NFKB1 Research Articles

Glycyrrhiza glabra and Saussurea costus extracts mitigate arsenic-induced nephrotoxicity via orchestrating Nrf2/HO-1 and NF-kB crosstalk and repressing the expression of HSPs genes, and apoptosis in broiler chickens

This research aimed to evaluate the role of Glycyrrhiza glabra (GGE) and Saussurea costus (Costus) extracts in alleviating arsenic (As2O3)-evoked nephrotoxicity in chickens. Seven groups (36 chicks/group) were treated daily for 42 days as follows: control group; GGE group, obtained GGE (500 mg/kg feed); Costus group was given Costus orally (300 mg/kg bodyweight); As group, received As2O3 (30 mg/kg diet); As + GGE; As + Costus; As + GGE + Costus. The administration of GGE and/or Costus in As-intoxicated birds significantly decreased (p < 0.001) creatinine level relative to As group. Additionally, both extracts markedly reduced (p < 0.001) the renal malondialdehyde content and enhanced the antioxidant enzymes performance, which function via Nrf2/HO-1 signaling. Moreover, They downregulated the renal inflammatory cascade by suppressing the expression of TNF-α and NF-κB genes compared to As group. Furthermore, a significant decline in the levels of HSPs mRNA was recorded following treatment with GGE and/or Costus. Conclusively, GGE and Costus can be accounted as prospective antidotes in controlling As poisoning.

Expression of CCL2 signaling pathway genes in patients with periodontitis and atherosclerosis.

Periodontitis and atherosclerosis are chronic inflammatory diseases characterized by leukocyte infiltration. We investigated the expression of CCL4, CCR5, c-Jun, c-Fos, NF-κB, and CCL2 as well as the possible mechanism involved in the regulation of CCL2 in human periodontitis tissues and atherosclerotic aorta based on previous research on the CCL4/CCR5/c-Jun and c-Fos/CCL2 pathway leading to CCL2 expression in collagen-induced arthritis (CIA) rat. Sixty-five volunteers were recruited and the condition of their gingiva and coronary arteries were assessed. The subjects were divided into four groups: healthy control, chronic periodontitis (CP), coronary artery diseases (CAD), and noncoronary artery diseases (non-CAD). Total RNA was isolated from gingiva in periodontitis patients and control populations and from the aorta in patients with and without CAD. PCR was used to examine CCL4, CCR5, c-Jun, c-Fos, NF-κB, and CCL2 levels. The production of CCL2 in the gingiva and aorta was analyzed by immunostaining. PCR revealed that CCL4, CCR5, and CCL2 mRNA levels were increased in CP patients' gingivae and aortas from coronary artery bypass grafting (CABG) patients. Marked c-Jun, c-Fos, and NF-κB gene productions were detected in CP patients' gingivae but did not show statistical differences between the CAD and non-CAD groups. Stronger immunoreactivity against CCL2 was observed in periodontitis gingiva and aorta from CABG patients. Our findings suggest that the CCL4/CCR5/c-Jun and c-Fos/CCL2 pathways may be involved in CCL2 expression in periodontitis. CCL4, CCR5, and CCL2 might act as possible nodes to link the presence of periodontitis and atherosclerosis.

Supplementation of Chlorogenic Acid Alleviates the Effects of H2O2-Induced Oxidative Stress on Laying Performance, Egg Quality, Antioxidant Capacity, Hepatic Inflammation, Mitochondrial Dysfunction, and Lipid Accumulation in Laying Hens

This research examined the impact of chlorogenic acid (CGA) on laying performance, antioxidant capacity, egg quality, hepatic inflammation, mitochondrial function, and lipid metabolism in hens subjected to hydrogen peroxide (H2O2)-induced oxidative stress (OS). Three hundred sixty healthy 43-wk-old Hy-Line brown hens were randomly assigned to six treatments: a basal diet + 0 (control and H2O2), 600 (600 mg/kg CGA and 600 mg/kg CGA + H2O2), and 800 (800 mg/kg CGA and 800 mg/kg CGA + H2O2) mg/kg CGA for 84 d. On the 64th and 78th days of the trial, hens in groups H2O2, 600 mg/kg CGA + H2O2, and 800 mg/kg CGA + H2O2 were injected intraperitoneally with 10% H2O2. The results demonstrated that 600 and 800 mg/kg CGA significantly improved the egg production rate (EPR) and egg quality and reduced lipid peroxidation compared to the control group. The 800 mg/kg CGA showed greater improvements in the EPR and average egg weight (AEW) compared to the 600 mg/kg dose. Conversely, H2O2 exposure significantly decreased the EPR, AEW, and egg quality and increased feed conversion rate and average daily feed intake. H2O2 exposure significantly decreased serum T-AOC and increased serum MDA levels while reducing hepatic T-SOD, GSH-Px, and CAT activities. Meanwhile, H2O2 exposure significantly elevated liver reactive oxygen species levels, pathological damage, and NF-κB, TNFα, and IL-1β gene expression. Additionally, H2O2 treatment disrupted hepatocyte mitochondrial structure and significantly increased the expression of VDAC1 protein, and IP3R, GRP75, MCU, Fis1, and MFF genes, while downregulating the expression of MFN2 protein and PGC1α gene. Oil Red O staining demonstrated that H2O2 induced significant lipid accumulation in hepatocytes. Concurrently, H2O2 significantly increased serum triglycerides, total cholesterol, and liver triglycerides levels while decreasing serum hepatic lipase activity. This was primarily attributed to the significant upregulation of liver SREBP1, FASN, and ACC genes and the downregulation of the liver CPT1 gene induced by H2O2. Furthermore, CGA pretreatment effectively prevented the degeneration in laying performance and egg quality, as well as OS, liver inflammation, pathological damage, and mitochondrial dysfunction induced by H2O2. CGA inhibited H2O2-induced hepatic lipid accumulation by upregulating fatty acid oxidation-related gene expression and downregulating fatty acid synthesis-related gene expression. These findings indicate that the dietary addition of 800 mg/kg of CGA is the optimum supplementation dose. CGA can enhance laying performance and egg quality while alleviating OS, hepatic inflammation, mitochondrial dysfunction, and lipid accumulation in H2O2-challenged laying hens.

Immune alterations in children with autism spectrum disorders

Autism spectrum disorders (ASD) are a heterogeneous group of mental and nervous system disorders. Patients with ASD are characterized by communication and cognitive impairments and obsessive behavior. The pathogenesis and etiology of ASD are still unclear. According to the literature, patients suffering from ASD have not only mental, but also somatic disorders, including changes in the immune system. The aim of this work was to study the concentration of cytokines in the blood plasma of children with ASD and the level of expression of proinflammatory genes in peripheral blood mononuclear cells. The clinical group included 71 children aged 4-12 years with a diagnosis of ASD (F84.02). Patients scored more than 36 on the Childhood Autism Rating Scale (CARS). The control sample included 27 apparently healthy children of the same age. The following methods were used in this study: isolation of mononuclear cells from heparinized peripheral blood, Ficoll-Verografin density gradient centrifugation, evaluation of cytokine blocks using commercially available enzyme immunoassay kits, isolation of random total RNA, reverse transcription using hexaprimers, and real-time polymerase chain reaction using intercalating dye SYBR Green. The concentration of proinflammatory cytokines IL-1β, IL-8, and IL-17A in the peripheral blood plasma of children with ASD was statistically significantly increased compared to the control sample. Moreover, the concentration of the anti-inflammatory cytokine IL-10 in patients with ASD was 3.6 times lower compared to the control sample (p 0.001). The level of expression of the NF-κB1, IL1β, IL8 and TNFα genes at the RNA level in peripheral blood mononuclear cells was increased by 2.8, 2.5, 4.8 and 4.2 times in patients with ASD compared to the control sample (all p 0.01). The results obtained indicate an increase in the concentration of proinflammatory cytokines (IL-1β, IL-8, IL-17A) in the blood plasma and a decrease in the concentration of anti-inflammatory cytokines (IL-10) in patients with ASD compared to the control sequence.

Preparation of New Liposomal Daunorubicin and Evaluation of its Anti-colorectal Cancer in HCT116 Cells

Background: Colorectal cancer (CRC) is the third most common cause of cancerrelated deaths worldwide. To develop more effective anti-CRC drugs, this research evaluated the impact of synthesized liposomal daunorubicin on HTC116 colon cancer cell line. Methods: Liposomal daunorubicin (LDNR) was synthesized by the thin layer hydration method and size was determined by dynamic light diffraction (DLS). MTT assay was used to determine the cytotoxicity and IC50 of LDNR against the HCT116 CRC cell line. Relative mRNA expression of the NF-κB gene and apoptosis were evaluated in 24 hours treatments of HCT116 cells by qRT-PCR and flow cytometry, respectively. Results: The hydrodynamic diameter of liposomes containing daunorubicin (DNR) was determined 25.2 nm. MTT assay showed a 38% decrease in HCT116 cells viability after 24-hour treatment with the DNR (0.5 μM). The lowest (0.125 μM) and highest (2 μM) dose of LDNR showed 20.4% and 71.6% cytotoxicity, respectively. LDNR showed dose-dependent cytotoxicity with the IC50 of 0.87 μM. The phase contrast microscope evaluation confirmed the LDNR cytotoxicity. The DNR and LDNR (0.87 μM) decreased relative mRNA levels of NF-κB 63% (P= 0.023) and 99.6% (P=0.003), respectively. The percentage of apoptotic cells in the DNR and LDNR increased by 27.1% (P&lt;0.0001) and 49.7% (P&lt;0.0001), respectively. Conclusion: DNR increases the rate of apoptosis by decreasing the NF-κB gene expression in HCT116 cells. These effects are intensified in the liposomal form. Therefore, the LDNR produced in this research can be considered in the treatment of CRC.

Pirfenidone mitigates demyelination and electrophysiological alterations in multiple sclerosis: Targeting NF-κB, sirt1, and neurotrophic genes.

Multiple sclerosis (MS) is a demyelinating disease affecting thecentral nervous system associated with progressive neurodegeneration. Pirfenidone (Pir) is a well-known antifibrotic agent; however, Pir's function in MS is little explored. We evaluated the neuroprotective effects of Pir in MS and its possible underlying mechanisms. Forty male Swiss mice were divided equally into control, cuprizone (CPZ), Pir, and CPZ + Pir groups. Assessment of motor function was conducted using neurobehavioral tests, EMG, and nerve conduction velocity (NCV). Mice's brains were extracted to measure oxidative stress, neuroinflammatory markers, and the expression of neurotrophic genes. The corpus callosum and the sciatic nerve were subjected to histopathological and immunohistochemical studies. The CPZ group was associated with significant reductions in muscle power, frequency of contraction, sciatic NCV, SOD, IL-10, SIRT1, NGF, and neuregulin-1. Significant increases in MDA, TNF-α, INF-γ, IL-17, TGF-β, and NF-κB were also detected. Multiple areas of partially demyelinated nerve fibers in the corpus callosum, the loss of oligodendrocyte nuclei, and increased microglia and astrocytes were also observed. The sciatic nerve revealed partial demyelination with significantly reduced myelin basic protein (MBP) expression. Pir significantly restored motor function, demyelination, and neurodegenerative changes induced by CPZ. Besides the antifibrotic action of Pir, we concluded that it improves motor function in MS by alleviating the demyelinating process and neurodegeneration. Its potential anti-inflammatory, antioxidant, and antifibrotic properties could be contributing factors. These effects could be mediated by modulating the NF-κB, SIRT1, NGF, and neuregulin-1 pathways. Pir is a promising agent for treating MS.

Acetamiprid elicits oxidative stress, pro-inflammatory response, and cellular proliferation in human bronchial epithelial cells in vitro and in silico: alleviative implications of the mixture of heat-killed Lactobacillus strains

BackgroundAcetamiprid (ACE), a neonicotinoid insecticide, has been extensively used to control pests in agricultural and industrial environments. It has been reported that ACE is detrimental to the lungs. Nevertheless, the extent to which the activation of oxidative stress, inflammation, and cellular proliferation contributes to the pulmonary toxicity induced by ACE exposure remains insufficiently understood. This study explored the mechanism of toxicological consequences after ACE exposure in bronchial epithelial cells (BEAS-2B cells). The research also examined the potential ameliorative effects of the mixture of heat-killed Lactobacillus delbrueckii and Lactobacillus fermentum (HKL) on the toxicities of ACE.ResultsFollowing 14 days of exposure to ACE at 0.5 and 1 μM, oxidative stress was induced, as evidenced by the decreased levels of reduced glutathione, catalase, glutathione peroxidase, and superoxide dismutase, along with increased levels of malondialdehyde. Also, ACE exposure results in overexpression and raised protein levels of the IL-25, NF-κB1, NF-κB2, IL-33, TSLP, and NF-κB target genes, which induce inflammatory responses. In addition, ACE boosted Ki-67-positive BEAS-2B cells. The molecular docking of ACE with target genes and their proteins demonstrated a potent binding affinity, further supported by the presence of hydrophobic contacts, electrostatic interactions, and hydrogen bonds. The post-treatment of HKL following the ACE (1 μM) exhibited its antioxidant, anti-inflammatory, and antiproliferative activities in suppressing ACE-induced toxicity.ConclusionsOur research revealed that ACE toxicity in BEAS-2B cells is caused by driving oxidative stress, pro-inflammatory response, and cellular proliferation. This study would give us a strategy to alleviate ACE-induced lung impairment by heat-killed probiotic supplements. As a result, dietary supplements that contain these microorganisms may potentially be beneficial in countries with high levels of pesticide contamination.

Synergistic Effect of Some Molecular Biomarkers in The Development of Preeclampsia and Abortion in Pregnant Women Suffer from Toxoplasmosis

The current study summarized the effect of toxoplasmosis, which is caused by parasitic infection with protozoan known as Toxoplasma gondii, on pregnant women who suffer from repeated miscarriages, especially in the first trimester of pregnancy, this research documented the reduction of sex hormones values in healthy pregnant women, association with down ROP16 regulation(T.gondii-I virulence factor). While the average of the same parameters was increased in pregnant women who suffered from toxoplasmosis, which in turn led to inhibition of the transcription factor NFKB in parasite`s infected women, and inhibition of the patient's immune response. On the other hand, both of ROP16 and NFKB genes play a critical role in an increase of miR146 transcription, it consider a significant factor that activate epigenetic effect perhaps play role in reducing of host's immune system. At the end the placental cell signaling pathway was modified and increased atrophy of placental trophoblast with association of serious complications led at the end to emergence of early abortion.

Importin α4 deficiency induces psychiatric disorder-related behavioral deficits and neuroinflammation in mice

Importin α4, which is encoded by the Kpna4 gene, is a well-characterized nuclear-cytoplasmic transport factor known to mediate transport of transcription factors including NF-κB. Here, we report that Kpna4 knock-out (KO) mice exhibit psychiatric disorder-related behavioral abnormalities such as anxiety-related behaviors, decreased social interaction, and sensorimotor gating deficits. Contrary to a previous study predicting attenuated NF-κB activity as a result of Kpna4 deficiency, we observed a significant increase in expression levels of NF-κB genes and proinflammatory cytokines such as TNFα, Il-1β or Il-6 in the prefrontal cortex or basolateral amygdala of the KO mice. Moreover, examination of inflammatory responses in primary cells revealed that Kpna4 deficient cells have an increased inflammatory response, which was rescued by addition of not only full length, but also a nuclear transport-deficient truncation mutant of importin α4, suggesting contribution of its non-transport functions. Furthermore, RNAseq of sorted adult microglia and astrocytes and subsequent transcription factor analysis suggested increases in polycomb repressor complex 2 (PRC2) activity in Kpna4 KO cells. Taken together, importin α4 deficiency induces psychiatric disorder-related behavioral deficits in mice, along with an increased inflammatory response and possible alteration of PRC2 activity in glial cells.

Whole transcription analysis identified the regulation of hypoxia-inducible factors in monocytes with immune suppression: implications for clinical outcomes.

Sepsis progression is marked by a complex immune response, where the involvement of hypoxia-inducible factors (HIF) plays an uncertain role. The study aims to elucidate the involvement of HIF-1α in monocyte function during sepsis and its potential as a prognostic indicator. Transcriptomic data from healthy individuals and septic patients in datasets GSE54514, GSE167363, and GSE46955 were analyzed. Additionally, human monocytes were employed to elucidate how HIF regulates immune responses in the context of sepsis. Septic non-survivors exhibited sustained upregulation of HIF-1α expression alongside compromised inflammatory response and antigen presentation, with downregulation of NF-κB and HLADRB1 genes associated with poor sepsis prognosis. Conversely, septic survivors displayed an increased proportion of classical monocytes and enhanced inflammation and expression of antigen presentation-related genes. During the recovery phase of sepsis, monocytes continued to demonstrate elevated HIF-1α expression. In cultured THP1 cells and septic CD14+ monocytes, HIF hindered inflammatory responses and antigen presentation, while also suppressing the proportion of classical monocytes after LPS stimulation. Mechanistically, HIF significantly attenuated LPS-induced immune responses in monocytes by inhibiting the phosphorylation of IKK. HIF in monocytes acts as a suppressor of immune-inflammatory responses and antigen presentation, and may serve as a negative molecular marker for sepsis development.

Integrative multiomic analysis unveils the molecular nexus of mitochondrial dysfunction in the pathogenesis of age-related macular degeneration

Mitochondrial dysfunction is linked to age-related macular degeneration (AMD), but its mechanisms and related molecular networks remain unclear. We explored the association between mitochondrial-related genes and AMD by integrating multiomic data. We acquired summary-level data on mitochondrial-related protein abundance, gene expression, and gene methylation from quantitative trait locus studies. Genetic associations with AMD were sourced from the International Age-related Macular Degeneration Genomics Consortium (discovery), FinnGen (replication), and UK Biobank (replication) studies. We used summary-data-based Mendelian randomization to assess the correlations between mitochondrial-related gene molecular characteristics and AMD. Furthermore, colocalization analysis was performed to ascertain if the detected signal pairings had a common causative genetic variation. Mitochondrial-relatedl gene NFKB1 demonstrated a protective role in AMD (tier 1 evidence), whereas HSPA1A and HSPA1B genes were also associated with decreased AMD risk (tier 2 evidence). The methylation of cg09390974 and cg15409712 in NFKB1 was associated with increased NFKB1 expression, consistent with the protective effect on AMD risk, whereas inverse associations were observed between gene methylation and gene expression for HSPA1B (cg04835051 and cg16372051), supporting the risk roles of methylation in AMD. At circulating protein level, genetically predicted higher levels of HSPA1A (odds ratio [OR] 0.28, 95% confidence interval [CI] 0.19−0.41, P<0.001), HSPA1B (OR 0.13, 95% CI 0.06−0.27, P<0.001), and NFKB1 (OR 0.43, 95% CI 0.27−0.68, P<0.001) were inversely associated with AMD risk. These associations were corroborated in the colocalization analysis. We identified AMD-linked mitochondrial-related genes, potentially improving the understanding of its pathophysiological mechanisms and aiding the identification of novel pharmaceutical targets.

Metabolomics and 16S rDNA sequencing of intestinal flora reveal the regulation of Sparassis latifolia polysaccharides on splenic immune function in lead-exposed mice

Sparassis latifolia polysaccharides (SLPs) have immunomodulatory activity and lead excretion ability, but its regulatory mechanism through the gut microbiota-spleen axis has not been elucidated. In this study, spleen metabolomics and intestinal flora sequencing were combined to explore the regulatory mechanism of SLPs on spleen immune function in lead-exposed mice. The results showed that SLPs effectively reduced spleen lead content, alleviated spleen enlargement and oxidative stress. SLPs changed glycerophospholipid metabolism, increased lysophosphatidylcholine content and inhibited the expression of G2A, ERK2 and NF-kB genes and the phosphorylation of ERK2 and NF-kB in lead-exposed mice. Furthermore, SLPs inhibited potential intestinal pathogens such as Clostridium_sensu_stricto_1, Lachnospiraceae, Oscillospiraceae and Alistipes_indistinctus, which were positively correlated with phosphatidylethanolamine metabolites. In addition, SLPs reduced the spleen tissue damage of lead-exposed mice by co-housing, and reduced the relative abundance of Clostridium_sensu_stricto_1, Prevotellaceae, and RF39, which were positively correlated with spleen enlargement, and inhibited the expression of ERK2/NF-κB signaling pathway-related genes such as G2A, ERK2 and Fas. In summary, SLPs can reduce the relative abundance of pathogenic microorganisms by regulating the structure of intestinal flora, regulate the glycerophospholipid metabolism of spleen in lead-exposed mice, alleviate oxidative damage and inflammatory response, and restore spleen immune function.

Remifentanil-induced inflammation in microglial cells: Activation of the PAK4-mediated NF-κB/NLRP3 pathway and onset of hyperalgesia

BackgroundThe perioperative use of remifentanil is associated with postoperative hyperalgesia, which can impair recovery and extend hospitalization. Recent studies have revealed that microglia-mediated activation of the NLRP3 inflammasome plays a critical role in opioid-induced hyperalgesia, with NF-κB acting as a pivotal activation point for NLRP3. Despite these findings, the specific molecular mechanisms underlying remifentanil-induced postoperative hyperalgesia remain unclear. This study aims to develop a model of remifentanil-induced hyperalgesia and investigate the molecular mechanisms, focusing on the NF-κB/NLRP3 pathway, using both in vitro and in vivo approaches. MethodWe established a remifentanil-induced hyperalgesia model and performed proteomic analysis to identify differential protein expression in the spinal cord tissue of rats. NLRP3 or PAK4 antagonists were administered intrathecally in vivo, and mechanical pain thresholds in the hind paws were measured using Von Frey testing. In vitro, we applied NLRP3 or PAK4 inhibitors or used lentivirus infection to silence PAK4, NF-κB, and NLRP3 genes. Protein expression was assessed through immunohistochemistry, immunofluorescence, and Western blotting. Additionally, ELISA was performed to measure IL-1β and IL-18 levels, and RT-qPCR was conducted to evaluate the transcription of target genes. ResultsProteomic analysis revealed that remifentanil upregulates PAK4 protein in spinal cord tissue two hours after the surgery. In addition, remifentanil induces morphological changes in the spinal cord dorsal horn, characterized by increased expression of PAK4, p-p65, NLRP3 and Iba-1 proteins, which in turn leads to elevated IL-1β and IL-18 levels and an inflammatory response. Intrathecal injection of NLRP3 or PAK4 inhibitors mitigates remifentanil-induced hyperalgesia and associated changes. In vitro, downregulation of PAK4 inhibits the increase in PAK4, p-p65, NLRP3 and Caspase-1 induced by LPS. Conversely, the downregulation of NLRP3 does not impact the levels of PAK4 and p-p65 proteins, aligning with the in vivo results and suggesting that PAK4 acts as an upstream signaling molecule of NLRP3. ConclusionRemifentanil can increase PAK4 expression in spinal cord dorsal horn cells by activating the NF-κB/NLRP3 pathway and mediating microglial activation, thereby contributing to postoperative hyperalgesia.

The Effect of Increasing Aerobic Exercise on the Expression of NF-κB and COX-2 Genes in Heart Tissue of Rats Under a High-fat Diet

Background: Several studies have shown that obesity alters the function and structure of the heart. Objectives: This study examined the impact of increasing aerobic exercise (IAE) on the mRNA expression of Cyclooxygenase-2 (COX-2) and nuclear factor Kappa B (NF-κB) in the cardiac tissue of rats fed a high-fat diet (HFD). Methods: Twenty-four male Wistar rats were divided into two groups and fed two types of diets for eight weeks: Control and HFD groups. After eight weeks, the rats on the HFD were further divided into HFD and HFD + IAE groups. The exercise program was conducted for six weeks, with five sessions per week, progressing from moderate to high intensity. The program followed the principle of gradual overload and was based on the maximum speed of the rats. The expression of COX-2 and NF-κB genes was assessed. Results: The expression of COX-2 and NF-κB genes increased in the HFD group compared to the control group. After six weeks, the expression of NF-κB and COX-2 genes decreased in the HFD + IAE group compared to the HFD group. Conclusions: Six weeks of IAE appears to reduce the inflammatory process in rats with HFD-induced obesity.

Assessing the association between common functional Nuclear Factor Kappa-b gene polymorphisms (NFKB1, NFKBIZ, NFKBIA) and Alzheimer´s disease

The Nuclear Factor Kappa-b (NF-Κb) pathway has been implicated in the pathogenesis of Alzheimer´s disease (AD). We determined whether common variants in the NF-Κb genes were associated with the risk of developing late-onset AD (LOAD). A total of 639 Spanish LOAD and 500 controls were genotyped for the NFKB1 rs28362491/rs7667496, NFKBIA rs696, NFKBIZ rs3217713 and APOE-Ɛ2/3/4 polymorphisms. Rs7667496 C was increased in the patients (p<0.001) with the CC genotype showing a significant risk (CC vs T+, OR= 1.58, 95 %CI=1.25–2.01). The CC genotype was significantly associated with LOAD after correction by APOE-4+ genotypes, age and sex (p=0.0003, OR=1.88, 95 %CI=1.28–2.78). The NFKB1 rs28362491 I - rs7667496 C haplotype was significantly increased in the patients (p=0.02). NFKBIA and NFKBIZ variants were not associated with the risk of LOAD in our population. In conclusion, NFKB1 variants were associated with the risk of LOAD in our population. This finding encourages further studies to determine the involvement of the NF-kB components in LOAD.

Curcumin attenuated neuroinflammation via the TLR4/MyD88/NF-κB signaling way in the juvenile rat hippocampus following kainic acid-induced epileptic seizures.

The study examined curcumin's impart on relieving neuroinflammation of juvenile rats in kainic acid (KA) induced epileptic seizures by inhibiting the TLR4/MyD88/NF-κB pathway. There were five groups: control, KA, KA + curcumin (KC), KA + oxcarbazepine (OXC) (KO), KA + curcumin + OXC (KCO) groups. KA was stereotactically injected into right hippocampus following intraperitoneal injection of curcumin or (and) OXC for seven days. The rats in the above groups were randomly divided into three subgroups (at 6h, 24h, and 72h of KA administration) following the seizure degree assessed. The number of NeuN (+) neurons and GFAP (+) astrocytes was counted. The gene and protein levels of TLR4, MyD88, and NF-κB were detected. Compared with the KA group, the seizure latency was longer, and the incidence of status epilepticus (SE) was lower in the KC, KO, and KCO groups. The most significant changes were in the KCO group. At 72h following KA injected, the number of neurons was the least, and the number of astrocytes was the most in the KA group. The number of neurons was the most and the number of astrocytes was the least in the KCO group. At 24h, the mRNA and protein levels of TLR4, MyD88, and NF-κB in the KA group were the most. The above valves were the least in the KCO group. Therefore, curcumin could enhance anti-epileptic effect of OXC, protect injured neurons and reduce proliferated glial cells of the hippocampus of epileptic rats by inhibiting inflammation via the TLR4/MyD88/NF-κB pathway.

Transcriptional Activity of Genes Regulating T-Helper Differentiation in the Accidentally Exposed Population of the Southern Urals.

The objective of this work was to study the expression of the TBX21, RORC, GATA3, NFKB1, MAPK8, and STAT3 genes responsible for the regulation of the differentiation of various T-helper subpopulations in individuals chronically exposed to radiation. The object of the study was peripheral blood cells obtained from 120persons chronically exposed to radiation in a wide range of doses on the Techa River. The mean cumulative absorbed dose to red bone marrow in the examined exposed individuals was 742.7 ± 78.6 mGy (dose range, 73.5-3516.1 mGy); in the comparison group, 17.4 ± 2.2 mGy (dose range, 0.0-55.5 mGy). The subpopulation composition of T-helpers (Th1, Th2, and Th17) was analyzed by flow cytofluorometry. The relative mRNA content of the TBX21, RORC, GATA3, NFKB1, MAPK8, and STAT3 genes was estimated by real-time PCR. The study made it possible to note a decrease in the relative number of T-helpers 2 in the populations of T-helpers of the central memory in the group of chronically exposed persons compared to the comparison group. In the population of T-helpers of the central memory, a statistically significant increase in the relative number of T-helpers 1 was shown, depending on the accumulated absorbed dose to red bone marrow. No changes in mRNA expression of the studied genes were observed. The analysis of the correlation between the expression of GATA3, MAPK8, STAT3, RORC, and TBX21 mRNA and the relative number of cells in subpopulations of T-helper types 1, 2, and 17 in the examined people did not reveal statistically significant patterns.

Exploring the Anti-Inflammatory and Antioxidative Potential of Selenium Nanoparticles Biosynthesized by Lactobacillus casei 393 on an Inflamed Caco-2 Cell Line.

Selenium (Se) plays a crucial role in modulating inflammation and oxidative stress within the human system. Biogenic selenium nanoparticles (SeNPs) synthesized by Lactobacillus casei (L. casei) exhibit anti-inflammatory and anti-oxidative properties, positioning them as a promising alternative to traditional supplements characterized by limited bioavailability. With this context in mind, this study investigates the impact of selenium and L. casei in ameliorating inflammation and oxidative stress using a cell line model. The study is centered on the biosynthesis of selenium nanoparticles (SeNPs) by L. casei 393 under anaerobic conditions using a solution of sodium selenite (Na2SeO3) in the bacterial culture medium. The generation of SeNPs ensued from the interaction of L. casei bacteria with selenium ions, a process characterized via transmission electron microscopy (TEM) to confirm the synthesis of SeNPs. To induce inflammation, the human colonic adenocarcinoma cell line, Caco-2 was subjected to interleukin-1 beta (IL-1β) at concentrations of 0.5 and 25 ng/ml. Subsequent analyses encompass the evaluation of SeNPs derived from L. casei, its supernatant, commercial selenium, and L. casei probiotic on Caco2 cell line. Finally, we assessed the inflammatory and oxidative stress markers. The assessment of inflammation involved the quantification of NF-κB and TGF-β gene expression levels, while oxidative stress was evaluated through the measurement of Nrf2, Keap1, NOX1, and SOD2 gene levels. L. casei successfully produced SeNPs, as confirmed by the color change in the culture medium and TEM analysis showing their uniform distribution within the bacteria. In the inflamed Caco-2 cell line, the NF-κB gene was upregulated, but treatment with L. casei-SeNPs and selenium increased TGF-β expression. Moreover, L. casei-SeNPs upregulated SOD2 and Nrf2 genes, while downregulating NOX1, Keap1, and NF-κB genes. These results demonstrated the potential of L. casei-SeNPs for reducing inflammation and managing oxidative stress in the Caco-2 cell line. The study underscores the ability of L. casei-SeNPs to reduce oxidative stress and inflammation in inflamed Caco-2 cell lines, emphasizing the effectiveness of L. casei as a source of selenium. These insights hold significant promise for the development of SeNPs derived from L. casei as potent anti-inflammatory and anti-cancer agents, paving the way for novel therapeutic applications in the field.

An Organic Fraction of Oenothera rosea L'Her Ex. Aiton Prevents Neuroinflammation in a Rat Ischemic Model.

Oenothera rosea L'Her Ex. Aiton, presenting antioxidant and anti-inflammatory activities, is traditionally used to treat bruises and headaches and as a healing agent. This study aimed to investigate whether its organic fraction (EAOr) has neuroprotective properties against neuroinflammation in the context of ischemia/reperfusion. The chemical composition of EAOr was determined using HPLC techniques, and its neuroprotective activities were evaluated in a common carotid-artery ligation model for the induction of ischemia/reperfusion (I/R). The animals were supplemented with EAOR for 15 days. On the last day, the animals were rested for one hour, following which the common carotid-artery ligation procedure was performed to induce I/R. The neurological deficit was evaluated at 24 h after I/R using Bederson's scale, and the relative expression of inflammatory genes and structure of hippocampal neurons were analyzed at 48 h. The chemical analysis revealed five major compounds in EAOr: gallic acid, rutin, ellagic acid, and glucoside and rhamnoside quercetin. EAOr prevented neurological deficit 24 h after I/R; led to the early activation of the AIF and GFAP genes; reduced Nfkb1, IL-1beta, Il-6 and Casp3 gene expression; and protected hippocampal neurons. Our findings demonstrate that EAOr contains polyphenol-type compounds, which could exert a therapeutic effect through the inhibition of neuroinflammation and neuronal death genes, thus maintaining hippocampal neurons.

Molecular mechanism of IKK catalytic dimer docking to NF-κB substrates

The inhibitor of κB (IκB) kinase (IKK) is a central regulator of NF-κB signaling. All IKK complexes contain hetero- or homodimers of the catalytic IKKβ and/or IKKα subunits. Here, we identify a YDDΦxΦ motif, which is conserved in substrates of canonical (IκBα, IκBβ) and alternative (p100) NF-κB pathways, and which mediates docking to catalytic IKK dimers. We demonstrate a quantitative correlation between docking affinity and IKK activity related to IκBα phosphorylation/degradation. Furthermore, we show that phosphorylation of the motif’s conserved tyrosine, an event previously reported to promote IκBα accumulation and inhibition of NF-κB gene expression, suppresses the docking interaction. Results from integrated structural analyzes indicate that the motif binds to a groove at the IKK dimer interface. Consistently, suppression of IKK dimerization also abolishes IκBα substrate binding. Finally, we show that an optimized bivalent motif peptide inhibits NF-κB signaling. This work unveils a function for IKKα/β dimerization in substrate motif recognition.