Search Results (176)

Background: Various studies have demonstrated fucoidan’s immunomodulatory effects. A previous study reported the anticancer effects of Durvillaea antarctica fucoidan (DAF) via immune activation in mice. Methods: In this study, we confirmed the DAF’s pulmonary immune activation ability by nasal administration of the dendritic cells (DCs) and T cells. Furthermore, we examined its ability to enhance the efficacy of lung cancer treatment by combining it with anti-PD-L1 antibodies to activate the lung immune response. Results: Nasal DAF administration increased C-C chemokine receptor type 7 expression in DCs and promoted DC migration to the mediastinal lymph nodes (mLN). Specifically, DAF increased conventional DC type 1 (cDC1) and cDC2 numbers in mLN and potently activated cDC1. Furthermore, the nasal administration of DAF increased the production of inflammatory cytokines in the lungs and peripheral blood. Repeated intranasal administration of DAF induced T-cell activation, resulting in the enhanced production of interferon-gamma and tumor necrosis factor-alpha in CD4 T and CD8 T cells. CD8 T cells also showed increased secretion of cytotoxic mediators after DAF treatment, and the proportion of Tregs expressing FoxP3 decreased in the mLN. DAF inhibited lung cancer growth in Lewis lung carcinoma 2 cells, which was enhanced by combining it with an anti-programmed death-ligand 1 antibody. Finally, the anticancer effects of DAF were not observed in mice with depleted CD4-positive and CD8-positive cells. Conclusions: Nasal administration of DAF may inhibit lung cancer growth by inducing lung immune activation and is expected to be helpful as an immune activator for nasal administration. Full article

Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus that is associated with long-term morbidity and mortality. Pathomorphological findings of LN are broadly divided into proliferative lupus nephritis (PLN) and membranous lupus nephritis (MLN). PLN is characterized by diffuse global or segmental proliferative glomerulonephritis with significant infiltration of inflammatory cells. Type 1 T-helper (Th1) cells, which predominate under inflammatory conditions, and NETosis, as the process of forming neutrophil extracellular traps (NETs), are key factors in the development of PLN. Meanwhile, MLN is characterized by diffuse membranous nephropathy (MN) with global granular subepithelial immune deposits. MLN patients usually experience massive proteinuria, and occasionally show an unfavorable renal prognosis despite aggressive treatment, similar to PLN patients. Intriguingly, in some instances, MLN patients do not show the general immunoserological characteristics of SLE, such as low serum complement and elevated anti-DNA antibody titers. Several reports have indicated an association between Th2 cell dominance and the development of MLN. Moreover, exostosin 1 (EXT1) and exostosin 2 (EXT2) on the glomerular basement membrane have recently been discovered as novel putative antigens for secondary MN, and have been shown to be up-regulated in patients with MLN. To date, many studies have focused on the dissimilarities between PLN and MLN. However, the reason for two polar morphological forms existing within the same disease is not completely clear. The present review addresses published observations on this topic in addition to providing our assertion regarding characteristic NETosis and glomerular EXT1/EXT2 expressions between PLN and MLN. Full article

Azole resistance in dermatophytes, particularly Trichophyton indotineae, has become a growing global concern. Current antifungal susceptibility testing protocols (EUCAST, CLSI) have limitations in reproducibility and sensitivity. This study aimed to evaluate how medium composition, incubation temperature, and spore concentration influence itraconazole susceptibility testing across various dermatophyte species. Thirty-eight clinical isolates representing Trichophyton, Microsporum, and Epidermophyton species were tested using a microplate laser nephelometry system (MLN). IC₅₀ values for itraconazole were determined in three different media (Sabouraud glucose (SG), RPMI-based (RG), and RG supplemented with casein (RGC)) at 28 °C and 34 °C. Effects of spore concentration on growth dynamics and lag phase were also analyzed. SG medium provided clear phenotypic separation between resistant and sensitive isolates. In contrast, RG and RGC showed overlapping IC₅₀ values. Lower spore concentrations revealed underlying growth differences, which were masked at higher inoculum levels. Temperature and media composition significantly affected IC₅₀ outcomes. Genotypic analysis confirmed resistance-associated Erg11B point mutations and genomic amplifications in T. indotineae, particularly in combination with Erg1 mutations, forming distinct subpopulations. SG medium combined with reduced spore concentrations offered improved differentiation of resistant versus sensitive strains. These findings support the development of more accurate susceptibility testing protocols and highlight the need to establish species-specific ECOFF values for dermatophytes. Full article

Background: The treatment landscape for multiple myeloma (MM) has significantly evolved in recent decades with novel therapies like proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. However, MM remains incurable, necessitating new pharmacological strategies. Mitotic kinases, such as Aurora proteins, have emerged as potential targets. Selective inhibitors of Aurora A and B,- alisertib (MLN8237) and barasertib (AZD1152), respectively, have shown anti-myeloma activity in preclinical studies, with alisertib demonstrating modest efficacy in early clinical trials. Methods and Results: This study investigated the mechanisms of action of alisertib and barasertib and their combination with antitumor agents in a panel of five MM cells lines. Both drugs induced cell cycle arrest phase and abnormal nuclear morphologies. Alisertib caused prolonged mitotic arrest, whereas barasertib induced transient arrest, both resulting in the activation of mitotic catastrophe. These findings revealed three potential outcomes: cell death, senescence, or polyploidy. High mitochondrial reactive oxygen species (mROS) were identified as possible drivers of cell death. Caspase inhibition reduced caspase-3 activation but did not prevent cell death. Interestingly, alisertib at low doses remained toxic to Bax/Bak^DKO cells, although mitochondrial potential disruption and cytochrome c release were observed. Sequential combinations of high-dose Aurora kinase inhibitors with BH3-mimetics, and in specific cases with panobinostat, showed a synergistic effect. Conversely, the simultaneous combination of alisertib and barasertib showed mostly antagonistic effects. Conclusions: Alisertib and barasertib emerge as potential in vitro candidates against MM, although further studies are needed to validate their efficacy and to find the best combinations with other molecules. Full article

Background:Salmonella Typhimurium is a major zoonotic pathogen, in which type 1 fimbriae play a crucial role in intestinal colonization and immune modulation. This study aimed to improve the protective immunity of a previously developed growth-deficient strain—a double auxotroph for D-glutamate and D-alanine—by engineering the inducible expression of type 1 fimbriae. Methods: P_tetA-driven expression of the fim operon was achieved by λ-Red mutagenesis. fimA expression was quantified by qRT-PCR, and fimbriation visualized by transmission electron microscopy. Adhesive properties were evaluated through FimH sequence analysis, yeast agglutination, mannose-binding/inhibition assays, and HT-29 cell adherence. BALB/c mice were immunized orogastrically with IRTA ΔΔΔ or IRTA ΔΔΔ P_tetA::fim. Safety and immunogenicity were assessed by clinical monitoring, bacterial load, fecal shedding, ELISA tests, and adhesion/blocking assays using fecal extracts. Protection was evaluated after challenging with wild-type and heterologous strains. Results: IRTA ΔΔΔ P_tetA::fim showed robust fimA expression, dense fimbrial coverage, a marked mannose-sensitive adhesive phenotype and enhanced HT-29 attachment. Fimbrial overexpression did not alter intestinal colonization or translocation to mesenteric lymph nodes (mLNs). Immunization elicited a mixed IgG1/IgG2a, significantly increased IgA and IgG against type 1 fimbriae-expressing Salmonella, and enhanced the ability of fecal extracts to inhibit the adherence of wild-type strains. Upon challenge (IRTA wild-type/20220258), IRTA ΔΔΔ P_tetA::fim reduced infection burden in the cecum (−1.46/1.47-log), large intestine (−1.35/2.17-log), mLNs (−1.32/0.98-log) and systemic organs more effectively than IRTA ΔΔΔ. Conclusions: Inducible expression of type 1 fimbriae enhances mucosal immunity and protection, supporting their inclusion in next-generation Salmonella vaccines. Future work should assess cross-protection and optimize FimH-mediated targeting for mucosal delivery. Full article

Myeloid/lymphoid neoplasms with tyrosine kinase gene fusions (MLN-TK) represent a distinct group of hematologic malignancies recognized in the latest WHO classification due to shared clinical, morphological, and molecular features, and their responsiveness to tyrosine kinase inhibitors (TKIs). Among these, fusions involving the SYK gene, such as ETV6::SYK and ITK::SYK, have emerged as rare but potentially targetable genetic events in both myeloid and lymphoid neoplasms. SYK, a non-receptor tyrosine kinase critical for hematopoietic signalling, can become constitutively activated through gene fusions, driving oncogenesis via the PI3K/AKT, MAPK, and JAK-STAT pathways. ETV6::SYK has been primarily associated with myeloid neoplasms, often presenting with eosinophilia, bone marrow dysplasia, and skin involvement. In vitro and in vivo models confirm its leukemogenic potential and identify SYK as a therapeutic target. Although SYK inhibitors like fostamatinib have shown transient efficacy, resistance mechanisms, possibly involving alternative pathway activation, remain a challenge. The ITK::SYK fusion, on the other hand, has been identified in peripheral T-cell lymphomas, particularly of the follicular helper T-cell subtype, with similar pathway activation and potential for targeted intervention. Additional rare SYK fusions, such as PML::SYK and CTLC::SYK, have been reported in myeloid neoplasms and juvenile xanthogranuloma, respectively, expanding the spectrum of SYK-driven diseases. Accumulating evidence supports the inclusion of SYK fusions in future classification systems and highlights the need for broader molecular screening and clinical evaluation of SYK-targeted therapies. Full article

Salmonella enterica serovar Typhimurium (S. Typhimurium) is an intracellular pathogen that survives and replicates within host cells. Macrophages, key immune cells in infection defense, play a vital role in pathogen clearance through polarization (M1/M2) and NLRP3 inflammasome activation. While TRIM67 regulates macrophage recruitment in the liver, its role in S. Typhimurium infection remains unclear. In this study, a S. Typhimurium infection model was established by orally infecting streptomycin-pretreated TRIM67 WT and KO mice with 1 × 10⁹ CFU of S. Typhimurium. TRIM67 expression in the ileum, colon, mesenteric lymph nodes (MLNs), and peritoneal macrophages (PMs) was assessed via qRT-PCR and Western blotting. Histopathological changes were analyzed using HE and PAS staining. IHC staining, flow cytometry (FCM), qRT-PCR, and Western blotting were used to evaluate TRIM67 knockout effects on macrophage recruitment, polarization, and NLRP3 inflammasome activation. In vitro, PMs were infected with S. Typhimurium (MOI 1:20), and TRIM67’s role in macrophage polarization and NLRP3 activation was validated. S. Typhimurium infection significantly upregulated TRIM67 in the ileum, colon, and MLN. TRIM67 knockout reduced intestinal inflammatory cell infiltration but worsened goblet cell loss and impaired digestion. Bacterial load assays revealed weakened pathogen clearance, leading to weight loss and increased mortality. TRIM67 knockout inhibited intestinal macrophage recruitment, M1 polarization in MLN, and NLRP3 activation. In vitro, TRIM67 knockout increased PMs’ intracellular bacterial load and suppressed NLRP3, caspase-1, and IL-1β expression. TRIM67 knockout impairs the host’s ability to clear S. Typhimurium by inhibiting M1 macrophage polarization and NLRP3 inflammasome activation. Full article

The presence of multiplex edges and sparse links often hampers the efficacy of link prediction (LP) tasks. By harnessing the expressive power of Markov logic network (MLN) formulations, multiplex edges can be unified to enhance LP effectiveness. However, scaling up inferences for effective LP remains challenging due to the inefficiency of traditional MLN inference methods. To tackle this issue, we redefine LP tasks within heterogeneous networks using MLN inferences and introduce a tailored inference framework to handle unobserved nodes and complex MLN structures. We propose a method to partition the MLN structure into discrete substructures and compute node label distributions using the variational expectation maximization (VEM) algorithm. Additionally, we establish a termination condition to streamline inference search space and present the MLN-based LP algorithm. Experimental findings demonstrate the efficacy of our VEM-driven MLN inference framework for LP tasks in heterogeneous networks, showcasing superior accuracy compared to existing approaches. Full article

The pandemic of coronavirus disease 2019 (COVID-19), brought about by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has significantly impacted public health and the economy. A fundamental aspect of addressing this virus lies in elucidating the mechanisms through which it induces disease. Our study reveals that Non-structural protein 6 (NSP6) of SARS-CoV-2 promotes the initiation of autophagy by activating Beclin1. In the later stage of autophagy, however, NSP6 causes a blockage in the autophagy–lysosome degradation via the inhibition of Mucolipin 1 (MLN1). The single nucleotide polymorphism (SNP) L37F in NSP6, which is associated with asymptomatic infection, similarly enhances the initiation of autophagy but displays a reduced ability to impede lysosome-dependent degradation. In summary, we demonstrated the dual-regulation mechanism of NSP6 in autophagy, which may be one of the reasons for targeting cellular autophagy to induce viral pathogenesis. This finding may provide promising new directions for future research and clinical interventions. Full article

Urbanization and economic growth have substantially modified the land utilization structure, affecting ecosystem services and their spatial distribution. As a crucial component of Beijing’s urban framework, the city’s green belts, located at the periphery of its core metropolitan area, play a vital role in supplying urban ecosystem services. They also represent a focal point for land use transformation conflicts, making them an important study area. This research utilizes land utilization data from 2000, 2005, 2010, 2015, and 2020 as the primary dataset. It adopts a modified standard equivalent factor and integrates it with the Patch-Generaling Land Use Simulation (PLUS) model to model land utilization in Beijing’s green belts for 2035 under three scenarios: the natural development scenario (NDS), ecological protection scenario (EPS) and cultivated protection scenario (CPS). The study aims to analyze and project the spatial and temporal evolution of ecosystem service values (ESVs) in 2035 under different scenarios in the green belts of Beijing. The results indicate that (1) land use in Beijing’s green belts is dominated by cropland and construction land. Construction land has expanded significantly since 2000, increasing by 500.78 km², while cropland has decreased by 488.47 km². Woodland, grassland, and water have also seen a reduction. Overall, there is a trend of woodland and water being converted into cropland, with cropland subsequently transitioning into construction land. (2) In the NDS, construction land increases by 91.76 km², while cropland, grassland, and water decrease. In EDS, the growth of construction land decelerates to 22.09 km², the reduction in cropland decelerates, and the conversion of cropland to construction land is limited. Grassland and water remain largely unchanged, and woodland experiences a slight increase. In CPS, the conversion of cropland to construction land is notably reduced, with construction land increasing by 11.97 km², woodland increasing slightly, and grassland and water decreasing slightly. (3) The ESV ranking across scenarios is as follows: EPS 1830.72 mln yuan > CPS 1816.23 mln yuan > NDS 1723.28 mln yuan. Hydrological regulation and climate regulation are the dominant services in all scenarios. ESV in EPS attains the greatest economic gains. This study contributes to understanding the effects of land utilization changes on ESV, offering valuable empirical evidence for sustainable development decision-making in swiftly urbanizing areas. Full article

Background/Objectives: Chronic lymphocytic leukemia (CLL) remains an incurable B-cell malignancy. B-CLL cells exhibit an extended lifespan in part due to the activation of survival pathways such as NF-kB. A crosstalk between NF-kB and GSK-3β pathways has been reported. NF-kB has also been identified as a primary target of the NEDD8-activating enzyme inhibitor MLN4924. Our objective was to investigate potential synergies of MLN4924 with other NF-kB-targeting agents for the treatment of CLL and elucidate the mechanisms of action underlying this pathway regulation. Methods: To assess the cytotoxic efficacy of the combined ex vivo treatment with CHIR-99021 and MLN4924, we employed 7-AAD staining and XTT viability assays on primary samples from CLL patients. Subsequently, we conducted various analyses to identify the molecular mechanisms underlying the cytotoxic effects of this combination. Results: We discovered a discrepancy between the mRNA and protein levels of IkBɑ and provided evidence of translational control over its expression. This observation may explain why, unlike other cell types, B-CLL cells did not activate NF-kB signaling following inhibition of GSK-3ß. Furthermore, we describe a synergistic effect between a specific GSK-3ß inhibitor, CHIR-99021/Laduviglusib, and the NEDD8-activating enzyme inhibitor MLN4924/Pevonedistat, at doses that only slightly affect healthy B cell viability ex vivo. We investigated the molecular basis of this co-induction of cell death by analyzing the alterations in apoptosis-related gene expression. We found that the combinational treatment enhances a reduction in BCL2 mRNA expression levels, providing an alternative approach for BCL-2 inhibition in CLL that could have therapeutic implications for the treatment of refractory CLL cases. Conclusions: our findings revealed a unique interaction between GSK-3ß and NF-kB pathways in CLL and their regulation of BCL2 expression. Full article

A surge has been observed in the use of pesticides to boost agricultural yield in order to feed the continuously increasing human population. Different types and classes of broad-spectrum insecticides are in use, and the number is constantly increasing with the introduction of new ones. Keeping in view the broad-spectrum effects of organophosphate pesticides including Malathion (MLN), their use is continuously increasing without appraising their toxic impacts on non-target organisms. The continuous rise in the use of MLN has led to its presence, persistence, and transport to water bodies globally, subsequently affecting commercially valuable aquatic organisms. The current study was conducted to assess MLN-induced hematological and biochemical toxicities in the brain of a commercially valuable indigenous major carp, rohu, Labeo rohita. The fish was exposed to an acute concentration of commercial-grade MLN. The LC₅₀ of MLN (5 µg/L) led to behavioral inconsistencies and subtle impacts on the hematology (an increase in white blood cells and a reduction in red blood cells, hemoglobin, packed cell volume level, and mean corpuscular hemoglobin concentration) and biochemistry (an increase in reactive oxygen species, lipid peroxidation, activities of antioxidant enzymes (catalase, peroxidase, superoxide dismutase, glutathione, glutathione reductase, glutathione peroxidase, and glutathione-S-transferase) but a reduction in total protein content and activity of Na⁺/K⁺ ATPases) in the brain tissues. MLN also inhibited the activity of Acetylcholinesterase, while it led to an increase in Acetylcholine. Significant changes were observed in the serum biochemical profile; for example, glucose, cholesterol, potassium, urea, and total bilirubin increased, whereas total protein, sodium, chloride, albumin, and inorganic phosphate decreased after exposure. The current study clearly classified MLN as highly toxic to rohu. Therefore, the extra-judicious use of MLN should be strictly supervised. Studies concerning the real-world concentration of pesticides should be carried out on regular basis to mitigate the echoing issue of pesticide-based pollution. Full article

Maize lethal necrosis (MLN) is a significant threat to food security in Sub-Saharan Africa (SSA), with limited commercial inbred lines displaying tolerance. This study analyzed the transcriptomes of four commercially used maize inbred lines and a non-adapted inbred line, all with varying response levels to MLN. RNA-Seq revealed differentially expressed genes in response to infection by maize chlorotic mottle virus (MCMV) and sugarcane mosaic virus (SCMV), the causative agents of MLN. Key findings included the identification of components of the plant innate immune system, such as differentially regulated R genes (mainly LRRs), and activation/deactivation of virus resistance pathways, including RNA interference (RNAi) via Argonaute (AGO), Dicer-like proteins, and the ubiquitin–proteasome system (UPS) via RING/U-box and ubiquitin ligases. Genes associated with redox signaling, WRKY transcription factors, and cell modification were also differentially expressed. Additionally, the expression of translation initiation and elongation factors, eIF4E and eIF4G, correlated with the presence of MLN viruses. These findings provide valuable insights into the molecular mechanisms of MLN resistance and highlight potential gene candidates for engineering or selecting MLN-resistant maize germplasm for SSA. Full article

Background/Objectives: Lumbar spinal stenosis (LSS) is a degenerative condition characterized by the narrowing of the spinal canal, resulting in chronic pain and impaired mobility. However, the molecular mechanisms underlying LSS remain unclear. In this study, we performed RNA sequencing (RNA-seq) to investigate differential gene expression in a rat LSS model and identify the key genes and pathways involved in its pathogenesis. Methods: We used bioinformatics analysis to identify significant alterations in gene expression between the LSS-induced and sham groups. Results: Pearson’s correlation analysis demonstrated strongly consistent intragroup expression (r > 0.9), with distinct gene expression between the LSS and sham groups. A total of 113 differentially expressed genes (DEGs) were identified, including upregulated genes such as Slc47a1 and Prg4 and downregulated genes such as Higd1c and Mln. Functional enrichment analysis revealed that these DEGs included those involved in key biological processes, including synaptic plasticity, extracellular matrix organization, and hormonal regulation. Gene ontology analysis highlighted critical molecular functions such as mRNA binding and integrin binding, as well as cellular components such as contractile fibers and the extracellular matrix, which were significantly affected by LSS. Conclusions: Our findings provide novel insights into the molecular mechanisms underlying LSS and offer potential avenues for the development of targeted therapies aimed at mitigating disease progression and improving patient outcomes. Full article

Neuroinflammation is a complex and multifaceted process that involves dynamic interactions among various cellular and molecular components. This sophisticated interplay supports both environmental adaptability and system resilience in the central nervous system (CNS) but may be disrupted during neuroinflammation. In this article, we first characterize the key players in neuroimmune interactions, including microglia, astrocytes, neurons, immune cells, and essential signaling molecules such as cytokines, neurotransmitters, extracellular matrix (ECM) components, and neurotrophic factors. Under homeostatic conditions, these elements promote cellular cooperation and stability, whereas in neuroinflammatory states, they drive adaptive responses that may become pathological if dysregulated. We examine how neuroimmune interactions, mediated through these cellular actors and signaling pathways, create complex networks that regulate CNS functionality and respond to injury or inflammation. To further elucidate these dynamics, we provide insights using a multilayer network (MLN) approach, highlighting the interconnected nature of neuroimmune interactions under both inflammatory and homeostatic conditions. This perspective aims to enhance our understanding of neuroimmune communication and the mechanisms underlying shifts from homeostasis to neuroinflammation. Applying an MLN approach offers a more integrative view of CNS resilience and adaptability, helping to clarify inflammatory processes and identify novel intervention points within the layered landscape of neuroinflammatory responses. Full article