Search Results (335)

Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of advanced hepatocellular carcinoma (HCC), establishing immunotherapy-based combinations as the standard of care. Improved treatment responses have expanded liver transplant eligibility for selected patients with advanced HCC through downstaging or bridging strategies. Such advances have directly influenced transplant candidacy and post-transplant outcomes. However, accumulating evidence indicates that pretransplant exposure to ICIs may disrupt post-transplant immune homeostasis, increasing the risk of acute allograft rejection and graft failure requiring retransplantation. From an immunological perspective, rejection following pretransplant ICI therapy predominantly manifests as T cell-mediated rejection and is characterized by the sustained activation of effector T cells and impairment of regulatory immune pathways. Blockade of immune checkpoint signaling interferes with mechanisms critical for allograft tolerance, including T cell apoptosis and regulatory T cell induction. Recent studies further underscore the importance of the washout period between ICI discontinuation and LT, with longer washout intervals being associated with lower rejection rates. Importantly, timely recognition and appropriate immunosuppressive management can often resolve acute rejection without adversely affecting long-term graft outcomes. This review integrates current immunological insights with emerging clinical evidence to inform optimal transplant timing and management strategies for liver transplant candidates receiving ICIs. Full article

Breast cancer represents a persistent global health burden, marked by extensive molecular heterogeneity and frequent therapeutic resistance in aggressive subtypes, particularly triple-negative breast cancer (TNBC). These clinical challenges underscore the urgency for alternative therapeutic strategies. Bioactive alkaloids isolated from Nelumbo nucifera, especially the bisbenzylisoquinoline compounds liensinine (LIE), isoliensinine (ISO), and neferine (NEF), have emerged as promising candidates due to their ability to disrupt oncogenic signaling pathways and inhibit malignant cellular transformation. The present study conducted a systematic investigation of LIE, ISO, and NEF across multiple breast cancer cell lines, including highly aggressive TNBC models. Results revealed potent growth-inhibitory effects mediated through apoptosis induction and cell cycle arrest at both the G1 and G2/M phases. Furthermore, transcriptomic profiling and molecular analysis identified LIE as a principal effector, driving extensive transcriptional reprogramming and targeting the MAPK and mTOR pathways as core regulators of its anti-cancer efficacy. Collectively, these findings define a mechanistic framework for the anti-cancer potential of N. nucifera-derived alkaloids and provide a compelling foundation for their development as therapeutic candidates for advanced breast cancer. Full article

The early identification of patients with highly active multiple sclerosis (HAMS) is crucial for guiding therapeutic decisions and initiating high-efficacy treatment strategies. This study aimed to characterize peripheral immune profiles that can distinguish between patients who are candidates for intensive therapy at disease onset and in later stages. Using spectral flow cytometry, we identified distinct immune signatures to differentiate early-stage patients from those with refractory, long-standing disease. In newly diagnosed individuals, decreased herpesvirus entry mediator (HVEM) expression on effector T helper (Th) cells distinguished HAMS from non HAMS cases. In contrast, patients with therapeutic resistance exhibited reduced CD28 expression on naïve regulatory and CD8⁺ T cells. Disability progression was associated with elevated HVEM on classical monocytes, decreased CD70 on CD56^bright natural killer cells (NK), and lower programmed cell death protein 1 (PD-1) expression on memory Th cells. Notably, CD28 expression on terminal effector CD8⁺ T cells and HVEM levels on plasmablasts emerged as strong predictors of progression independent of relapse activity, while higher PD-1 memory Th cell frequencies predicted clinical stability. This study identifies two panels of immune biomarkers: one distinguishing candidates for early high-efficacy intervention, and another defining patients with refractory disease. The immunological landscape of HAMS evolves across disease stages. In addition, we defined progression-associated markers detectable at the outset of follow-up, enabling the timely recognition of patients at heightened risk of disability accumulation, discriminating between neurodegeneration-driven and inflammation-driven mechanisms of progression. Full article

Background: Oxidative stress (OS) has been widely implicated in pathophysiology of major psychiatric disorder. However, establishing robust causal links and delineating the specific molecular mechanisms involved continue to pose significant research challenges. Methods: We performed a multi-omics analysis focusing on 817 oxidative stress-related genes (OSGs) in major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ). We applied summary data-based Mendelian randomization (SMR), integrating large-scale genome-wide association studies for MDD, BD, and SCZ with quantitative trait loci datasets from both blood and brain tissues, including measures of DNA methylation, gene expression, and protein abundance. Results: Multi-omics integration yielded supportive evidence across blood and brain tissues implicating ACE and ACADVL in SCZ, where genetically predicted increases in their methylation, expression, and protein abundance were associated with reduced disease risk. IGF1R was associated with bipolar disorder (BD) risk in blood-specific analyses. Brain-specific analyses further nominated ENDOG as a candidate gene for SCZ. Single-cell SMR indicated that increased ENDOG expression was associated with higher SCZ risk in astrocytes, CD4⁺ naïve T cells, CD8⁺ effector T cells, and natural killer cells, suggesting a potential immune–brain interaction. Conclusions: This study provides multi-level genetic evidence supportive of a potential causal role for specific OSGs in major psychiatric disorders. We identify ACE, ACADVL, IGF1R, and ENDOG as candidate genes for further investigation, offering insights into epigenetic and transcriptional mechanisms that could inform future research on therapeutic targets. Full article

The majority of terrestrial plants can interact with arbuscular mycorrhizal fungi (AMF) to form symbiotic relationships. AMF colonization not only enhances the host plant’s uptake of mineral nutrients but also improves its tolerance to biotic and abiotic stresses. In return, the host plant supplies the AMF with carbon sources essential for completing its life cycle. How AMF overcome the plant immune system to successfully establish symbiosis has remained an unresolved question. During colonization, AMF also secrete effector proteins, similar to how pathogenic fungi utilize effectors to promote virulence. In this study, we employed machine learning models such as SignalP 6.0 and EffectorP 3.0 to predict potential effectors in Rhizophagus irregularis, leading to the identification of 227 effector candidates. Using EffectorP 3.0, ApoplastP, and LOCALIZER, most R. irregularis effectors were predicted to be localized in the cytoplasm rather than the apoplast, suggesting a functional role in regulating symbiotic development. Only 26% of the predicted effectors were annotated by Pfam, indicating that the majority are proteins of unknown function. Effector proteins from 14 microbial species representing five ecological types (Ectomycorrhizae, Ericoid mycorrhizae, Endophyte, Arbuscular mycorrhizae, and Pathogen) clustered distinctly by species, highlighting the high degree of species specificity among effectors. Two R. irregularis effectors containing the RxLR motif were identified. Although these effectors localized to the cytoplasm, they did not exhibit virulence factor activity. Additionally, we characterized a functionally conserved chitin deacetylase effector, RiPDA1, which localized to the apoplastic space. The Y2H assay indicated that RiPDA1 forms homodimers. The in vitro chitin-binding assay showed that RiPDA1 has an affinity for chitin. RiPDA1 may function as a secretory polysaccharide deacetylase that facilitates symbiosis by deacetylating chitin oligomers. In summary, this study systematically identified and characterized effector proteins in R. irregularis. Similar to pathogenic fungi, AMF appear to employ cell wall-modifying enzymes to overcome plant immune defenses. Full article

The pressing need for sustainable, plant-based alternatives is highlighted by the growing resistance of agricultural pests to synthetic pesticides. This study examined the pesticidal potential of phytocompounds from C. tora discovered by GC–MS analysis against important tomato insect (T. absoluta) and fungal pathogen (A. solani). The binding stability and interaction dynamics of specific metabolites with fungal virulence (polygalacturonase, MAP kinase HOG1, and effector AsCEP50) and insect neuromuscular (ryanodine receptor and sodium channel protein) targets were assessed using molecular docking and 100 ns molecular dynamics simulations. Among the screened compounds, squalene and 4,7,10,13,16,19-docosahexaenoic acid, methyl ester (DHAME) exhibited the strongest binding affinities and conformational stability, with MM-GBSA binding free energies of −38.09 kcal·mol⁻¹ and −52.81 kcal·mol⁻¹ for squalene complexes in T. absoluta and A. solani, respectively. Persistent hydrophobic and mixed hydrophobic–polar contacts that stabilised active-site residues and limited protein flexibility were found by ProLIF analysis. These lively and dynamic profiles imply that DHAME and squalene may interfere with calcium signalling and stress-response pathways, which are essential for the survival and pathogenicity of pests. Hydrophobic interactions were further confirmed as the primary stabilising force by the preponderance of van der Waals and nonpolar solvation energies. The findings show that C. tora metabolites, especially squalene and DHAME, are promising environmentally friendly biopesticide candidates that have both insecticidal and antifungal properties. Their development as sustainable substitutes in integrated pest management systems are supported by their stability, binding efficacy and predicted biosafety. Full article

Oncofetal reprogramming has recently emerged as a critical concept in translational cancer research, particularly for its role in driving therapeutic resistance across a variety of malignancies. This biological process refers to a pattern of gene expression that is restricted to embryogenesis, but becomes expressed again in a subpopulation of cancer cells. These genes are typically suppressed after embryogenesis, and their aberrant re-expression in tumors endows cancer cells with stem-like properties and enhanced adaptability. The goal of this review is the following: (i) comprehensively examine the multifaceted nature of oncofetal reprogramming; (ii) elucidate its underlying molecular mechanisms, including its regulators and effectors; and (iii) evaluate its consequences for the therapeutic response in different cancer types. We comprehensively integrate the latest findings from colorectal, breast, lung, liver, and other cancers to provide a detailed understanding of how oncofetal programs interfere with tumor response to treatment. Among the candidates, YAP1 and AP-1 have emerged as central transcriptional drivers of this reprogramming process, especially in colorectal and breast cancers. We also explore the distinct expression patterns of oncofetal genes across different tumor types and how these patterns correlate with treatment outcomes and patient survival. Lastly, we propose a dual-targeting therapeutic strategy that simultaneously targets both cancer stem cells and oncofetal-reprogrammed populations as a more effective approach to overcome resistance and limit recurrence. Full article

Mounting evidence from large-scale association studies has identified transmembrane BAX inhibitor motif-containing 1 (TMBIM1) as a promising candidate gene in colorectal cancer (CRC) pathogenesis. Our clinical analysis confirmed this association, demonstrating significantly reduced TMBIM1 expression in human colon cancer tissues. To elucidate its functional role, we employed complementary experimental approaches across different cellular contexts. In normal colonic epithelial cells (NCM460), TMBIM1 deficiency triggered distinct morphological changes and suppressed cellular growth. Conversely, in malignant HCT-116 cells, TMBIM1 knockdown paradoxically enhanced proliferation and other pro-tumorigenic characteristics, suggesting context-dependent functions. Transcriptomic profiling via RNA-seq revealed that TMBIM1 suppression enhances cell viability, and the specific mutational background of HCT-116 cells appears to exploit the consequent loss of E-cadherin to further drive progression. Mechanistic investigations further identified E-cadherin (CDH1) as a key downstream effector, showing significant down-regulation following TMBIM1 knockdown. We therefore define a context-dependent tumor-suppressive mechanism for TMBIM1, wherein its loss in MSI-H cells promotes tumorigenesis via E-cadherin suppression and the consequent loss of epithelial integrity. Full article

Candidatus Liberibacter spp. can infect most citrus plants and rely entirely on phloem sieve tube cells of the host plant for survival. Candidatus Liberibacter primarily contains Ca. L. asiaticus (CLas), Ca. L. africanus (CLaf), and Ca. L. americanus (CLam). Among these, CLas is the most harmful and widely distributed and is the primary pathogen of the devastating citrus disease Huanglongbing (HLB). Effectors are among the core weapons secreted by pathogens into plant cells to attack the plant immune system. In this study, we focused on CLas-specific effectors and those that are highly expressed during the infection stage to identify essential virulence effectors. Using secretion signal peptide prediction analysis, 40 candidate effectors with potential secretory capabilities were identified. Transient expression of these candidate effectors in Nicotiana benthamiana revealed their impact on pattern-triggered immunity, including INF-induced cell death and microbial pattern-induced reactive oxygen species (ROS) bursts, and the resistance of N. benthamiana to the bacterial pathogen Pst DC3000. 10 candidate effectors capable of suppressing plant immunity were identified. The stable expression of these candidate effectors in Arabidopsis showed that several candidate effectors enhanced plant susceptibility to Pst DC3000 and inhibited flg22-induced ROS production and MAPK activation. Among the three candidate effectors that significantly suppressed ROS burst, one effector, E3 (CLIBASIA_03085), interacts with the plant NADPH oxidase RbohD, a key enzyme responsible for ROS production. This suggests that E3 likely inhibits ROS accumulation by directly targeting RbohD. Here, we identified multiple candidate effectors capable of suppressing microbial pattern-triggered immunity that may be essential virulence factors for CLas infection, enhancing our understanding of CLas pathogenesis. Full article

Maize (Zea mays L.) is a major economic crop highly susceptible to Colletotrichum graminicola, the causal agent of anthracnose leaf blight, which causes substantial annual yield losses. This fungal pathogen employs numerous effectors to manipulate plant immunity, yet the functions of many secreted proteins during biphasic infection remain poorly characterized. In this study, we identified CgMas2, a candidate secreted protein in C. graminicola and a homolog of Magnaporthe oryzae MoMas2. Deletion of CgMAS2 in the wild-type strain CgM2 did not affect fungal vegetative growth or conidial morphology but significantly impaired virulence on maize leaves. Leaf sheath infection assays revealed that CgMas2 is required for biotrophic invasive hyphal growth, as the mutant showed defective spreading of invasive hyphae to adjacent cells. Subcellular localization analysis indicated that CgMas2 localizes to the cytoplasm of conidia and to the primary infection hyphae. Furthermore, DAB staining demonstrated that disrupt of CgMAS2 leads to host reactive oxygen species (ROS) accumulation. Comparative transcriptome analysis of maize infected with ΔCgmas2 versus CgM2 revealed enrichment of GO terms related to peroxisome and defense response, along with up-regulation of benzoxazinoid biosynthesis genes (benzoxazinone biosynthesis 3, 4 and 5) at 60 h post-inoculation (hpi). Conversely, six ethylene-responsive transcription factors (ERF2, ERF3, ERF56, ERF112, ERF115 and ERF118) involved in ethylene signaling pathways were down-regulated at 96 hpi. These expression patterns were validated by RT-qPCR. Collectively, our results demonstrate that CgMas2 not only promotes invasive hyphal growth during the biotrophic stage but may also modulate phytohormone signaling and defense compound biosynthesis during the necrotrophic phase of infection. Full article

Root rot disease severely threatens tropical fruit production, leading to plant mortality and reduced yields; however, the mechanisms of host defense responses and pathogen infection remain poorly understood. In this study, Fusarium acutatum was isolated from diseased Annona squamosa roots and identified through morphological features and ITS phylogeny (99.8% identity). Infection triggered a marked activation of antioxidant defenses, with elevated POD, SOD, PAL, PPO, and CAT activities. Transcriptomic and TMT-based quantitative proteomic analyses identified 23,791 and 74,403 differentially expressed genes (DEGs) and 367 and 609 differentially expressed proteins (DEPs) in root at 5 and 10 days post inoculation, respectively, relative to the control. These DEGs and DEPs were consistently enriched in pathways involving redox regulation, protein synthesis and processing, ubiquitin-mediated proteolysis, phenylpropanoid and flavonoid metabolism, cell wall remodeling, plant–pathogen interaction and MAPK signaling. Integrated transcriptomic–proteomic correlation analysis showed clear positive associations between key defense-related genes and proteins, suggesting that phenylpropanoid metabolism and reactive oxygen species (ROS) scavenging play central roles in resistance. Key genes such as CHI2, CHS, and CYP were strongly induced and validated by qPCR, supporting coordinated activation of the defense systems. Furthermore, F. acutatum exhibited upregulation of 50 pathogenic-related proteins, including 4 cell wall-degrading enzymes (e.g., CBH1, pectate lyase), 5 metabolic regulation or signal transduction enzymes (e.g., gabD, TPI, and ENO) and 3 potential effectors, suggesting coordinated pathogen strategies for host colonization. Collectively, this study provides comprehensive multi-omics insight into the molecular mechanisms underlying A. squamosa defense against F. acutatum and offers candidate targets supported by omics evidence, serving as a theoretical reference for the management of root rot. Full article

Nucleotide-binding site-leucine-rich repeat (NLR) proteins are key intracellular immune receptors in plants. Integrated domains (IDs) can occasionally be fused with NLRs, contributing to their functional diversity. However, the diversity and evolutionary patterns of NLR-IDs across angiosperms remain poorly understood. In this study, we analyzed 305 angiosperm genomes and found that the proportion of NLR genes containing IDs (NLR-ID genes) ranges from 0% to 38.3%, with an average of 10.6%. A total of 1226 unique IDs were identified, some of which are widely distributed, while others are specific to particular taxa. Notably, 415 of these IDs are homologous to plant proteins targeted by pathogen effectors, suggesting their role as candidate decoys. Comparative analysis of NLR-IDs in two subfamilies—TIR-NLR (TNL) and CC-NLR (CNL)—revealed that TNL genes have a significantly higher frequency of IDs, with the C-JID and DUF3542 domains being most prevalent. N-terminal fusion of the DUF3542 domain in CNL genes correlates with the loss of the MADA motif. Our findings expand the understanding of NLR-ID diversity and provide insights into the dynamic evolution of NLR protein architecture in angiosperms. Full article

Background: Rheumatoid arthritis (RA) is a chronic and debilitating autoimmune disease with a complex etiology, creating a significant unmet clinical need for safer and more effective therapeutics. Coix seed oil (CSO), a traditional Chinese medicine with a long history of use against RA, represents a promising candidate; however, its precise mechanisms of action remain largely unexplored. Objectives: This study aimed to elucidate the mechanistic basis for the anti-arthritic effects of CSO, with a specific focus on its role in modulating the gut-joint axis. Methods: A collagen-induced arthritis (CIA) rat model was employed. The therapeutic efficacy of CSO was evaluated through detailed assessments of arthritic symptoms, joint histopathology, and Micro-CT analysis. To unravel the mechanism, an integrative multi-omics approach was applied, combining untargeted fecal metabolomics with targeted serum metabolomics, which pinpointed butyric acid as a key differential metabolite. This was integrated with 16S rRNA sequencing to profile gut microbiota remodeling. The causal role of butyrate was further verified by exogenous sodium butyrate supplementation in CIA mice. Finally, network pharmacology predictions of potential effector proteins were experimentally validated in vivo using immunofluorescence and qPCR. Results: CSO treatment significantly alleviated joint swelling and bone damage in CIA rats after the treatment of 7 days, especially on day 35. CSO primarily restored gut dysbiosis in the CIA model by upregulating butyrate levels, increasing four butyrate-producing probiotics at the genus level, and reducing two pathogenic bacteria. Further exogenous butyrate supplementation validated its ability to improve RA phenotypes. Network pharmacology analysis speculated that there were 142 common targets between CSO and RA, among which NLRP3 was its potential effector protein. In vivo studies verified the suppression of NLRP3 inflammasome activation and reduced expression of subsequent inflammatory mediators by CSO. Conclusions: Coix Seed Oil alleviates RA by orchestrating a dual-mechanism action, it remodels the gut microbiota to enhance the production of the microbiotic metabolite butyrate, while also inhibiting the NLRP3 inflammasome pathway. These findings collectively elucidate that CSO mediates its anti-arthritic effects through a novel “gut-butyrate-joint” axis, underscoring its potential as a promising dietary supplement or therapeutic agent derived from medicine-food homology for the management of RA. Full article

The functional landscape of the skin microbiome is largely defined by dominant genera such as Cutibacterium and Staphylococcus, whereas rare commensals remain poorly understood. In this study, we identified Rothia kristinae BF00107, a skin-resident strain with a complete pantothenate biosynthesis pathway, as a novel postbiotic candidate with distinct dermatological benefits. BF00107 fermentation filtrate suppressed pro-inflammatory cytokines (IL-1β and TNF-α) in keratinocytes and restored extracellular matrix homeostasis in UVB-irradiated fibroblasts by upregulating COL1A1 expression and reducing MMP-1 levels. Consistent with the observed phenotypes, transcriptomic profiling revealed a strain-specific signature characterized by downregulation and upregulation of the expression of inflammatory mediators and barrier- and ECM-associated genes, respectively. Comparative genomics and metabolite profiling confirmed BF00107 as a unique high-pantothenate producer. Supplementation with pantothenic acid reproduced the anti-inflammatory and barrier-supporting effects of the strain, confirming its role as a key effector metabolite. Furthermore, BF00107 passed standard safety assessments, including the Human Repeat Insult Patch Test (HRIPT), Ames, and irritation tests, supporting its suitability for human applications. These findings establish the pantothenate-producing R. kristinae BF00107 as the first functionally validated Rothia strain with anti-inflammatory and photoaging-protective properties. This study expands the functional scope of the skin microbiome and highlights rare commensals as valuable reservoirs for safe, strain-specific postbiotic development. Full article

Background/Objectives: Toxoplasmosis caused by Toxoplasma gondii still poses a serious threat to public health in most countries and regions. Currently, the lack of effective vaccines necessitates the urgent development of a safe and effective vaccine. Methods: In this study, we combined the inactivated T. gondii vaccine with a colloidal manganese salt (Mn jelly [MnJ]) adjuvant. Results: This triggered a powerful innate immunity, significantly increased the number of CD4⁺ and CD8⁺ T cells secreting interferon γ (IFN-γ) in mice, and enhanced the generation of CD8⁺ central memory T cells and CD8⁺ effector memory T cells. Compared to the control groups, mice in experimental groups produced more specific IgG, and produced high levels of IL-2, IL-12 and IFN-γ. The survival rate of mice in experimental groups reached 50%, while all control group mice died within 9 days during T. gondii acute infection. Furthermore, the burden of brain cysts in experimental group mice was also significantly reduced by 90.77% compared to the control group during chronic infection. Conclusions: These results suggested that the incorporation of an MnJ adjuvant significantly enhances the immunoprotective efficacy of inactivated T. gondii vaccine, positioning this formulation as a promising candidate for development against toxoplasmosis. Full article