Nucleotide Oligomerization Domain Research Articles

Ferulic Acid Reduces Inflammatory Response Induced by Radiation through Sirt1-NLRP3 Pathway

Background: A model of inflammatory damage was induced by radiation to investigate whether ferulic acid (FA) can reduce the inflammatory response through the Sirt1-NLRP3 inflammatory pathway. This will help discover radiation-protective drugs and elucidate the molecular mechanisms related to radiation-induced inflammatory damage. Methods: A mouse model of radiation-induced immunoinflammatory injury was established to verify the anti-inflammatory effects of FA in vivo. C57BL/6J mice were randomly divided into six groups, and 5 Gy whole body irradiation was used for modeling. Mice were administered a gastric solvent, amifostine, or 25, 50, or 100 mg/kg FA daily for 12 d, consecutively, before irradiation. The serum of mice was collected 24 h after irradiation to observe the content of inflammatory factors interleukin (IL)-1β, IL-18, IL-6, and tumor necrosis factor (TNF)-α. The spleen and thymus tissues of mice were weighed and the organ index was calculated for pathological testing and immunofluorescence detection. Results: FA reduced the radiation-induced decrease in the spleen and thymus indices. FA significantly reduced the secretion of inflammatory factors in the serum and reversed the radiation-induced reduction in lymphocytes in the spleen and thymus of mice. FA activated Sirt1 and inhibited the expression of the NLRP3 inflammasome to alleviate the inflammatory response. Conclusions: FA reduced radiation-induced inflammation in animals, possibly by activating Sirt1 and reducing nucleotide oligomerization domain (NOD)-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome expression, thereby reducing the secretion of inflammatory factors.

Functional transcriptome analysis revealed upregulation of MAPK-SMAD signalling pathways in chronic heat stress in crossbred cattle.

Animal geneticists and breeders have the impending challenge of enhancing the resilience of Indian livestock to heat stress through better selection strategies. Climate change's impact on livestock is more intense in tropical countries like India where dairy cattle crossbreeds are more sensitive to heat stress. The main reason for this study was to find the missing relative changes in transcript levels in thermo-neutral and heat stress conditions in crossbred cattle through whole-transcriptome analysis of RNA-Seq data. Differentially expressed genes (DEGs) identified based on the minimum log twofold change value and false discovery rate 0.05 revealed 468 up-regulated genes and 2273 down-regulated significant genes. Functional annotation and pathway analysis of these significant DEGs were compared based on Gene Ontology (Biological process), Kyoto Encyclopedia of Genes and Genome (KEGG), and Reactome pathways using g: Profiler, ShinyGO v0.76, and iDEP.951 web tools. On finding network visualization, the most over-represented and correlated pathways were neuronal and sensory organ development, calcium signalling pathway, Mitogen-activated protein kinase (MAPK) and Smad signalling pathway, Ras-proximate-1, or Ras-related protein 1 (Rap 1) signalling pathway, apoptosis, and oxidative stress. Similarly, down-regulated genes were most expressed in mRNA processing, immune system, B-cell receptor signalling pathway, Nucleotide oligomerization domain(NOD)-like receptors (NLRs) signalling pathway and nonsense-mediated decay (NMD) pathway. The heat stress-responsive genes identified in this study will facilitate our understanding of the molecular basis for climate resilience and heat tolerance in Indian dairy crossbreeds.

Protective effect of melatonin on imidacloprid-induced pyroptosis and ferroptosis by mediating peptidoglycan in the gut of the common carp (Cyprinus carpio)

Imidacloprid (IMI) is a contaminant widespread in surface water, causing serious intestinal damage in the common carp. Melatonin (MT), an endogenous indoleamine hormone, plays a crucial role in mitigating pesticide-induced toxicity. Our previous research has demonstrated that MT effectively reduces the production of intestinal microbial-derived signal peptidoglycan (PGN) induced by IMI, thereby alleviating intestinal tight junction injuries in the common carp. In this study, we performed a transcriptomic analysis to explore the effect of MT on the IMI exposure-induced gut damage of the common carp. The results elucidated that the ferroptosis, mitogen-activated protein kinases (MAPKs), and nucleotide oligomerization domain (NOD)-like signaling pathways were significantly associated with IMI exposure and MT treatment. Meanwhile, the exposure to IMI resulted in the formation of pyroptotic bodies and distinct morphological features of ferroptosis, both mitigated with the addition of MT. Immunofluorescence double staining demonstrated that MT abolished the elevated expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and Gasdermin D (GSDMD) induced by IMI, as well as reduced expression of ferritin heavy chains (FTH) and glutathione peroxidase 4 (GPX4) in gut tissues. Subsequently, we found that the exposure to IMI or PGN enhanced the expression of toll-like receptors (TLR) 2 (a direct recognition receptor of PGN) triggering the P38MAPK signaling pathway, thereby aggravating the process of pyroptosis and ferroptosis of cell models. The addition of MT or SB203580 (a P38MAPK inhibitor) significantly reduced pyroptotic cells, and also decreased iron accumulation. Consequently, these results indicate that MT alleviates IMI-induced pyroptosis and ferroptosis in the gut of the common carp through the PGN/TLR2/P38MAPK pathway.

Monogenic Autoinflammatory Disease Due to Blau Syndrome with Nucleotide Oligomerization Domain 2 Gene Mutation in an Indian Family

Background: Blau syndrome is a monogenic disease resulting from mutations in nucleotide oligomerization domain 2 (NOD2) and is phenotypically characterized by a triad of dermatitis, arthritis, and uveitis. We report Blau syndrome in a child who had been symptomatic for years, without the typical clinical triad. Clinical Description: A 7-year-old girl child presented with bilateral knee, wrist, and ankle joint swelling since the age of 2 years. She had recently developed a rash on the body. Her mother, mother’s identical twin sister, and the latter’s 5-year-old daughter had similar joint pain and swellings since childhood. In view of the strong positive family history of polyarthritis, monogenic cause of arthritis was suspected. Management and Outcome: Complete blood count was unremarkable. Erythrocyte sedimentation rate was 20 mm at C-reactive protein was 36 mg/L, antinuclear antibody and rheumatoid arthritis factor were negative. X-ray of the knee joints and wrist joints showed soft-tissue swellings around the knee and lumbar scoliosis. A heterozygous pathogenic variant in NOD2 gene confirmed the diagnosis of Blau syndrome. After receiving the genetic report, the girl was started on prednisolone and weekly methotrexate. Conclusion: Early-onset arthritis, with recurrent episodes of fever, is not to be ignored if autoimmune markers are negative. Knowledge about the clinical features of autoinflammatory diseases and the spectrum of NOD2 variants will enable physicians to carry out specific investigations, especially genetic analysis for confirmation of the diagnosis and hence administer the right treatment.

NLRP3 Cys126 palmitoylation by ZDHHC7 promotes inflammasome activation

Nucleotide oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome hyperactivation contributes to many human chronic inflammatory diseases, and understanding how NLRP3 inflammasome is regulated can provide strategies to treat inflammatory diseases. Here, we demonstrate that NLRP3 Cys126 is palmitoylated by zinc finger DHHC-type palmitoyl transferase 7 (ZDHHC7), which is critical for NLRP3-mediated inflammasome activation. Perturbing NLRP3 Cys126 palmitoylation by ZDHHC7 knockout, pharmacological inhibition, or modification site mutation diminishes NLRP3 activation in macrophages. Furthermore, Cys126 palmitoylation is vital for inflammasome activation invivo. Mechanistically, ZDHHC7-mediated NLRP3 Cys126 palmitoylation promotes resting NLRP3 localizing on the trans-Golgi network (TGN) and activated NLRP3 on the dispersed TGN, which is indispensable for recruitment and oligomerization of the adaptor ASC (apoptosis-associated speck-like protein containing a CARD). The activation of NLRP3 by ZDHHC7 is different from the termination effect mediated by ZDHHC12, highlighting versatile regulatory roles of S-palmitoylation. Our study identifies an important regulatory mechanism of NLRP3 activation that suggests targeting ZDHHC7 or the NLRP3 Cys126 residue as a potential therapeutic strategy to treat NLRP3-related human disorders.

REV-ERBα negatively regulates NLRP6 transcription and reduces the severity of Salmonella infection in mice

Non-typhoidal Salmonella infection is among the most frequent foodborne diseases threatening human health worldwide. The host circadian clock orchestrates daily rhythms to adapt to environmental changes, including coordinating immune function in response to potential infections. However, the molecular mechanisms underlying the interplay between the circadian clock and the immune system in modulating infection processes are incompletely understood. Here, we demonstrate that NLRP6, a novel nucleotide-oligomerization domain (NOD)-like receptor (NLR) family member highly expressed in the intestine, is closely associated with the differential day–night response to Salmonella infection. The core clock component REV-ERBα negatively regulates NLRP6 transcription, leading to the rhythmic expression of NLRP6 and the secretion of IL-18 in intestinal epithelial cells, playing a crucial role in mediating the differential day–night response to Salmonella infection. Activating REV-ERBα with agonist SR9009 in wild-type mice attenuated the severity of infection by decreasing the NLRP6 level in intestinal epithelial cells. Our findings provide new insights into the association between the host circadian clock and the immune response to enteric infections by revealing the regulation of Salmonella infection via the inhibitory effect of REV-ERBα on NLRP6 transcription. Targeting REV-ERBα to modulate NLRP6 activation may be a potential therapeutic strategy for bacterial infections.

Resveratrol Suppresses “Metabolic Memory” by Inhibiting Inflammation and Apoptosis Through the ROS/TXNIP/NLRP3 Signaling Pathway

Aim: This research endeavored to explore the impact and underlying mechanisms of resveratrol on the phenomenon of “metabolic memory” in cultured human retinal vascular endothelial cells (HRVECs) under high-glucose (HG) conditions. Materials and Methods: According to the glucose level and treatment, cultured HRVECs were divided into seven groups: normal glucose (NG), HG, high glucose followed by NG (HN), mannitol (Man), resveratrol, thioredoxin-interacting protein (TXNIP)-small interfering ribonucleic acid (siRNA), and N-acetylcysteine (NAC). The expression levels of TXNIP, nucleotide oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, intercellular adhesion molecule 1 (ICAM-1), caspase-1, interleukin-1β (IL-1β), B-cell lymphoma 2 (Bcl-2), caspase-3, and Bcl-2-associated X (BAX), as well as reactive oxygen species (ROS) production, were measured. Cell apoptosis was assessed through a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Results: In HRVECs from the HG group, expression levels of TXNIP, NLRP3, caspase-1, ICAM-1, and IL-1β were upregulated. However, in the HN group, the above upregulations were not reversed. After the administration of resveratrol, the expression levels of TXNIP, NLRP3, and other inflammatory cytokines were significantly reduced. Resveratrol mitigated the elevated ROS production induced by HG conditions. In the NAC group, the expression of TXNIP and inflammatory cytokines was downregulated. TXNIP-siRNA treatment showed similar effects. Resveratrol inhibited apoptosis as well as reversed the downregulation of BCL-2 and the upregulation of caspase-3 and BAX induced by HG conditions. Conclusion: Resveratrol mitigated the HG-induced phenomenon of “metabolic memory” by inhibiting inflammation and apoptosis via modulation of the ROS/TXNIP/NLRP3 signaling pathway in cultured HRVECs. Therefore, resveratrol may have therapeutic potential to treat diabetic retinopathy and related metabolic memory complications.

M6A/m1A/m5C-Associated Methylation Alterations and Immune Profile in MDD.

Major depressive disorder (MDD) is a prevalent psychiatric condition often accompanied by severe impairments in cognitive and functional capacities. This research was conducted to identify RNA modification-related gene signatures and associated functional pathways in MDD. Differentially expressed RNA modification-related genes in MDD were first identified. And a random forest model was developed and distinct RNA modification patterns were discerned based on signature genes. Then, comprehensive analyses of RNA modification-associated genes in MDD were performed, including functional analyses and immune cell infiltration. The study identified 29 differentially expressed RNA modification-related genes in MDD and two distinct RNA modification patterns. TRMT112, MBD3, NUDT21, and IGF2BP1 of the risk signature were detected. Functional analyses confirmed the involvement of RNA modification in pathways like phosphatidylinositol 3-kinase signaling and nucleotide oligomerization domain (NOD)-like receptor signaling in MDD. NUDT21 displayed a strong positive correlation with type 2T helper cells, while IGF2BP1 negatively correlated with activated CD8 T cells, central memory CD4 T cells, and natural killer T cells. In summary, further research into the roles of NUDT21 and IGF2BP1 would be valuable for understanding MDD prognosis. The identified RNA modification-related gene signatures and pathways provide insights into MDD molecular etiology and potential diagnostic biomarkers.

Inhibiting Peptidoglycan Hydrolase Alleviates MRSA Pneumonia Through Autolysin-Mediated MDP-NOD2 Pathway.

Methicillin-resistant Staphylococcus aureus (MRSA) is a cause of staph infection that is difficult to treat because of resistance to some antibiotics. A recent study indicated that diarylurea ZJ-2 is a novel antibacterial agent against multi-drug resistant Enterococcus faecium. In this work, we refined the bactericidal mechanism of ZJ-2 as a peptidoglycan (PG) hydrolase by affecting AtlA-mediated PG homeostasis. A wild-type strain (WT) and a mutant strain (ΔatlA) were used to investigate the effects of ZJ-2 on the cell wall, PG, and autolysin regulatory system by antimicrobial susceptibility testing, hemolytic toxin assay, microanalysis, autolysis assay, qRT-PCR, ELISA and mouse model of pneumonia. The results revealed that ZJ-2 down-regulated the expression of genes related to peptidoglycan hydrolase (PGH) (sprX, walR, atlA, and lytM), and reduced the levels of PG, muramyl dipeptide (MDP), cytokines, and hemolytic toxin, while ΔatlA interfered with the genes regulation and PG homeostasis. In the mouse MRSA pneumonia model, the same trend was observed in the nucleotide oligomerization domain protein 2 (NOD2) and relative proinflammatory factors. ZJ-2 may act as a novel inhibitor of PG hydrolyse, disrupting autolysin-mediated PG homeostasis, and reducing inflammation by down-regulating the MDP-NOD2 pathway.

Aldehyde dehydrogenase 2-mediated aldehyde metabolism promotes tumor immune evasion by regulating the NOD/VISTA axis

BackgroundAldehyde dehydrogenase 2 (ALDH2) is a crucial enzyme involved in endogenous aldehyde detoxification and has been implicated in tumor progression. However, its role in tumor immune evasion remains unclear.MethodsHere, we...

Crosstalk of NLRP3 inflammasome and noncoding RNAs in cardiomyopathies.

Cardiovascular diseases (CVDs) identified as a serious public health problem. Although there is a lot of evidence that inflammatory processes play a significant role in the progression of CVDs, however, the precise mechanism is not fully understood. Nevertheless, recent studies have focused on inflammation and its related agents. Nucleotide oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) is a type of pattern recognition receptor (PRR) that can recognize pathogen-associated molecular patterns and trigger innate immune response. NLRP3 is a component of the NOD-like receptor (NLR) family and have a pivotal role in detecting damage to cardiovascular tissue. It is suggested that activation of NLRP3 inflammasome leads to initiating and propagating the inflammatory response in cardiomyopathy. So, late investigations have highlighted the NLRP3 inflammasome activation in various forms of cardiomyopathy. On the other side, it was shown that noncoding RNAs (ncRNAs), particularly, microRNAs, lncRNAs, and circRNAs possess a regulatory function in the immune system's inflammatory response, implicating their involvement in various inflammatory disorders. In addition, their role in different cardiomyopathies was indicated in recent studies. This review article provides a summary of recent advancements focusing on the function of the NLRP3 inflammasome in common CVDs, especially cardiomyopathy, while also discussing the therapeutic potential of inhibiting the NLRP3 inflammasome regulated by ncRNAs.

Idiopathic Ileal Ulceration After Intestinal Transplantation.

Idiopathic ileal ulceration after intestinal transplantation (ITx) has been discussed infrequently and has an uncertain natural history and relation to graft rejection. Herein, we review our experience with this pathology. We retrospectively reviewed 225 ITx in 217 patients with minimum 1 y graft survival. Routine graft endoscopy was conducted up to twice weekly within the first 90 d after ITx, gradually decreasing to once yearly. Risks for ulceration over time were evaluated using Cox regression. Of 93 (41%) patients with ulcers, 50 were found within 90 d after ITx mostly via ileoscopy; delayed healing after biopsy appeared causal in the majority. Of the remaining 43 patients with ulcers found >90 d after ITx, 36 were after ileostomy closure. Multivariable modeling demonstrated within 90-d ulcer associations with increasing patient age (hazard ratio [HR], 1.027; P < 0.001) and loop ileostomy (versus Santulli ileostomy; HR, 0.271; P < 0.001). For ulcers appearing after ileostomy closure, their sole association was with absence of graft colon (HR, 7.232; P < 0.001). For ulcers requiring extended anti-microbial and anti-inflammatory therapy, associations included de novo donor-specific antibodies (HR, 3.222; P < 0.007) and nucleotide oligomerization domain mutations (HR, 2.772; P < 0.016). Whole-cohort post-ITx ulceration was not associated with either graft rejection (P = 0.161) or graft failure (P = 0.410). Idiopathic ulceration after ITx is relatively common but has little independent influence on outcome; risks include ileostomy construction, colon-free ITx, immunologic mutation, and donor sensitization.

Evaluation of serum levels of interferon beta and nucleotide binding and oligomerization domain 2 gene polymorphism in children with cough asthma phenotype: a case–control study

BackgroundIndividuals with asthma are thought to suffer from a variety of distinct disorders, or phenotypes, each of which is characterized by a unique combination of genetic and environmental factors. Syndromes that are exacerbated by allergens, non-allergic factors, and aspirin, as well as syndromes that are best differentiated by pathologic findings, response to therapy, and natural history, fall into this category. The best course of treatment for an individual patient with asthma can be determined by first determining his or her specific asthma phenotype and its underlying pathophysiology.Aim of the workExplore clinical characteristics, serum INF-β in cough asthma phenotype and allergic march asthmatic children. Also, to assess the association of NOD2 (rs2066845) gene polymorphism among those asthma phenotypes in Egyptian asthmatic children.Patients and methodsThe study included 64 cough phenotypic asthmatic children and 60 allergic march phenotypic asthmatic children in addition to 39 healthy controls (control group). The included children were subjected to full clinical history taking, full clinical examination, assessment of (total serum IgE, CBC for peripheral eosinophil percentage, cytokine profile (serum levels of INF-B), and genetic analysis: SNPs of NOD2 (rs2066845).ResultsThere was a significant increase in G allele frequency, in both homozygous (GG) and heterozygous (GC) states, among asthmatic children of cough and allergic march phenotypes compared to healthy controls, with no significant difference between the two phenotypes. In addition, serum INF-β was significantly lower in cough and allergic march phenotypic asthmatics with GG genotypes versus healthy controls of the same genotype.ConclusionsNOD2 (rs2066845) gene polymorphism is associated with both cough and allergic march asthma phenotypes in Egyptian asthmatic children. It was also shown that G allele may be implicated in asthma pathophysiology.

Knockdown of PHLDA1 alleviates sepsis-induced acute lung injury by downregulating NLRP3 inflammasome activation.

To investigate the regulatory mechanism of pleckstrin homology-like domain, family A, member 1 (PHLDA1) in sepsis-induced acute lung injury (ALI). Mice model of sepsis were established by cecal ligation and puncture (CLP). The expression of PHLDA1 was reduced by injecting short hairpin RNA (shRNA)-PHLDA1 into the tail vein. The levels of PHLDA1, pro-inflammatory cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), IL-1β, IL-18, super-oxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH), molecular mechanism related to pyroptosis, such as caspase 1, adaptor apoptosis-associated speck-like protein containing a CARD (ASC), and gasdermin D (GSDMD)-N, and nucleotide oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) were tested by Western blot analysis, quantitative real-time polymerase chain reaction, and enzyme-linked-immunosorbent serologic assay. Pathological changes in lung tissues were examined by hematoxylin and eosin staining. Wet-dry weight ratio of lung tissues was observed. The expression of PHLDA1 was up-regulated in lung tissues from CLP-induced septic mice. Knockdown of PHLDA1 could reduce lung injury and wet-dry weight ratio in mice with sepsis-induced ALI. Moreover, silencing of PHLDA1 decreased the expressions of IL-1β, TNF-α, IL-18, IL-6, and MDA but increased SOD and GSH expressions in CLP-induced septic mice. The expressions of NLRP3, GSDMD-N, ASC, and caspase 1 were decreased by PHLDA1 silencing. Knockdown of PHLDA1 inhibited lung inflammation and pyroptosis in mice with sepsis-induced ALI by down-regulating NLRP3.

A comprehensive analysis of type 1 interferon gene signatures in systematic lupus erythematosus and prediction of the crucial susceptible factor for Sjögren syndrome.

This study aimed to determine the role of IFN-1 gene signatures in SLE and their association with Sjögren syndrome (SS). Publicly available data from the Gene Expression Omnibus database were used to construct the models. The random forest tree model was used to screen key IFN-1 gene signatures, and consensus clustering algorithms were used for unsupervised cluster analysis of these signatures. CIBERSORT and gene set variation analyses were used to evaluate the relative immune cell infiltration and enriched molecular pathways of the samples, respectively. Weighted gene co-expression network analysis was used to identify the co-expression modules and hub genes. Finally, univariate and multivariate logistic regression models were used to evaluate differences in clinical and laboratory characteristics between the different groups. The role of IFN-1 gene signatures in SLE was comprehensively assessed, which revealed an IFN-1 gene signature including six genes that could easily distinguish SLE patients and healthy individuals and identified two distinct IFN-1 subtypes exhibiting significant differences in clinical characteristics, immune microenvironment, and biological functional pathways. The SLE disease activity index, lower lymphocyte count, nucleotide oligomerization domain (NOD)-like receptor signaling pathway, and dendritic cell activation were strongly correlated with the IFN-1 gene signatures. In addition, we found that IFN-1 gene signatures in SLE may be an important susceptibility factor for SS, and the NOD-like receptor signaling pathway was identified as a common pathway. This study provides a comprehensive evaluation of the IFN-1 gene signatures, which may provide a new direction for the understanding of SLE and SS and help in the selection of optimal strategies for personalized immunotherapy.

Tannerella forsythia scavenges Fusobacterium nucleatum secreted NOD2 stimulatory molecules to dampen oral epithelial cell inflammatory response.

The oral organism Tannerella forsythia is auxotrophic for peptidoglycan amino sugar N-acetylmuramic acid (MurNAc). It survives in the oral cavity by scavenging MurNAc- and MurNAc-linked peptidoglycan fragments (muropeptides) secreted by co-habiting bacteria such as Fusobacterium nucleatum with which it forms synergistic biofilms. Muropeptides, MurNAc-l-Ala-d-isoGln (MDP, muramyl dipeptide) and d-γ-glutamyl-meso-DAP (iE-DAP dipeptide), are strong immunostimulatory molecules that activate nucleotide oligomerization domain (NOD)-like innate immune receptors and induce the expression of inflammatory cytokines and antimicrobial peptides. In this study, we utilized an in vitro T. forsythia-F. nucleatum co-culture model to determine if T. forsythia can selectively scavenge NOD ligands from the environment and impact NOD-mediated inflammation. The results showed that NOD-stimulatory molecules were secreted by F. nucleatum in the spent culture broth, which subsequently induced cytokine and antimicrobial peptide expression in oral epithelial cells. In the spent broth from T. forsythia-F. nucleatum co-cultures, the NOD-stimulatory activity was significantly reduced. These data indicated that F. nucleatum releases NOD2-stimulatory muropeptides in the environment, and T. forsythia can effectively scavenge the muropeptides released by co-habiting bacteria to dampen NOD-mediated host responses. This proof-of-principle study demonstrated that peptidoglycan scavenging by T. forsythia can impact the innate immunity of oral epithelium by dampening NOD activation.

Veillonella parvula promotes the proliferation of lung adenocarcinoma through the nucleotide oligomerization domain 2/cellular communication network factor 4/nuclear factor kappa B pathway

Enrichment of Veillonella parvula in the lung microbiota is strongly associated with non-small cell lung cancer (NSCLC) and induces the progression of lung adenocarcinoma in vivo, but its actual role and mechanism remain unexplored. This study analyzed the correlation between NSCLC and V. parvula abundance based on 16 s rRNA sequencing results. The effects of V. parvula on the progression of lung adenocarcinoma were observed in vivo and in vitro using a C57 bl/6j mouse tumor-bearing model, a bacterial cell co-culture model, combined with transcriptome sequencing, and a TCGA database to explore and validate the growth promotion of lung adenocarcinoma by V. parvula and its molecular mechanism. 16 s rRNA sequencing revealed that V. parvula was significantly enriched in lung adenocarcinoma. In vivo, V. parvula promoted the growth of lung adenocarcinoma in mice by suppressing the infiltration of tumor-associated T lymphocytes and peripheral T lymphocytes. It showed a higher affinity for lung adenocarcinoma in vitro and promoted lung adenocarcinoma cell proliferation through adhesion or intracellular invasion. Further analysis of differential gene expression and KEGG enrichment by transcriptome sequencing revealed that V. parvula induced CCN4 expression and activated NOD-like receptor and NF-κB signaling pathway in lung adenocarcinoma cells. Further analysis clarified that V. parvula promoted activation of the NF-κB pathway via Nod2/CCN4 signaling, which promoted lung adenocarcinoma cell proliferation. Thus, V. parvula mediates activation of the Nod2/CCN4/NF-κB signaling pathway to promote non-small cell lung adenocarcinoma progression, thereby providing a potential target for diagnosing and treating lung adenocarcinoma.Graphical

Red blood cells of Labeo rohita express Toll-like receptors, NOD- like receptors, interleukins, and interferon-I in response to Gram-negative bacterial infections and lipopolysaccharide stimulations.

Red blood cells (RBCs) are the most abundant cell types in the circulatory system of vertebrates. In fish, RBCs retain their nuclei throughout their lifetime and remain transcriptionally and translationally active. While their primary function is typically associated with gas exchange, recent reports indicate that nucleated red blood cells can play a significant role in regulating the body's innate immune response. The current article describes the innate immune role of red blood cells in rohu (Labeo rohita), a freshwater fish species that holds significant commercial importance in India and South-East Asian nations. From the whole blood and mucosal surface RBCs have been isolated through density gradient centrifugation with HiSep™LSM 1077 (density 1.007 ± 0.0010) and their purity has been confirmed by the Giemsa staining followed by microscopical observations. Toll-like receptors (TLR2, 3, 4, 5) and nucleotide oligomerization domain (NOD)-like receptors (NOD1 and NOD2) in RBCs of rohu fingerlings were observed to be significantly activated (P < 0.05) on infection with Aeromonas hydrophila and Edwardsiella tarda. This activation resulted in increased expression of interleukins (IL-8, IL-1β) and interferon (IFN)-I genes. The activation of TLR4, NOD1 and NOD2, as well as the expression of interleukins and IFN-I genes have been observed in both in vivo and in vitro stimulation of rohu RBCs with lipopolysaccharides. These findings highlight the importance of fish RBCs in enhancing innate immunity against various pathogenic invasions in rohu.

FDX1 serves as a prognostic biomarker and promotes glioma progression by regulating the immune response.

The present study investigates the prognostic value of the FDX1 gene and its association with immune infiltration in gliomas. Gene expression profiles and corresponding clinical parameters of glioma patients were obtained from the Cancer Genome Atlas and Chinese Glioma Genome Atlas databases. In vitro experiments were also performed to validate its impact on malignant phenotypes of glioma cells. Kaplan-Meier analysis demonstrated that high FDX1 expression was associated with poor prognosis in glioma. Function and pathway enrichment for FDX1 predominantly demonstrated immunomodulatory function. In addition, the high-FDX1 expression group had higher Estimation of Stromal and Immune cells in malignant tumor tissues using Expression data, stromal, and immune scores (p<0.001). On evaluation of immunotherapy response, TIDE and dysfunction scores were higher in the low-FDX1 group, while the exclusion score demonstrated an opposite trend. In vitro tests showed that FDX1 silencing-induced inhibition of cell invasion and migration inactivated the nucleotide oligomerization domain (NOD)-like receptor signaling pathway by regulating PD-L1 expression. Notably, NOD1 expression was reversed in FDX1-knockdown cells after treatment with NOD1 agonists. In conclusion, FDX1 may play an important role in the diagnosis and treatment of gliomas. Regulating its expression may therefore help improve immunotherapy for these tumors.

RIPK2: a promising target for cancer treatment.

As an essential mediator of inflammation and innate immunity, the receptor-interacting serine/threonine-protein kinase-2 (RIPK2) is responsible for transducing signaling downstream of the intracellular peptidoglycan sensors nucleotide oligomerization domain (NOD)-like receptors 1 and 2 (NOD1/2), which will further activate nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, leading to the transcription activation of pro-inflammatory cytokines and productive inflammatory response. Thus, the NOD2-RIPK2 signaling pathway has attracted extensive attention due to its significant role in numerous autoimmune diseases, making pharmacologic RIPK2 inhibition a promising strategy, but little is known about its role outside the immune system. Recently, RIPK2 has been related to tumorigenesis and malignant progression for which there is an urgent need for targeted therapies. Herein, we would like to evaluate the feasibility of RIPK2 being the anti-tumor drug target and summarize the research progress of RIPK2 inhibitors. More importantly, following the above contents, we will analyze the possibility of applying small molecule RIPK2 inhibitors to anti-tumor therapy.