Search Results (10,414)

Parkinson’s disease (PD) is one of the most rapidly growing neurological disorders globally. The molecular relationship between common respiratory infections (RIs) and idiopathic Parkinson’s disease (iPD) remains a controversial issue. Multiple studies have linked acute respiratory infections to PD, but the molecular mechanism behind this connection is not significantly defined. Therefore, the aim of our study was to investigate potential molecular interactions between RIs and PD. We retrieved eight publicly available RNA-seq datasets from the NCBI Gene Expression Omnibus (NCBI GEO) and performed extensive bioinformatics analysis, including differential gene expression (DGE) analysis, the identification of overlapped differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA), pathway and functional enrichment analysis, the construction of protein–protein networks, and the identification of hub genes. Additionally, we applied a machine learning method, a Random Forest model (RF), to external RIs datasets to identify the most important genes. We found that ribosomal subunits, mitochondrial complex proteins, proteasome subunits, and proteins encoding ubiquitin are simultaneously downregulated and co-expressed in RIs and PD. Dysregulation of these proteins may disturb multiple pathways, such as those responsible for ribosome biogenesis, protein synthesis, autophagy, and apoptosis; the ubiquitin–proteasome system (UPS); and the mitochondrial respiratory chain. These processes have been implicated in PD’s pathology, namely in the aggregation of α-synuclein, mitochondrial dysfunction, and the death of dopaminergic neuron cells. Our findings suggest that there are significant similarities in transcriptional responses and dysfunctional molecular mechanisms between RIs, PD, and aging. RIs may modulate PD-relevant pathways in an age- or immune-dependent manner; longitudinal studies are needed to examine the RIs risk factor. Therefore, future studies should experimentally investigate the influence of age, vaccination status, infection type, and severity to clarify the role of RIs in PD’s pathogenesis. Full article

Background/Objectives: The effects of PD-L1 are mediated via its binding to the PD-1 receptor, which mediates the signals intracellularly to suppress T-cell responses. The expression levels of PD-L1 on cancer cells are an important indicator of immunosuppression and cause poor prognosis in several types of cancers. Therefore, the identification and characterization of mechanisms that regulate the expression of PD-L1 in cancer patients is very critical. Method: Our experiment was designed to determine the impact of histone deacetylase (HDAC) inhibitor on PD-L1 expression to reverse tumor-induced immunosuppression using H460 and HCC827 lung cancer cell lines. These cells were treated with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). PD-L1 expression levels were assessed along with key regulatory proteins, including p53, p21, acetyl-histones, DNMT3B, MGMT, and trimethyl histones. Results: In our experiments, suberoylanilide hydroxamic acid (SAHA) was able to reduce the expression of PD-L1 by 60% in a dose-dependent manner. While the level of PD-L1 was significantly reduced, a concurrent increase in levels of p53, p21, and acetyl histone levels were observed in H460 and HCC827 cells following SAHA treatment. Furthermore, SAHA treatment was able to decrease the levels of DNMT3B, MGMT, and tri-methyl histones. It appears that the decrease in PD-L1 expression observed is solely because of p53 or p21WAF1/CIP1-mediated negative control on the transcription process. Conclusion: Our results suggest that SAHA can be used along with immune checkpoint inhibitors to potentiate the therapeutic outcomes in patients with excessive immunosuppression due to PD-L1 expression. Full article

Coxiella burnetii, the causative agent of Q fever, is a highly infectious pathogen capable of invading diverse cell types, from alveolar macrophages to trophoblasts. Within host cells, it establishes a replicative niche named Coxiella-containing vacuole (CCV). This is driven by effector proteins secreted by the bacterium into the host cell cytoplasm via a Type 4b Secretion System (T4SS). Advances in axenic culture and mutagenesis allowed the characterization of Coxiella effector proteins, revealing their host targets and strategies of cellular subversion. This review highlights recent insights into Coxiella effector proteins and their manipulation of host processes, from vesicular trafficking to innate immunity. Full article

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of certain hematologic malignancies, yet its success in solid tumors has been limited by antigen heterogeneity, an immunosuppressive tumor microenvironment, and barriers to cell trafficking and persistence. To expand the reach of cellular immunotherapy, multiple immune cell types—γδ T cells, invariant NKT cells, virus-specific T cells, natural killer (ΝΚ) cells, and myeloid effectors such as macrophages and dendritic cells—are now being explored as alternative or complementary CAR platforms. Each lineage brings unique advantages, such as the innate cytotoxicity and safety profile of CAR NK cells, the tissue infiltration and microenvironment-modulating capacity of CAR macrophages, or the MHC-independent recognition offered by γδ T cells. Recent advances in pharmacological strategies, synthetic biology, and artificial intelligence provide additional opportunities to overcome barriers and optimize CAR design and manufacturing scale-up. Here, we review the state of the art in engineering diverse immune cells for solid tumor therapy, highlight safety considerations across autologous, allogeneic, and in vivo CAR cell therapy approaches, and provide our perspective on which platforms might best address current unmet clinical needs. Collectively, these developments lay the foundation for next-generation strategies to achieve durable immunotherapy responses in solid tumors. Full article

The 2022 global mpox outbreak highlighted the risk of sustained human-to-human transmission of monkeypox virus (MPXV) in non-endemic regions, yet genomic surveillance in Asia, particularly in China, remains limited. This study conducted horizontal genomic surveillance of MPXV in Shenzhen from 2023 to 2024 to characterize the phylogenetic structure, mutational patterns, and adaptive evolution of locally circulating strains. Phylogenetic analysis showed 95.2% of strains belonged to the dominant lineage C.1.1, with 4.8% in lineage E.3, forming three distinct genetic clusters that indicate multiple independent introductions and established local transmission chains. Whole-genome mutational analysis identified 146 single-nucleotide polymorphisms (SNPs), 81.5% of which carried APOBEC3-mediated mutation signatures (TC > TT and GA > AA), reflecting host-driven antiviral editing. Notably, dynamic changes in low-complexity regions (LCRs) were observed, implying potential roles in genome plasticity and adaptive evolution. Functional analysis revealed non-synonymous substitution biases in host-interacting proteins OPG064, OPG145, and OPG210, while replication protein OPG105 remained conserved. Structural modeling identified critical substitutions in OPG002 (S54F), OPG016 (R84K), and OPG036 (R48C) that may enhance immune evasion by modulating TNF-α signaling, NKG2D engagement, and Type I interferon antagonism. These findings illuminate unique MPXV evolutionary dynamics in Shenzhen, emphasizing continuous genomic surveillance for non-endemic outbreak preparedness. Full article

Background: The efficacy of a novel combined vaccine targeting porcine circovirus types 2a/d (PCV2a/d), Mycoplasma hyopneumoniae, and M. hyorhinis was evaluated in a controlled challenge study. Methods: A total of 45 pigs were randomly allocated into nine groups (five pigs per group). Vaccinated groups received a single 2 mL intramuscular dose of the combined vaccine and were subsequently challenged with PCV2a, PCV2d, M. hyopneumoniae, and M. hyorhinis. Unvaccinated groups received a single 2 mL intramuscular dose of phosphate-buffered saline (0.01 M, pH 7.4). Growth performance, systemic adaptive immune (humoral and cellular) responses, viremia, laryngeal and nasal mycoplasma loads, and histopathological lesions were assessed. Results: Vaccinated pigs exhibited enhanced growth performance and elicited systemic immune responses, including both humoral and cellular immunity, against all four pathogens. Vaccination also significantly reduced viremia, mycoplasmal loads in laryngeal and nasal swabs, and the severity of associated lesions compared with unvaccinated controls. Conclusions: These results indicated that the combined vaccine was efficacious and conferred protection against PCV2a, PCV2d, M. hyopneumoniae, and M. hyorhinis challenge under experimental conditions. This combined vaccine represented an effective strategy to enhance growth performance and control complex co-infection in swine populations. Full article

The low immunogenicity and immune escape are bottlenecks for effective hepatocellular carcinoma (HCC) immunotherapy. We prepared and characterized a dual-target liposome complex, XA5508, by encapsulating the STING agonist cGAMP in liposomes and conjugating an anti-PD-L1 nanobody to the liposome surface. The anti-tumor effect and pharmacological mechanism of XA5508 were investigated using an in situ HCC mouse model. XA5508 can effectively inhibit in situ HCC with the characteristics of tumor-targeted delivery and sustained release of STING agonist cGAMP. The pharmacological mechanism study indicates that XA5508 activates the STING signaling pathway, increases the cytotoxicity of CD8⁺ T cells, reverses the immunosuppressive tumor microenvironment (TME) represented by M2-type macrophages, and transforms cold tumors into hot tumors. On the other hand, cGAMP induces the upregulation of PD-L1 expression in HCC, enhances the response of anti-PD-L1 nanobody (Nb) and the escape blockade of immune checkpoint PD-1/PD-L1. XA5508 shows remarkable anti-tumor effects of STING agonist and anti-PD-L1 nanobody against HCC, providing an innovative strategy for the development of new drugs for HCC. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly heterogeneous malignancy, characterized by low tumor cellularity, a dense stromal response, and intricate cellular and molecular interactions within the tumor microenvironment (TME). Although bulk omics technologies have enhanced our understanding of the molecular landscape of PDAC, the specific contributions of non-malignant immune and stromal components to tumor progression and therapeutic response remain poorly understood. Methods: We explored genome-wide DNA methylation and transcriptomic data from the Cancer Genome Atlas Pancreatic Adenocarcinoma cohort (TCGA-PAAD) to profile the immune composition of the TME and uncover gene co-expression networks. Bioinformatic analyses included DNA methylation profiling followed by hierarchical deconvolution, epigenetic age estimation, and a weighted gene co-expression network analysis (WGCNA). Results: The unsupervised clustering of methylation profiles identified two major tumor groups, with Group 2 (n = 98) exhibiting higher tumor purity and a greater frequency of KRAS mutations compared to Group 1 (n = 87) (p < 0.0001). The hierarchical deconvolution of DNA methylation data revealed three distinct TME subtypes, termed hypo-inflamed (immune-deserted), myeloid-enriched, and lymphoid-enriched (notably T-cell predominant). These immune clusters were further supported by co-expression modules identified via WGCNA, which were enriched in immune regulatory and signaling pathways. Conclusions: This integrative epigenomic–transcriptomic analysis offers a robust framework for stratifying PDAC patients based on the tumor immune microenvironment (TIME), providing valuable insights for biomarker discovery and the development of precision immunotherapies. Full article

The American cockroach (Periplaneta americana) serves as an exemplary model for regeneration research due to its exceptional regenerative capabilities, particularly in appendage regeneration. In this study, regenerated coxa tissue underwent histological analysis through H & E straining. Microscopic examination revealed the progression of regeneration. To elucidate the underlying mechanisms, a comparative transcriptomic analysis was conducted between regenerating legs and non-amputated control legs. This analysis identified 2343 differentially expressed genes (DEGs) between 0 days post-amputation (0 dpa) and 7 dpa, 2963 DEGs between 14 dpa and 0 dpa, and 3135 DEGs between 14 dpa and 7 dpa. Significantly, several DEGs are associated with growth- or regeneration-related processes, including extracellular matrix (different collagen, Pro-resilin isoforms, integrin beta (itgb) and matrix metalloproteinase (mmp)), immune-related genes (Toll-like receptor 13 (tlr13), defensin (def), drosomycin-like defensin (dld), Polyphenoloxidases2 (ppo2), cytochrome P450 (p450), peptidoglycan recognition protein (pgrp) and secreted C-type lectin (sClec)), insulin-like growth factor (IGF) and Epidermal Growth Factor Receptor (EGFR). Functional validation through RNA interference (RNAi) further suggested that EGFR and a specific C-type lectin (Regenectin) regulate leg regeneration in Periplaneta americana. These findings enhance our understanding of the molecular mechanisms governing regeneration in this species. Full article

Background/Objectives: Microplastics are ubiquitous pollutants that pose physical toxicity and serve as vectors for antimicrobial agents, altering their bioavailability and toxicity. Unlike previous reviews that focus solely on antibiotics and terrestrial or aquatic ecosystems, this review integrates recent findings on the combined impacts of microplastics and antimicrobials on both aquatic and terrestrial animals, highlighting their biological responses. Methods: Recent experimental studies involving aquatic and terrestrial animals published in peer-reviewed journals were reviewed. These studies employed co-exposure designs using microplastics of different sizes, aging conditions, and surface chemistries in combination with antimicrobial compounds. Results: Microplastics combined with antimicrobials cause species-specific and often synergistic toxicity in aquatic organisms, affecting reproduction, immunity, oxidative stress, gene expression, and microbiota, with co-exposure often amplifying adverse physiological and developmental effects. Similarly, co-exposure to microplastics and antimicrobials in rodents, amphibians, birds, and soil invertebrates frequently leads to synergistic toxicity, oxidative stress, disrupted gut microbiota, and enhanced accumulation and bioavailability of pollutants, promoting inflammation, neurotoxicity, metabolic dysfunction, and increased antibiotic resistance gene propagation. Particle size, aging, and antimicrobial type influence toxicity severity. Certain microplastic-antimicrobial combinations can exhibit antagonistic effects, though less frequently reported. Conclusions: The interactions between microplastics and antimicrobials pose heightened risks to the health of organisms and ecological stability. These findings underscore the need to revise current risk assessment protocols to consider pollutant mixtures and microplastics-mediated transport. Future research should focus on environmentally relevant exposures, mechanistic studies using omics tools, and long-term ecological impacts. Integrated regulatory strategies are essential to address the compounded effects of microplastics and chemical contaminants. Full article

The innate immune system protects against infection and cellular damage by recognizing conserved pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Emerging evidence suggests that aberrant epigenetic modifications—such as altered DNA methylation and histone marks—can serve as immunogenic signals that activate pattern recognition receptor (PRR)-mediated immune surveillance. This review explores the concept that epigenetic marks may function as DAMPs or even mimic PAMPs. I highlight how unmethylated CpG motifs, which are typically suppressed using host methylation, are recognized as foreign via Toll-like receptor 9 (TLR9). I also examine how cytosolic DNA sensors, including cGAS, detect mislocalized or hypomethylated self-DNA resulting from genomic instability. In addition, I discuss how extracellular histones and nucleosomes released during cell death or stress can act as DAMPs that engage TLRs and activate inflammasomes. In the context of cancer, I review how epigenetic dysregulation can induce a “viral mimicry” state, where reactivation of endogenous retroelements produces double-stranded RNA sensed by RIG-I and MDA5, triggering type I interferon responses. Finally, I address open questions and future directions, including how immune recognition of epigenetic alterations might be leveraged for cancer immunotherapy or regulated to prevent autoimmunity. By integrating recent findings, this review underscores the emerging concept of the epigenome as a target of innate immune recognition, bridging the fields of immunology, epigenetics, and cancer biology. Full article

Background: The circadian rhythm regulates important functions in the body, such as metabolism, the cell cycle, DNA repair, and immune balance. Disruption of this rhythm can contribute to the development of cancer. Circadian rhythm genes (CRGs) are attracting attention for their connection to various cancers. However, their roles in LUAD are not yet well understood. Additionally, our knowledge of how they function at both the bulk tissue and single-cell levels is limited. This gap hinders a complete understanding of how CRGs impact the development and outcomes of LUAD. Methods: We selected 554 CRGs from public databases. We then obtained transcriptome data from TCGA and GEO. A total of 101 machine learning algorithm combinations were tested using 10 algorithms and 10-fold cross-validation. The best-performing model was based on Stepwise Cox regression and SuperPC. This model was validated with additional datasets. We also examined the relationships between CRGs, immune features, tumor mutation burden (TMB), and the response to immunotherapy. Drug sensitivity was also assessed. Single-cell data identified the cell types with active CRGs. Next, we performed qRT-PCR and other basic experiments to validate the expression of ARNTL2 in LUAD tissues and cell lines. The results indicated that ARNTL2 may play a key role in lung adenocarcinoma. Results: The CRG-based model clearly distinguished LUAD patients based on their risk. High-risk patients exhibited low immune activity, high TMB, and poor predicted responses to immunotherapy. Single-cell data revealed strong CRG signals in epithelial and fibroblast cells. These cell groups also displayed different communication patterns. Laboratory experiments showed that ARNTL2 was highly expressed in LUAD. It promoted cell growth, movement, and invasion. This suggests that ARNTL2 may play a role in promoting cancer. Conclusions: This study developed a machine learning model based on CRGs. It can predict survival and immune status in LUAD patients. The research also identified ARNTL2 as a key gene that may contribute to cancer progression. These findings highlight the significance of the circadian rhythm in LUAD and provide new perspectives for diagnosis and treatment. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD)—previously known as non-alcoholic fatty liver disease (NAFLD)—is currently the most common chronic liver disease globally. Observational studies have reported that MASLD is independently associated with extrahepatic disorders, such as chronic kidney disease (CKD). Severe forms of MASLD (i.e., steatohepatitis and liver fibrosis) are even more strongly associated with the risk of incident kidney dysfunction. Hypothetically, MASLD could directly promote CKD through liver-derived endocrine and metabolic mediators, hemodynamic alterations, immune-mediated mechanisms, and oxidative or cellular stress. However, proving that MASLD directly causes CKD is difficult due to the multiple shared cardiometabolic and systemic risk factors, such as obesity, hypertension, and type 2 diabetes mellitus, which serve as confounding variables. Moreover, studies on the association between MASLD and CKD have differed in their designs, sampling methods, disease definitions, and inclusion criteria, precluding more robust evidence supporting a causal relationship. Furthermore, few studies have explored specific issues, such as the new nomenclature for steatotic liver disease, the relationship between these diseases in pediatric populations, the impact of MASLD plus alcohol intake (MetALD) on CKD, and therapeutic options targeting MASLD and CKD simultaneously. Answers to these issues are essential, as the appropriate management of patients with MASLD may prevent or ameliorate kidney dysfunction. The aims of the present study are to describe shared risk factors between MASLD and CKD, the possible direct pathogenic effect of MASLD on kidney structure and function, and gaps in the current literature, to indicate future research directions. Full article

Background: The SUMO E3 ligase PIAS1 (Protein Inhibitor of Activated STAT1) regulates pathways such as TGFβ signaling and has been implicated in multiple cancers. However, its role in the tumor microenvironment (TME), particularly in non-malignant stromal and immune cells, remains poorly understood. This study aimed to characterize the expression and functional relevance of PIAS1 within the TME of oral squamous cell carcinoma (OSCC). Methods: PIAS1 protein expression was assessed via immunohistochemistry (IHC) on OSCC tissue microarrays. Single-cell RNA-sequencing (scRNA-seq) datasets from OSCC tumors and normal tissues were analyzed to map cell-type-specific PIAS1 expression. Downstream effects were evaluated using differential gene expression, Ingenuity Pathway Analysis (IPA), gene set enrichment analysis (GSEA), and cell–cell communication inference. Results: IHC analysis revealed that higher stromal PIAS1 levels correlated with improved survival. scRNA-seq analysis showed an increase in the proportion of PIAS1-expressing cells across most stromal and immune cell populations within OSCC-derived tumors compared to their counterparts in adjacent normal tissue. However, when comparing PIAS1-positive cells, expression levels were significantly reduced in cancer cells, CAFs, TAMs, T cells, and endothelial cells within the TME. PIAS1-positive CAFs, TAMs, and T cells exhibited activation of apoptotic and tumor-suppressive pathways, while PIAS1-negative counterparts showed enrichment of immunosuppressive signaling and immune checkpoint expression. Cell–cell communication analyses indicated that PIAS1 fosters an immune-activated TME by promoting pro-inflammatory signaling, M1-like TAM polarization, and T cell activation. Conclusions: PIAS1 expression in stromal and immune cells is associated with tumor-suppressive reprogramming of the OSCC microenvironment. These findings position PIAS1 as a potential modulator of anti-tumor immunity and candidate target for therapeutic intervention. Full article

Background: Staphylococcus aureus is a major zoonotic and foodborne pathogen with substantial One Health implications, yet its prevalence, resistance, and virulence potential within the aquaculture sector in Nigeria remains poorly characterized. Objectives: To supplement existing information, this current study investigated the prevalence, clonal distribution, antimicrobial resistance, and virulence gene profiles of S. aureus isolates from fish, fish water, and occupationally exposed fish handlers in Anambra State, Southeast Nigeria. Methods: A total of 607 samples—comprising 465 surface swabs from raw and processed fish, 36 fish water samples, and 106 nasal swabs from fish handlers—were processed using selective culture, biochemical tests, antimicrobial susceptibility testing, DNA microarray analysis, spa typing, and SCCmec typing. Results: S. aureus was recovered from 16.5% (100/607) of the samples. Fourteen (14%) isolates were methicillin-resistant (MRSA), harboring mecA and SCCmec types IV and V, with a combined MRSA prevalence of 2.3%. Multidrug resistance was observed in 52.2% of isolates (mean Multiple Antimicrobial Resistance index: 0.23), with 19 resistance genes spanning nine antimicrobial classes—including heavy metal and biocide resistance. Twenty-eight spa types across 13 clonal complexes (CCs) were identified, with CC1, CC5, and CC8 predominating. The detection of shared spa types between fish and handlers indicates potential cross-contamination. Detected virulence genes included those for accessory gene regulators (agrI-IV), Pantone–Valentine leucocidin (lukFS-PV), toxic shock syndrome (tsst-1), hemolysins (hla, hlb, hld/hlIII, hlgA), biofilm formation (icaA, icaD), immune evasion (chp, scn, sak), enterotoxins (sea, seb, sec, sed, egc, and others), exfoliative toxins (etA, etB), epidermal cells differentiation (edinA, edinB), and capsular types (cap5, cap8). Conclusions: This study reveals that the aquaculture sector in Southeast Nigeria serves as a significant reservoir of genetically diverse, multidrug-resistant S. aureus strains with robust virulence profiles. These findings highlight the necessity of integrated One Health surveillance and targeted interventions addressing antimicrobial use and hygiene practices within aquatic food systems. Full article