Modulation Of NF-κB Signaling Research Articles

ISG15 regulates auto-inflammation by modulating NF-κB signaling pathway

ISG15 regulates auto-inflammation by modulating NF-κB signaling pathway

Aquaporins in sepsis- an update.

Aquaporins (AQPs), a family of membrane proteins that facilitate the transport of water and small solutes, have garnered increasing attention for their role in sepsis, not only in fluid balance but also in immune modulation and metabolic regulation. Sepsis, characterized by an excessive and dysregulated immune response to infection, leads to widespread organ dysfunction and significant mortality. This review focuses on the emerging roles of aquaporins in immune metabolism and their potential as therapeutic targets in sepsis, with particular attention to the modulation of inflammatory responses and organ protection. Additionally, it explores the diverse roles of aquaporins across various organ systems, highlighting their contributions to renal function, pulmonary gas exchange, cardiac protection, and gastrointestinal barrier integrity in the context of sepsis. Recent studies suggest that AQPs, particularly aquaglyceroporins like AQP3, AQP7, AQP9, and AQP10, play pivotal roles in immune cell metabolism and offer new therapeutic avenues for sepsis treatment. In the context of sepsis, immune cells undergo metabolic shifts to meet the heightened energy demands of the inflammatory response. A key adaptation is the shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, where pyruvate is converted to lactate, enabling faster ATP production. AQPs, particularly aquaglyceroporins, may facilitate this process by transporting glycerol, a substrate that fuels glycolysis. AQP3, for example, enhances glucose metabolism by transporting glycerol and complementing glucose uptake via GLUT1, while also regulating O-GlcNAcylation, a post-translational modification that boosts glycolytic flux. AQP7 could further contributes to immune cell energy production by influencing lipid metabolism and promoting glycolysis through p38 signaling. These mechanisms could be crucial for maintaining the energy supply needed for an effective immune response during sepsis. Beyond metabolism, AQPs also regulate key immune functions. AQP9, highly expressed in septic patients, is essential for neutrophil migration and activation, both of which are critical for controlling infection. AQP3, on the other hand, modulates inflammation through the Toll-like receptor 4 (TLR4) pathway, while AQP1 plays a role in immune responses by activating the PI3K pathway, promoting macrophage polarization, and protecting against lipopolysaccharide (LPS)-induced acute kidney injury (AKI). These insights into the immunoregulatory roles of AQPs suggest their potential as therapeutic targets to modulate inflammation in sepsis. Therapeutically, AQPs present promising targets for reducing organ damage and improving survival in sepsis. For instance, inhibition of AQP9 with compounds like HTS13286 or RG100204 has been shown to reduce inflammation and improve survival by modulating NF-κB signaling and decreasing oxidative stress in animal models. AQP5 inhibition with methazolamide and furosemide has demonstrated efficacy in reducing immune cell migration and lung injury, suggesting its potential in treating acute lung injury (ALI) in sepsis. Additionally, the regulation of AQP1 through non-coding RNAs (lncRNAs and miRNAs) may offer new strategies to mitigate organ damage and inflammatory responses. Moreover, AQPs have emerged as potential biomarkers for sepsis progression and outcomes. Altered expression of AQPs, such as AQP1, AQP3, and AQP5, correlates with sepsis severity, and polymorphisms in AQP5 have been linked to better survival rates and improved outcomes in sepsis-related acute respiratory distress syndrome (ARDS). This suggests that AQP expression could be used to stratify patients and tailor treatments based on individual AQP profiles. In conclusion, AQPs play a multifaceted role in the pathophysiology of sepsis, extending beyond fluid balance to crucial involvement in immune metabolism and inflammation. Targeting AQPs offers novel therapeutic strategies to mitigate sepsis-induced organ damage and improve patient survival. Continued research into the metabolic and immune functions of AQPs will be essential for developing targeted therapies that can be translated into clinical practice.

Protective effects of Boswellia and Curcuma extract on oxaliplatin-induced neuropathy via modulation of NF-κB signaling

Oxaliplatin is a third-generation anticancer agent with better efficacy, lower toxicity, and a broad spectrum of antineoplastic activity. Its use is frequently associated with chronic oxaliplatin-induced neuropathy (OIN), a cumulative phenomenon manifesting as loss of sensation, paresthesia, dysesthesia, and irresolvable fluctuations in proprioception that greatly affect the patients’ quality of life. The inevitable nature and high incidence of OIN, along with the absence of efficacious preventive agents, necessitate the development of effective and reliable protective options for limiting OIN while maintaining anticancer activity. The pathogenesis of chronic OIN involves neuroinflammation and oxidative stress. This study aimed to explore the neuroprotective effects of Boswellia serrata and Curcuma longa via modulation of nuclear factor-kappa B (NF-κB) signaling. Behavioral tests were conducted to assess cold allodynia, heat hyperalgesia, mechanical allodynia, mechanical hyperalgesia, and slowed nerve conduction velocity associated with chronic oxaliplatin administration. The modulation of NF-κB signaling and the subsequent activation of cytokines were evaluated through quantitative analysis of inflammatory cytokines in sciatic nerve homogenates. Additional assessments included oxidative stress parameters, serum neuronal biomarkers, and examination of sciatic nerve cross-sections. The findings indicate improvements in behavioral and biochemical parameters, as well as nerve histology, with the combined extract of Boswellia serrata and Curcuma longa at doses of 50 mg/kg and 75 mg/kg. Thus, this study presents evidence for the protective potential of the combined extract of Boswellia serrata and Curcuma longa in OIN through modulation of NF-κB signaling.

Protective effect of astaxanthin on chronic prostatitis/chronic pelvic pain syndrome in rat through modulating NF-κB signaling pathway.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common male urological disease characterized by chronic pelvic pain and various discomforts. Astaxanthin (AST) has multiple functions, including anti-inflammatory property, but it is unclear whether AST plays a key role in CP/CPPS and how it works. This study aimed to investigate the protective effect of AST on CP/CPPS in rats and the underlying mechanism. A CP/CPPS rat model was induced by intraprostatic injection of carrageenan and the blood specimens and prostates were harvested for further research after oral administration of AST for 4 weeks. Tactile allodynia test showed that AST ameliorated chronic pelvic pain in a dose-depended manner. In addition, histological evaluation indicated that AST alleviated CP/CPPS rat prostate histological inflammation. Meanwhile, AST suppressed the expression of proinflammatory cytokines, including interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor-α (TNF-α). Besides, AST inhibited the activities of prostaglandin E2 (PGE2) and cyclooxygenase 2 (COX2). Furthermore, AST decreased the activation of the nuclear factor-κB (NF-κB) signaling pathway. Our study has shown that AST exerts an anti-inflammatory and protective effect against CP/CPPS and the function is mediated at least through the suppression of NF-κB signaling pathway. These results provide evidence of AST as the potential agents for the treatment of CP/CPPS.

Role of miR-9 in Modulating NF-κB Signaling and Cytokine Expression in COVID-19 Patients.

Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has had a significant impact on global health, with severe cases often characterized by a worsening cytokine storm. Since it has been described that the NF-κB signaling pathway, regulated by microRNAs, could play a pivotal role in the inflammatory response, in this study, the role of miR-9 in modulating NF-κB signaling and inflammatory cytokine expression in COVID-19 patients was investigated. This observational retrospective single-center study included 41 COVID-19 patients and 20 healthy controls. Serum samples were analyzed for miR-9, NF-κB, and IκBα expression levels using RT-PCR. The expression levels and production of pro-inflammatory cytokines IL-6, IL-1β, and TNF-α were measured using RT-PCR and ELISA. Statistical analyses, including correlation and regression, were conducted to explore relationships between these variables. COVID-19 patients, particularly non-survivors, exhibited significantly higher miR-9 and NF-κB levels compared to controls. A strong positive correlation was found between miR-9 and NF-κB expression (r = 0.813, p < 0.001). NF-κB levels were significantly correlated with IL-6 (r = 0.971, p < 0.001), IL-1β (r = 0.968, p < 0.001), and TNF-α (r = 0.968, p < 0.001). Our findings indicate that miR-9 regulates NF-κB signaling and inflammation in COVID-19. Elevated miR-9 levels in non-survivors suggest its potential as a severity biomarker. While COVID-19 cases have decreased, targeting miR-9 and NF-κB could improve outcomes for other inflammatory conditions, including autoimmune diseases, highlighting the need for continued research in this area.

Role of Inflammation and the NF-κB Signaling Pathway in Hirschsprung's Disease.

Hirschsprung's disease (HSCR, incidence 1/5000 live births) is caused by the failure of neural crest-derived precursors to migrate, survive, proliferate, or differentiate during the embryonic development of the Enteric Nervous System (ENS), which could be disrupted by many factors, including inflammatory processes. The NF-κB family controls several biological processes, including inflammation, neurogenesis, and cell migration. With the aim of studying the potential role of NF-κB in HSCR, we have analyzed the expression of the NF-κB main subunits and other NF-κB-related genes by RT-qPCR in HSCR tissue samples (sub-divided into ganglionic and aganglionic segments). We found decreased gene expression of the NF-κB main subunit RELA but also of NFKBIA, TNFA, TFGBR2, and ERBB3 in the pathologic distal aganglionic segments compared to the proximal ganglionic segments. Moreover, we could also confirm the lower protein expression of RelA/p65 in the aganglionic distal segments by immunofluorescence staining. Further, we show that the expression of RelA/p65 protein in the proximal segments concurs with lymphocyte infiltration in the bowel tissue, indicating a pro-inflammatory activation of p65 in the proximal ganglionic HSCR tissue in the patients analyzed. All in all, our findings suggest that the modulation of NF-κB signaling in the neuro-enteric system does obviously contribute to the pathological effects of HSCR.

Therapeutic targeting of immunometabolism reveals a critical reliance on hexokinase 2 dosage for microglial activation and Alzheimer’s progression

Neuroinflammation is a prominent feature of Alzheimer's disease (AD). Activated microglia undergo a reprogramming of cellular metabolism necessary to power their cellular activities during disease. Thus, selective targeting of microglial immunometabolism might be of therapeutic benefit for treating AD. In the AD brain, the levels of microglial hexokinase 2 (HK2), an enzyme that supports inflammatory responses by promoting glycolysis, are significantly increased. In addition, HK2 displays non-metabolic activities that extend its inflammatory role beyond glycolysis. The antagonism of HK2 affects microglial phenotypes and disease progression in a gene-dose-dependent manner. HK2 complete loss fails to improve pathology by exacerbating inflammation, while its haploinsufficiency reduces pathology in 5xFAD mice. We propose that the partial antagonism of HK2 is effective in slowing disease progression by modulating NF-κB signaling through its cytosolic target, IKBα. The complete loss of HK2 affects additional inflammatory mechanisms related to mitochondrial dysfunction.

Chronic Lead Exposure in Adult Mice: Associations with miR-671/CDR1as Regulation, NF-κB Signaling, and Alzheimer's Disease-like Pathology.

Long-term exposure to lead (Pb) can result in chronic damage to the body through accumulation in the central nervous system (CNS) leading to neurodegenerative diseases, such as Alzheimer's disease (AD). This study delves into the intricate role of miR-671/CDR1as regulation in the etiology of AD-like lesions triggered by chronic Pb exposure in adult mice. To emulate the chronic effects of Pb, we established a rodent model spanning 10 months of controlled Pb administration, dividing 52 C57BL/6J mice into groups receiving varying concentrations of Pb (1, 2, or 4 g/L) alongside an unexposed control. Blood Pb levels were monitored using serum samples to ensure accurate dosing and to correlate with observed toxicological outcomes. Utilizing the Morris water maze, a robust behavioral assay for assessing cognitive functions, we documented a dose-dependent decline in learning and memory capabilities among the Pb-exposed mice. Histopathological examination of the hippocampal tissue revealed tell-tale signs of AD-like neurodegeneration, characterized by the accumulation of amyloid plaques and neurofibrillary tangles. At the molecular level, a significant upregulation of AD-associated genes, namely amyloid precursor protein (APP), β-secretase 1 (BACE1), and tau, was observed in the hippocampal tissue of Pb-exposed mice. This was accompanied by a corresponding surge in the protein levels of APP, BACE1, amyloid-β (Aβ), and phosphorylated tau (p-tau), further implicating Pb in the dysregulation of these key AD markers. The expression of CDR1as, a long non-coding RNA implicated in AD pathogenesis, was found to be suppressed in Pb-exposed mice. This observation suggests a potential mechanistic link between Pb-induced neurotoxicity and the dysregulation of the CDR1as/miR-671 axis, which warrants further investigation. Moreover, our study identified a dose-dependent alteration in the intracellular and extracellular levels of the transcription factor nuclear factor-kappa B (NF-κB). This finding implicates Pb in the modulation of NF-κB signaling, a pathway that plays a pivotal role in neuroinflammation and neurodegeneration. In conclusion, our findings underscored the deleterious effects of Pb exposure on the CNS, leading to the development of AD-like pathology. The observed modulation of NF-κB signaling and miR-671/CDR1as regulation provides a plausible mechanistic framework for understanding the neurotoxic effects of Pb and its potential contribution to AD pathogenesis.

Ursodeoxycholic Acid Modulates the Interaction of miR-21 and Farnesoid X Receptor and NF-κB Signaling.

(1) Background: This study investigates the effects of Ursodeoxycholic acid (UDCA) on NF-κB signaling, farnesoid X receptor (FXR) singling, and microRNA-21 in HepG2 cells. (2) Methods: HepG2 cells were treated with lipopolysaccharide (LPS) to simulate hepatic inflammation. The investigation focused on the expression of NF-κB activation, which was analyzed using Western blot, confocal microscopy, and Electrophoretic Mobility-shift Assays (EMSA). Additionally, NF-κB and farnesoid X receptor (FXR) singling expressions of micro-RNA-21, COX-2, TNF-α, IL-6, cyp7A1, and shp were assessed by RT-PCR. (3) Results: UDCA effectively downregulated LPS-induced expressions of NF-κB/65, p65 phosphorylation, and also downregulated FXR activity by Western blot. Confocal microscopy and EMSA results confirmed UDCA's role in modulating NF-κB signaling. UDCA reduced the expressions of LPS-induced COX-2, TNF-α, and IL-6, which were related to NF-κB signaling. UDCA downregulated LPS-induced cyp7A1 gene expression and upregulated shp gene expression, demonstrating selective gene regulation via FXR. UDCA also significantly decreased micro-RNA 21 levels. (4) Conclusions: This study demonstrates UDCA's potent anti-inflammatory effects on NF-κB and FXR signaling pathways, and thus its potential to modulate hepatic inflammation and carcinogenesis through interactions with NF-κB and FXR. The decrease in micro-RNA 21 expression further underscores its therapeutic potential.

1598: A synthetic LipoxinA4 analog improves radiation-induced lung injury by modulating NFκB signaling

1598: A synthetic LipoxinA4 analog improves radiation-induced lung injury by modulating NFκB signaling

Icariin mitigates anxiety-like behaviors induced by hemorrhagic shock and resuscitation via inhibiting of astrocytic activation

BackgroundAbnormal activation of astrocytes in the amygdala contributes to anxiety after hemorrhagic shock and resuscitation (HSR). Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB)-associated epigenetic reprogramming of astrocytic activation is crucial to anxiety. A bioactive monomer derived from Epimedium icariin (ICA) has been reported to modulate NF-κB signaling and astrocytic activation. PurposeThe present study aimed to investigate the effects of ICA on post-HSR anxiety disorders and its potential mechanism of action. MethodsWe first induced HSR in mice through a bleeding and re-transfusion model and selectively inhibited and activated astrocytes in the amygdala using chemogenetics. Then, ICA (40 mg/kg) was administered by oral gavage once daily for 21 days. Behavioral, electrophysiological, and pathological changes were assessed after HSR using the light-dark transition test, elevated plus maze, recording of local field potential (LFP), and immunofluorescence assays. ResultsExposure to HSR reduced the duration of the light chamber and attenuated open-arm entries. Moreover, HSR exposure increased the theta oscillation power in the amygdala and upregulated NF-κB p65, H3K27ac, and H3K4me3 expression. Contrarily, chemogenetic inhibition of astrocytes significantly reversed these changes. Chemogenetic inhibition in astrocytes was simulated by ICA, but chemogenetic activation of astrocytes blocked the neuroprotective effects of ICA. ConclusionICA mitigated anxiety-like behaviors induced by HSR in mice via inhibiting astrocytic activation, which is possibly associated with NF-κB-induced epigenetic reprogramming.

ITF2357 regulates NF-κB signaling pathway to protect barrier integrity in retinal pigment epithelial cells.

The robust integrity of the retinal pigment epithelium (RPE), which contributes to the outer brain retina barrier (oBRB), is compromised in several retinal degenerative and vascular disorders, including diabetic macular edema (DME). This study evaluates the role of a new generation of histone deacetylase inhibitor (HDACi), ITF2357, in regulating outer blood-retinal barrier function and investigates the underlying mechanism of action in inhibiting TNFα-induced damage to RPE integrity. Using the immortalized RPE cell line (ARPE-19), ITF2357 was found to be non-toxic between 50 nM and 5 μM concentrations. When applied as a pre-treatment in conjunction with an inflammatory cytokine, TNFα, the HDACi was safe and effective in preventing epithelial permeability by fortifying tight junction (ZO-1, -2, -3, occludin, claudin-1, -2, -3, -5, -19) and adherens junction (E-cadherin, Nectin-1) protein expression post-TNFα stress. Mechanistically, ITF2357 depicted a late action at 24 h via attenuating IKK, IκBα, and p65 phosphorylation and ameliorated the expression of IL-1β, IL-6, and MCP-1. Also, ITF2357 delayed IκBα synthesis and turnover. The use of Bay 11-7082 and MG132 further uncovered a possible role for ITF2357 in non-canonical NF-κB activation. Overall, this study revealed the protection effects of ITF2357 by regulating the turnover of tight and adherens junction proteins and modulating NF-κB signaling pathway in the presence of an inflammatory stressor, making it a potential therapeutic application for retinal vascular diseases such as DME with compromised outer blood-retinal barrier.

Non-coding RNA LINC01010 regulates macrophage polarization and innate immune functions by modulating NFκB signaling pathway.

Innate immune response is regulated by tissue resident or infiltrating immune cells such as macrophages (Mφ) that play critical role in tissue development, homeostasis, and repair of damaged tissue. However, the epigenetic mechanisms that regulate Mφ plasticity and innate immune functions are not well understood. Long non-coding RNA (lncRNA) are among the most abundant class of transcriptome but their function in myeloid cell biology is less explored. In this study, we deciphered the regulatory role of previously uncharacterized lncRNAs in Mφ polarization and innate immune responses. Two lncRNAs showed notable changes in their levels during M1 and M2 Mφ differentiation. Our findings indicate that LINC01010 expression increased and AC007032 expression decreased significantly. LINC01010 exhibit myeloid cell-specificity, while AC007032.1 is ubiquitous and expressed in both myeloid and lymphoid (T cells, B cells and NK cells) cells. Expression of these lncRNAs is dysregulated in periodontal disease (PD), a microbial biofilm-induced immune disease, and responsive to lipopolysaccharide (LPS) from different oral and non-oral bacteria. Knockdown of LINC01010 but not AC007032.1 reduced the surface expression of Mφ differentiation markers CD206 and CD68, and M1Mφ polarization markers MHCII and CD32. Furthermore, LINC01010 RNAi attenuated bacterial phagocytosis, antigen processing and cytokine secretion suggesting its key function in innate immunity. Mechanistically, LINC01010 knockdown Mφ treated withEscherichia coli LPS exhibit significantly reduced expression of multiple nuclear factor kappa B pathway genes. Together, our data highlight functional role of a PD-associated lncRNA LINC01010 in shaping macrophage differentiation, polarization, and innate immune activation.

Sphingomyelin synthase 2 promotes the stemness of breast cancer cells via modulating NF-κB signaling pathway

ObjectivesMulti-drug resistance (MDR) to chemotherapy is the main obstacle influencing the anti-tumor effect in breast cancer, which might lead to the metastasis and recurrence of cancer. Until now, there are still no effective methods that can overcome MDR. In this study, we aimed to investigate the role of sphingomyelin synthase 2 (SMS2) in breast cancer resistance.MethodsQuantitative RT-PCR analysis was performed to assess changes in mRNA expression. Western blot analysis was performed to detect protein expression. Inhibitory concentration value of adriamycin (ADR) was evaluated using CCK 8 assay. The stemness ability of breast cancer cells was assessed by spheroid-formation assay. Immunofluorescence staining was conducted to show the cellular distribution of proteins. Breast tumor masses were harvested from the xenograft tumor mouse model.ResultsSMS2 overexpression increased the IC50 values of breast cancer cells. SMS2 decreased the CD24 transcription level but increased the transcription levels of stemness-related genes including CD44, ALDH, OCT 4 and SOX2 in breast cancer cells. SMS2 overexpression promoted the nuclear translocation of phosphorylated NF-κB, while suppression of SMS2 could inhibit the NF-κB pathway.ConclusionsSMS2 increased the stemness of breast cancer cells via NF-κB signaling pathway, leading to resistance to the chemotherapeutic drug ADR. Thus, SMS2 might play a critical role in the development of breast cancer resistance, which is a previously unrecognized mechanism in breast cancer MDR development.

Suppression of long noncoding RNA SNHG6 alleviates cigarette smoke-induced lung inflammation by modulating NF-κB signaling.

Chronic obstructive pulmonary disease (COPD) is a widespread inflammatory disease with a high mortality rate. Long noncoding RNAs play important roles in pulmonary diseases and are potential targets for inflammation intervention. The expression of small nucleolar RNA host gene 6 (SNHG6) in mouse lung epithelial cell line MLE12 with or without cigarette smoke extract (CSE) treatment was first detected using quantitative reverse-transcription PCR. ELISA was used to evaluate the release of inflammatory cytokines (TNF-α, IL-1β, and IL-6). The binding site of miR-182-5p with SNHG6 was predicted by using miRanda, which was verified by double luciferase reporter assay. Here, we revealed that SNHG6 was upregulated in CS-exposed MLE12 alveolar epithelial cells and lungs from COPD-model mice. SNHG6 silencing weakened CS-induced inflammation in MLE12 cells and mouse lungs. Mechanistic investigations revealed that SNHG6 could upregulate IκBα kinase through sponging the microRNA miR-182-5p, followed by activated NF-κB signaling. The suppressive effects of SNHG6 silencing on CS-induced inflammation were blocked by an miR-182-5p inhibitor. Overall, our findings suggested that SNHG6 regulates CS-induced inflammation in COPD by activating NF-κB signaling, thereby offering a novel potential target for COPD treatment.

Peste des petits ruminants virus non-structural V and C proteins interact with the NF-κB p65 subunit and modulate pro-inflammatory cytokine gene induction.

Peste des petits ruminants virus (PPRV) is known to induce transient immunosuppression in infected small ruminants by modulating several cellular pathways involved in the antiviral immune response. Our study shows that the PPRV-coded non-structural proteins C and V can interact with the cellular NF-κB p65 subunit. The PPRV-C protein interacts with the transactivation domain (TAD) while PPRV-V interacts with the Rel homology domain (RHD) of the NF-κB p65 subunit. Both viral proteins can suppress the NF-κB transcriptional activity and NF-κB-mediated transcription of cellular genes. PPRV-V protein expression can significantly inhibit the nuclear translocation of NF-κB p65 upon TNF-α stimulation, whereas PPRV-C does not affect it. The NF-κB-mediated pro-inflammatory cytokine gene expression is significantly downregulated in cells expressing PPRV-C or PPRV-V protein. Our study provides evidence suggesting a role of PPRV non-structural proteins V and C in the modulation of NF-κB signalling through interaction with the NF-κB p65 subunit.

Glycerol monolaurate improves intestinal morphology and antioxidant status by suppressing inflammatory responses and nuclear factor kappa-B signaling in lipopolysaccharide-exposed chicken embryos

Medium-chain fatty acids and their derivatives are natural ingredients that support immunological functions in animals. The effects of glycerol monolaurate (GML) on intestinal innate immunity and associated molecular mechanisms were investigated using a chicken embryo model. Sixty-four Arbor Acres broiler embryos were randomly allocated into four groups. On embryonic day 17.5, the broiler embryos were administered with 9 mg of GML, which was followed by a 12-h incubation period and a 12-h challenge with 32 μg of lipopolysaccharide (LPS). On embryonic day 18.5, the jejunum and ileum were harvested. Results indicated that GML reversed the LPS-induced decline in villus height and upregulated the expression of mucin 2 (P < 0.05). GML decreased LPS-induced malondialdehyde production and boosted antioxidant enzyme activity (P < 0.05). GML alleviated LPS-stimulated intestinal secretion of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) (P < 0.05). GML also normalized LPS-induced changes in the gene expression of Toll-like receptor 4, nuclear factor kappa-B p65 (NF-κB p65), cyclooxygenase-2, NOD-like receptor protein 3, IL-18, zonula occludens 1, and occludin (P < 0.05). GML enhanced as well the expression of AMP-activated protein kinase α1 and claudin 1 (P < 0.05). In conclusion, GML improved intestinal morphology and antioxidant status by alleviating inflammatory responses and modulating NF-κB signaling in LPS-challenged broiler embryos.

Inhibition of VCP modulates NF-κB signaling pathway to suppress multiple myeloma cell proliferation and osteoclast differentiation.

Multiple myeloma (MM) is the second most common hematological malignancy, in which the dysfunction of the ubiquitin-proteasome pathway is associated with the pathogenesis. The valosin containing protein (VCP)/p97, a member of the AAA+ ATPase family, possesses multiple functions to regulate the protein quality control including ubiquitin-proteasome system and molecular chaperone. VCP is involved in the occurrence and development of various tumors while still elusive in MM. VCP inhibitors have gradually shown great potential for cancer treatment. This study aims to identify if VCP is a therapeutic target in MM and confirm the effect of a novel inhibitor of VCP (VCP20) on MM. We found that VCP was elevated in MM patients and correlated with shorter survival in clinical TT2 cohort. Silencing VCP using siRNA resulted in decreased MM cell proliferation via NF-κB signaling pathway. VCP20 evidently inhibited MM cell proliferation and osteoclast differentiation. Moreover, exosomes containing VCP derived from MM cells partially alleviated the inhibitory effect of VCP20 on cell proliferation and osteoclast differentiation. Mechanism study revealed that VCP20 inactivated the NF-κB signaling pathway by inhibiting ubiquitination degradation of IκBα. Furthermore, VCP20 suppressed MM cell proliferation, prolonged the survival of MM model mice and improved bone destruction in vivo. Collectively, our findings suggest that VCP is a novel target in MM progression. Targeting VCP with VCP20 suppresses malignancy progression of MM via inhibition of NF-κB signaling pathway.

GSK-J4 Inhibition of KDM6B Histone Demethylase Blocks Adhesion of Mantle Cell Lymphoma Cells to Stromal Cells by Modulating NF-κB Signaling.

Multiple signaling pathways facilitate the survival and drug resistance of malignant B-cells by regulating their migration and adhesion to microenvironmental niches. NF-κB pathways are commonly dysregulated in mantle cell lymphoma (MCL), but the exact underlying mechanisms are not well understood. Here, using a co-culture model system, we show that the adhesion of MCL cells to stromal cells is associated with elevated levels of KDM6B histone demethylase mRNA in adherent cells. The inhibition of KDM6B activity, using either a selective inhibitor (GSK-J4) or siRNA-mediated knockdown, reduces MCL adhesion to stromal cells. We showed that KDM6B is required both for the removal of repressive chromatin marks (H3K27me3) at the promoter region of NF-κB encoding genes and for inducing the expression of NF-κB genes in adherent MCL cells. GSK-J4 reduced protein levels of the RELA NF-κB subunit and impaired its nuclear localization. We further demonstrated that some adhesion-induced target genes require both induced NF-κB and KDM6B activity for their induction (e.g., IL-10 cytokine gene), while others require induction of NF-κB but not KDM6B (e.g., CCR7 chemokine gene). In conclusion, KDM6B induces the NF-κB pathway at different levels in MCL, thereby facilitating MCL cell adhesion, survival, and drug resistance. KDM6B represents a novel potential therapeutic target for MCL.

Ogt-mediated O-GlcNAcylation inhibits astrocytes activation through modulating NF-κB signaling pathway

Previous studies have shown that Ogt-mediated O-GlcNAcylation is essential for neuronal development and function. However, the function of O-GlcNAc transferase (Ogt) and O-GlcNAcylation in astrocytes remains largely unknown. Here we show that Ogt deficiency induces inflammatory activation of astrocytes in vivo and in vitro, and impairs cognitive function of mice. The restoration of O-GlcNAcylation via GlcNAc supplementation inhibits the activation of astrocytes, inflammation and improves the impaired cognitive function of Ogt deficient mice. Mechanistically, Ogt interacts with NF-κB p65 and catalyzes the O-GlcNAcylation of NF-κB p65 in astrocytes. Ogt deficiency induces the activation of NF-κB signaling pathway by promoting Gsk3β binding. Moreover, Ogt depletion induces the activation of astrocytes derived from human induced pluripotent stem cells. The restoration of O-GlcNAcylation inhibits the activation of astrocytes, inflammation and reduces Aβ plaque of AD mice in vitro and in vivo. Collectively, our study reveals a critical function of Ogt-mediated O-GlcNAcylation in astrocytes through regulating NF-κB signaling pathway.