NF-κB Signaling Pathway Research Articles

Exercise Promotes Hippocampal Neurogenesis in T2DM Mice via Irisin/TLR4/MyD88/NF-κB-Mediated Neuroinflammation Pathway.

Neuroinflammation is a major feature of type 2 diabetic mellitus (T2DM), adversely affecting hippocampal neurogenesis. However, the precise mechanism is not fully understood, and therapeutic approaches are currently lacking. Therefore, we determined the effects of exercise on neuroinflammation and hippocampal neurogenesis in T2DM mice, with a specific focus on understanding the role of the irisin and related cascade pathways in modulating the beneficial effects of exercise in these processes. Ten-week exercise significantly decreased T2DM-induced inflammation levels and markedly promoted hippocampal neurogenesis and memory function. However, these positive effects were reversed by 10 weeks of treatment with cyclo RGDyk, an inhibitor of irisin receptor signaling. Additionally, exercise helped reduce the M1 phenotype polarization of hippocampal microglia in diabetic mice; this effect could be reversed with cyclo RGDyk treatment. Moreover, exercise markedly increased the levels of fibronectin type III domain-containing protein 5 (FNDC5)/irisin protein while decreasing the expression of Toll-like receptor 4 (TLR4), myeloid differential protein-88 (MyD88), and nuclear factor kappa-B (NF-κB) in the hippocampus of T2DM mice. However, blocking irisin receptor signaling counteracted the down-regulation of TLR4/MyD88/NF-κB in diabetic mice undergoing exercise intervention. Conclusively, exercise appears to be effective in reducing neuroinflammation and enhancing hippocampal neurogenesis and memory in diabetes mice. The positive effects are involved in the participation of the irisin/TLR4/MyD88/NF-κB signaling pathway, highlighting the potential of exercise in the management of diabetic-induced cognitive decline.

Exploring the Phytochemistry, Signaling Pathways, and Mechanisms of Action of Tanacetum parthenium (L.) Sch.Bip.: A Comprehensive Literature Review.

The traditional use of Tanacetum parthenium (L.) Sch.Bip., commonly known as feverfew, extends across various medical conditions, notably those associated with pain and inflammation. In alignment with the growing trend towards developing medications that target specific signaling pathways for enhanced efficacy and reduced side effects, extensive research has been conducted to investigate and validate the pharmacological effects of feverfew. Among its bioactive compounds, parthenolide stands out as the most potent, categorized as a germacranolide-type sesquiterpene lactone, and has been extensively studied in multiple investigations. Significantly, the anti-inflammatory properties of feverfew have been primarily attributed to its capacity to inhibit nuclear factor-kappa B (NF-κB), resulting in a reduction in pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α). Furthermore, the anticancer properties of feverfew have been associated with the modulation of Mitogen-Activated Protein Kinase (MAPK) and NF-κB signaling pathways. This study further delves into the neuroprotective potential of feverfew, specifically in the management of conditions such as migraine headaches, epilepsy, and neuropathic pain through various mechanisms. The core objective of this study is to elucidate the phytochemical composition of feverfew, with a particular emphasis on understanding the molecular mechanisms and examining the signaling pathways that contribute to its pharmacological and therapeutic effects. Additionally, the safety, toxicity, and potential adverse effects of feverfew are comprehensively evaluated, with an overarching goal of providing valuable insights into the plant's potential for targeted and effective treatments.

Edaravone Dexborneol provides neuroprotective effect by inhibiting neurotoxic activation of astrocytes through inhibiting NF-κB signaling in cortical ischemia

Edaravone Dexborneol (EDB), comprised of edaravone and (+)- bornel, has been demonstrated to have synergistic effects of antioxidant and anti-inflammatory, which makes it to be applied for stroke as a protectant. However, the underlying mechanism of neuroprotection of EDB has not been fully elucidated. Increasing evidence has shown that neurotoxic A1 astrocytes were closely related to neuronal death after cerebral ischemia. However, whether EDB could provide neuroprotection by modulating the activation of astrocytes has not yet been elucidated. The present study aimed to explore whether EDB afforded neuroprotection by modulating A1 polarization of astrocytes and the down-stream signaling after cerebral ischemia. We first validated the neuroprotective effects of EDB in mice suffering focal cerebral ischemia via evaluating behavioral test, infarct volumes and neuronal survival. As for the down-stream signaling, our data further showed that EDB alleviated neuronal death by suppressing activation of neurotoxic A1 astrocytes via inhibition of NF-κB signaling pathway in vitro. Additionally, administration of EDB reduced the number of A1 reactive astrocytes in mice of focal cerebral ischemia. The above findings demonstrated that EDB provided neuroprotective effect by inhibiting neurotoxic activation of A1 astrocytes in animal model of cerebral ischemia, which indicated that EDB-mediated phenotypic regulation of astrocytes is a potential research direction to promote neurological recovery in central nervous system (CNS) diseases.

Bibliometric analysis of the interplay between epilepsy and microglia: trends, hotspots, and emerging research areas.

Epilepsy, a common neurological disorder, has been increasingly associated with neuroinflammation, especially microglia activation. To gain insights into the research trends and patterns in this intersection, we conducted a bibliometric analysis of studies published between 2005 and 2024. Using the Web of Science Core Collection, we identified 1,229 relevant articles and reviews, focusing on the relationship between epilepsy and microglia. We employed the Bibliometrix R package and VOSviewer to analyze the data. Our search strategy combined epilepsy-related terms with microglia and microglial cell keywords. The analysis encompassed publication trends, country and institutional contributions, journal sources, authors, keywords, and thematic evolution. The number of publications has steadily increased, particularly after 2019, indicating growing research interest. The United States, China, and Germany emerged as the most productive countries, with extensive collaboration between China and the United States. Epilepsia and Journal of Neuroinflammation were the most influential journals. Aronica E, Vezzani A, and Engel T were the most prolific authors. Thematic analysis revealed clusters focused on temporal lobe epilepsy, epilepsy-related disorders, and microglia activation. Over the past several years, research has shifted from fundamental brain function studies to in-vivo investigations of specific molecular mechanisms. The CSTB (-) mouse model and NF-κB signaling pathway both merit further in-depth investigation. In conclusion, this bibliometric study reveals a surge in epilepsy-microglia research, led by key countries, journals, and researchers. Temporal lobe epilepsy, epilepsy-related disorders, and microglia activation are focal themes. Future directions include exploring microglia activation mechanisms, utilizing animal models, and interdisciplinary approaches.

Morinda officinalis iridoid glycosides, as an inhibitor of GSK-3β, alleviates rheumatoid arthritis through inhibition of NF-κB and JAK2/STAT3 pathway.

Morinda officinalis iridoid glycosides (MOIG) showed potential benefits in the treatment of rheumatoid arthritis (RA), but their exact mechanism has yet to be explored. To evaluate the effects of MOIG on RA, and explore the potential targets and molecular mechanism of MOIG in RA. The collagen-induced arthritis (CIA) rats were used to evaluate the effects of MOIG on RA. The proliferation, migration and invasion of fibroblast-like synoviocytes (FLSs) stimulated with or without tumor necrosis factor (TNF)-α were examined by CCK-8, wound healing and transwell assays, respectively. IF and WB were applied to investigate related mechanism in FLSs. The molecular docking, molecular dynamics simulation, CETSA and siRNA were used to analyze the interaction of MOIG with target. Finally, the adjuvant-induced arthritis (AA) mice model with gene knockdown was used to confirm the effect of MOIG on glycogen synthase kinase-3β (GSK-3β). MOIG significantly alleviated the paw swelling and synovial hyperplasia in CIA rats. Moreover, MOIG suppressed proliferation, migration and invasion, the secretion of inflammatory factors, and the expression of adhesion related proteins in TNF-α-stimulated FLSs. MOIG also inhibited the activation of Janus activating kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-B (NF-κB) signaling pathway in FLSs. Interestingly, the plant metabolites in MOIG had a good affinity with GSK-3β, and inhibition of GSK-3β attenuated the effects of MOIG on FLSs. Knockdown GSK-3β gene could inhibit the paw swelling and inflammatory indicators, decrease the arthritis score and synovial hyperplasia, reduce the phosphorylation of p65 and STAT3 in AA mice, thereby suppressing the NF-κB and STAT3 signaling activation, and MOIG treatment had no significant effects on AA mice with si-GSK-3β. MOIG alleviates joint inflammation in RA through inhibition NF-κB and JAK2/STAT3 pathway via suppression of GSK-3β in FLSs, which provides supports for MOIG as a promising therapeutic agent of RA.

Sika Deer antler protein antagonizes the inflammatory response and oxidative damage induced by jellyfish venom

The investigation into specific treatments for jellyfish stings has consistently presented a significant medical challenge. Sika Deer antler protein (DAP), a valuable component of traditional Chinese medicine (TCM) known for its various pharmacological properties, has been widely utilized for the prevention and treatment of numerous diseases. In this study, proteome analysis and biological activity assays of DAP identified 94 distinct protein components and demonstrated its capability to scavenge free radicals. Moreover, administration of 50 mg/kg DAP notably enhanced survival rates in mice, mitigated increases in hematological indicators and inflammatory markers (IL-6, IL-1β, and TNF-α), and alleviated pathological abnormalities induced by jellyfish venom. Additionally, DAP intervention significantly decreased the hemolysis rate and improved the viability of RAW264.7 cells, while reducing cell apoptosis and oxidative stress. Transcriptome analysis and western blotting of RAW264.7 cells further confirmed that DAP inhibited the activation of the NF-κB and MAPK signaling pathways. Overall, DAP effectively countered the toxicity of jellyfish venom by reducing oxidative damage and inflammatory response, highlighting the potential of TCM in treating jellyfish stings.

A neolignan enantiomer from Piper hancei with anti-neuroinflammatory effect by attenuating NF-κB signaling pathway

BackgroundIn the traditional “Yao” ethno-medicine system, Piper hancei Maxim. is used to treat rheumatism, wind-cold, and inflammation. Previous studies indicate that lignans obtained from P. hancei stems have anti-neuroinflammatory potential in LPS-stimulated microglial cells. However, identification of the lignan enantiomers and the precise mechanism by which they work to reduce inflammation is yet to be explored. PurposeTo identify the active anti-neuroinflammatory lignan enantiomers isolated from P. hancei stems and to elucidate the mechanism of action both in vitro and in vivo. MethodsThe lignan enantiomers from P. hancei stems were isolated and elucidated using various chromatographic and spectroscopic methods. The anti-neuroinflammatory potential of all the compounds was initially screened by measuring nitric oxide (NO) inhibition in LPS-stimulated BV-2 microglial cells. Then anti-neuroinflammatory efficacy of the most active compound was assessed with LPS-stimulated microglial cell model, microglia-induced neuronal injury SH-SY5Y cell model, and LPS-intracerebroventricular injection neuroinflammation mouse model. The underlying mechanism was further explored by qRT-PCR analysis, Western blot analysis, and immunofluorescence staining experiments to understand the intervention pathway. ResultsPhytochemical analysis of P. hancei stems resulted in the isolation of 13 pairs of neolignan enantiomers (1–13), including 4 new pairs named piperhancin D–G (1–4). All right-handed (+) and left-handed (–) enantiomers of each pair (1–13) were isolated successfully. Notably, (+)-futoquinol (5) demonstrated significant anti-neuroinflammatory activity without cytotoxicity, unlike its inactive enantiomer (–)-5 in LPS-stimulated microglial cells. The representative compound (+)-5 effectively suppressed pro-inflammatory cytokines in LPS stimulated BV-2 cells and mouse brains, and alleviated microglia-induced neuronal damage in SH-SY5Y cells. Behavioral tests showed that (+)-5 alleviated the LPS-induced cognitive dysfunction in mice. Furthermore, the compound was able to reduce LPS-induced neuronal damage and microglial activation in mouse brains. A mechanistic study demonstrated that (+)-5 hindered the nuclear translocation of NF-κB p65 and downregulated the pro-inflammatory mediators to relieve neuroinflammation. ConclusionThis is the first example of both in vitro and in vivo study on the anti-neuroinflammatory effects and underlying mechanism of the neolignan enantiomers isolated from P. hancei. Notably, (+)-futoquinol (5) emerged as a potential lead for further drug development to treat neurodegenerative diseases.

The role of the S100A8/S100A9 in gastric tumor progression

Gastric premalignant lesions can develop into cancer through multiple steps and inflammation plays a critical role. The aim of this study is to uncover the characteristics of macrophages and their gene expression in premalignant gastric lesions to identify novel biomarkers and potential targets for treatment. We used the computational algorithm CIBERSORT to estimate immune cell subsets present in gastric tissue. We applied WGCNA to identify inflammation-related modules and hub genes. Single-cell analysis was used to identify macrophage sub-clusters specific to pathology. In addition, the in-vitro experiment was performed to verify the mechanism of the key inflammatory factors in the growth of gastric cancer. WGCNA identified a module that was positively correlated with pathological changes and highly related to inflammation scores. Single-cell analysis revealed a macrophage subset, and we observed that S100A8 and S100A9 + macrophages made up a significantly higher proportion in early gastric cancer (EGC) tissues. Our functional enrichment analysis suggested that these macrophages may play a role in gastric tumorigenesis through the activation of the NFκB signaling pathway. In vitro experiments verified that S100A9 can promote the proliferation and migration of AGS cells through the TLR4-NFκB signaling pathway, and the S100A8/S100A9 inhibitor Paquinimod can inhibit their proliferation and migration. Our findings suggest that S100A8 and S100A9 + macrophages may activate the TLR4-NFκB signaling pathway to promote cell proliferation and migration leading to gastric tumor progression. Macrophages with high expression of S100A8/S100A9 are critical in the progression of gastric inflammation to cancer. Cytokine S100A9 can activate the TLR4-NFκB signaling pathway and promote the proliferation and migration of gastric adenocarcinoma cells.

The long non-coding RNA GAS5 contributes to the suppression of inflammatory responses by inhibiting NF-κB activity.

Nuclear factor kappa B (NF-κB) is a key regulator of immune and inflammatory responses. Glucocorticoid drugs (GC) act through the glucocorticoid receptor (GR) as immunosuppressant also in pediatric patients inhibiting NF-κB activity. The long non-coding RNA GAS5 interacts with the GR, influencing GC activity. No data on the role of GAS5 on GR-dependent inhibition of NF-κB activity have been published. This study investigated the impact of GAS5 on NF-κB activity in HeLa cells overexpressing GAS5, both under basal conditions and during GC treatment. The study used EMSA, RNA-immunoprecipitation (RIP), Western blotting, and bioinformatic analyses to assess NF-κB DNA binding, GAS5-p65 interaction, and NF-κB signaling pathway modulation. GAS5 overexpression increased NF-κB DNA binding activity in untreated cells. RNA-IP confirmed a direct interaction between GAS5 and the NF-κB subunit p65, suggesting a potential regulatory mechanism. GAS5 overexpression led to downregulation of NF-κB target genes, TNF-α, and NR3C1. GC treatment reduced NF-κB DNA binding activity in GAS5-overexpressing cells, indicating a potential synergistic effect. Furthermore, GAS5 overexpression increased IκB levels and reduced p-p65/pan-p65 levels during GC treatment. GAS5 appears to modulate NF-κB activity in a complex manner, influencing both basal and GC-induced signaling. The interaction between GAS5, GCs, and NF-κB is multi-faceted, and further research is needed to fully elucidate the underlying mechanisms. These findings suggest that GAS5 could be a potential target for personalized therapy, particularly in pediatric patients with inflammatory conditions.

Unveiling the role of CXCL8/CXCR2 in intervertebral disc degeneration: A path to promising therapeutic strategies

BackgroundIntervertebral disc degeneration(IVDD) is the primary etiology of low back pain and radicular pain. Recent studies have found that chemokines play a role in IVDD, but the underlying mechanism is largely unclear. MethodsBioinformatics analysis was employed to screen CXCL8 as the target gene. The expression levels of CXCL8 and CXCR2 were quantified using RT-qPCR, western blot(WB), immunohistochemistry(IHC), and enzyme-linked immuno-sorbent assay(ELISA). In the IVDD mouse model, X-ray images, Safranin O-fast green staining(SO-FG), IHC, and WB were conducted to assess the therapeutic effects of CXCL8 on IVDD. Reactive oxygen species (ROS) production, apoptosis of nucleus pulposus cells (NPCs), and the involvement of the NF-κB pathway were evaluated through WB, flow cytometry, immunofluorescence(IF), and Tunnel assay. ResultsIn our study, we observed that CXCL8 emerged as one of the chemokines that were up-regulated in IVDD. The mitigation of extracellular matrix degradation (ECM) and the severity of IVDD were significantly achieved by neutralizing CXCL8 or its receptor CXCR2(SB225002, CXCR2 antagonist). The release of CXCL8 from infiltrated macrophages within intervertebral discs (IVDs) was predominantly observed upon stimulation. CXCL8 exerted its effects on NPCs by inducing apoptosis and ECM degradation through the activation of CXCR2. Specifically, the formation of the CXCL8/CXCR2 complex triggered the NF-κB signaling pathway, resulting in an abnormal increase in intracellular ROS levels and ultimately contributing to the development of IVDD. ConclusionOur findings suggest that macrophage-derived CXCL8 and subsequent CXCR2 signaling play crucial roles in mediating inflammation, oxidative stress, and apoptosis in IVDD. Targeting the CXCL8/CXCR2 axis may offer promising therapeutic strategies to ameliorate IVDD. The translational potential of this articleThis study indicates that CXCL8 can effectively exacerbate the excessive apoptosis and oxidative stress of NPCs through activating the NF-κB pathway. This study may provide new potential targets for preventing and reversing IVDD.

The Protective Effects of Methionine on Nickel-Induced Oxidative Stress via NF-κB Pathway in the Kidneys of Mice.

Nickel (Ni) is a human carcinogen that causes oxidative damage to many organs, and methionine has been studied to protect mammals from similar toxic effects by other heavy metals possibly through sulfur metabolism. This study aimed to investigate the protective effects of methionine on Ni-induced injuries to the kidneys. In this study, the mice were randomly divided into BC (normal diet), MD (methionine deficiency diet), MN (methionine plus nickel diet), and MDN (methionine deficiency plus nickel diet) treatment groups. Their renal function, histological changes, cell cycle, apoptosis, oxidative damage, and NF-κB inflammatory cytokines were detected after 21days by HE, immunohistochemistry, TUNEL staining, and biochemical and ELISA methods. The results showed that serum Cr, BUN, and the NAG content increased in MDN (P < 0.01), MN (P < 0.05), and MD (P < 0.05) group mice compared to BC group mice. Glomerulus atrophy and renal tubular atrophy were observed in the MDN, MN, and MD groups but less severe in MN group mice. The PCNA protein content was the highest in BC group mice followed by MD, MN, and MDN. The activities of antioxidant enzymes (SOD, CAT, GSH, GSH-Px, and GSH-ST) were lower significantly in MD, MN, and MDN group mice, and the oxidant products content (MDA, LPO, and ROS) in the BC group were higher than those in other groups with a similar trend. The contents of NF-κB, TNF-α, IFN-γ, IL-1a, and IL-6 in the BC group were found to increase significantly in MD, MN, and MDN groups. In conclusion, Ni-induced kidney injury was indicated by renal tissue and cell damage, increased kidney metabolism products release in the serum, and renal oxidative stress while methionine addition helped alleviate the injury. In addition, the NF-κB signal pathway was involved in the renal inflammatory reaction induced by Ni where methionine helped mitigate it.

Effects of Leaf Extracts from Genetic Resource of Capsicum spp. on Neuroprotection and Anti-Neuroinflammation in HT22 and in BV2 Cells.

To develop functional varieties of Capsicum spp. leaves, 40 genetic resources were collected and extracted with 30% aqueous-fermented ethanol. We investigated the protective effects of extracts from 40 genetic resources of Capsicum spp. on glutamate-induced HT22 and LPS-induced BV2 cells. The results showed that the five extracts exhibited cell-protective activities. We also investigated the anti-inflammatory effects of these five extracts on LPS-induced BV2 cell neuroinflammation and found that 23OM18 exhibited superior anti-inflammatory effects. We further investigated the protective activity and anti-inflammatory mechanisms of 23OM18 in these two cell models. In addition, the profiles of 16 metabolites were compared between the representative accessions and among the five genetic resources using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS). The results showed that 23OM18 protected HT22 cells by inhibiting reactive oxygen species generation and regulating the MAPK-JNK signaling pathway, thereby reducing LPS-induced BV2 cell neuroinflammation by regulating the NF-κB and MAPK signaling pathways. Based on these results, 23OM18 has the potential to be developed as a functional food for the treatment of neurodegenerative diseases.

The protective effect of Amitriptyline on experimental colitis through inhibiting TLR4/MD2 signaling pathway.

Amitriptyline, a pleiotropic tricyclic antidepressant, possesses anti-oxidant and anti-inflammatory properties. Despite its diverse benefits, the specific effects of amitriptyline on IBD are not yet well defined. To explore this, we utilized a DSS-induced colitis model to examine the anti-inflammatory effects of amitriptyline and the underlying mechanisms by which it operates. Our research revealed that amitriptyline is effective in alleviating several pathological manifestations associated with colitis. This includes improvements in body weight retention, reductions in DAI, lessening of colon length shortening, and repair of colonic mucosal damage. Treatment with amitriptyline significantly protected mucosal injury by preserving the population of goblet cells and increasing the expression of tight junction proteins. Furthermore, we observed that amitriptyline effectively countered immune cell infiltration, specifically neutrophils and macrophages, while simultaneously lowering the levels of inflammatory cytokines such as TNF-α, IL-1β, and IL-6. Additionally, RNA sequencing analysis pointed to the potential involvement of the TLR pathway in the anti-colitic effects induced by amitriptyline. Subsequent Western blot analysis indicated that amitriptyline significantly inhibited the TLR4-mediated NF-κB signaling pathway. To bolster our findings, in vitro studies demonstrated that amitriptyline down-regulated the TLR4/NF-κB/MAPK signaling cascades in mouse macrophages stimulated with LPS. Further molecular investigations revealed that amitriptyline was able to suppress the elevated expression of MD-2 that LPS stimulation typically induces. In summary, our findings suggest that amitriptyline effectively mitigates DSS-induced colitis in mice through the inhibition of TLR4/MD-2 pathway signaling, indicating its potential repurposing for IBD treatment. Significance Statement The potential of utilizing amitriptyline in treating IBD appears promising, leveraging its established safety and dosing profile as an antidepressant. Our observations show that amitriptyline can alleviate pathological symptoms, inflammation, and intestinal mucosal damage in mice with colitis induced by DSS. The protective effect observed appear to be linked to the inhibition of the TLR4/MD2 signaling pathway. By exploring novel applications for existing medications, we can optimize amitriptyline's efficacy and broaden its impact in both medical and commercial contexts.

Prenylated Dihydroflavonol from Sophora flavescens Regulate the Polarization and Phagocytosis of Macrophages In Vitro

As an important member of innate immunity, macrophages show remarkable plasticity and heterogeneity, and play an important role in immune regulation, tissue development, homeostasis of the internal environment and injury repair. However, the excessive activation of macrophages is closely related to the occurrence and development of many diseases. The prenylated flavonoid structure is one of the characteristic structures isolated from Sophora flavescens, with anti-inflammatory, anti-tumor, anti-allergy and other effects. In this study, the effects of (2R)-3β,7,4′-trihydroxy-5-methoxy-8-prenylflavanone (TMP), a prenylated dihydroflavonol, on the polarization and phagocytosis of macrophages were systematically studied. In LPS-induced M1-type macrophages, TMP dose-dependently inhibited the expression of COX-2, iNOS and the secretion of NO, IL-1β, IL-6 and IL-18, showing an inhibitory effect on M1 polarization. Further experiments revealed that it was related to the inhibition of TLR4-related AKT/mTOR, MAPK and NF-κB signaling pathways; in IL-4-induced M2-type macrophages, TMP down-regulated the expression of M2-related Arg1, IL-10, TGF-β, CD206 and CD163, as well as the phosphorylation levels of AKT1 and STAT6. For macrophages in a physiological state, it was very important for cells to return from a stress state to a phenotypic stability in the M0 state. These results indicated that TMP negatively regulated the M1/M2 polarization of macrophages, and made them tend to M0 homeostasis, which might provide new theoretical and data support for explaining the anti-inflammatory immunoregulatory activity of Sophora flavescens.

Biomimetic Scaffolds Regulating the Iron Homeostasis for Remolding Infected Osteogenic Microenvironment.

The treatment of infected bone defects (IBDs) needs simultaneous elimination of infection and acceleration of bone regeneration. One mechanism that hinders the regeneration of IBDs is the iron competition between pathogens and host cells, leading to an iron deficient microenvironment that impairs the innate immune responses. In this work, an in situ modification strategy is proposed for printing iron-active multifunctional scaffolds with iron homeostasis regulation ability for treating IBDs. As a proof-of-concept, ultralong hydroxyapatite (HA) nanowires are modified through in situ growth of a layer of iron gallate (FeGA) followed by incorporation in the poly(lactic-co-glycolic acid) (PLGA) matrix to print biomimetic PLGA based composite scaffolds containing FeGA modified HA nanowires (FeGA-HA@PLGA). The photothermal effect of FeGA endows the scaffolds with excellent antibacterial activity. The released iron ions from the FeGA-HA@PLGA help restore the iron homeostasis microenvironment, thereby promoting anti-inflammatory, angiogenesis and osteogenic differentiation. The transcriptomic analysis shows that FeGA-HA@PLGA scaffolds exert anti-inflammatory and pro-osteogenic differentiation by activating NF-κB, MAPK and PI3K-AKT signaling pathways. Animal experiments confirm the excellent bone repair performance of FeGA-HA@PLGA scaffolds for IBDs, suggesting the promising prospect of iron homeostasis regulation therapy in future clinical applications.

Neuroprotective Effects of Astragalus Polysaccharide on Retina Cells and Ganglion Cell Projection in NMDA-Induced Retinal Injury.

Astragalus polysaccharide (APS), a water-soluble heteropolysaccharide, possesses immunomodulatory, anti-inflammatory, and cardioprotective properties. This study investigates the neuroprotective potential of APS in a model of N-Methyl-d-aspartic acid (NMDA)-induced retinal neurodegeneration, aiming to explore its potential as a treatment for retinal degenerative diseases. Retinal function was evaluated using electroretinography (ERG), optomotor reflex (OMR), and flash visual evoked potentials (FVEP). Retinal inflammatory responses were examined through immunohistochemistry, western blotting (WB), and quantitative reverse transcription PCR (qRT-PCR). To assess the integrity of visual projections, an intravitreal injection of adeno-associated virus (AAV) was employed to trace the projections of retinal ganglion cells (RGCs) to the visual centers. APS treatment conferred protection to retinal cells, as indicated by ERG and OMR assessments. And APS intervention mitigated NMDA-induced apoptosis, evidenced by a decrease in TUNEL-positive cells. Furthermore, APS treatment attenuated the NMDA-induced reduction in RGC projections to the visual centers, including the superior colliculus and lateral geniculate nucleus, as demonstrated by AAV tracing. Our findings reveal that APS shields the retina from NMDA-induced damage by inhibiting the NF-κB signaling pathway and reduces the detrimental effects of NMDA on RGC projections to the visual centers. These findings propose APS as a potential novel therapeutic agent for the treatment of retinal diseases.

A20 Alleviates the Inflammatory Response in Bovine Endometrial Epithelial Cells by Promoting Autophagy.

Endometritis represents a prevalent condition in perinatal dairy cows. Bovine endometrial epithelial cells (BEECs), as the primary interface between cavity and the external environment, are particularly vulnerable to infection by pathogenic bacteria following parturition. A20 is essential for regulating inflammation and modulating immune responses. Nevertheless, the exact role of A20 in the BEECs in response to inflammatory response is not fully understood. An endometritis model infected by Escherichia coli (E. coli) in vivo and a BEECs inflammation model induced with lipopolysaccharide (LPS) in vitro were built to investigate the function and governing mechanisms of A20 in endometritis. The results showed that infection with E. coli resulted in endometrial damage, inflammatory cell infiltration, and upregulation of inflammatory factors in dairy cows. Furthermore, A20 expression was upregulated in the endometrium of cows with endometritis and in BEECs following LPS stimulation. A20 overexpression attenuated the level of proinflammatory cytokines in LPS-stimulated BEECs; conversely, A20 knockdown lead to an exacerbated response to LPS stimulation. The overexpression of A20 was shown to activate autophagy and suppress the NF-κB signaling pathway in LPS-stimulated BEECs. However, blocking autophagy with chloroquine notably attenuated the anti-inflammatory effect of A20, leading to the activation of the NF-κB signaling pathway. In summary, the study demonstrated that A20's suppression of inflammation in LPS-stimulated BEECs is associated with the activation of autophagy. Therefore, the A20 protein showed potential as a novel treatment focus for managing endometritis in dairy cows.

Study on the relationship between NF-kB pathway and skeletal muscle dopamine receptors in muscle-attenuated mice

Background: To investigate the relationship between the NF-kB signaling pathway and muscle-attenuated skeletal muscle dopaminereceptor (DR) in mice. Methodology: 40 specific pathogens free (SPF) C57BL/6 mice aged 6 to 7 months were randomly divided into a model group and control group by random number table method, with 20 mice in each group. Muscle-attenuated mice were established in model group, and the expression of NF-kB protein was detected by Western-blot, and the expressions of IL-β1, TNF-a, DRD1, and DRD2 were detected by enzyme linked immunosorbent assay (ELISA). Meanwhile, the muscle fiber cross-sectional area was determined. Results: The relative expression of NF-kB protein, IL-,1 and TNF-a in model group were significantly higher than those in control group (P &lt; 0.05). The levels of DRD1 and DRD2 in skeletal muscle in model group were significantly lower than those in control group (P &lt; 0.05). The cross-sectional are the model group was significantly lower than in the control group (P &lt; 0.05). The relative expression of NF-kB protein was negatively correlated with DRD1, DRD2 and muscle fiber cross-sectional area. DRD1 and DRD2 were positively correlated with muscle fiber cross-sectional area. Conclusion: In muscle-atrophied mice, NF-kB protein, an indicator of the NF-kB signaling pathway, was negatively correlated with DR, and both had an important role in muscle atrophy. Keywords: Nuclear factor kB signaling pathway; Muscle attenuation; Mice; Skeletal muscle; Dopamine receptor.

Mapping the proteomic landscape and anti-inflammatory role of Streptococcus parauberis extracellular vesicles

Bacterial extracellular vesicles (BEVs) are nanoscale membrane-bound structures involved in intercellular communication and transport of bioactive molecules. In this study, we described the proteomic insight and anti-inflammatory activity of Streptococcus parauberis BEVs (SpEVs). Proteomics analysis of SpEVs identified 6209 distinct peptides and 1039 proteins. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis demonstrated enrichment in pathways related to the biosynthesis of aminoacyl tRNA, amino acids, and secondary metabolites. Based on the predicted protein-protein interactions, we discovered key immunological proteins such as IL12A, IL12B, IL8, CD28, and NF-κB between SpEVs and human proteins. Functionally, SpEVs exhibit strong anti-inflammatory activity in LPS-stimulated Raw 264.7 cells by reducing the production of key inflammatory mediators. These include nitric oxide (NO), reactive oxygen species (ROS), inflammatory cytokines such as TNFα and IL6, as well as inflammation-related proteins like inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). qRT-PCR and immunoblotting results clearly indicate that SpEVs modulate the NF-κB and MAPK pathways to induce anti-inflammatory activity. Furthermore, in vivo experiments with zebrafish larvae demonstrated that SpEVs treatment reduced the NO and ROS production with minimal cell mortality. Finally, we validated the anti-inflammatory activity of SpEVs in vivo by systematically assessing the inhibition of NO production, reduction in ROS generation, prevention of cell death, and modulation of NF-κB and MAPK signaling pathways. In conclusion, SpEVs contain rich in unique proteins that play crucial roles in mediating anti-inflammatory effects.

Modulatory Effects of Chalcone Thio-Derivatives on NF-κB and STAT3 Signaling Pathways in Hepatocellular Carcinoma Cells: A Study on Selected Active Compounds.

Our previous studies demonstrated the modulatory effects of new synthetic thio-chalcone derivatives in dishes on the Nrf2, NF-κB, and STAT3 signaling pathways in colon cancer cells. This study aimed to evaluate the effect of four selected active chalcone thio-derivatives on the NF-κB and STAT3 signaling pathways involved in inflammatory processes and cell proliferation in human liver cancer cells. Cell survival was assessed for cancer (HepG2) and normal (THLE-2) cell lines. Activation of NF-κB and STAT3 signaling pathways and the expression of proteins controlled by these pathways were estimated by Western blot, and qRT-PCR assessed the expression of NF-κB and STAT3 target genes. We also evaluated the impact on the selected kinases responsible for the phosphorylation of the studied transcription factors by MagneticBead-Based Multiplex Immunoassay. Among the thio-derivatives tested, especially derivatives 1 and 5, there was an impact on cell viability, cell cycle, apoptosis, and activation of NF-κB and STAT3 pathways in hepatocellular carcinoma (HCC), which confirms the possibilities of using them in combinatorial molecular targeted therapy of HCC. The tested synthetic thio-chalcones exhibit anticancer activity by initiating proapoptotic processes in HCC while showing low toxicity to non-cancerous cells. These findings confirm the possibility of using chalcone thio-derivatives in molecularly targeted combination therapy for HCC.