Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory disease that imposes a heavy economic burden on patients and society. Bone and cartilage destruction is considered an important factor leading to RA, and inflammation, oxidative stress, and mitochondrial dysfunction are closely related to bone erosion and cartilage destruction in RA. Currently, there are limitations in the clinical treatment methods for RA, which urgently necessitates finding new effective treatments for patients. Nuclear transcription factor-κB (NF-κB) is a signaling transcription factor that is widely present in various cells. It plays an important role as a stress source in the cellular environment and regulates gene expression in processes such as immunity, inflammation, cell proliferation, and apoptosis. NF-κB has long been recognized as a pathogenic factor of RA, and its activation can exacerbate RA by promoting inflammation, oxidative stress, mitochondrial dysfunction, and bone destruction. Conversely, inhibiting the activity of the NF-κB pathway effectively inhibits these pathological processes, thereby alleviating RA. Therefore, NF-κB may be a potential therapeutic target for RA. This article describes the physiological structure of NF-κB and its important role in RA through the regulation of oxidative stress, inflammatory response, mitochondrial function, and bone destruction. Meanwhile, we also summarized the impact of NF-κB crosstalk with other signaling pathways on RA and the effect of related drugs or inhibitors targeting NF-κB on RA. The purpose of this article is to provide evidence for the role of NF-κB in RA and to emphasize its significant role in RA by elucidating the mechanisms, so as to provide a theoretical basis for targeting the NF-κB pathway as a treatment for RA.

Dipeptidyl peptidase 9 (DPP9) is an indispensable intracellular protease. Among its many molecular functions is suppression of the NLRP1 inflammasome. Inhibitors targeting all four proteases of the DPP4 family, including DPP9, can reduce tumour burden, including in mouse liver. To explore hepatocyte DPP9 in experimental hepatocellular carcinoma (HCC), we generated hepatocyte-specific DPP9-KO mice by crossing albumin-Cre mice with DPP9 floxed mice and treated sequentially with diethylnitrosamine, then with thioacetamide combined with an atherogenic high-fat diet until 28 weeks of age. DPP9-KO mice had less body, liver and subcutaneous adipose tissue mass, lower fasting plasma glucose and fewer small macroscopic liver nodules compared to DPP9-WT control mice. However, there were no differences in the total number of macroscopic liver nodules, or of microscopic tumour burden, inflammation, fibrosis or steatosis. Consistent with the known function of DPP9 to suppress NLRP1 activation, activated caspase-1 protein and inflammation markers Nfkbib, Cxcl10 and Ccl5 were elevated in DPP9-KO liver. The tumour suppressor protein p53 was increased and the autophagy proteins beclin1, LC3B and p62 were altered. In conclusion, hepatocyte-specific DPP9 gene deletion in experimental primary liver cancer improved energy metabolism and may reduce liver cancer initiation, via mechanisms that may include increased autophagy and tumour suppression.

Galangin (GAL), a flavonol found in Alpinia officinarum and propolis, is a promising functional food. This study investigated the therapeutic effects and mechanisms of GAL in mice with hyperuricemic nephropathy (HN) by focusing on renal metabolomics and network pharmacology. In this study, we conducted untargeted metabolomic analysis and network pharmacology prediction. Subsequently, a compound-reaction-enzyme-gene network was constructed based on the results of metabolomics and network pharmacology to elucidate potential connections. The results demonstrated that GAL can improve renal interstitial fibrosis and inflammatory infiltration and reduce serum levels of uric acid (UA), urea nitrogen (UREA), and creatinine (CREA). Metabolome analysis indicated that GAL affected thiamine, pyrimidine, nicotinate, nicotinamide, pyruvate, glyoxylate, and dicarboxylate metabolism. Network pharmacology and experimental results showed that GAL reduced the key target expression of the tumor protein P53 (TP53), tumor necrosis factor (TNF), signal transducer and activator of transcription 3 (STAT3), heat shock protein 90 alpha family class A member 1 (HSP90aa1), albumin (ALB), and caspase-3 (CASP3). GAL also downregulated the expression of Janus kinase 2 (JAK2), phospho-JAK2 (P-JAK2), and phospho-STAT3 (P-STAT3). Furthermore, a joint analysis of the metabolome and network pharmacology showed that GAL can reverse HN through amino acid metabolism, nucleotide metabolism, energy metabolism, and endocrine system pathways. GAL can alleviate HN effectively and might play synergistic therapeutic roles through regulating metabolic profiles and the JAK2/STAT3 signaling pathway.

Ovarian endometriosis(OEM) is the most common type of endometriosis, but there is still a lack of simple and easy-to-promote animal models. Therefore, it is necessary to establish a feasible animal model of OEM and analyze its pathogenesis. In this study, a novel insertional surgical method was used to construct the OEM rat model. The rat model group's morphology and HE staining revealed a close relationship between the transplanted ectopic tissue and the ovary. Compared to the surgery group and the normal group, the bilateral OEM group's level of Anti-mullerian hormone(AMH) was noticeably lower. There was no discernible difference in the unilateral OEM group's AMH level between the normal and sham operation groups. Serum interleukin-1beta(IL-1β) levels in four groups of rats showed bilateral OEM had the greatest level, followed by unilateral OEM. Compared to the normal group, the two model groups had greater serum levels of IL-1β. According to immunohistochemistry, unilateral OEM had higher Intercellular adhesion molecule 1(ICAM1), Matrix metalloproteinase-9(MMP9), Tumor necrosis factor-α(TNF-a), and IL-1β expression levels than the normal rat endometrium. WB revealed that bilateral and unilateral ectopic tissues had higher levels of MMP9, TNF-a, Vascular endothelial growth factor D and IL-1β expression than normal tissues. Transcriptome research revealed that ectopic tissues had higher pro-inflammatory, immunological, and ectopic endometrial proliferation pathways than normal tissues. The ovaries of unilateral OEM have down-regulated immune and inflammation-related pathways and up-regulated steroid hormones compared to normal ovarian tissue. GSEA enrichment analysis comparisons between rat and human endometriotic tissue revealed that Janus kinase-signal transducer and activator of transcription(JAK-STAT), Nuclear factor-kappa B(NFκB), and Toll-like receptors were up-regulated. The intercalation approach of OEM building used in this work is more akin to the human OEM lesion type. It deserves promotion that modeling is more straightforward and has a higher success rate than the suture approach.

Nuclear factor (NF) κB as a redox sensitive, anti-apoptotic and pro-inflammatory signaling molecule has been studied extensively for more than three decades. Its role in inducing antioxidant enzymes, defending against extracellular and intracellular stress and maintaining redox homeostasis in skeletal muscle has also been recognized. New research continues to explore the polytropic nature of NFκB in cellular function, especially its crosstalk with other important signaling pathways. Understanding of the broad impact of these functions has significant implications in health and disease of skeletal muscle as an organ designed for contraction and mobility. Two important aspects of muscle wellbeing, i.e., disease and aging, are not discussed in this review. This review will provide an update on the new findings related to NFκB involvement in multiple signaling pathways and refresh our knowledge of its activation in skeletal muscle with a special reference to physical exercise.

Inflammatory Bowel Disease (IBD) is a chronic, idiopathic inflammatory disorder of the intestines. Oxymatrine (OMT) is a naturally active substance found in the desiccated roots of Sophora flavescens. It possesses anti-tumor, antiviral, and anti-inflammatory properties. In recent years, its therapeutic role in IBD has gradually been discovered. This review aims to explore the impact of OMT on inflammatory bowel disease by animal models.

Conduct a systematic search in the PubMed, Embase, Web of Science, Cochrane, and Medline databases. Using SYRCLE's risk of bias tool to assess the bias risk and quality of the included studies. For some data presented as figures, Web Plot Digitizer 4.2 software was used to extract it. STATA 16.0 was selected for the final meta-analysis.

After rigorous literature screening, 12 studies were included. The data analysis results indicated that the disease activity index (DAI), histopathological score (HS), interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), nuclear factor-κB (NF-κB), and myeloperoxidase (MPO) activity in the IBD animal models significantly decreased following intervention with oxymatrine. Furthermore, OMT also extended the colon length in the animal models and improved the expression level of zonula occludens-1(ZO-1) and occludin. These results suggested that OMT may improve the condition of IBD through anti-inflammatory, antioxidative stress and protecting the intestinal barrier.

Meta-analysis suggests oxymatrine positively affects IBD animal models. This provides new insights for the clinical treatment of inflammatory bowel disease.

https://www.crd.york.ac.uk/PROSPERO/view/CRD42024570580, identifier [CRD42024570580].

This study presents an innovative approach to the sustainable valorization of industrial sweet cherry (Prunus avium L.) waste from the Vignola Region, Italy, transforming what is typically discarded into a high-value bioactive resource. Unlike conventional extractions, our hydroethanolic extract (VCE) was obtained from the entire cherry waste, including the pericarp, pulp, and stone, as generated by industrial processing. This full-fruit extraction strategy represents a novel and efficient use of agricultural by-products, aligning with circular bioeconomy principles. Sweet cherries are known for their phenolic richness, and spectrophotometric assays (TPC, TFC, reducing power, DPPH, and ABTS) confirmed the extract's antioxidant capacity. In vitro studies using RAW 264.7 macrophages revealed no cytotoxic effects (MTT assay), along with significant anti-inflammatory activity, evidenced by reduced ROS and NO production and downregulation of iNOS and COX-2. Western blotting showed inhibition of NF-κB nuclear translocation and MAPK pathway signaling. Additionally, agarose gel electrophoresis showed protection against oxidative DNA damage. UPLC-MS/MS analysis identified sakuranetin, aequinetin, and dihydrowogonin as the most representative compounds in VCE. Molecular docking simulations revealed strong and specific binding affinities of these compounds to NF-κB p65 and key MAPK targets. These findings highlight whole sweet cherry waste-including the pit-as a potent and sustainable source of bioactive compounds with promising nutraceutical and pharmaceutical applications.

The IKKβ signaling pathway regulates NF-κB, influencing inflammation and cell survival in the brain. Radial glia cells are crucial for hippocampal neurogenesis and cognition. However, the role and mechanisms of IKKβ in modulating radial glia behavior and its impact on memory and neurogenesis remain unclear. Further studies are needed to understand how alterations in this pathway affect hippocampal function.

The role of IKKβ in memory and hippocampal neurogenesis was examined using GFAP-CreERT2/IKKβflox/flox mice with IKKβ knockdown in radial glia cells. IKKβ expression, NSC proliferation, and differentiation were assessed by immunohistochemistry. NF-κB and β-catenin interactions were evaluated by immunoprecipitation. Cultured adult hippocampal NSCs, with IKKβ or β-catenin shRNA transfection, were analyzed by flow cytometry and western blot to examine stem cell characteristics, NF-κB signaling, cell cycle, and β-catenin pathways.

Our results showed IKKβ cKD increased exploratory activity in the open-field and hyperactivity in the Y-maze, as well as enhanced spatial memory in the object location and Morris water maze tests. It also promoted adult hippocampal NSC proliferation by upregulating positive and inhibiting negative cell cycle regulators. Neuronal differentiation was enhanced, affecting β-catenin signaling and NeuroD1 expression. Additionally, IKKβ cKD promoted NSC survival, as shown by decreased cleaved caspase-3 and reduced Bax and cytochrome c in the hippocampus.

These findings suggest that in hippocampal NSCs, IKKβ inhibits locomotion, cognitive function, and adult hippocampal neurogenesis by suppressing the β-catenin signaling, highlighting its key role in decreasing hippocampal neurogenesis and cognitive function through NF-κB signaling in adult NSCs.

Inflammation appears to play a crucial role in the development and progression of penile cancer (PeCa). Two molecular pathways of PeCa are currently described: HPV-dependent and HPV-independent. The tumor immune microenvironment (TIME) of PeCa is characterized by the presence of tumor-associated macrophages, cancer-associated fibroblasts, and tumor-infiltrating lymphocytes. The components of the TIME produce pro-inflammatory cytokines and chemokines, which have been found to be overexpressed in PeCa tissues and are associated with tumor progression and unfavorable prognoses. Additionally, the nuclear factor kappa B (NF-κB) pathway and secreted phosphoprotein 1 (SPP1) have been implicated in PeCa pathogenesis. Elevated C-reactive protein (CRP) levels and the neutrophil-to-lymphocyte ratio (NLR) have been identified as potential prognostic biomarkers in PeCa. This overview presents the complex contribution of the inflammatory process and collates projects aimed at modulating TIME in PeCa.

This study compared the protective effects of both live Lacticaseibacillus paracasei 6235 (LLP 6235) and heat-killed Lacticaseibacillus paracasei 6235 (HK-LP 6235) on ulcerative colitis. Using a dextran sulfate sodium (DSS)-induced colitis mouse model, we evaluated physiological state, colon tissue integrity, inflammatory factors, tight junction (TJ) proteins, and intestinal microbiota variations. The findings demonstrated that both LLP 6235 and HK-LP 6235 have the capacity to mitigate colitis damage, enhance TJ protein levels, and restore colon morphology. In addition, these interventions modulated the intestinal inflammatory response by inhibiting pro-inflammatory factors and upregulating anti-inflammatory factors through the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling pathways. Moreover, treatment with LLP 6235 and HK-LP 6235 significantly altered intestinal microbiota diversity, increased the relative abundance of beneficial bacteria, and regulated the short-chain fatty acid (SCFA) levels. Spearman correlation analysis revealed a strong association between TJ proteins, SCFAs, intestinal microbiota, and inflammatory response, suggesting that LLP 6235 and HK-LP 6235 may provide an effective approach to colitis prevention. In conclusion, LLP 6235 and HK-LP 6235 have similar abilities; furthermore, HK-LP 6235 modulated the intestinal microbiota through lipid metabolic pathways, resulting in a greater improvement. Moreover, considering the high stability and safety of prebiotics and their wide applicability, HK-LP 6235 is recommended for use as a modulator of intestinal inflammatory diseases.

The cellular enzyme poly (ADP-ribose) polymerase-1 (PARP-1) is required for NF-κB to activate inflammatory and immune response gene expression. NF-κB is also an important transcription factor in HIV-1 gene expression during active replication and latency reactivation. Therefore, enhancing NF-κB signaling is an alternative for HIV-1 latency reactivation, but significant systemic side effects related to the NF-κB role in inflammatory and immune responses are predictable. To verify this prediction, we determined whether PARP-1 is required in NF-κB-dependent HIV-1 gene expression in a human CD4+ T lymphoblastoid cell line (SUP-T1) and HEK 293T cells. Our findings indicated that PARP-1 knockout does not impair HIV-1 infection or gene expression. Specifically, NF-κB-dependent HIV-1 gene expression was not impaired by PARP-1 deficiency, highlighting an important transcriptional regulatory difference between HIV-1 and inflammatory and immune activation genes. Our findings define a negligible role of PARP-1 in HIV-1 gene expression, suggesting that PARP-1 antagonism could ameliorate the expected inflammatory response with latency-reactivating agents that act through the NF-κB signaling pathway.

Proteins are involved in multiple biological functions. High-throughput technologies have allowed the measurement of thousands of proteins in population biobanks. In this study, we aimed to identify proteins related to Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis by leveraging large-scale genetic and proteomic data. We performed a two-sample cis Mendelian randomization study by selecting instrumental variables for the abundance of >2700 proteins measured by either Olink or SomaScan platforms in plasma from the UK Biobank and the deCODE Health Study. We also used the latest publicly available genome-wide association studies for the neurodegenerative diseases of interest. The potentially causal effect of proteins on neurodegenerative diseases was estimated based on the Wald ratio. We tested 13 377 protein-disease associations, identifying 169 associations that were statistically significant (5% false discovery rate). Evidence of co-localization between plasma protein abundance and disease risk (posterior probability > 0.80) was identified for 61 protein-disease pairs, leading to 50 unique protein-disease associations. Notably, 23 of 50 protein-disease associations corresponded to genetic loci not previously reported by genome-wide association studies. The two-sample Mendelian randomization and co-localization analysis also showed that APOE abundance in plasma was associated with three subcortical volumes (hippocampus, amygdala and nucleus accumbens) and white matter hyper-intensities, whereas PILRA and PILRB abundance in plasma was associated with caudate nucleus volume. Our study provided a comprehensive assessment of the effect of the human proteome that is currently measurable through two different platforms on neurodegenerative diseases. The newly associated proteins indicated the involvement of complement (C1S and C1R), microglia (SIRPA, SIGLEC9 and PRSS8) and lysosomes (CLN5) in Alzheimer's disease; the interleukin-6 pathway (CTF1) in Parkinson's disease; lysosomes (TPP1), blood-brain barrier integrity (MFAP2) and astrocytes (TNFSF13) in amyotrophic lateral sclerosis; and blood-brain barrier integrity (VEGFB), oligodendrocytes (PARP1), node of Ranvier and dorsal root ganglion (NCS1, FLRT3 and CDH15) and the innate immune system (CR1, AHSG and WARS) in multiple sclerosis. Our study demonstrates how harnessing large-scale genomic and proteomic data can yield new insights into the role of the plasma proteome in the pathogenesis of neurodegenerative diseases.

The current study isolated a homogeneous polysaccharide (AP) with a molecular weight of 7.9 kDa from the pomace of Fuji apples. AP was found to consists of rhamnose, galactose, arabinose, glucose, and galacturonic acid in a ratio of 4.3:5.2:2.6:1.0:11.9. Ten sugar residues in AP, including T-Araf, 1,5-Araf, 1,2-Rhap, 1,3-Rhap, T-Galp, 1,3,5-Araf, 1,4-Galp, 1,4-GalpA, 1,6-Glcp, and 1,3,6-Glcp were identified using methylation and GC-MS. Combined with 1D and 2D NMR, it was further revealed that AP possesses a backbone of α-Galp-(1 → [3)-α-Rhap-(1 → 2)-α-Rhap-(1]2 → [4)-α-GalpA-(1]10 → 3,6)-β-Glcp-(1 → 6)-β-Glcp-(1 → 4)-β-Galp-(1 → 4)-β-Galp-(1→, with two branches: α-Araf-(1 → 5)-α-Araf-(1 → 5)-α-Araf-(1 → 3,5)-α-Araf-(1 → 6)-β-Glcp-(1→ and →3)-α-Rhap-(1 → 5)-α-Araf-(1 → 3,6)-β-Glcp-(1→ bonded to the C-3 of β-1,3,6-Glcp. AP significantly inhibited the release of cytokines and inflammatory mediators, such as TNF-α, IL-1β, IL-6, reactive oxygen species (ROS) and nitric oxide (NO). Western blotting results indicated that AP treatment markedly downregulated iNOS and NF-κB protein expression in LPS-induced RAW264.7 cells, leading to decreased levels of phosphorylated proteins (p-NF-κB and p-ΙκΒα) and preventing the degradation of ΙκΒα. Furthermore, in LPS-induced RAW264.7 macrophages, AP inhibited the expression of TLR4 protein, which in turn inhibited the activity of the NF-κB pathway. The findings demonstrated that AP exhibits anti-inflammatory properties in vitro by targeting the TLR4/NF-κB signaling pathway, thus impeding the nuclear translocation of NF-κBp65, suppressing the expression of related pro-inflammatory factors.

The base excision repair pathway protects DNA from base damage via oxidation, deamination, alkylation and methylation. DNA glycosylases are key enzymes that recognize damaged bases in a lesion-specific manner and initiate the base excision repair process. Among these, the endonuclease VIII-like 1-3 (NEIL1-3) family, which is found in mammalian genomes, is a homolog of bacterial DNA glycosylases known as Fpg/Nei. NEIL enzymes have similar structures and substrates but with slight differences. When repair proteins are impaired, the accumulation of damaged bases can lead to increased genomic instability, which is implicated in various pathologies, including cancer and neurodegeneration. Notably, mutations in these proteins also influence a range of other diseases and inflammation. This review focuses on the influence of the NEIL family on human health across different organ systems. Investigating the relationship between NEIL mutations and diseases can improve our understanding of how these enzymes affect the human body. This information is crucial for understanding the basic mechanisms of DNA repair and enabling the development of novel inhibitors or gene therapies that target only these enzymes. Understanding the role of the NEIL family provides insights into novel therapies and improves our ability to combat genetic diseases.

The exploitation of micro-RNA (miR) sequences as therapeutics has become highly attractive for the treatment of several diseases, including those still lacking effective cures such as retinitis pigmentosa (RP). Interestingly, miR-155-5p plays a role in photo-oxidative inflammation in wild-type mice and is up-regulated in rd10 mice showing peak rod degeneration, suggesting its inhibition by the corresponding anti-miR as a viable therapeutic strategy for RP. However, biomedical application of (anti-)miRs is limited by their oligonucleotide nature, suffering from low solubility and bioavailability along with a very low half-life in vivo due to enzymatic degradation. Thereby, the need for suitable delivery systems led to the development of various nanocarriers, including oligosaccharide-based polymers. In this context, we designed and prepared an innovative nanosponge (NS) with a β-cyclodextrin (β-CD) motif payload with a bridge-like molecule, the amphipathic adamantane derivative (ADM), able to establish strong interactions with both NS and the therapeutic miR, thereby delivering and eventually releasing it close to the active site. Through an in vivo study, we both validated the NS system as a useful tool for miR topical administration by eye drop formulation and the functional activity of anti-miR-155-5p in RP.

Excessive endoplasmic reticulum (ER) stress in intestinal epithelial cells can lead to damage to the intestinal mucosal barrier, activate the signal transducer and activator of transcription 3 (STAT3)/nuclear factor kappa B (NF-κB) signaling pathway, and exacerbate the inflammatory response, thus participating in the pathogenesis of ulcerative colitis (UC). Mesalazine is a commonly used drug in the clinical treatment of UC. However, further studies are needed to determine whether mesalazine regulates the ER stress of intestinal epithelial cells, down-regulates the STAT3/NF-κB pathway to play a role in the treatment of UC.

To study the therapeutic effects of mesalazine on spontaneous colitis in interleukin-10 (IL-10)-/- mice.

The 24-week-old IL-10-/- mice with spontaneous colitis were divided into the model group and the 5-amino salicylic acid group. Littermates of wild-type mice of the same age group served as the control. There were eight mice in each group, four males and four females. The severity of symptoms of spontaneous colitis in IL-10-/- mice was assessed using disease activity index scores. On day 15, the mice were sacrificed. The colon length was measured, and the histopathological changes and ultrastructure of colonic epithelial cells were detected. The protein expressions of STAT3, p-STAT3, NF-κB, IκB, p-IκB, and glucose-regulated protein 78 were identified using Western blotting. The STAT3 and NF-κB mRNA expressions were identified using real-time polymerase chain reaction. The glucose-regulated protein 78 and C/EBP homologous protein expressions in colon sections were detected using immunofluorescence.

Mesalazine reduced the symptoms of spontaneous colitis in IL-10 knockout mice and the histopathological damage of colonic tissues, and alleviated the ER stress in epithelial cells of colitis mice. Western blotting and quantitative real-time polymerase chain reaction results showed that the STAT3/NF-κB pathway in the colon tissue of model mice was activated, suggesting that this pathway was involved in the pathogenesis of UC and might become a potential therapeutic target. Mesalazine could down-regulate the protein expressions of p-STAT3, NF-κB and p-IκB, and down-regulate the mRNA expression of STAT3 and NF-κB.

Mesalazine may play a protective role in UC by reducing ER stress by regulating the STAT3/NF-κB signaling pathway.

Celiac disease (CD) is a chronic autoimmune disorder driven by both genetic and environmental factors, with the HLA DQ2/DQ8 genotypes playing a central role in its development. Despite the genetic predisposition, only a small percentage of individuals carrying these genotypes develop the disease. Gluten, a protein found in wheat, rye, and barley, is the primary environmental trigger, but other factors, such as the intestinal microbiota, may also contribute to disease progression. While the gluten-free diet (GFD) remains the cornerstone of treatment, many CD patients experience persistent inflammation and gut dysbiosis, leading to ongoing symptoms and complications. This chronic inflammation, which impairs nutrient absorption, increases the risk of malnutrition, anemia, and other autoimmune disorders. Recent studies have identified an altered gut microbiota in CD patients, both on and off the GFD, highlighting the potential role of the microbiota in disease pathogenesis. An emerging area of interest is the supplementation of n-3 polyunsaturated fatty acids (PUFAs), known for their anti-inflammatory properties, as a potential therapeutic strategy. n-3 PUFAs, found in fish oil and certain plant oils, modulate the immune cell function and cytokine production, making them a promising intervention for controlling chronic inflammation in CD. This review explores the current understanding of n-3 PUFAs' effects on the gut microbiota's composition and inflammation in CD, with the goal of identifying new avenues for complementary treatments to improve disease management.

To date, no drugs are approved for BK polyomavirus (BKPyV) reactivation, a major cause of nephropathy after kidney transplantation. Recently, tumor necrosis factor-α (TNF-α) blockade has been proposed as a promising therapy, however, the effect of TNF-α on the clinically most common archetype (ww) BKPyV remained unclear. Assays in primary renal proximal tubule epithelial cells (RPTEC) allowed efficient replication only of BKPyV strains with rearranged (rr) non-coding control regions (NCCR), which may develop at later disease stages, but not of ww-BKPyV. Here, we optimized culture conditions allowing robust replication of patient-derived ww-BKPyV, while efficiently preserving their ww-NCCR. TNF-α promoted rr-BKPyV replication, while the TH1 cytokine IFN-γ suppressed it, also in the presence of TNF-α. Surprisingly, TNF-α alone was sufficient to suppress all ww-BKPyV strains tested. Comprehensive analysis using siRNAs, and chimeric or mutated BKPyV-strains revealed that the response to TNF-α depends on the NCCR type, and that the NF-κB p65 pathway but not the conserved NF-κB binding site is essential for the TNF-α-induced enhancement of rr-BKPyV replication. Our data suggest that in immunosuppressed patients with archetype-dominated infections, TNF-α blockade could interfere with natural TNF-α-mediated anti-BKPyviral control, and this could be detrimental when IFN-γ-driven TH1 responses are impaired. Ongoing inflammation, however, could lead to the selection of rearrangements responding to NCCR-activating pathways downstream of NF-κB p65 signaling, that may overcome the initial TNF-α-mediated suppression. Our findings also highlight the importance of using clinically relevant BKPyV isolates for drug testing and discovery, for which this new assay paves the way.

Deoxynivalenol (DON) is a common mycotoxin in crops that could induce intestinal inflammation, affecting the susceptibility of intestinal epithelial cells (IECs) to pathogen infection. This study aimed to investigate DON's effects on mucin and cytokine production as part of the local immune system and how it affected intestinal susceptibility to pathogen infection. Caco-2 cells were exposed to DON followed by acute enteroinvasive Escherichia coli (EIEC) infection. An increase in EIEC attachment to DON-exposed cells was observed, probably in part, mediated by secretory MUC5AC mucins and membrane-bound MUC4 and MUC17 mucins. Additionally, DON with EIEC posttreatment led to significant changes in the gene expression of several proinflammatory cytokines (IL1α, IL1β, IL6, IL8, TNFα, and MCP-1), which may be in part, mediated by NK-κB and/or MAPK signaling pathways. These data suggested DON may exert immunomodulatory effects on IECs, altering the IEC susceptibility to bacterial infection. PRACTICAL APPLICATION: The results suggested that DON might modulate immune responses by affecting mucus and cytokine production, which may affect the susceptibility of intestinal epithelial cells to pathogen infection.

We have previously shown that the hepatitis C virus (HCV) E1E2 envelope glycoprotein can regulate HIV-1 long-terminal repeat (LTR) activity through disruption to NF-κB activation. This response is associated with upregulation of the endoplasmic reticulum (ER) stress response pathway. Here, we demonstrate that the SARS-CoV-2 S, M, and E but not the N structural protein can perform similar downmodulation of HIV-1 LTR activation, and in a dose-dependent manner, in both HEK293 and lung BEAS-2B cell lines. This effect is highest with the SARS-CoV-2 Wuhan S strain and decreases over time for the subsequent emerging variants of concern (VOC), with Omicron providing the weakest effect. We developed pseudo-typed viral particle (PVP) viral tools that allowed for the generation of cell lines constitutively expressing the four SARS-CoV-2 structural proteins and utilising the VSV-g envelope protein to deliver the integrated gene construct. Differential gene expression analysis (DGEA) was performed on cells expressing S, E, M, or N to determine cell activation status. Gene expression differences were found in a number of interferon-stimulated genes (ISGs), including IF16, IFIT1, IFIT2, and ISG15, as well as for a number of heat shock protein (HSP) genes, including HSPH1, HSPA6, and HSPBP1, with all four SARS-CoV-2 structural proteins. There were also differences observed in expression patterns of transcription factors, with both SP1 and MAVS upregulated in the presence of S, M, and E but not the N protein. Collectively, the results indicate that gene expression patterns associated with ER stress pathways can be activated by SARS-CoV-2 envelope glycoprotein expression. The results suggest the SARS-CoV-2 infection can modulate an array of cell pathways, resulting in disruption to NF-κB signalling, hence providing alterations to multiple physiological responses of SARS-CoV-2-infected cells.

Acute myeloid leukemia (AML) is an aggressive hematological neoplasm. Little improvement in survival rates has been achieved over the past few decades. Necroptosis has relationship with certain types of malignancies outcomes. Here, we evaluated the diagnostic ability, prognostic capacity of necroptosis-related genes (NRGs) and the effect of their copy number variations (CNVs) in AML.

Necroptosis-related differentially expressed genes (NRDEGs) were identified after intersecting differentially expressed genes (DEGs) from the Gene Expression Omnibus(GEO) database with NRGs from GeneCards, the Molecular Signatures Database (MSigDB) and literatures. Machine learning was applied to obtain hub-NRDEGs. The expression levels of the hub-NRDEGs were validated in vitro. The mRNA-miRNA and mRNA-TF interaction networks with the hub-NRDEGs were screened using Cytoscape@. Single-sample gene set enrichment analysis (ssGSEA) was utilized to calculate correlations between the hub-NRDEGs and immune cells. CNV analysis of the hub-NRDEGs was carried out on the TCGA-LAML datasets from the TCGA database. Kaplan-Meier (K-M) survival analyses were utilized to evaluate the prognostic values along with Cox model.

Six hub-NRDEGs (SLC25A5, PARP1, CTSS, ZNF217, NFKB1, and PYGL) were obtained and their expression changes derived from CNVs in AML were visualized. In total, 65 mRNA-miRNA and 80 mRNA-TF interaction networks with hub-NRDEGs were screened. The ssGSEA result showed the expression of RAPR1 was inversely related to CD56dim natural killer cells and the expression of CTSS was positive related to Myeloid-derived suppressor cells (MDSCs) in AML. The K-M results demonstrated that ZNF217 had significant difference in the duration of survival in AML patients. Cox regression models revealed that the hub-NRDEGs had better predictive power at year-1 and year-5.

These screened NRDEGs can be exploited as clinical prognostic predictions in AML patients, as well as potential biomarkers for diagnosis and therapeutic targeting.

Ulcerative colitis (UC) is an inflammatory bowel disease characterized by inflammation and ulceration of the digestive tract.

Photodynamic therapy (PDT) with a novel photosensitizer LD4 was used to treat UC rat models to explore the therapeutic effect and mechanism of LD4-PDT on UC. 16S ribosomal RNA was used to detect the composition of Gut microbiota.

Our findings indicate that LD4-PDT could protect the integrity of the colonic mucosa, alleviate the inflammatory response and promote the healing of colonic mucosa. Mechanism studies demonstrated that LD4-PDT could inhibit the NF-κB signaling pathway, downregulated the expression of the inflammatory factors' tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and myeloperoxidase (MPO), increased the contents of glutathione (GSH) and superoxide dismutase (SOD) and decreased the content of malondialdehyde (MDA). Additionally, analysis of gut microbiota revealed that LD4-PDT treatment could decrease the abundance of the Proteobacteria phylum in fecal samples, while no significant differences were observed in the Firmicutes, Bacteroidetes, or Actinobacteria phyla among the three groups using 16S rRNA analysis.

In summary, our data suggested that LD4-PDT could inhibit DSS-induced UC in rats via the NF-κB signaling pathway, indicating its potential as a novel photosensitizer for the treatment of UC.

Hirschsprung's disease (HSCR) is characterized by congenital absence of ganglion cells in the gastrointestinal tract, which leads to impaired defecation, constipation and intestinal obstruction. The current diagnosis of HSCR is based on Rectal Suction Biopsies (RSBs), which could be complex in newborns. Occasionally, there is a delay in diagnosis that can increase the risk of clinical complications. Consequently, there is room for new non-invasive diagnostic methods that are objective, more logistically feasible and also deliver a far earlier base for a potential surgical intervention. In recent years, microRNA (miRNA) has come into the focus as a relevant early marker that could provide more insights into the etiology and progression of diseases. Therefore, in the search of a non-invasive HSCR biomarker, we analyzed miRNA expression in urine samples of HSCR patients. Results from 5 HSCR patients using microarrays, revealed hsa-miR-378 h, hsa-miR-210-5p, hsa-miR-6876-3p, hsa-miR-634 and hsa-miR-6883-3p as the most upregulated miRNAs; while hsa-miR-4443, hsa-miR-22-3p, hsa-miR-4732-5p, hsa-miR-3187-5p, and hsa-miR-371b-5p where the most downregulated miRNAs. Further search in miRNAwalk and miRDB databases showed that certainly most of these dysregulated miRNAs identified target HSCR associated genes, such as RET, GDNF, BDNF, EDN3, EDNRB, ERBB, NRG1, SOX10; and other genes implied in neuronal migration and neurogenesis. Finally, we could also validate some of these miRNA changes in HSCR urine by RT-qPCR. Altogether, our analyzed HSCR cohort presents a dysregulated miRNA expression presents that can be detected in urine. Our findings open the possibility of using specific urine miRNA signatures as non-invasive HSCR diagnosis method in the future.

6:2 Chlorinated polyfluoroalkyl ether sulfonate (trade name F-53B) is a substitute for perfluorooctane sulfonate (PFOS) used in the plating industry, and has been found in a range of environmental matrices and livings. There are numerous ways by which it is biotoxic to mammals. The kidneys are critical for maintaining homeostasis. However, little research has been conducted on how F-53B affects the kidneys. In this work, we investigated the renal toxicity of long-term oral F-53B treatment in C57BL/6J mice. Mice were allowed to drink F-53B freely at concentrations of 0, 0.057, 0.57, and 5.7 mg/L for 8 weeks. Renal oxidative stress, inflammation, and fibrosis were detected in mice exposed to F-53B, and the expression of related biochemical markers was significantly altered. Further investigations revealed that the TGF-β1/Smad3 and NF-κB signaling pathways may be associated with F-53B-induced renal fibrotic damage and inflammation. Overall, this study suggested that F-53B causes renal injury possibly via oxidative stress, activating the TGF-β1/Smad3 and NF-κB signaling pathways. This provides a foundation for further research into the harmful mechanism of F-53B in mammals.

Hypoxia induces the expression of nuclear factor kappa B (NF-kappa-B). NF-kappa-B functions by forming dimers from five main subunits: p65 (RelA), RelB, p52, p50, and c-Rel. In the classical pathway, NF-kappa-B activity is regulated by the degradation-inducing factor I kappa B kinase (IKK). IKK is composed of an α/β isomer and essential modulator NEMO (γ) subunits in the classical pathway, which may be the major pathway for NF-kappa-B signaling. In the present study, we focused on factor-inhibiting HIF-1 (FIH-1) and Prolyl hydroxylase domain enzyme (PHD), which have been identified as oxygen concentration-dependent regulators of HIF-1α. PHD has three isoforms: PHD1, PHD2, and PHD3, which have different affinities towards HIF-1α. We examined the interactions between IKKα/β and PHD1-3 by immunoprecipitation. PHDs efficiently interacted with IKKα/β. Furthermore, the overexpression of PHDs decreased the mRNA level of IL-1β, a downstream factor of NF-kappa-B activated by LPS. The overexpression of PHD1 and PHD2 markedly reduced IKKα/β protein levels; however, the effects of PHD3 were weaker than those of PHD1 and PHD2. Mutants of the active sites of PHD1 and PHD2 did not decrease IKKα/β protein levels, and a mutation in the active site of PHD3 did not affect IKKα/β protein levels. We also attempted to investigate the interactions of FIH-1 with IKKα/β and IκBα by immunoprecipitation, but found none. Moreover, IKKα/β and p65 protein levels were not affected by the overexpression of FIH-1. Collectively, these results suggest that PHDs directly regulated IKK protein levels, while FIH-1 did not affect the NF-kappa-B classical pathway.

Sepsis-associated acute kidney injury (S-AKI) is a prevalent and life-threatening complication in hospitalized and critically ill patients. Recent researches indicates that immunoproteasome, especially proteasome 20S subunit beta 8 (PSMB8), is highly associated with various kidney diseases. This study aims to investigate the potential involvement of PSMB8 in S-AKI and its impact on apoptosis and inflammation. The model of S-AKI induced by LPS (10 mg/kg) was assessed by histological examination. ELISA and Real-time PCR were used to detect the levels of inflammatory cytokines in the renal cortex. The role of shPSMB8 in LPS-induced apoptosis was detected by flow cytometry. Finally, western blot was performed to assess the NF-κB signaling pathway related proteins, and the nuclear translocation of NF-kB P65 was detected by immunofluorescence microscopy. PSMB8 knockdown substantially protected against renal injury by reducing blood urea nitrogen and creatinine levels and ameliorating inflammation. PSMB8 knockdown inhibited renal expression of interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α) and COX-2 to improve inflammatory response. Mechanistic studies demonstrated that downregulation of PSMB8 blocked LPS-induced S-AKI phosphorylation and nuclear translocation of NF-κB P65. Collectively, our results suggest that inhibition of PSMB8 significantly contributes to S-AKI via regulation of NF-κB. These findings reveal the pathogenic role of PSMB8 in AKI and suggest a novel therapeutic target for the condition.

The noncanonical NF-κB2 (nuclear factor kappa B subunit 2) pathway is integral in regulating immunologic responses, supervising immune function, development, and homeostasis. NFKB2 encodes the cytoplasmic precursor p100, which undergoes processing of its inhibitory C-terminal half to generate p52. Impeding C-terminal defects are well established to cause primary immunodeficiency disorder. In contrast, the mechanism of truncating N-terminal defects remains obscure.

We characterized clinical phenotypes associated with 3 distinct protein-defect types: (1) early truncations: typically occurring N-terminal relative to the nuclear localization sequence and affecting the Rel homology domain, predicting p100 expression to be halved and subsequent p52 generation by processing to be diminished; (2) central truncations: mainly affecting the ARD and predicting immediate expression of p52-like proteins and a 50% reduction of p100; and (3) C-terminal phosphorylation-/ubiquitination domain defects: causing expression of nonprocessable p100 with retained IκB-like activity and subsequently reducing generation of p52.

We performed literature research on PubMed, Clinvar, and Human Gene Mutation Database collecting clinical and immunologic data on NFKB2 patients, focusing on comparing protein-defect-specific impacts.

The highest prevalence of early-onset primary immunodeficiency disorder and antibody deficiency occurred in the CTD-defect group. In addition, endocrinological abnormalities and T-cell-mediated autoimmunity were common and frequently required immunosuppression. An extensive immunologic workup revealed patients with C-terminal defects to have pan-hypogammaglobulinemia and reduced specific antibody responses and markedly impaired B-cell differentiation, but normal to elevated T-cell counts. In contrast, pathogenic NFKB2 variants causing central or early-truncating protein defects were only partially penetrant, with ameliorated symptoms and diminished T-cell-mediated autoimmunity.

Our work defines a clear genotype-phenotype correlation for NFKB2 mutations.

This study describes the first successful cloning and functional characterization of chicken CX3CL1, a chemokine involved in immune cell migration and inflammatory responses. Evolutionary analyses revealed its close relation to CX3CL1 from other avian species, particularly duck, turkey, and quail. Structurally, chicken CX3CL1 includes a signal peptide and a chemokine interleukin-8-like domain characterized by unique alpha-helices and disulfide bonds. Additionally, we produced and purified recombinant CX3CL1 protein and assessed its endotoxin levels. Chemotaxis assays revealed that CX3CL1 significantly enhances the migration of HD11 macrophages and CU91 T cells. Furthermore, recombinant CX3CL1 induced the expression of pro-inflammatory cytokines (TNF-α, IFN-β, IFN-γ, IL-6, and CCL20) in a time-dependent manner, while exerting differential effects on anti-inflammatory cytokines (IL-4, IL-10). Conversely, transfection with siCX3CL1 or siCX3CR1 led to the downregulation of these responses. We also observed activation of the MAPK, NF-κB, and JAK/STAT pathways, evidenced by increased phosphorylation of key signaling molecules. These findings underscore the crucial role of chicken CX3CL1 in regulating immune responses, cell migration, and the activation of key signaling pathways. This study provides valuable insights into the immunomodulatory functions of soluble CX3CL1, highlighting its potential as a therapeutic target for inflammatory conditions and enhancing our understanding of immune cell dynamics.

The gut-brain axis (GBA) is a complex communication network connecting the gastrointestinal tract (GIT) and the central nervous system (CNS) through neuronal, endocrine, metabolic, and immune pathways. Omega-3 (n-3) fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are crucial food components that may modulate the function of this axis through molecular mechanisms. Derived mainly from marine sources, these long-chain polyunsaturated fatty acids are integral to cell membrane structure, enhancing fluidity and influencing neurotransmitter function and signal transduction. Additionally, n-3 fatty acids modulate inflammation by altering eicosanoid production, reducing proinflammatory cytokines, and promoting anti-inflammatory mediators. These actions help preserve the integrity of cellular barriers like the intestinal and blood-brain barriers. In the CNS, EPA and DHA support neurogenesis, synaptic plasticity, and neurotransmission, improving cognitive functions. They also regulate the hypothalamic-pituitary-adrenal (HPA) axis by reducing excessive cortisol production, associated with stress responses and mental health disorders. Furthermore, n-3 fatty acids influence the composition and function of the gut microbiota, promoting beneficial bacterial populations abundance that contribute to gut health and improve systemic immunity. Their multifaceted roles within the GBA underscore their significance in maintaining homeostasis and supporting mental well-being.

Anti-programmed cell death 1 (PD-1) antibody combined with chemotherapy simultaneously is regarded as the standard treatment for patients with advanced non-small cell lung cancer (NSCLC) by current clinical guidelines. Different immune statuses induced by chemotherapy considerably affect the synergistic effects of the chemo-anti-PD-1 combination. Therefore, it is necessary to determine the optimal timing of combination treatment administration.

The dynamic immune status induced by chemotherapy was observed in paired peripheral blood samples of patients with NSCLC using flow cytometry and RNA sequencing. Ex vivo studies and metastatic lung carcinoma mouse models were used to evaluate immune activity and explore the optimal combination timing. A multicenter prospective clinical study of 170 patients with advanced NSCLC was performed to assess clinical responses, and systemic immunity was assessed using omics approaches.

PD-1 expression on CD8+ T cells was downregulated on day 1 (D1) and D2, but recovered on D3 after chemotherapy administration, which is regulated by the calcium influx-P65 signaling pathway. Programmed cell death 1 ligand 1 expression in myeloid-derived suppressor cells was markedly reduced on D3. RNA sequencing analysis showed that T-cell function began to gradually recover on D3 rather than on D1. In addition, ex vivo and in vivo studies have shown that anti-PD-1 treatment on D3 after chemotherapy may enhance the antitumor response and considerably inhibit tumor growth. Finally, in clinical practice, a 3-day-delay sequential combination enhanced the objective response rate (ORR, 68%) and disease control rate (DCR, 98%) compared with the simultaneous combination (ORR=37%; DCR=81%), and prolonged progression-free survival to a greater extent than the simultaneous combination. The new T-cell receptor clones were effectively expanded, and CD8+ T-cell activity was similarly recovered.

A 3-day-delay sequential combination might increase antitumor responses and clinical benefits compared with the simultaneous combination.

Cardiovascular disease (CVD) has been the leading cause of death worldwide for many years. In recent years, exosomes have gained extensive attention in the cardiovascular system due to their excellent biocompatibility. Studies have extensively researched miRNAs in exosomes and found that they play critical roles in various physiological and pathological processes in the cardiovascular system. These processes include promoting or inhibiting inflammatory responses, promoting angiogenesis, participating in cell proliferation and migration, and promoting pathological progression such as fibrosis.

This systematic review examines the role of exosomes in various cardiovascular diseases such as atherosclerosis, myocardial infarction, ischemia-reperfusion injury, heart failure and cardiomyopathy. It also presents the latest treatment and prevention methods utilizing exosomes. The study aims to provide new insights and approaches for preventing and treating cardiovascular diseases by exploring the relationship between exosomes and these conditions. Furthermore, the review emphasizes the potential clinical use of exosomes as biomarkers for diagnosing cardiovascular diseases.

Exosomes are nanoscale vesicles surrounded by lipid bilayers that are secreted by most cells in the body. They are heterogeneous, varying in size and composition, with a diameter typically ranging from 40 to 160 nm. Exosomes serve as a means of information communication between cells, carrying various biologically active substances, including lipids, proteins, and small RNAs such as miRNAs and lncRNAs. As a result, they participate in both physiological and pathological processes within the body.

Inflammation can be an unwanted consequence or cause of debilitating diseases of infectious and non-infectious aetiologies. Current anti-inflammatory medications have several deficiencies including lack of specificity and undesirable side effects. Herein, the potential of non-ionic surfactant vesicles (NISV) comprised of monopalmityol glycerol, dicetyl phosphate and cholesterol) as an anti-inflammatory drug and their mode of action is investigated. NISV were able to inhibit LPS-induced IL-6 from BMD macrophages. The individual components of NISV, monopalmityol glycerol, dicetyl phosphate and cholesterol did not affect LPS induced IL-6 levels, proving that formulation of NISV is essential for their anti-inflammatory effects. Transcriptomic analyses showed NISV mediated down-regulation of transcripts for inflammatory mediators in LPS stimulated macrophages. Notably, NISV downregulate NF-κB transcripts in LPS stimulated macrophages. Measurement of inflammatory mediators by cytometric bead array validated a number of transcriptomic findings as NISV were found to inhibit LPS induced IL-6, IL-12, and multiple chemokines. Further investigation demonstrated that NISV inhibited Poly(I:C) or Pam3csk4 induced inflammatory mediators. This indicates that the effects of NISV are distal to both MyD88 and TRIF signalling. Overall, the data generated highlights the potential of NISV as an anti-inflammatory therapeutic.

The functional derangement affecting human chondrocytes during osteoarthritis (OA) onset and progression is sustained by the failure of major homeostatic mechanisms. This makes them more susceptible to oxidative stress (OS), which can induce DNA damage responses and exacerbate stress-induced senescence. The knockdown (KD) of IκB kinase α (IKKα), a dispensable protein in healthy articular cartilage physiology, was shown to increase the survival and replication potential of human primary OA chondrocytes. Our recent findings showed that the DNA Mismatch Repair pathway only partially accounts for the reduced susceptibility to OS of IKKαKD cells. Here we therefore investigated other ROS-mediated DNA damage and repair mechanisms. We exposed IKKαWT and IKKαKD chondrocytes to sub-cytotoxic hydrogen peroxide and evaluated the occurrence of double-strand breaks (DSB), 8-oxo-2'-deoxyguanosine (8-oxo-dG) and telomere shortening. ROS exposure was able to significantly increase the number of γH2AX foci (directly related to the number of DSB) in both cell types, but IKKα deficient cells undergoing cell division were able to better recover compared to their IKKα proficient counterpart. 8-oxo-dG signal proved to be the highest DNA damage signal among those investigated, located in the mitochondria and with a slightly higher intensity in IKKα proficient cells immediately after OS exposure. Furthermore, ROS significantly reduced telomere length both in IKKαWT and IKKαKD, with the former showing more pervasive effects, especially in dividing cells. Assessment of the HIF-1α>Beclin-1>LC3B axis after recovery from OS showed that IKKα deficient cells exhibited a more efficient autophagic machinery that allowed them to better cope with oxidative stress, possibly through the turnover of damaged mitochondria. Higher Beclin-1 levels likely helped in rescuing dividing cells (identified by coupled cell cycle analysis) because of Beclin-1's involvement in both autophagy and mitotic spindle organization. Therefore, our data further confirm the higher capacity of IKKαKD chondrocytes to cope with oxidative stress-induced DNA damage.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a severe inflammatory condition that remains refractory; however, its molecular mechanisms are largely unknown. Previous studies have shown numerous compounds containing 4-indolyl-2-aminopyrimidine that display strong anti-inflammatory properties. In our research, we identified that a 4-Indole-2-Arylaminopyrimidine derivative named "IAAP" suppressed lipopolysaccharide (LPS)-induced inflammation. Immunoprecipitation and liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified that IAAP interacts with a lysosomal cysteine protease, cathepsin L (CTSL), and restrains its activity. The nuclear factor kappa B (NF-κB) family plays a central role in controlling innate immunity. Canonical NF-κB activation, such as stimulation with lipopolysaccharide (LPS), typically involves the degradation of A20. We observed that IAAP suppression of CTSL prevented the LPS-induced degradation of A20, thereby ameliorating NF-κB activation. This study identifies CTSL as a crucial regulator of A20/NF-κB signaling and suggests IAAP as a potential lead compound for developing drugs to treat ALI/ARDS.

Oxidative stress induced by medium-wavelength ultraviolet radiation (UVB) is one of the most dangerous environmental stressors for the skin. Therefore, various medicinal remedies aim to prevent the harmful effects of UVB or support the recovery of the damaged cells. This study aimed to evaluate the impact of bioactive phytocannabinoid cannabigerol (CBG) together with 3-O-ethyl ascorbic acid (EAA), a stable, lipophilic derivative of the antioxidant vitamin C, on UVB-induced changes of proteome in cultured human keratinocytes 24 h after treatment. Surprisingly, proteomic analysis revealed very prominent CBG and EAA effects on kinases. These changes mainly influenced ERK1/2, IKK, MAP3K7, MAPK14, RIPK2, and NLK. Their expression was decreased by CBG and EAA, especially if used together after UVB-irradiation, so the effects of UVB were abolished restoring the profile of kinases to non-irradiated control. Moreover, CBG and EAA also reduced the UVB-induced modifications of proteins by the lipid peroxidation product 4-hydroxynonenal, especially in the case of AKT, Camkk1, cJun, ERK1, IKKα, MAPK11 and PERK. We conclude that, by maintaining proteome stability and kinase-dependent signalling, both CBG and EAA may support the recovery of human keratinocytes exposed to UVB radiation, especially if applied together, while the time-dependence of these effects should be further studied.

FK506-binding protein 5 (FKBP5), encoded by FKBP5 gene, has been reported as a scaffolding protein in various mammalian pathways related to immunity, inflammation, apoptosis and autophagy. However, the role of FKBP5 in lower vertebrates remains unknown. In this study, we identified zebrafish FKBP5 (DrFKBP5), an ortholog of mammalian FKBP5, which shows high homology with its counterpart in Anabarilius grahami based on amino acid alignment and phylogenetic analysis. DrFKBP5 was found to express ubiquitously across all tested tissues. Its expression were significantly upregulated in eye, intestine, gill, skin, heart, liver and kidney following SVCV treatment. A similar expression pattern was also observed in EPC and ZFIN cells. DrFKBP5 decreased the promoter activitiy of NF-κB and IL-6 rather than IFN I. It also inhibited the expression of inflammatory factor genes such as IL-6, IL-1β and TNF-α. In molecular mechanism, we found that DrFKBP5 interacted with IKKβ (an activator of NF-κB pathway), but not with IKKα or IKKγ, suggesting that DrFKBP5 regulates NF-κB pathway by targeting IKKβ. Then, DrFKBP5 significantly reduced the phosphorylation of IKKβ. Furthermore, it inhibited SVCV-induced nuclear translocation, phosphorylation of p65 and promoted SVCV replication in ZFIN cells. Finally, DrFKBP5 activated the expression of apoptosis-related genes, including BAX, Bcl2, caspase-3 and induced apoptosis under SVCV treatment.