Role Of Nuclear Factor Kappa Research Articles

Role of Nuclear Factor-Kappa B Activation and Inflammatory Biomarkers in Critically Ill Children.

Mortality prediction is important for cautious monitoring and optimal management of critically ill children. The serum cytokine levels are elevated early in critical illness before the physiological parameters are deranged. This cross-sectional descriptive study included the critically ill children admitted in intensive care unit. Serial serum levels of IL-6, NF-κB and PELOD 2 scoring were measured and compared in 45 children (40 survivors, 5 non-survivors). The median IL-6 levels at 24h and 72h were significantly high in non-survivors when compared to survivors [median (IQR) = 1122 (1305) pg/ml vs. 564.39 (153) pg/ml and 1263 (626) pg/ml vs. 82 (191) pg/ml respectively; p <0.0001)]. There was an increasing trend of IL-6 in non-survivors when compared to the survivors. The NF-κB values were comparable. The IL-6 levels correlated well with the illness severity. IL-6 had superior prognostic value compared with NF-κB in predicting mortality.

Nuclear factor kappa B (NF-κB) participates in the aluminum-induced down-regulation of miR29a/b1

BackgroundStudies have shown that aluminum (Al) is one of the environmental risk factors leading to Alzheimer's disease (AD), and Al exposure can cause elevated levels of BACE1mRNA, β-secretase (BACE1), and amyloid beta (Aβ) in vivo and in vitro. Previous studies by our research group have shown that this is partly caused by the negative regulation of BACE1 by miRNA29a/b1 (miR29a/b1). Despite the observed the role of nuclear factor kappa B (NF-κB) on many miRNAs, the upstream regulation of NF-κB protein on miR29 remains poorly understood. The purpose of this study was to better define the relationship between NF-κB and miR29a/b1 and the potentially relevant signaling pathways. MethodsOn the one hand, we constructed the animal model of Al exposure by the intraperitoneal injection of aluminum-maltolate (Al(mal)3) in rats. Conversely, NF- κB inhibitors were added to adrenal phaeochromocytoma (PC12) cells exposed to Al(mal)3. ResultsWe verified that NF-κB shows an increasing trend with Al accumulation in the brain of rats, which is accompanied by a downward trend of miR29a/b1. Notably, the suppression of NF-κB significantly increased miR29a/b1 and affected the expression of BACE1mRNA and downstream proteins. ConclusionAl-induced NF-κB can negatively regulate the expression of miR29a/b1, which then significantly enhances the expression of BACE1 and Aβ plaques.

Lutein Modulates Oxidative Stress, Inflammatory and Apoptotic Biomarkers Related to Di-(2-Ethylhexyl) Phthalate (DEHP) Hepato-Nephrotoxicity in Male Rats: Role of Nuclear Factor Kappa B.

Phthalates are widely distributed in our environment due to their usage in many industries, especially in plastic production, which has become an essential part of daily life. This investigation aimed to assess the potential remedial influence of lutein, a naturally occurring carotenoid, on phthalate-triggered damage to the liver and kidneys. When di-(2-ethylhexyl) phthalate (DEHP) was administered to male albino rats over sixty straight days at a dosage of 200 mg/kg body weight, it resulted in a significant increase in the serum activity of liver enzymes (AST, ALT, and GGT), alpha-fetoprotein, creatinine, and cystatin-C, as well as disruptions in the serum protein profile. In addition, intoxication with DEHP affected hepato-renal tissues' redox balance. It increased the content of some proinflammatory cytokines, nuclear factor kappa B (Nf-κB), and apoptotic marker (caspase-3); likewise, DEHP-induced toxicity and decreased the level of anti-apoptotic protein (Bcl-2) in these tissues. Lutein administration at a dose level of 40 mg/kg b.w efficiently facilitated the changes in serum biochemical constituents, hepato-renal oxidative disturbance, and inflammatory, apoptotic, and histopathological alterations induced by DEHP intoxication. In conclusion, it can be presumed that lutein is protective as a natural carotenoid against DEHP toxicity.

The Role of NF-κB, PPAR-α, and PPAR-γ in Older Adults with Metabolic Syndrome.

The etiopathogenesis of metabolic syndrome (MetS) has not been fully understood yet, and chronic low-grade inflammation is thought to be associated with the development of complications related to MetS. We aimed to investigate the role of Nuclear factor Kappa B ( NF-κB ), Peroxisome Proliferator-Activated Receptor- α and γ (PPAR-α, and PPAR-γ) which are the main markers of inflammation in older adults with MetS. A total of 269 patients aged≥18, 188 patients with MetS who met the diagnostic criteria of the International Diabetes Federation, and 81 controls who applied to geriatrics and general internal medicine outpatient clinics for various reasons were included in the study. Patients were separated into four groups: young with MetS (< 60, n=76), elderly with MetS (≥60, n=96), young control (< 60, n=31), elderly controls (≥60, n=38). Carotid intima-media thickness (CIMT) and NF-κB , PPAR-α, and PPAR-γ plasma levels were measured in all of the participants. Age and sex distribution were similar between MetS and control groups. C-reactive protein (CRP), NF-κB levels (p=0.001) and CIMT (p<0,001) of MetS group were significantly higher than in the control groups. On the other hand, the PPAR-γ (p=0.008) and PPAR-α (p=0.003) levels were significantly lower in MetS. ROC analysis revealed that the NF-κB, PPAR-α, and PPAR-γ could be used to indicate MetS in younger adults (AUC: 0.735, p<0.000; AUC: 0.653, p=0.003), whereas it could not be an indicator in older adults (AUC: 0.617, p=0.079; AUC:0.530, p=0.613). It seems that these markers have important roles in MetS-related inflammation. In our results, suggest that the indicator feature of NF-κB , PPAR-α and PPAR-γ in recognizing MetS in young individuals is lost in older adults with Mets.

Brucella abortus modulates macrophage polarization and inflammatory response by targeting glutaminases through the NF-κB signaling pathway.

The mechanism of Brucella infection regulating macrophage phenotype has not been completely elucidated until now. This study aimed to determine the mechanism of Brucella abortus in the modulation of macrophage phenotype using RAW264.7 cells as a model. RT-qPCR, ELISA and flow cytometry were used to detect the inflammatory factor production and phenotype conversion associated with M1/M2 polarization of macrophages by Brucella abortus infection. Western blot and immunofluorescence were used to analyze the role of nuclear factor kappa B (NF-κB) signaling pathway in regulation of Brucella abortus-induced macrophage polarization. Chromatin immunoprecipitation sequencing (Chip-seq), bioinformatics analysis and luciferase reporter assay were used to screen and validate NF-κB target genes associated with macrophage polarization and further verify its function. The results demonstrate that B. abortus induces a macrophage phenotypic switch and inflammatory response in a time-dependent manner. With the increase of infection time, B. abortus infection-induced M1-type increased first, peaked at 12h, and then decreased, whereas the M2-type decreased first, trough at 12h, and then increased. The trend of intracellular survival of B. abortus was consistent with that of M2 type. When NF-κB was inhibited, M1-type polarization was inhibited and M2-type was promoted, and the intracellular survival of B. abortus increased significantly. Chip-seq and luciferase reporter assay results showed that NF-κB binds to the glutaminase gene (Gls). Gls expression was down-regulated when NF-κB was inhibited. Furthermore, when Gls was inhibited, M1-type polarization was inhibited and M2-type was promoted, the intracellular survival of B. abortus increased significantly. Our data further suggest that NF-κB and its key target gene Gls play an important role in controlling macrophage phenotypic transformation. Taken together, our study demonstrates that B. abortus infection can induce dynamic transformation of M1/M2 phenotype in macrophages. Highlighting NF-κB as a central pathway that regulates M1/M2 phenotypic transition. This is the first to elucidate the molecular mechanism of B. abortus regulation of macrophage phenotype switch and inflammatory response by regulating the key gene Gls, which is regulated by the transcription factor NF-κB.

The Role of Nuclear Factor-Kappa B in Fibrinogen-Induced Inflammatory Responses in Cultured Primary Neurons.

Traumatic brain injury (TBI) is an inflammatory disease associated with a compromised blood-brain barrier (BBB) and neurodegeneration. One of the consequences of inflammation is an elevated blood level of fibrinogen (Fg), a protein that is mainly produced in the liver. The inflammation-induced changes in the BBB result in Fg extravasation into the brain parenchyma, creating the possibility of its contact with neurons. We have previously shown that interactions of Fg with the neuronal intercellular adhesion molecule-1 and cellular prion protein induced the upregulation of pro-inflammatory cytokines, oxidative damage, increased apoptosis, and cell death. However, the transcription pathway involved in this process was not defined. The association of Fg with the activation of the nuclear factor-κB (NF-κB) and the resultant expression of interleukin-6 (IL-6) and C-C chemokine ligand-2 (CCL2) were studied in cultured primary mouse brain cortex neurons. Fg-induced gene expression of CCL2 and IL-6 and the expression of NF-κB protein were increased in response to a specific interaction of Fg with neurons. These data suggest that TBI-induced neurodegeneration can involve the direct interaction of extravasated Fg with neurons, resulting in the overexpression of pro-inflammatory cytokines through the activation of transcription factor NF-κB. This may be a mechanism involved in vascular cognitive impairment during neuroinflammatory diseases.

The Effect of Melon Seed Extract on the Transcription of NF-κB and Myeloperoxidase in the Liver Tissue of Mice Poisoned with Ethylene Glycol

Background and Objectives: The liver is exposed to poisoning caused by various chemical compounds. Considering the antioxidant effects found in melon seeds and the role of nuclear factor kappa B (NF-κB) and Myeloperoxidase (MPO) in inflammation caused by oxidative stress, the present study aims to assess the effect of hydroethanolic extract of melon seeds on the transcriptional of NF-κB encoding genes and the MPO gene expression in rats with ethylene glycol-induced toxicity. Methods: Thirty male rats were randomly divided into five groups of healthy control, poisoned control (0.75% ethylene glycol), and three melon extract-treated poisoned groups (0.75% ethylene glycol and 150, 300, or 600 mg/kg body weight of melon extract) and were treated for 38 days. Then, the liver tissue of the rats was removed to evaluate the transcription of NF-κB encoding genes and the MPO level by real-time PCR method. Results: The transcription level of NF-κB encoding genes and the MPO level in the poisoned control group rats significantly increased compared to the healthy group. Treatment with hydroethanolic extract of melon seeds at concentrations of 300 and 600 mg/kg body weight caused a significant decrease in the transcription of NF-κB encoding genes. Treatment with hydroethanolic extracts at concentrations of 150, 300, and 600 mg/kg body weight caused a significant decrease in the MPO level compared to the poisoned control group. Conclusion: The decrease in MPO and NF-κB encoding genes after administration of hydroethanolic extract of melon seeds indicates the therapeutic effect of this extract on liver damage.

Role of nuclear factor kappa B, interleukin-19, interleukin-34, and interleukin-37 expression in diabetic nephropathy

BackgroundThe long-term effects of diabetes mellitus (DM) can impair several organs, including the kidney, resulting in serious health problems. Diabetic nephropathy (DN), a primary contributor in end-stage renal failure worldwide, affects 20–30% of patients with type 2 DM (T2DM). This study was designed to assess the contribution of nuclear factor kappa B (NF-κB) and interleukin (IL)-6, IL-19, IL-34, and IL-37 in the development of DN.MethodsThe study included 160 participants, of which 130 were allocated into the patients with diabetes group, patients with chronic kidney disease (CKD), and patients with diabetic chronic kidney disease (DCKD), and 30 were healthy controls.ResultsThe obtained data revealed a significant (p < 0.05) increase in IL-19, IL-34, and NF-κB mRNA expression and serum IL-6 levels in patient groups (CKD and DCKD) compared with the healthy control group, whereas IL-19, IL-34, and NF-κB mRNA expression showed a marked elevation in the DCKD group when compared with patients with CKD. Conversely, IL-37 mRNA expression and serum superoxide dismutase (SOD) activity were significantly (p < 0.05) decreased in both groups relative to the healthy controls, whereas the decrease was markedly higher in the DCKD group when compared with the CKD group.ConclusionThe obtained results could indicate the potential implication of NF-κB, IL-19, IL-34, and IL-6 levels, along with the decrease in IL-37 expression and serum SOD activity, in the pathophysiology of kidney disease in diabetes. Moreover, designing drugs targeting these cytokines and/or their signal pathways may prevent or alleviate the progression of kidney disease.

The Role of Nuclear Factor Kappa B (NF-κB) in Development and Treatment of COVID-19: Review.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 19 (COVID-19), a disease that has affected more than 500 million people worldwide since the end of 2019. Due to its high complications and death rates, there is still a need to find the best therapy for SARS-CoV-2 infection. The dysregulation of the inflammatory response in COVID-19 plays a very important role in disease progression. It has been observed that abnormal activity of Nuclear Factor kappa B (NF-κB) is directly associated with, inter alia, increased synthesis of proinflammatory factors. Therefore, this review paper focuses on the functions of NF-κB in the development of SARS-CoV-2 infection and potential application of NF-κB inhibitors in COVID-19 immunotherapy. A comprehensive literature search was performed using the MEDLINE/PubMed database. In the current review, it is highlighted that NF-κB plays important functions in the modulation of an adaptive inflammatory response, including inducing the expression of proinflammatory genes. Increased activation of NF-κB in SARS-CoV-2 infection was observed. The association between NF-κB activation and the expression of SARS-CoV-2 structural and non-structural proteins were also reported. It was observed that modulation of NF-κB using, e.g., traditional Chinese medicine or glucocorticosteroids resulted in decreased synthesis of proinflammatory factors caused by SARS-CoV-2 infection. This review summarizes the role of NF-κB in COVID-19 and describes its potential immunotherapeutic target in treatment of SARS-CoV-2 infection. However, indisputably more studies involving patients with a severe course of COVID-19 are sorely needed.

Staphylococcus aureus enhances gelatinase activities in monocytic U937 cells and in human gingival fibroblasts

Background/purposeStaphylococcus aureus (S. aureus) has been suggested to be an initiative pathogen in peri-implantitis because of the solid affinity to titanium. However, the detail pathogenesis for the peri-implantitis initiation by S. aureus is still lacking. This study aimed to in vitro examine the gelatinases’ activities of monocytic U937 cell and human gingival fibroblast after challenges with S. aureus lipoteichoic acid (LTA) and peptidoglycan (PGN). Materials and methodsReleases of gelatinases, including matrix metalloproteinase (MMP)-2 and −9, from cells were measured by zymography. The releases were further examined after being given the S. aureus LTA/PGN. Roles of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways on the enzyme releases were examined by administrating inhibitors. ResultsS. aureus LTA and PGN increased the activities of pro-MMP-9 from U937 cells and pro-MMP-2 and MMP-2 from gingival fibroblasts. By giving the NF-κB inhibitor, the enhanced gelatinase activities in both cells were attenuated. In U937 cells, the enhanced pro-MMP-9 could further be attenuated by MAPK inhibitors, including extracellular signal-regulated kinase 1 and 2 (ERK1/2), P38 MAPK, and c-Jun N-terminal kinase (JNK) inhibitors; however, the attenuation by MAPK inhibitors could not be observed for MMP-2 in gingival fibroblasts. Nevertheless, in gingival fibroblasts, the pro-MMP-2 could be attenuated by JNK inhibitor. ConclusionS. aureus could enhance gelatinase activities of gingival fibroblasts and U937 cells, via NF-κB. The MAPK pathway was also involved in MMP-9 activity of U937 cells; however, the involvement of MAPK in MMP-2 activity of gingival fibroblasts was questioned.

The Role of Nuclear Factor Kappa B (NF-κB) in the Immune Response against Parasites.

The immune system consists of various cells, organs, and processes that interact in a sophisticated manner to defend against pathogens. Upon initial exposure to an invader, nonspecific mechanisms are raised through the activation of macrophages, monocytes, basophils, mast cells, eosinophils, innate lymphoid cells, or natural killer cells. During the course of an infection, more specific responses develop (adaptive immune responses) whose hallmarks include the expansion of B and T cells that specifically recognize foreign antigens. Cell to cell communication takes place through physical interactions as well as through the release of mediators (cytokines, chemokines) that modify cell activity and control and regulate the immune response. One regulator of cell states is the transcription factor Nuclear Factor kappa B (NF-κB) which mediates responses to various stimuli and is involved in a variety of processes (cell cycle, development, apoptosis, carcinogenesis, innate and adaptive immune responses). It consists of two protein classes with NF-κB1 (p105/50) and NF-κB2 (p100/52) belonging to class I, and RelA (p65), RelB and c-Rel belonging to class II. The active transcription factor consists of a dimer, usually comprised of both class I and class II proteins conjugated to Inhibitor of κB (IκB). Through various stimuli, IκB is phosphorylated and detached, allowing dimer migration to the nucleus and binding of DNA. NF-κB is crucial in regulating the immune response and maintaining a balance between suppression, effective response, and immunopathologies. Parasites are a diverse group of organisms comprised of three major groups: protozoa, helminths, and ectoparasites. Each group induces distinct effector immune mechanisms and is susceptible to different types of immune responses (Th1, Th2, Th17). This review describes the role of NF-κB and its activity during parasite infections and its contribution to inducing protective responses or immunopathologies.

Role of nuclear factor-kappa B in bleomycin induced pulmonary fibrosis and the probable alleviating role of ginsenoside: histological, immunohistochemical, and biochemical study.

Bleomycin (BLM) is one of anti-cancerous drugs. One of its limitation is the development of pulmonary fibrosis during therapy So, we proposed to examine the outcome of BLM take on the light and electron microscopic design of rat lung. Along with, assessment the probable protecting role of ginsenoside on BLM induced pulmonary changes. In this study, thirty adult male albino rats were comprised and were classified to four clusters; Negative & positive control group, BLM treated group and BLM& ginsenoside treated group. The lung was treated for histological and immunohistochemical (anti-p65) studies. Light microscopic examination of H&E stained sections of BLM treated group showed huge distortion of the lung building. Mallory trichrome stain of this group showed evident deposition of collagen fibers in the markedly thickened interalveolar septa and around intrapulmonary bronchi, bronchioles and blood vessels. Moreover, strong positive staining for nuclear factor (NF)-κB in the wall of bronchiole as well as the thickened interalveolar septa were observed. Ultrastructural inspection of lung of this group revealed muddled lung planning. Marked improvement of the lung structure and marked reduction in NF-κB immunoexpression was appeared in BLM and ginsenoside treated group. So, we concluded that co-administration of ginsenoside with BLM significantly enhanced the histological and morphometric image of the lung.

Monozygotic twins with hypothyroidism responding to T3/T4 combination: a role for Nuclear Factor-kappa B (NF-κB)?

Monozygotic twins with hypothyroidism responding to T3/T4 combination: a role for Nuclear Factor-kappa B (NF-κB)?

Role of hippocampal NF-\u03baB and GluN2B in the memory acquisition impairment of experiences gathered prior to cocaine administration in rats

Cocaine can induce severe neurobehavioral changes, among others, the ones involved in learning and memory processes. It is known that during drug consumption, cocaine-associated memory and learning processes take place. However, much less is known about the effects of this drug upon the mechanisms involved in forgetting.The present report focuses on the mechanisms by which cocaine affects memory consolidation of experiences acquired prior to drug administration. We also study the involvement of hippocampus in these processes, with special interest on the role of Nuclear factor kappa B (NF-κB), N-methyl-D-aspartate glutamate receptor 2B (GluN2B), and their relationship with other proteins, such as cyclic AMP response element binding protein (CREB). For this purpose, we developed a rat experimental model of chronic cocaine administration in which spatial memory and the expression or activity of several proteins in the hippocampus were assessed after 36 days of drug administration. We report an impairment in memory acquisition of experiences gathered prior to cocaine administration, associated to an increase in GluN2B expression in the hippocampus. We also demonstrate a decrease in NF-κB activity, as well as in the expression of the active form of CREB, confirming the role of these transcription factors in the cocaine-induced memory impairment.

The Protective role of Nigella sativa versus Lepidium sativum on the submandibular salivary gland in hypercholesterolemic albino rat (Histological and Immunohistochemical study)

Abstract Background: Direct relation between hypercholesterolemia and hyposalivation was suggested. Phytosterols of herbal origin have been used as prophylactic or curative agents against many disorders. Objectives: Evaluate the protective role of Nigella sativa (Ns) versus Lepidium sativum (Ls) on the histological picture of submandibular salivary glands in hypercholesterolemic albino rat; and its immunomodulatory role of nuclear factor kappa B cell (NF-κB) and alpha smooth muscle actin (α-SMA) expression on the tissues. Materials and method: This study was performed with forty male albino rats, divided into four equal groups as follow: Group 1 (n=10): served as negative control, Group 2 (n=10): were fed with hypercholesteremic supplement (HCS) for 8 weeks. Group 3 (n=10): were fed HCS with oral administration of (Ns) seeds for 8 weeks. Group 4 (n=10): were fed HCS with oral administration of (Ls) seeds suspension for 8 weeks. Results: Histological results of submandibular salivary gland in group 2 revealed severe atrophic and degenerative changes in the secretory terminal portions & ducts. In group 3, the tissues appeared with nearly normal histological structures which reflect the beneficial effects of Ns. In group 4, a lesser degree of improvement was noticed with Ls. Quantitative analysis for α-SMA and NF-κB revealed highly statistically significant decrease in group 3 and 4 in comparison with group 2. Conclusion: The immunohistochemical finding confirmed the histological results of the present study that proved the superior protective effects of Ns rather than Ls seeds against hypercholesterolemia on the submandibular salivary glands of albino rats.

Inhibition of nuclear factor kappa B inducing kinase suppresses inflammatory responses and the symptoms of chronic periodontitis in a mouse model.

Chronic periodontitis is an inflammatory disease that represents a major public health issue nowadays. Here, we investigated the protective role of nuclear factor kappa B (NF-κB) inducing kinase (NIK)-inhibitor on chronic periodontitis and revealed the underlying molecular mechanism. NIK-inhibitor was synthesized, and its functions were examined in primary osteoclasts and wild-type (WT) and NIK-/- chronic periodontitis mouse model. Lipopolysaccharides (LPS) or activator of NF-κB was applied to stimulate inflammatory response of osteoclasts. The qRT-PCR, ELISA and Western blot were used to measure the expression of pro-inflammatory and osteoclast-related genes, and the activation of NF-κB signaling. Osteoclastogenesis and bone damage were detected by TRAP staining and micro-CT. NIK knockdown mice had lower expression of osteoclast-related genes and improved CEJ-ABC damage. Similarly, NIK-inhibitor administration inhibited inflammatory responses and CEJ-ABC damage in chronic periodontitis models. NIK-inhibitor suppressed osteoclastogenesis and osteoclast-related genes expression through inhibiting the non-canonical NF-κB signaling. NIK plays important role in bone destruction of chronic periodontitis and NIK-inhibitor represents a promising therapeutic strategy for this disease.

High Glucose and Advanced Glycation End Products Induce CD147-Mediated MMP Activity in Human Adipocytes.

Basigin (CD147) is a transmembrane glycoprotein that regulates several physiological processes, including the production and activity of matrix metalloproteinases (MMPs). The activity of CD147 depends mainly on its glycosylation, which varies among pathophysiological conditions. However, it is unknown whether CD147 activity or its function in MMP regulation are affected by the diabetic environment, which is characterized by high glucose (HG) levels and an excess of glycation end products (AGEs). In this study, we investigated the effect of HG and AGEs on CD147 expression in human adipocytes. We also examined the mediating role of nuclear factor kappa B (NFκB) and receptor of AGE (RAGE) to this effect. Our findings show that carboxymethyl lysine and HG increased CD147 expression and glycosylation, which was accompanied by increases in MMP2 and MMP9 expression and activity, as well as upregulations of the N-acetylglucosaminyltransferase, MGAT5. These effects were abolished by NFκB and RAGE inhibition, CD147 gene silencing, and by the glycosylation inhibitor, tunicamycin. In conclusion, the current findings indicate that AGEs and HG induce CD147 expression and glycosylation in adipocytes, with possible mediation by NFκB and RAGE. One of the critical outcomes of this pathway is augmented MMP activity known to contribute to cardiovascular complications in diabetes.

Giant Cell Tumor of Bone: An Update.

To highlight the new developments in the management of advanced giant cell tumor of bone, a rare locally aggressive benign tumor, which was traditionally managed with surgery alone by either curettage and local adjuvant therapy, wide resection, or marginal excision. Here, we review the current role of systemic therapy for management of locally advanced or metastatic giant cell tumor of bone (GCTB). The elucidation of the pathophysiology of giant cell tumor of bone, especially with regards to the role of nuclear factor kappa B ligand (RANKL), has led to the Food and Drug Administration (FDA) approval of denosumab in the management of locally advanced or metastatic GCTB. For advanced giant cell tumor where surgical resection alone can cause severe morbidity, the paradigm has shifted from local treatment alone to multidisciplinary management with the consideration of use of denosumab.

Bcl-3 suppresses differentiation of RORγt+ regulatory T cells.

Regulatory T cells (Tregs) exert inhibitory function under various physiological conditions and adopt diverse characteristics following environmental cues. Multiple subsets of Tregs expressing master transcription factors of helper T cells such as RORγt, T-bet, Gata3 and PPARγ have been characterized, but the molecular mechanism governing the differentiation of these subsets remains largely unknown. Here we report that the atypical IκB protein family member Bcl-3 suppresses RORγt+ Treg accumulation. The suppressive effect of Bcl-3 was particularly evident in the mouse immune tolerance model of anti-CD3 therapy. Using conditional knockout mice, we illustrate that loss of Bcl-3 specifically in Tregs was sufficient to boost RORγt+ Treg formation and resistance of mice to dextran sulfate sodium-induced colitis. We further demonstrate the suppressive effect of Bcl-3 on RORγt+ Treg differentiation in vitro. Our results reveal a novel role of nuclear factor-kappa B signaling pathways in Treg subset differentiation that may have clinical implications in immunotherapy.

Neuroprotective Effect of Fisetin Against the Cerebral Ischemia-Reperfusion Damage via Suppression of Oxidative Stress and Inflammatory Parameters.

It is well established that inflammatory reactions and oxidative stress play an imperial role in cerebral ischemia-reperfusion pathogenesis. Fisetin is a flavonoid and has an antioxidant and anti-inflammatory effect on various diseases. In this study, we have been working to examine the neuroprotective effect of fisetin in brain injuries triggered by cerebral ischemic-reperfusion and explore the potential role of nuclear factor kappa B (NF-κB) signaling. In vitro, fisetin was examined against the cell viability, lactate dehydrogenase (LDH) leakage, cytokines, and apoptosis after ischemia/reperfusion (I/R) induced in the cells. In vivo, I/R injury was induced in the brain via transient middle cerebral artery occlusion (2 h) and reperfusion (20 h). The infarction area, brain water content, and neurofunctional parameters were also estimated. Inflammatory cytokines and brain injury markers were scrutinized at the end of the study. Fisetin treatment alleviated cell injury and suppressed the inflammatory cytokines (interleukin-1 (IL-1), tumor necrosis factor- α (TNF-α), inducible nitric oxide synthase (iNOS), interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2), interleukin-16 (IL-6), and prostaglandin E2 (PGE2)) and antioxidant parameters in a dose-dependent manner. Fisetin significantly (P < 0.001) reduced the infarct volume, brain water content. Fisetin significantly (P < 0.001) suppressed the neurological parameters and inflammatory cytokines such as IL-1, TNF-α, iNOS, IL-1β, COX-2, IL-6, PGE2, and oxidative markers in a dose-dependent manner. Fisetin significantly (P < 0.001) reduced the inflammatory mediators including NF-κB and intercellular adhesion molecule 1 (ICAM-1). Further studies also showed that fisetin significantly inhibited the NF-κB activity via inflammatory and antioxidant pathways. In conclusion, by suppressing inflammatory cytokines, fisetin protected the brain tissue against I/R injury, and this effect could be due to reduced NF-κB activity.