CC cells inhibits CC growth, improves survival in tumor-bearing C57BL/6 mice, and enhances anti-tumor immune responses by natural killer and CD8+ T cells. Protein expression of sterol regulatory element-binding transcription factor 2 (SREBF2) is elevated in CC and mediates the transcriptional activation of ACAT2. E3 ubiquitin-protein ligase parkin (PRKN) expression is attenuated in CC, which results in a diminished level of ubiquitination of SREBF2 and enhanced stability of SREBF2. PRKN inhibits cholesterol accumulation in CC, activates mitophagy, and ameliorates immune evasion through inhibition of SREBF2/ACAT2. Overexpression of SREBF2 blocks the anti-tumor effects of PRKN in an ACAT2-dependent manner. The present study underscores the pivotal function of ACAT2 in CC progression and delineates its potential as a therapeutic latent strategy. This approach involves the strategic obstruction of the metabolic pathway associated with ACAT2.

To survive in challenging environments, plants must rapidly activate immune responses while maintaining developmental plasticity and reproductive success. This requires continuous negotiation of limited energy and metabolic resources between growth, development, and defense. Ubiquitin-mediated proteolysis has emerged as a versatile regulatory mechanism that may integrate immune responses with plant developmental programs. In this review, we summarize accumulating evidence that ubiquitination shapes immune responses at multiple regulatory levels. Many of these immune-regulatory mechanisms depend on ubiquitin-dependent pathways that also govern developmental processes and cell cycle regulation. This overlap points to shared molecular nodes that integrate defense with growth. This functional overlap provides a mechanistic basis for growth–defense trade-offs and highlights how plants optimize fitness under stress conditions. Together, these findings position ubiquitin-mediated proteolysis as a unifying regulatory framework through which plants integrate immune responses with developmental programs and cell cycle control. This coordination helps maintain resilience and productivity in a fluctuating environment.

Candida albicans–induced immunometabolic changes drive complex responses in immune cells. However, whether and how C. albicans causes remodeling of oral epithelial cell (OEC) metabolism is unclear. Here, we use in vitro experiments and patient biopsies to demonstrate that OECs undergo metabolic reprogramming when infected by C. albicans independently of candidalysin secretion, increasing glycolysis and decreasing tricarboxylic acid (TCA) cycle activity. Glycolysis and glucose transport inhibition show that these pathways support OEC cytokine release, highlighting the partial control of antifungal epithelial immunity by cellular metabolism. However, glucose supplementation disrupts OEC responses both in vitro and in vivo, suggesting that the fungus benefits from these metabolic shifts and that increased aerobic glycolysis in OECs is detrimental. Genome-scale metabolic modeling predicted a shutdown of the TCA cycle and a previously unidentified role for glutamic-oxaloacetic transaminase 1 (GOT1) in response to C. albicans, which was subsequently shown to be important for OEC survival during infection. This study reveals a fundamental role for hexose metabolism and identifies a GOT1-mediated TCA cycle shunt in regulating OEC survival and immune responses during mucosal fungal infections.

Pulmonary hypertension (PH) underscores the urgent need for novel therapeutic targets. This study aimed to employ a proteome-wide Mendelian randomization (MR) approach to systematically identify circulating proteins causally associated with PH, thereby providing genetically validated candidate targets for drug development. We adopted a 2-sample MR design, integrating large-scale plasma proteomic quantitative trait loci (pQTL) data (encompassing 4148 proteins) and summary statistics from a large-scale PH genome-wide association study (2047 cases, 8301 controls). Candidate targets were screened through a multilayered analytical pipeline comprising proteomic MR, transcriptomic MR, and summary-data-based Mendelian randomization. The ultimately identified MR-Identified Causal Candidate Targets (MR-ICTs) underwent rigorous Bayesian colocalization analysis, followed by biological characterization through functional enrichment analysis, single-cell transcriptomics, and phenome-wide association studies. Through robust genetic causal inference, this study provides that circulating proteins such as LYZ, GREM2, NID1, and PF4V1 play causal roles in PH pathogenesis. These findings offer a set of rigorously genetically validated, high-priority therapeutic targets for developing novel PH treatments, specifically addressing key pathological mechanisms such as innate immunity, BMP signaling pathway dysregulation, and platelet activation. Our multi-dimensional analysis ultimately identified 6 MR-ICTs causally associated with PH. Notably, the causal associations for lysozyme C (LYZ), gremlin-2 (GREM2), nidogen-1 (NID1), and platelet factor 4 variant 1 (PF4V1) were stringently validated by Bayesian colocalization analysis (posterior probability for hypothesis 4 [PPH4], indicating a shared causal variant, > 0.99). Functional enrichment analysis revealed significant involvement of these targets in immune response and TGF-β signaling pathways. Single-cell analysis further elucidated their cell-type-specific expression, with LYZ predominantly expressed in monocytes and PF4V1 almost exclusively in platelets.

Reactive oxygen species (ROS) play a central role in plant defense, especially during interactions with plant-parasitic nematodes (PPNs). These molecules act as early signals that activate immune responses and help reinforce plant cell walls to block nematode invasion. However, PPNs have evolved specialized effector proteins (small, secreted molecules, typically proteins, that enter host cells to directly suppress immunity and manipulate host processes), which they secrete into host tissues and cells to interfere with ROS production and signaling. These effectors can suppress ROS bursts, detoxify reactive molecules, or manipulate host pathways to reduce immune responses. This review synthesizes current knowledge on these effector-driven strategies, from their discovery using advanced genomics to their specific molecular mechanism of ROS suppression. We also explore the critical interplay between ROS signaling and plant hormone pathways during infection, and provide an overview of the key techniques used to detect and quantify ROS in plant-nematode interactions.

Effect of completed COVID-19 vaccination on serum interferon λ3: a single-center retrospective study.

Immune homeostasis is indispensable for preserving organismal integrity, orchestrated through complex molecular networks encompassing immune cell dynamics, microbial cues, and epigenetic regulation. Among these, the gut microbiota-non-coding RNA (ncRNA) axis has recently garnered substantial attention as a multifaceted modulator of host immunity. Emerging evidence indicates that microbial-derived metabolites can reprogram ncRNA expression, thereby modulating immune cell differentiation, activation, and effector responses. Notably, dysregulation of this axis has been mechanistically implicated in the etiology of diverse immune-related pathologies, including colorectal cancer, sepsis, atherosclerosis, and neuroimmune conditions. Particularly intriguing is its translational potential: both microbial signatures and ncRNA profiles are being leveraged as diagnostic biomarkers and actionable targets for immune modulation. In this review, we delineate the molecular frameworks underpinning the gut microbiota-ncRNA-immune and explore how its perturbation contributes to pathogenesis. We further highlight emerging therapeutic strategies targeting this axis, underscoring its significance in precision immunology and host-microbiota co-regulation.

Phlebotomus chinensis is the primary vector of visceral leishmaniasis (VL) in China. However, the lack of a high-quality genome assembly for this species has limited research on its biology, vector-pathogen interactions, and evolutionary adaptations. To address this critical gap, the first chromosome-level genome assembly of Ph. chinensis was constructed. Nanopore long-read sequencing served as the primary method, complemented by Illumina short-read sequencing for base-level error correction and Hi-C mapping for chromosomal anchoring and chromosome-level scaffolding. Genome annotation integrated transcriptome data from adult, larvae and pupae, homologous protein predictions from closely related sand fly species, and ab initio gene prediction. Comparative genomic analyses were further performed to explore evolutionary relationships and genomic differences between Ph. chinensis, Ph. papatasi, and Lutzomyia longipalpis. A total of 127.05Gb of Nanopore data, 10.57Gb of Illumina clean data, 52.95Gb of Hi-C clean data, and 14.95Gb of RNA-seq data were obtained. The final assembled genome size was 195.21Mb with a scaffold N50 of 49.30Mb, and 97.24% of the sequences were successfully anchored to 4 chromosomes. Annotation identified 10,909 protein-coding genes (91.48% of which were functionally annotatable), along with 73 rRNAs, 92 small RNAs, 82 regulatory RNAs, 374 tRNAs, 11,870 simple sequence repeats, 6053 tandem repeats, and 478,622 transposable elements. Phylogenetic analysis revealed that Ph. chinensis is phylogenetically closest to Ph. papatasi, with an estimated divergence time of approximately 27.1 million years ago. Gene family evolution was dominated by contraction, with 229 expanded and 575 contracted gene families identified in the Ph. chinensis branch. Additionally, 209 positively selected genes were detected, which are crucial for immune response regulation and metabolic processes related to its vectorial capacity. Furthermore, 95 P450 genes were identified, classified into four subfamilies: CYP2, CYP3, mitochondrial CYP (mito), and CYP4. A high-quality chromosome-level genome assembly of Ph. chinensis is reported here for the first time. This assembly serves as a critical genomic resource to advance research into the vector biology, insecticide resistance mechanisms, and evolutionary history, and lays a solid foundation for the development of precision VL control strategies in China.

The mitochondrial transcription factor A (TFAM) is essential for mitochondrial genome maintenance. It binds to mitochondrial DNA (mtDNA) and determines the abundance, packaging, and stability of the mitochondrial genome. Because its function is tightly associated with mtDNA, TFAM has a protective role in mitochondrial diseases, and supportive studies demonstrate reversal of disease phenotypes by TFAM overexpression. In addition, TFAM deficiency has been shown to cause release of mtDNA into the cytosol and activation of the cGAS/STING innate immune response pathway. As such, TFAM presents as a unique target for therapeutic intervention, but limited efforts for activators have been reported. Herein, we disclose novel TFAM small-molecule modulators with sub-micromolar activity. Our results demonstrate that these compounds result in an increase of TFAM protein levels and mtDNA copy number. This results in inhibition of a mtDNA stress-mediated inflammatory response by preventing mtDNA escape into the cytosol. Furthermore, we see beneficial effects in cellular disease models in which boosting TFAM activity has been advanced as a disease-modifying strategy including improved energetics in MELAS cybrid cells and a decrease of fibrotic markers in systemic sclerosis fibroblasts. These results highlight the therapeutic potential of using small-molecule TFAM activators in indications characterized by mitochondrial dysfunction.

Alzheimer’s disease (AD) is marked by amyloid plaques, hyperphosphorylated TAU proteins, and neuroinflammation. The APP/PS1 mouse model is widely used to study AD pathogenesis. In this study, we investigated the expression of chemokines and their receptors, which may play a role in AD’s pathological mechanisms, using brain cortex tissue from female APP/PS1 mice aged 20–21 months. We analyzed several chemokine receptors (CCR1, CCR2, CCR3, CCR4, CCR6, CCR7, CCR9, and CCR10) by Western blot and focused on CCR6, CCR7, and CCR10 using RT-PCR. Additionally, we quantified the levels of chemokines (CCL6, CCL8, CCL19, CCL20, CCL24, and CCL27) by RT-PCR. Our results showed a significant decrease in CCL8 and CCL19, along with their respective receptors, in the APP/PS1 mice compared to controls. On the other hand, we observed a notable increase in CCL6, CCL24, CCL20, CCL27, and their receptors. Chemokines like CCL8 and CCL20, involved in inflammatory responses, may reveal how neuroinflammation contributes to AD. CCL19 and CCL27 are linked to immune cell trafficking, which may help explain immune cell interactions with amyloid plaques and TAU tangles in the CNS. Overall, the altered expression of chemokines such as CCL24 could serve as biomarkers for early AD detection and monitoring disease progression. These findings suggest potential therapeutic targets to modulate immune responses and reduce neuroinflammation in AD.

Gastric cancer (GC) is one of the most prevalent and lethal gastrointestinal malignancies. MutS homolog 2 (MSH2), a DNA mismatch repair protein, has emerged as a promising prognostic biomarker. However, traditional histopathological evaluation is limited by restricted fields compared with whole-slide imaging. This study aimed to investigate whether machine learning-derived digital pathomics features could predict MSH2 expression and clinical outcomes in GC. Hematoxylin and eosin-stained whole-slide images from 234 patients were analyzed to extract quantitative pathological features. A pathomics score (PS) was developed to estimate MSH2 expression. The association between PS and overall survival (OS) was assessed using univariate and multivariate Cox regression. Survival differences between high- and low-PS groups were evaluated using Kaplan-Meier analysis. Functional enrichment and immune infiltration analyses were performed to explore potential biological mechanisms. Digital image analysis identified pathomics features associated with MSH2 expression. The PS served as a surrogate marker for MSH2 and effectively stratified patients into prognostic subgroups with significant different OS. High PS was associated with features suggestive of a stronger anti-tumor immune response, whereas low PS was linked to an immunosuppressive microenvironment. The machine learning-derived pathomics signature shows potential in predicting MSH2 expression. It can serve as a complementary research tool and provide clinically meaningful prognostic information for GC.

Background/Objectives: The rapid development of safe and efficacious vaccines is often hindered by extensive, mandated non-clinical safety evaluations in animals. With the aim to provide scientific evidence supporting a “vaccine platform approach”, here we present the complete non-clinical studies for two investigational vaccines, GRAd-COV2 and GRAdHIVNE1, based on GRAd, a gorilla-derived group C adenoviral vector. Methods: The biodistribution of GRAd genomes following the intramuscular administration of the vaccines was assessed in rats by a sensitive qPCR method. Local tolerance and systemic toxic effects were evaluated in single- and repeated-dose toxicity studies in rabbits. Results: GRAd-COV2 and GRAdHIVNE1 were well-tolerated. Distribution was highly confined to the injection site and draining lymph nodes, and toxicity profile consisted of transient, non-adverse inflammatory responses, while the expected immune responses to the encoded antigens were successfully induced. Notably, both vaccines demonstrated a consistent safety profile despite transgene and backbone differences, comparable to other replication-defective adenoviral vectors. Conclusions: The established non-clinical safety profile of the GRAd platform provides a robust foundation for a more efficient and streamlined regulatory pathway. By leveraging this prior knowledge, future GRAd-based vaccines can achieve accelerated clinical development while fully adhering to the ethical principles of replacement, reduction, and refinement of animal use in research.

In recent years, the incidence and complexity of autoimmune diseases (AIDs) have been steadily increasing, posing grim challenges to clinical management. These diseases often involve multi-organ dysfunction and impose a pronounced burden on patients' physical and mental health. Current therapeutic strategies remain suboptimal, frequently limited by poor specificity and severe systemic side effects. With the rapid advancement of nanotechnology, nanodrugs have emerged as a potential approach on account of their enhanced targeting capability, high therapeutic efficacy, and reduced toxicity. In particular, macrophage-targeted nanodrugs have gained considerable attention, given that macrophages act as a key mediator in the onset and progression of various AIDs. This review systematically summarizes the molecular basis of macrophage involvement in autoimmunity, the design strategies of nanodrugs, and their applications across different AIDs, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), multiple sclerosis (MS), psoriasis (PSO), and systemic lupus erythematosus (SLE). These nanodrugs exert their therapeutic effects primarily by modulating macrophage-mediated immune responses, specifically through reprogramming macrophage phenotypes to promote anti-inflammatory and tissue-reparative functions. By precisely reprogramming macrophage function, these nanotherapeutics offer a novel approach for AID treatment.