Immune Signaling Pathways Research Articles

Overexpression of metalloproteinase PAPPA accelerates cancer progression and correlates with immune cell infiltration in gastric cancer: insights from bioinformatics and in vitro investigations

BackgroundGastric cancer (GC) is one of the most common malignant tumors in the digestive system. However, the development of its targeted therapies has been slow. Therefore, exploring the mechanisms of malignant behavior of GC is key to developing their treatment methods. Pregnancy-associated plasma protein-A(PAPPA) is thought to play an important role in the occurrence and progression of cancer, yet its significance in the development of GC has not been reported.MethodsBioinformatics analysis elucidated PAPPA's expression in GC and its prognostic significance. The study correlated PAPPA expression with immune infiltration and signaling pathways. Cellular assays, including CCK-8, Western blotting, and flow cytometry, were utilized to examine PAPPA's role in gastric cancer cell apoptosis, migration, and invasion.ResultsBioinformatics analysis has demonstrated that the expression of PAPPA is upregulated in GC and correlates with poor prognosis. Correlation and Cox regression analyses have revealed that TNM staging, pathological staging, age, outcome assessment, postoperative tumor residue, and PAPPA expression are prognostic determinants in GC. Further analysis indicates that PAPPA is associated with the infiltration of various immune cells and pathways related to GC. Cellular experiments have shown that PAPPA promotes cell proliferation, and its deficiency can inhibit the proliferation of GC cells, inducing cell cycle arrest at the G1/S phase.ConclusionsThe findings of this investigation suggest that PAPPA serves as a crucial modulator of GC, underscoring its potential as a GC treatment target.

Convalescent COVID-19 monocytes exhibit altered steady-state gene expression and reduced TLR2, TLR4 and RIG-I induced cytokine expression.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, can induce trained immunity in monocytes. Trained immunity is the result of metabolic and epigenetic reprogramming of progenitor cells leading to an altered inflammatory response to subsequent activation. To investigate the monocyte response 3-6months post SARS-CoV-2 infection, steady-state gene expression and innate immune receptor stimulation were investigated in monocytes from unvaccinated SARS-CoV-2 naïve individuals and convalescent COVID-19 participants. The differentially expressed genes (DEGs) identified were involved in the regulation of innate immune signalling pathways associated with anti-viral defence. COVID-19 participants who had experienced severe symptoms exhibited a larger number of DEGs than participants that had mild symptoms. Interestingly, genes encoding receptors that recognise SARS-CoV-2 RNA were downregulated. DDX58, encoding retinoic-acid inducible gene I (RIG-I), was downregulated which corresponded with a reduced response to RIG-I activation. Furthermore, toll-like receptor (TLR)1/2 and TLR4 activation also exhibited reduced cytokine secretion from convalescent COVID-19 monocytes. These data suggest that following SARS-CoV-2 infection, monocytes exhibit altered steady-state gene expression and reduced responsiveness to innate immune receptor activation. As both RIG-I and TLRs recognise components of SARS-CoV-2, this may lead to a moderated inflammatory response to SARS-CoV-2 reinfection in the months following the initial infection.

Comprehensive SUMO Proteomic Analyses Identify HIV Latency-Associated Proteins in Microglia

SUMOylation, the post-translational modification of proteins by small ubiquitin-like modifiers, plays a critical role in regulating various cellular processes, including innate immunity. This modification is essential for modulating immune responses and influencing signaling pathways that govern the activation and function of immune cells. Recent studies suggest that SUMOylation also contributes to the pathophysiology of central nervous system (CNS) viral infections, where it contributes to the host response and viral replication dynamics. Here, we explore the multifaceted role of SUMOylation in innate immune signaling and its implications for viral infections within the CNS. Notably, we present novel proteomic analyses aimed at elucidating the role of the small ubiquitin-related modifier (SUMO) in human immunodeficiency virus (HIV) latency in microglial cells. Our findings indicate that SUMOylation may regulate key proteins involved in maintaining viral latency, suggesting a potential mechanism by which HIV evades immune detection in the CNS. By integrating insights from proteomics with functional studies, we anticipate these findings to be the groundwork for future studies on HIV–host interactions and the mechanisms that underlie SUMOylation during latent and productive infection.

Lipoxin B4 and lipocalin play a crucial role in insect immune-priming induced by a gut microbial commensal.

Host cabbage possesses an endophyte, Bacillus subtilis, which induced immune-priming of the diamondback moth, Plutella xylostella. In contrast, larvae raised under axenic conditions lost the chance to feed the bacteria and were highly susceptible to various pathogens. Addition of B. subtilis to axenic larvae significantly restored immune responses and enhanced survival rates following pathogen infections. The immune-priming factor(s) was determined among 18 apolipoprotein D (ApoD) genes identified as lipocalin candidates in P. xylostella, in which ApoD1 expression was functionally linked with B. subtilis-induced immune-priming. In addition, lipoxins were analyzed in immune-primed larvae via LC-MS/MS, in which LXB4 was detected, but not LXA4. The LXB4 titer was significantly higher than that that in the larvae reared under axenic conditions. Notably, LXB4 alone sufficiently induced significant immune responses. To support lipoxin biosynthesis in insects, this study identified a lipoxygenase-like peroxidase gene, HemP2. Its expression was induced in the immune-primed larvae. However, its suppression prevented LXB4 production under the immune-priming conditions. To explain the up-regulations of lipocalin/lipoxin by the gut commensal, Toll and IMD immune signaling pathways were analyzed. The up-regulation of ApoD1 and HemP2 expressions was mediated through the IMD, but not the Toll, immune signaling pathway in the larval gut of P. xylostella under B. subtilis-induced immune-priming conditions. This study highlights the potential role of commensal gut microbes including B. subtilis in driving immune-priming via an insect lipoxin-lipocalin complex through the IMD immune signaling pathway.

High-fat diet and neuroinflammation: The role of mitochondria.

In recent years, increasing evidence has supported that high-fat diet (HFD) can induce the chronic, low-grade neuroinflammation in the brain, which is closely associated with the impairment of cognitive function. As the key organelles responsible for energy metabolism in the cell, mitochondria are believed to involved in the pathogenesis of a variety of neurological disorders. This review summarizes the current progress in the field of the relationship between HFD exposure and neurodegenerative diseases, and outline the major routines of HFD induced neuroinflammation and its pathological significance in the pathogenesis of neurodegenerative diseases. Furthermore, the article highlights the pivotal role of mitochondrial dysfunction in driving the neuroinflammation in the setting of HFD. Danger-associated molecular patterns (DAMPs) from damaged mitochondria can activate innate immune signaling pathways, while mitochondrial dysfunction itself can lead to metabolic remodeling of inflammatory cells, thus inducing neuroinflammation. More importantly, mitochondrial damage, neuroinflammation, and insulin resistance caused by HFD form a mutually reinforcing vicious cycle, ultimately leading to the death of neurons and promoting the progression of neurodegenerative diseases. Thus, in-depth elucidation of the role and underlying mechanisms of mitochondrial dysfunction in HFD-induced metabolic disorders may not only expand our understanding of the mechanistic linkages between HFD and etiology of neurodegenerative diseases, but also help develop the specific strategies for the prevention and treatment of neurodegenerative diseases.

Physiological impact of secondary nanoplastics on aquatic inhabitants in special reference to immunotoxicity.

Nanoplastic (NP) pollution poses serious health hazards to aquatic ecosystems, impacting various physiological systems of aquatic organisms. This review examines the complex interplay between NPs and different physiological systems. In the digestive system, NPs downregulate the hsp70-like gene in Mytilus galloprovincialis, leading to decreased metabolic processes and impaired digestion. Neural system exposure to NPs induces abnormal expression of genes like neurogenin1, GFAP, FBJ murine osteosarcoma viral oncogene, GAP-43, synapsin IIa, apoptosis regulator a, Bcl2 and Caspase a, and apoptosis-related cysteine peptidase. These genes play a crucial role in neurodevelopment, synaptic function and apoptosis regulation, potentially impacting neurobiology and cancer biology. NPs also affect reproduction, including gametogenesis, spawning, fertilization, embryogenesis and larval survivability. In the respiratory system, treatment with these causes inflammation in the lungs and gills, resulting in respiratory dysfunction. Moreover, this review investigates the complex interaction between NPs and the immune systems of both invertebrates (e.g., molluscs, arthropods, echinoderms) and vertebrates (e.g., zebrafish). NPs-induced alterations in immune cell function heightened the susceptibility to pathogens and disrupted immune signalling pathways. Subcellular inflammatory responses have been characterized by the secretion of inflammation-promoting and chemotactic cytokines such as irg1l, interleukin 1, interferon, interleukin 6, C-C motif chemokine ligand 20a and tumour necrosis factor. The assessment of the combined effects of NPs and other xenobiotics highlighted their possible synergistic impacts on aquatic fauna and the environment. This comprehensive review emphasizes the urgent need for further research to understand the cumulative effects of NPs on organism health and fitness across multiple physiological systems.

P-1198. Molecular and Microbiome/Metagenome Correlates of Illness in Respiratory Syncytial Virus (RSV) Infected Infants

Abstract Background Respiratory syncytial virus (RSV) epidemics are a leading cause of hospitalization in infants. Those infants with severe illness appear more likely to develop recurrent wheeze. We aimed to test if airway gene expression and microbiome/metagenome composition in the nasal epithelium during primary RSV infection are associated with illness severity and can identify infants with recurrent wheeze.Table 1.Subject Characteristics Methods Healthy infants with PCR confirmed RSV were prospectively recruited from inpatient and outpatient locations over three seasons (Dec 2019 to Dec 2023). Clinical and demographic data, 2 anterior nasal swabs and a nasal wash were collected. Microbiome/metagenome analysis and transcriptome/RNA sequencing were performed on the nasal biospecimens. Disease severity was measured by the Global Respiratory Severity Score (GRSS) and retrained improved Global Respiratory Severity Score (iGRSS). Subjects were followed for 12 months to identify recurrent wheezing.Figure 1.Top 20 genes associated with iGRSS Results 100 (80 hospitalized) infants were enrolled. Two children were found to be ineligible leaving 98 for analysis. The average age was 3.2 (2.3 SD) months. 60 (61%) were male. A multivariate linear regression model was used to associate gene expression profiles with GRSS and iGRSS. After controlling false discovery rate (FDR) at 0.10 level, 283 genes were significantly associated with iGRSS (95 at 0.05). Gene expression changes involved both Innate Immune and Interleukin Signaling pathways. Metagenome analysis identified microbial species and the microbial metabolic state of the nares during acute infection. We found an abundance of Moraxella in the anterior nares was inversely associated with iGRSS while the abundance of Haemophilus was directly associated with iGRSS. We also identified 29 metabolic pathways associated with the iGRSS including coenzyme A biosynthesis I (procaryotic), mixed acid fermentation, Cavin-Benson-Bassham cycle and superpathways of branched chain amino acid biosynthesis.Figure 2.Bacterial Abundance vs. iGRSS Conclusion We enrolled a cohort of previously healthy infants with primary RSV infection and identified associations between host nasal gene expression, nasal microbiome/metagenome composition/activity and disease severity. We are currently testing for associations between these biomarkers and recurrent wheeze.Figure 3.Metabolic Pathways associated with iGRSS Disclosures Mary T. Caserta, MD, Merck: Grant/Research Support|Moderna: Grant/Research Support|Pfizer: Grant/Research Support Edward E. Walsh, MD, Enanta: Advisor/Consultant|Enanta: Honoraria|GSK: Advisor/Consultant|Janssen: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support

TNIP1 Impacts Prognosis by Modulating the Immune Microenvironment in BRCA.

Breast invasive carcinoma (BRCA) affects women worldwide, and despite advancements in diagnosis, prevention, and treatment, outcomes remain suboptimal. TNIP1, a novel target involved in multiple immune signaling pathways, influences tumor development and survival. However, the connection between BRCA and TNIP1 remains unclear. Analysis of data from the TCGA, GEO, Sangerbox, and Ualcan databases revealed that TNIP1 is underexpressed in BRCA tissues. This finding was corroborated by RT-PCR and immunohistochemistry. Furthermore, data from the TCGA and GEPIA2 databases, along with Sangerbox, identified TNIP1 as a marker of poor prognosis in BRCA patients. TNIP1 expression shows significant positive correlations with the BRCA Tumor Microenvironment (TME) StromalScore (R = 0.22), ImmuneScore (R = 0.25), and ESTIMATEScore (R = 0.27). Various algorithms have demonstrated a strong association between TNIP1 expression and BRCA tumor-infiltrating immune cells (TIICs). Further analysis using EPIC, TIMER, MCPCounter, QUANTISEQ, xCell, and other computational tools revealed that elevated TNIP1 expression is significantly associated with increased immune cell scores. TNIP1 expression in BRCA tumor tissues also shows a strong correlation with immune checkpoint markers. Data from the HAP database indicate that TNIP1 expression is predominantly involved in the normal skin microenvironment. Subsequent analysis using the TISCH platform with the BRCA single-cell dataset demonstrated that TNIP1 exhibits higher expression levels in immune cells compared to non-immune cells in BRCA patients. This expression is significantly positively correlated with inflammation (R = 0.25) and differentiation (R = 0.28) within the TME, while showing negative correlations with BRCA stemness (R = -0.34) and invasion (R = -0.22). Consequently, TNIP1 is proposed as a potential prognostic marker and therapeutic target for BRCA.

MA104 cell line is permissive for human bocavirus 1 infection.

Human bocavirus 1 (HBoV1) has appeared as an emerging pathogen, causing mild to life-threatening respiratory tract infections, acute otitis media, and encephalitis in young children and immunocompromised individuals. The lack of cell lines suitable for culturing replicative viruses hinders research on HBoV1. Here, we characterized the susceptibility to HBoV1 of 29 human and 7 animal cell lines, and identified a permissive cell line, MA104. The complete HBoV1 life cycle was achieved in MA104 cells, including viral entry, complete replication, and infectious progeny virion production. Additionally, the suppression of the interferon pathway facilitated the viral genome replication in MA104 cells. RNA-sequencing showed that innate immunity, inflammation, the PI3K-Akt and MAPK signaling pathways, and the cellular membrane system were mobilized in response to HBoV1 infection. Overall, our study is the first to identify a cell line, MA104, that supports the complete HBoV1 life cycle, which will promote research on HBoV1 virology and pathogenesis and benefit drug and vaccine development.IMPORTANCEHBoV1 is an emerging pathogen that mainly causes respiratory tract infections, while the lack of cell lines suitable for culture replicative viruses hindered research on HBoV1. Here, we identify a permissive cell line for HBoV1 infection, MA104, and reveal that the complete life cycle of HBoV1 was supported in MA104 cells. Our findings provide a suitable cell model for the study of HBoV1 and explore its application for antiviral drug evaluation, which is vital for research on HBoV1 virology and pathogenesis, as well as for drug and vaccine development.

Exposure to Group B Streptococcus-induced chorioamnionitis alters the proteome of placental extracellular vesicles.

Group B Streptococcus (GBS) is an opportunistic pathogen that can induce chorioamnionitis (CA), increasing the risk of neurodevelopmental disorders (NDDs) in the offspring. The placenta facilitates maternal-fetal communication through the release of extracellular vesicles (EVs), which may carry inflammatory molecules such as interleukin (IL)-1. Although the role of EVs in immune modulation is well established, their specific characterization in the context of GBS-induced CA has not yet been investigated. Understanding placental-derived EVs could further define how IL-1 and other inflammatory factors contribute to NDDs. We used an established rat model of GBS-induced CA. EVs from control and GBS infected dams were isolated from placentas and characterized using nanoparticle tracking analysis and transmission electron microscopy. The protein content was assessed via mass spectrometry, followed by subsequent pathway analysis. ELISA was used to quantify cytokine levels. GBS-infected placentas exhibited calcification and increased weight, while fetal weight decreased. Analysis of the proteome from control versus GBS placental EVs revealed distinct profiles, with many proteins involved in the innate immune response, including alarmins (S100A8/9), complement pathways, and cytokine signaling pathways. Pathway analysis highlighted IL-1α and IL-1β identified as key upstream regulators. Notably, EVs from GBS-infected males showed a 44-fold increase in intracellular IL-1β compared to controls. These findings indicate that GBS-induced CA alters the protein content of EVs from placental cells. Our findings of increased IL-1β-associated EVs highlight the need for further investigation into the role of these cytokines from GBS-exposed placentas and their role in brain injuries leading to NDDs.

Regulating white blood cell activity through the novel Universal Receptive System.

The understanding of the mechanisms that control key features of immune cells in various disease contexts remains limited, and few techniques are available for manipulating immune cells. Thus, discovering novel strategies for regulating immune cells is essential for gaining insight into their roles in health and disease. In this study, we investigated the potential of the recently described Universal Receptive System to regulate human immune cell functions. This was achieved for the first time by specifically targeting newly discovered surface-bound DNA and RNA-based receptors on leukocytes and generating "Leukocyte-Tells." This approach upregulated numerous genes related to immune cell signaling, migration, endocytosis, and phagocytosis pathways. The antimicrobial and anticancer activities of Leukocyte-Tells exceeded the activity of control leukocytes in vitro . In some settings, such as in antibiofilm experiments, the Leukocyte-Tells showed up to 1,000,000-fold higher activities than control leukocytes. Our findings reveal, for the first time, that the Universal Receptive System can orchestrate fundamental properties of immune cells, including enhanced antimicrobial and anti-tumor activities. This novel approach offers a new avenue for understanding the biology and regulation of white blood cells.

PIASy of orange-spotted grouper (Epinephelus coioides) negatively regulates RLRs-mediated innate antiviral immunity.

During viral infection, RIG-I-like receptors (RLRs) are cytoplasmic pattern recognition receptors that recognize and bind to viral RNA components, initiating the transcription of interferon-related genes, inflammatory cytokines and other factors, thereby triggering the cellular production of an antiviral innate immune response. The protein inhibitor of activated signal transducer and activator of transcription (STAT) (PIAS) protein family has become a hot research topic due to its extensive involvement in the regulation of cytokines, inflammatory factors and innate immune signaling pathways. In the present study, we investigated the role of fish PIASy in Singapore grouper iridovirus (SGIV) and red spotted grouper nervous necrosis virus (RGNNV) infections. The homologous sequence of orange-spotted grouper (Epinephelus coioides) PIASy gene (EcPIASy) was cloned and characterized, which encoded a 498-amino acid protein with 99.20% homology to Plectropomus leopardus. EcPIASy is expressed mainly in gills, blood, and liver. Subcellular localization showed that EcPIASy was uniformly distributed in the nucleus. Overexpression of EcPIASy promoted SGIV and RGNNV replication, and inhibited the expression of interferon related genes and pro-inflammatory factors induced by viruses. In addition, EcPIASy interacts with RLR signaling pathway-related genes EcMDA5, EcIRF3 and EcIRF7, whereas the interaction between EcPIASy and EcIRF3 does not depend on any specific structural domain of EcPIASy.. The results provide a better understanding of the relationship between PIASy and viral infection in fish.

Medwakh smoking induces alterations in salivary proteins and cytokine expression: a clinical exploratory proteomics investigation

BackgroundMedwakh smoking has radically expanded among youth in the Middle East and around the world. The rising popularity of medwakh/dokha usage is linked to the onset of several chronic illnesses including cardiovascular diseases and cancers. Medwakh smoking is reported to increase the risk of inflammation in the lower respiratory tract owing to oxidative burden. To date, there are no reported studies investigating the impact of medwakh smoking on salivary protein profile. The current study aims to elucidate alterations in the salivary proteome profile of medwakh smokers.MethodsSaliva samples collected from 33 medwakh smokers and 30 non-smokers were subjected to proteomic analysis using UHPLC-ESI-QTOF-MS. Saliva samples were further subjected to validatory experiments involving analysis of inflammatory cytokine profile using LEGENDplex™ Human Essential Immune Response Panel.ResultsStatistical analysis revealed alterations in the abundance of 74 key proteins including immune mediators and inflammatory markers in medwakh smokers (Accession: PXD045901). Proteins involved in building oxidative stress, alterations in cell anchorage, and cell metabolic processes were enhanced in medwakh smokers. Salivary immune response evaluation further validated the proteome findings, revealing significantly higher levels of IL-1β, IL-12p70, IL-23, IFN-γ (Th1 cytokines), IL-6 (Th2 cytokine), and MCP-1 (chemokine) in medwakh smokers. In addition, a substantial increase in abundance of involucrin suggesting a plausible stratified squamous cell differentiation and increased cell lysis in the oral cavity of medwakh smokers akin to chronic obstructive pulmonary diseases (COPD). The protein–metabolite joint pathway analysis further showed significantly enriched differentially expressed proteins and metabolites of glycolysis/gluconeogenesis, pentose phosphate, fructose and mannose, nicotinate and nicotinamide, and glutathione metabolism pathways among medwakh smokers.ConclusionsThe findings of the study provide valuable insights on potential perturbations in various key immune molecules, cytokines, and signaling pathways among medwakh smokers. Medwakh smokers displayed elevated inflammation, increased oxidative stress and defective antioxidant responses, dysregulated energy metabolism, and alterations in proteins related to cell adhesion, migration, differentiation, and proliferation. The findings of study underscore the urgent need for comprehensive public health interventions among youth by raising awareness, implementing effective smoking cessation programs, and promoting healthy lifestyle to safeguard the well-being of individuals and communities worldwide.

Activation of the cGAS-sting Pathway Mediated by Nanocomplexes for Tumor Therapy.

cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway is an natural immune response signaling pathway in the human body that is essential for sensing abnormal DNA aggregation in the cell. When the cGAS protein senses abnormal or damaged DNA, it forms a second messenger called cyclic dinucleotide (cGAMP). The cycled dinucleotide will activate the downstream STING protein, thereby inducing the expression of inflammatory cytokines such as type I interferon, which binds to receptors on its own cell membrane and ultimately initiates multiple immune response pathways. This signaling pathway plays an important immune role in antimicrobial and antitumor functions, etc. so the development of drugs targeting this signaling pathway has important clinical application value. In recent years nanocomplexes based cGAS-STING signaling pathway activation and inhibition treatments have been gradually developed. In this review, on the basis of elaborating the main activation mechanism of the cGAS-STING pathway, we further introduced the nanocomplexes that effectively activate the cGAS-STING pathway, focusing on the composition, types and applications of the nanocomplexes. In addition, we discussed the key challenges and future research directions of the way that stimulating the cGAS-STING signaling pathway in the form of nanocomplexes to activate immuno-tumor therapy. Our work aims to provide a better understanding of the progress of nanotherapeutics in the cGAS-STING pathway, providing a promising anti-tumor therapeutic strategy.

Tgfβ1a/vegfa gene expression and methylation in response to acute hypoxia in Japanese flounder (Paralichthys olivaceus).

The physiological response and molecular mechanism of the immune response of Japanese flounder under hypoxia stress remain unclear. In this study, we examined the immune-related physiological indexes and the molecular mechanisms of Japanese flounders under acute hypoxia stress. The results showed that the levels of serum ALT, ALP, AST and LDH in hypoxia stress group were significantly increased (P<0.01). Through quantitative real-time PCR and double in situ hybridization, we found acute hypoxia stress induced immune response of skeletal muscle and gill filaments. The transcriptional regulation mechanism of this immune signaling pathway was investigated by dual luciferase assay. In addition, DNA methylation levels of genes were detected to explore epigenetic modifications of this pathway. As a transcription factor, Foxo1a can interact tgfβ1a(AGATGTTTTTT) and vegfa(TTCTTTTTATA, TACTGTTGCTA) sequences of the promoter regions. The DNA methylation levels of tgfβ1a and vegfa genes were significantly affected by hypoxia and negatively correlated with their expression. These experiments showed that the expression of immune related genes tgfβ1a and vegfa were regulated by transcription factor Foxo1a and DNA methylation. Our study provides theoretical foundations for acute hypoxia stress induced immune response of Japanese flounder.

Combined treatment of HCC with CTLA-4 inhibitors and PD-1/PD-L1 inhibitors: mechanisms, progress and challenges

HCC seriously threatens human health, and the treatment methods are of crucial importance. The tumor microenvironment is critical to the origin and progression of HCC, and aberrant regulation of the immune checkpoint signaling pathway is a key method by which tumor cells avoid immune surveillance. Conventional single-treatment approaches for HCC have drawbacks. Inhibitors of PD-1/PD-L1 and CTLA-4, together known as the "golden combination," are the primary treatment for primary HCC. Compared with single treatment, it has a synergistic effect and benefits in boosting the immune response against the tumor and growing the number of recipients. However, it also has challenges. This study examines the state of combination treatment in HCC clinical trials as well as the current understanding of immune checkpoint inhibitors. By elaborating the cancer immune mechanism, it examines the mechanisms of action of the CTLA-4 and PD-1/PD-L1 immune checkpoints, and also the theoretical underpinnings and synergistic mechanism of combination treatment in HCC. Together with clinical study data, it assesses the effectiveness and potential of combination treatment for the cure of HCC, thoroughly examines the effects of conjunction treatment of CTLA-4 inhibitors and PD-1/PD-L1 inhibitors in the immunologic therapy of HCC, and anticipates the future of combination treatment, offering useful references for HCC immunotherapy.

Mechanistic elucidation of Ayurvedic formulation Triphala in managing gastrointestinal and neurological disorders through in silico approach

Triphala is an Ayurvedic herbal formulation used to treat gastrointestinal disorders. The present study explored the underlying mechanisms of Ayurvedic formulation Triphala against integrated gastrointestinal and neurological disorders through network pharmacology and molecular docking. Components of Triphala were screened using Dr. Duke’s Phytochemical and Ethnobotanical Database, KNApSAcK database, and Indian Medicinal Plants, Phytochemistry and Therapeutics database while target prediction was done using SuperPred 3.0, followed by mapping with shared gastrointestinal and neurological disorders targets obtained from GeneCards and DisGenet databases. STRING and Cytoscape were utilized for protein–protein and protein-target interaction analyses and further screening of core clusters. GO, KEGG, and Reactome enrichment analysis were performed, and top targets were subject to binding affinity evaluation with major Triphala compounds. Based on ADME characteristics, seven screened Triphala components overlapped with 104 genes of gastrointestinal and neurological disorders. STAT3, ESR1, HIF1A, MTOR, PPARG, MAP2K2, TLR4, SLC2A1, NFKB1, and ESR1 were revealed as major interacting nodes through protein–protein interaction, compound-target interaction, and compound-target-disease-pathway network analysis. GO enrichment indicated genes involved in managing cell response to stress, stimuli, and metabolism while KEGG enrichment revealed pathways related to cancer, metabolism, and signalling. Reactome analysis implied an enrichment of the immune system, cell signalling, and disease pathways. Thannilignan, 7-Hydroxy-3',4'-methylenedioxyflavan, and Termilignan were identified as major phytocompounds of Triphala. Molecular docking indicated excellent interactions of Triphala components with all analysed receptors with mean binding energies ranging from − 7.58 to − 8.34 kcal/mol/receptor which was most notable in the compound 7-Hydroxy-3',4'-methylenedioxyflavan. Together, this work delineates the mechanisms of Triphala and identifies new drug candidates for the integrated management of gastrointestinal and neurological disorders.

Reverse transcriptase inhibitors diminish systemic proinflammatory responses to bacterial pathogens.

Bacterial infections can induce exuberant immune responses that can damage host tissues. Previously, we demonstrated that systemic Escherichia coli infection in mice causes tissue damage in the liver. This liver necrosis is associated with the expression of endogenous retroviruses, chromosomally integrated retroviruses that encode a reverse transcriptase. Furthermore, nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs) completely prevent tissue damage and subsequent bacterial growth within necrotic lesions. Since liver necrosis is linked to heightened systemic inflammatory responses, we hypothesized that NRTIs diminish inflammation caused by E. coli infection and may also have broad impacts on the systemic immune response to bacterial pathogens. Here, we tested this hypothesis by characterizing the effects of NRTIs on the innate immune response to bacteria. In the liver, NRTI administration following E. coli inoculation reduced the expression of a large repertoire of proinflammatory transcripts. NRTIs also had systemic anti-inflammatory effects, including reducing proinflammatory cytokine levels in serum in response to E. coli in different mouse strains. The anti-inflammatory effects of NRTIs were also apparent in response to lipopolysaccharide (LPS) and Staphylococcus aureus, suggesting that the molecular mechanisms underlying the immunomodulatory functions of NRTIs are likely conserved across distinct immune signaling pathways. Moreover, in a model of lethal LPS shock, NRTI administration prevented hypothermia and death. Together, our observations reveal that NRTIs can potently impede systemic inflammatory responses during Gram-positive and Gram-negative bacterial infections. Our findings lay the groundwork for further investigation of the therapeutic scope of NRTIs and the mechanisms underlying their anti-inflammatory effects across non-retroviral infectious diseases.IMPORTANCEInflammatory responses are critical for host control of bacterial infection, but excessive inflammation can damage host tissues and lead to sepsis. Understanding how innate immune responses are controlled during infection is important for developing new approaches to dampen excessive inflammation. In previous work, we found that tissue damage caused by excessive inflammatory responses may be driven by endogenous reverse transcriptases. Here we demonstrate that treatment of mice with reverse transcriptase inhibitors leads to broad reductions in systemic proinflammatory responses during bacterial infections and can protect mice from acute death in a lethal model of sepsis. Our findings indicate that uncovering the mechanisms underlying the anti-inflammatory functions of reverse transcriptase inhibitors may lead to new therapeutics for bacterial infectious diseases.

Investigating the Role of Osteopontin (OPN) in the Progression of Breast, Prostate, Renal and Skin Cancers.

Background/Objectives: Cancer is caused by disruptions in the homeostatic state of normal cells, which results in dysregulation of the cell cycle, and uncontrolled growth and proliferation in affected cells to form tumors. Successful development of tumorous cells proceeds through the activation of pathways promoting cell development and functionality, as well as the suppression of immune signaling pathways; thereby providing these cells with proliferative advantages, which subsequently metastasize into surrounding tissues. These effects are primarily caused by the upregulation of oncogenes, of which SPP1 (secreted phosphoprotein 1), a non-collagenous bone matrix protein, is one of the most well-known. Methods: In this study, we conducted a further examination of the transcriptomic expression profile of SPP1 (Osteopontin) during the progression of cancer in four human tissues, breast, prostate, renal and skin, in order to understand the circumstances conducive to its activation and dysregulation, the biological pathways and other mechanisms involved as well as differences in its splicing patterns influencing its expression and functionality. Results: A significant overexpression of SPP1, as well as a set of other highly correlated genes, was seen in most of these tissues, indicating their extensive implication in cancer. Increased expression was observed with higher tumor stages, especially in renal and skin cancer, while applying therapeutic modalities targeting these genes dampened this effect in breast, prostate and skin cancer. Pathway analyses showed gene signatures related to cell growth and development enriched in tumorigenic conditions and earlier cancer stages, while later stages of cancer showed pathways associated with weakened immune response, in all cancers studied. Moreover, the utilization of therapeutic methods showed the activation of immunogenic pathways in breast, prostate and skin cancer, thereby confirming their viability. Further analyses of differential transcript expression levels in these oncogenes showed their exonic regions to be selectively overexpressed similarly in tumorigenic samples in all cancers studied, while also displaying significant differences in exon selectivity between constituent transcripts, providing a basis for their high degree of multifunctionality in cancer. Conclusions: Overall, this study corroborates the entrenched role of SPP1 in the progression of these four types of cancer, as confirmed by its overexpression and activation of related oncogenes, their co-involvement in key cellular pathways, and predisposition to exhibit differential splicing between their transcripts, while the above effects were found to be highly inhibitable through treatment methods, thereby highlighting its promising role in therapeutic development.

Understanding the neurobiological mechanisms of LPS‑induced memory impairment.

In recent years, growing evidence suggests that lipopolysaccharide (LPS), a bacterial endotoxin found in the outer membrane of gram‑negative bacteria, can influence cognitive functions, particularly memory formation and retrieval. However, the underlying mechanisms through which LPS exerts its effects on memory remain incompletely understood. This review used various electronic databases, including PubMed, Scopus, and Web of Science, to identify relevant studies published between 2000 and 2024. Articles were selected based on their focus on LPS‑induced memory impairments, including experimental models, molecular pathways, and neurochemical alterations. LPS administration has been consistently shown to disrupt memory processes in both animals and humans, although the magnitude and duration of memory impairments might vary depending on factors such as dose, timing, and context of LPS exposure. Several potential mechanisms have been proposed to explain LPS‑induced memory deficits, including neuroinflammation, alterations in synaptic plasticity, disruption of neurotransmitter systems, and dysfunction of the blood‑brain barrier. Moreover, LPS has been found to activate immune signaling pathways, such as toll‑like receptors, interleukins, and microglia, which can further contribute to cognitive impairments. Such insights may pave the way for the development of targeted therapeutic interventions aimed at ameliorating memory deficits associated with conditions involving LPS exposure, including bacterial infections, sepsis, and neuroinflammatory disorders.