Nuclear factor-kappaB Inhibitor Research Articles

Postbiotic metabolites derived from lactobacillus fermentum as potent antiproliferative bioresources on HeLa cells with promising biocompatibility

Chemotherapy administrations for cervical malignancy possess a variety of unfavorable influences on the human body. Scientists are interested in microbial-derived biomolecules or postbiotics as an alternative therapeutic strategy in malignant patients. This research investigated the mechanisms related to the function of two potential postbiotic Lactobacillus isolates, Lactobacillus fermentum CH and L. fermentum KH, isolated from indigenous Iranian dairy products. The Lactobacillus isolates were recognized through 16S rDNA sequence analysis followed by characterization using morphological and biochemical assays. The bioactivity of postbiotics on the cervical cancer model was also assessed through a cytotoxic study and apoptosis analysis. In addition, the anticancer activity was evaluated by qPCR, followed by a confirmation of the flow cytometry. The results of the bioactivity assay revealed that these postbiotics had suitable anticancer influences on the cervical cancer model (HeLa cells) by increasing BAX, caspase8, and caspase9, followed by a decrease in BCl-2, iKB (Inhibitor of nuclear factor kappa-B), and RelA gene expressions. Thus, the findings of this study signify that the postbiotic derivate from Lactobacillus strains isolated from indigenous Iranian dairy products could be regarded as a topical treatment with a promising curative index due to their effectiveness on cervical malignancy cells.

Glucose inhibits the inflammatory response in goose fatty liver by increasing the ubiquitination level of PKA.

Protein kinase A (PKA) plays an important role in cellular life activities. Recently, PKA was found to bind to the inhibitor of nuclear factor-kappaB (IκB), a key protein in the nuclear factor-kappaB (NF-κB) pathway, to form a complex involved in the regulation of inflammatory response. However, the role of PKA in the anti-inflammatory of goose fatty liver is still unclear. A total of 14 healthy 70-d-old male Lander geese were randomly divided into a control group and an overfeeding group. Inflammation level was analyzed by histopathological method in the liver. The mRNA and protein abundance of PKA and tumor necrosis factor-alpha (TNFα), as well as the ubiquitination level of PKA, were detected. Moreover, goose primary hepatocytes were cotreated with glucose, harringtonine, and carbobenzoxy-l-leucyl-l-leucyl-l-leucinal (MG132). Finally, the co-immunoprecipitated samples of PKA from the control and overfeeding group were used for protein mass spectrometry. The results showed that no difference in PKA mRNA expression was observed (P > 0.05), while the PKA protein level in the overfed group was significantly reduced (P < 0.05) when compared with the control group. The ubiquitination level of PKA was higher than that of the control group in fatty liver. The mRNA expression of PKA was elevated but protein abundance was reduced in goose primary hepatocytes with 200mmol/L glucose treatment (P < 0.05). The PKA protein abundance was dramatically reduced in hepatocytes treated with harringtonine (P < 0.01) when compared with the glucose-supplemented group. Nevertheless, MG132 tended to alleviate the inhibitory effect of harringtonine on PKA protein abundance (P = 0.081). There was no significant difference in TNFα protein level among glucose-treated groups and control (P > 0.05). Protein mass spectrometry analysis showed that 29 and 76 interacting proteins of PKA were screened in goose normal and fatty liver, respectively. Validation showed that PKA interacted with the E3 ubiquitination ligases ring finger protein 135 (RNF135) and potassium channel modulatory factor 1 (KCMF1). In summary, glucose may inhibit the inflammatory response in goose fatty liver by increasing the ubiquitination level of PKA. Additionally, RNF135 and KCMF1 may be involved in the regulation of PKA ubiquitination level as E3 ubiquitination ligases.

Niga-ichigoside F1 alleviates DSS-induced ulcerative colitis by inhibiting the NF-κB pathway

Niga-ichigoside F1, an ursolic acid-type pentacyclic triterpenoid, possesses various pharmacological properties, including anti-tumor, anti-inflammatory, and antinociceptive potentials. However, its function and underlying mechanism in ulcerative colitis (UC) remain unknown. Hence, this study aimed to explore the effect of Niga-ichigoside F1 on dextran sulfate sodium (DSS)-induced colitis. The predictive results of network pharmacology identified 311 common targets of Niga-ichigoside F1 and ulcerative colitis. The 4 highest-scoring genes were screened by the BottleNeck method and they were, signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor (TNF), protein kinase B gamma (AKT3), and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit beta (PIK3CB). KEGG pathway analysis indicated that Niga-ichigoside F1 probably exerted a protective effect on UC through the nuclear factor-kappa B (NF-κB) pathways. Molecular docking results showed that Niga-ichigoside F1 had a high affinity for nuclear factor-kappa B-inhibitor of nuclear factor-kappa B (NF-κB-IκB) complex, with the lowest binding energy. Furthermore, our results in vivo showed that Niga-ichigoside F1 alleviated weight loss, colon shortening, disease activity index (DAI), and histological scoring in DSS-induced colitis mice. Moreover, Niga-ichigoside F1 decreased the levels of inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) and the expression of oxidative stress markers nitric oxide (NO), myeloperoxidase (MPO), and malonaldehyde (MDA) to mitigate inflammation and intestinal damage. Western blotting results evidenced that Niga-ichigoside F1 intervention significantly regulated the NF-κB pathway. In conclusion, this study highlighted the potential of Niga-ichigoside F1 in ameliorating colitis, indicating its potential application as a functional food.

Supramolecular prodrug inspiring from Rhizoma Coptidis - Fructus Mume herbal pair alleviated inflammatory diseases by inhibiting pyroptosis

Sustained inflammatory responses are closely related to various severe diseases, and inhibiting the excessive activation of inflammasomes and pyroptosis has significant implications for clinical treatment. Natural products have garnered considerable concern for the treatment of inflammation. Huanglian-Wumei decoction (HLWMD) is a classic prescription used for treating inflammatory diseases, but the necessity of their combination and the exact underlying anti-inflammatory mechanism have not yet been elucidated. Inspired by the supramolecular self-assembly strategy and natural drug compatibility theory, we successfully obtained berberine (BBR)-chlorogenic acid (CGA) supramolecular (BCS), which is an herbal pair from HLWMD. Using a series of characterization methods, we confirmed the self-assembly mechanism of BCS. BBR and CGA were self-assembled and stacked into amphiphilic spherical supramolecules in a 2:1 ratio, driven by electrostatic interactions, hydrophobic interactions and π-π stacking; the hydrophilic fragments of CGA were outside, and the hydrophobic fragments of BBR were inside. This stacking pattern significantly improved the anti-inflammatory performance of BCS compared with that of single free molecules. Compared with free molecules, BCS significantly attenuated the release of multiple inflammatory mediators and Lipopolysaccharide (LPS)-induced pyroptosis. Its anti-inflammatory mechanism is closely related to the inhibition of intracellular nuclear factor-kappaB (NF-κB) p65 phosphorylation and the noncanonical pyroptosis signalling pathway mediated by caspase11.

Short-term feeding of high-fat diet induces neuroinflammation and oxidative stress in arcuate nucleus in rats

Objectives: This study aimed to compare the effects of high-fat diet-induced neuroinflammation and oxidative stress in the arcuate nucleus (ARC) of obese-prone and obese-resistant rats. Materials and Methods: Rats were divided into obese-prone and obese-resistant groups based on their initial body weight. They were then fed either a 5% or 60% fat-containing diet. In the ARC, the expression of inflammatory markers [Interleukin (IL-6); Nuclear Factor Kappa-B Inhibitor Alpha (NFKBIA); Cluster of Differentiation (CD)-66; and mucin-like hormone receptor-like 1 (EMR-1)], as well as levels of reactive oxygen species (ROS) and antioxidant enzymes (glutathione and glutathione peroxidase and superoxide dismutase), was assessed along with body weight, blood glucose, Homeostatic Model Assessment for Insulin Resistance, plasma insulin and plasma leptin levels after ten days of intervention. Results: The results showed a significantly higher expression of inflammatory markers in the ARC of high-fat diet-induced obese rats after ten days. Body weight, plasma insulin, plasma leptin and hydrogen peroxide production were also significantly higher in obese-prone rats fed a high-fat diet. Conclusion: In conclusion, this study demonstrates that short-term consumption of a high-fat diet can lead to hypothalamic inflammation and ROS production in the ARC of rats. Obese-prone rats exhibited hyperinsulinaemia and hyperleptinaemia after short-term high-fat diet consumption.

Advanced glycation end product-modified low-density lipoprotein promotes pro-osteogenic reprogramming via RAGE/NF-κB pathway and exaggerates aortic valve calcification in hamsters

BackgroundAdvanced glycation end product-modified low-density lipoprotein (AGE-LDL) is related to inflammation and the development of atherosclerosis. Additionally, it has been demonstrated that receptor for advanced glycation end products (RAGE) has a role in the condition known as calcific aortic valve disease (CAVD). Here, we hypothesized that the AGE-LDL/RAGE axis could also be involved in the pathophysiological mechanism of CAVD.MethodsHuman aortic valve interstitial cells (HAVICs) were stimulated with AGE-LDL following pre-treatment with or without interleukin 37 (IL-37). Low-density lipoprotein receptor deletion (Ldlr−/−) hamsters were randomly allocated to chow diet (CD) group and high carbohydrate and high fat diet (HCHFD) group.ResultsAGE-LDL levels were significantly elevated in patients with CAVD and in a hamster model of aortic valve calcification. Our in vitro data further demonstrated that AGE-LDL augmented the expression of intercellular cell adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6) and alkaline phosphatase (ALP) in a dose-dependent manner through NF-κB activation, which was attenuated by nuclear factor kappa-B (NF-κB) inhibitor Bay11-7082. The expression of RAGE was augmented in calcified aortic valves, and knockdown of RAGE in HAVICs attenuated the AGE-LDL-induced inflammatory and osteogenic responses as well as NF-κB activation. IL-37 suppressed inflammatory and osteogenic responses and NF-κB activation in HAVICs. The vivo experiment also demonstrate that supplementation with IL-37 inhibited valvular inflammatory response and thereby suppressed valvular osteogenic activities.ConclusionsAGE-LDL promoted inflammatory responses and osteogenic differentiation through RAGE/NF-κB pathway in vitro and aortic valve lesions in vivo. IL-37 suppressed the AGE-LDL-induced inflammatory and osteogenic responses in vitro and attenuated aortic valve lesions in a hamster model of CAVD.Graphic

Interleukin-33 increases the sensitivity of multiple myeloma cells to the proteasome inhibitor bortezomib through reactive oxygen species-mediated inhibition of nuclear factor kappa-B signal and stemness properties.

The proteasome inhibitor bortezomib (BTZ) is the first-line therapy for multiple myeloma (MM). BTZ resistance largely limits its clinical application in MM. Interleukin-33 (IL-33) exerts antitumor effects through various mechanisms, including enhancing antitumor immunity and promoting the apoptosis of cancer cells. Here, the synergistic anti-MM effect of IL-33 and BTZ was verified, and the underlying mechanisms were elucidated. Bioinformatic analysis indicated that IL-33 expression levels were downregulated in MM, and that BTZ-treated MM patients with high IL-33 levels had better prognosis than those with low IL-33 levels. Moreover, the patients with high IL-33 levels had a better treatment response to BTZ. Further immune analysis suggested that IL-33 can enhance the anti-MM immunity. IL-33 and BTZ synergistically inhibited proliferation and induced apoptosis of MM cells, which was mediated by the excessive accumulation of cellular reactive oxygen species (ROS). Furthermore, increased ROS hindered the nuclear translocation of NF-κB-p65, thereby decreasing the transcription of target stemness-related genes (SOX2, MYC, and OCT3/4). These effects induced by the combination therapy could be reversed by eliminating ROS by N-acetylcysteine. In conclusion, our results indicated that IL-33 enhanced the sensitivity of MM to BTZ through ROS-mediated inhibition of nuclear factor kappa-B (NF-κB) signal and stemness properties.

Salvimulticanol from Salvia multicaulis suppresses LPS-induced inflammation in RAW264.7 macrophages: in vitro and in silico studies.

Sustained inflammatory responses can badly affect several vital organs and lead to chronic inflammation-related disorders, such as atherosclerosis, pneumonia, rheumatoid arthritis, obesity, diabetes, Alzheimer's disease, and cancers. Salvia multicaulis is one of the widely distributed plants that contains several biologically active phytochemicals and diterpenoids with anti-inflammatory effects. Therefore, finding alternative and safer natural plant-extracted compounds with good curative anti-inflammatory efficiencies is an urgent need for the clinical treatment of inflammation-related diseases. In the current study, S. multicaulis Vahl was used to extract and isolate two compounds identified as salvimulticanol and candesalvone B methyl ester to examine their effects against inflammation in murine macrophage RAW264.7 cells that were induced by lipopolysaccharide (LPS). Accordingly, after culturing RAW264.7 cells and induction of inflammation by LPS (100ng/ml), cells were exposed to different concentrations (9, 18, 37.5, 75, and 150µM) of each compound. Then, Griess assay for detection of nitric oxide (NO) levels and western blotting for the determination of inducible nitric oxide synthase (iNOS) expression were performed. Molecular docking and molecular dynamics (MD) simulation studies were employed to investigate the anti-inflammatory mechanism. Our obtained results validated that the level of NO was significantly decreased in the macrophage cell suspensions as a response to salvimulticanol treatment in a dose-dependent manner (IC50: 25.1 ± 1.2µM) as compared to the methyl ester of candesalvone B which exerted a weaker inhibition (IC50: 69.2 ± 3.0µM). This decline in NO percentage was comparable with a down-regulation of iNOS expression by western blotting. Salvimulticanol strongly interacted with both the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD-2) complex and the inhibitor of nuclear factor kappa-B (NF-κB) kinase subunit beta (IKKβ) to disrupt their inflammatory activation due to the significant hydrogen bonds and effective interactions with amino acid residues present in the target proteins' active sites. S.multicaulis is a rich natural source of the aromatic abietane diterpenoid, salvimulticanol, which exerted a strong anti-inflammatory effect through targeting iNOS and diminishing NO production in LPS-induced RAW264.7 cells in a mechanism that is dependent on the inhibition of TLR4-MD-2 and IKKβ as activators of the classical NF-κB-mediated inflammatory pathway.

Inhibition of NF-κB Activation Improves Non-Nitric Oxide-Mediated Cutaneous Microvascular Function in Reproductive-Aged Healthy Women

PURPOSE: The human cutaneous circulation is used as an in vivo bioassay to examine mechanisms of systemic vascular function and dysfunction in health and disease. In cohorts of patients with accelerated cardiovascular disease risk, systemic interventions to investigate inflammatory mechanisms [e.g., oral salsalate; nuclear factor kappa-B (NF-κB) inhibitor] have been used to elucidate mechanisms underlying microvascular dysfunction. In healthy control subjects, inhibition of inflammatory mechanisms modestly reduces microvascular function. We hypothesize that inhibition of NF-κB activation may impair nitric oxide (NO)-mediated cutaneous microvascular function in reproductive-aged healthy women. METHODS: In a randomized, single-blind, placebo-controlled design, oral salsalate (1500mg/b.i.d./5 days) was used to assess the impact of systemic inflammation on cutaneous microvascular function. Two intradermal microdialysis fibers were placed into the ventral forearm skin of eleven healthy women [Mean (SEM): 34 (2) yrs]. Laser-Doppler flowmetry was used to measure cutaneous blood flow while increasing concentrations of acetylcholine (10−10 to 10−1 M; endothelium-dependent vasodilator) were perfused with a control (lactated Ringer’s) or a NO synthase inhibitor (15 mM NG-nitro-L-arginine methyl ester). Following the dose-response protocol, maximal cutaneous vasodilation was induced by increasing local skin temperature to 43°C and perfusing 28 mM sodium nitroprusside. Cutaneous vascular conductance (CVC) was calculated as the quotient of red blood cell flux over mean arterial pressure and normalized as a percentage of the site-specific maximum (%CVCmax). The NO-dependent contribution was calculated as the difference between the area under the dose-response curve (AUC) of the control and the NO synthase-inhibited sites. RESULTS: There was an overall main effect of salsalate treatment ( p &lt; 0.001). Both the control and NO synthase-inhibited sites shifted upwards following salsalate treatment (Placebo - Control: 45.78 (8.81)% vs NO synthase inhibited: 33.62 (8.10)%; Salsalate - Control: 56.30 (8.48)% vs NO synthase inhibited: 41.57 (7.85)%; both p &lt; 0.05). There was no change in the NO-dependent contribution between treatments (Placebo: 164.30 (35.40) AU vs Salsalate: 180.30 (51.17) AU; p=0.7028).CONCLUSION: Inhibition of NF-κB activation improved cutaneous microvascular function in reproductive-aged healthy women. This improvement was mediated via non-nitric oxide-dependent mechanisms. Supported by NIH Grant R01 HL161000 (LMA) and Diversity Supplement R01 HL161000-02S2 (VGC). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Equisetum arvense standardized dried extract hinders age-related osteosarcopenia

Age-associated osteosarcopenia is an unresolved syndrome characterized by the concomitant loss of bone (osteopenia) and skeletal muscle (sarcopenia) tissues increasing falls, immobility, morbidity, and mortality. Unbalanced resorption of bone in the remodeling process and excessive protein breakdown, especially fast type II myosin heavy chain (MyHC-II) isoform and myofiber metabolic shift, are the leading causes of bone and muscle deterioration in the elderly, respectively. Equisetum arvense (EQ) is a plant traditionally recommended for many pathological conditions due to its anti-inflammatory properties. Thus, considering that a chronic low-grade inflammatory state predisposes to both osteoporosis and sarcopenia, we tested a standardized hydroalcoholic extract of EQ in in vitro models of muscle atrophy [C2C12 myotubes treated with proinflammatory cytokines (TNFα/IFNγ), excess glucocorticoids (dexamethasone), or the osteokine, receptor activator of nuclear factor kappa-B ligand (RANKL)] and osteoclastogenesis (RAW 264.7 cells treated with RANKL). We found that EQ counteracted myotube atrophy, blunting the activity of several pathways depending on the applied stimulus, and reduced osteoclast formation and activity. By in silico target fishing, IKKB-dependent nuclear factor kappa-B (NF-κB) inhibition emerges as a potential common mechanism underlying EQ′s anti-atrophic effects. Consumption of EQ (500 mg/kg/day) by pre-geriatric C57BL/6 mice for 3 months translated into: i) maintenance of muscle mass and performance; ii) restrained myofiber oxidative shift; iii) slowed down age-related modifications in osteoporotic bone, significantly preserving trabecular connectivity density; iv) reduced muscle- and spleen-related inflammation. EQ can preserve muscle functionality and bone remodeling during aging, potentially valuable as a natural treatment for osteosarcopenia.

Insights into the mechanism of action of pterostilbene against influenza A virus-induced acute lung injury

BackgroundSevere respiratory system illness caused by influenza A virus infection is associated with excessive inflammation and abnormal apoptosis in alveolar epithelial cells (AEC). However, there are limited therapeutic options for influenza-associated lung inflammation and apoptosis. Pterostilbene (PTE, trans-3,5-dimethoxy-4-hydroxystilbene) is a dimethylated analog of resveratrol that has been reported to limit influenza A virus infection by promoting antiviral innate immunity, but has not been studied for its protective effects on virus-associated inflammation and injury in AEC. PurposeOur study aimed to investigate the protective effects and underlying mechanisms of PTE in modulating inflammation and apoptosis in AEC, as well as its effects on macrophage polarization during influenza virus infection. Study design and methodsA murine model of influenza A virus-mediated acute lung injury was established by intranasal inoculation with 5LD50 of mouse-adapted H1N1 viruses. Hematoxylin and eosin staining, immunofluorescence, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, western blotting, Luminex and flow cytometry were performed. ResultsPTE effectively mitigated lung histopathological changes and injury induced by H1N1 viruses in vivo. These beneficial effects of PTE were attributed to the suppression of inflammation and apoptosis in AEC, as well as the modulation of M1 macrophage polarization. Mechanistic investigations revealed that PTE activated the phosphorylated AMP-activated protein kinase alpha (P-AMPKα)/sirtui1 (Sirt1)/PPARγ coactivator 1-alpha (PGC1α) signal axis, leading to the inhibition of nuclear factor kappa-B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) signaling induced by H1N1 viruses, thereby attenuating inflammation and apoptosis in AEC. PTE also forced activation of the P-AMPKα/Sirt1/PGC1α signal axis in RAW264.7 cells, counteracting the activation of phosphorylated signal transducer and activator of transcription 1 (P-STAT1) induced by H1N1 viruses and the augment of P-STAT1 activation in RAW264.7 cells with interferon-gamma (IFN-γ) pretreatment before viral infection, thereby reducing H1N1 virus-mediated M1 macrophage polarization as well as the enhancement of macrophages into M1 phenotypes elicited by IFN-γ pretreatment. Additionally, the promotion of the transition of macrophages towards the M2 phenotype by PTE was also related to activation of the P-AMPKα/Sirt1/PGC1α signal axis. Moreover, co-culturing non-infected AEC with H1N1 virus-infected RAW264.7 cells in the presence of PTE inhibited apoptosis and tight junction disruption, which was attributed to the suppression of pro-inflammatory mediators and pro-apoptotic factors in an AMPKα-dependent manner. ConclusionIn conclusion, our findings suggest that PTE may serve as a promising novel therapeutic option for treating influenza-associated lung injury. Its ability to suppress inflammation and apoptosis in AEC, modulate macrophage polarization, and preserve alveolar epithelial cell integrity highlights its potential as a therapeutic agent in influenza diseases.

Transcriptome analysis reveals the oxidative damage and immune-suppression of leech (Whitmania pigra Whitman) intestine induced by high-temperature stress

Temperature is a key component in regulating the survival and growth of aquatic animals. However, the mechanism of high-temperature stress in Whitmania pigra Whitman has received little attention. Therefore, the aim of this study was to investigate the possible mechanisms of high-temperature stress in W. pigra using transcriptome analysis and detection of antioxidant markers. Samples were collected at 1 d, 3 d, 5 d, and 7 d under stress in two experimental groups: the control group at 27 °C and the high-temperature stress group at 35 °C. High-temperature stress caused oxidative damage in the leech intestine, as indicated by decreased antioxidant enzyme activities (superoxide dismutase and total antioxidant capacity) and increased lipid hydroperoxide malondialdehyde. Transcriptome analysis revealed 425 DEGs in leech intestine during high-temperature stress, with 275 up-regulated and 150 down-regulated genes. According to KEGG enrichment analysis, 425 DEGs were involved in the immune system and induced abnormal expression of disease-related genes. Furthermore, when leeches were exposed to high-temperature stress, B-cell lymphoma-2, heat shock protein 70, heat shock protein 90, and nuclear factor erythroid 2-related factor 2 mRNAs were dramatically upregulated, whereas activating transcription factor, inhibitor of Nuclear factor kappa-B, sequestosome 1, and toll-like receptor 4 mRNAs were significantly downregulated. In conclusion, 35 °C high-temperature stress impaired leech intestinal function by decreasing antioxidant capacity, causing oxidative damage, and suppressing the activation of immune capacity. This study contributes to future research on the detailed mechanisms of high-temperature stress in leeches.

Lower vitamin D levels are associated with the pathogenesis of inflammatory bowel diseases.

Vitamin D plays a role in regulating immune homeostasis, inflammation and has an impact on the pathogenesis of inflammatory bowel diseases (IBD). IBD has a multifactorial pathogenesis primarily associated with immune dysregulation, dysbiosis, structurally altered intestinal mucosa, and genetic factors. The immunomodulatory function of this vitamin is linked to its control over innate and adaptive immunity, facilitated through its nuclear vitamin D receptor, leading to the inhibition of nuclear factor kappa-B. This study aimed to investigate serum vitamin D levels in patients with IBD compared to healthy individuals and to evaluate the relationship between vitamin D and inflammatory markers. Cross-sectional study. The study included 106 participants divided into 2 groups: patients with IBD (92), and healthy controls (14). The diagnosis of IBD was based on clinical, laboratory, fecal, endoscopic, and histological findings, following the European guidelines for diagnosis and follow-up ECCO-ESGAR guidelines for diagnostic assessment of IBD from 2019. Serum vitamin D levels were measured along with laboratory tests, imaging, and endoscopic examinations. IBD activity was evaluated using the Montreal classification and clinical and endoscopic indices. Data analysis involved calculating the mean, minimum, and maximum values, standard deviation, and Pearson coefficient. The level of statistical significance for this study was set at P < .05. The study found a prevalence of vitamin D deficiency in 32.6% of patients with IBD, while 66.3% had insufficiency, as compared with healthy individuals. The mean levels of vitamin D in UC and CD were 16 ± 8.6 ng/mL, whereas in the control healthy group, they were 26 ± 9.73 ng/mL. A statistically significant reverse correlation was observed between lower vitamin D levels and higher levels of the inflammatory markers. The study concluded that IBD patients exhibit lower levels of vitamin D, which is associated with inflammation and may contribute to the pathogenesis of the disease.

HM-chromanone alleviates hyperglycemia and inflammation in mice with endotoxin-induced insulin resistance.

This study was designed to investigate whether (E)-5-hydroxy-7-methoxy-3-(2'-hydroxybenzyl)-4-chromanone alleviates inflammation and hyperglycemia in mice with endotoxin-induced insulin resistance. (E)-5-hydroxy-7-methoxy-3-(2'-hydroxybenzyl)-4-chromanone (10, 30, and 50mg/kg bodyweight) was orally pre-administered to C57BL/6J mice. An hour later, lipopolysaccharides (20mg/kg bodyweight) was administered intraperitoneally to induce endotoxins. Blood samples were collected from the tail vein of the mice every 0, 30, and 90min. The results indicated that (E)-5-hydroxy-7-methoxy-3-(2'-hydroxybenzyl)-4-chromanone effectively regulated blood glucose levels in mice with endotoxin-induced insulin resistance. Furthermore, (E)-5-hydroxy-7-methoxy-3-(2'-hydroxybenzyl)-4-chromanone significantly reduced the phosphorylation of mammalian target of rapamycin, ribosomal protein S6 kinase 1, and protein kinase C θ. Additionally, (E)-5-hydroxy-7-methoxy-3-(2'-hydroxybenzyl)-4-chromanone suppressed the phosphorylation of c-Jun-NH2-terminal kinase and IkB kinase β, thereby decreasing the phosphorylation of inhibitor of nuclear factor kappa-B α and activating the nuclear factor-κB and activator protein-1 in the liver. Therefore, the expression of tumor necrosis factor-α, interleukin-6, and interleukin-1β was significantly reduced by suppressing the nuclear factor-κB and activator protein 1 activity. Suppression of mammalian target of rapamycin, S6 kinase 1, protein kinase C θ, c-Jun-NH2-terminal kinase, and IkB kinase β also ameliorated insulin resistance by reducing the phosphorylation of insulin receptor substrate-1 serine 307, thereby decreasing hyperglycemia. These findings suggest that (E)-5-hydroxy-7-methoxy-3-(2'-hydroxybenzyl)-4-chromanone can alleviate hyperglycemia and inflammation in mice with endotoxin-induced insulin resistance.

Atractylodes Processing Products Protect against Gastric Ulcers in Rats by Influencing the NF-κB-MMP-9/TIMP-1 Regulatory Mechanism and Intestinal Flora.

Atractylodes macrocephala Koidz. (AM) is a Chinese herbal medicine that is widely used for treating gastrointestinal diseases. However, little research has focused on it as a single medicine for treating gastric ulcers. Honey-bran stir-frying is a characteristic method of concocting AM, so we speculated that AM is more effective after this preparation process. Analysis by ultra-high-performance liquid chromatography-hybrid quadrupole-Orbitrap high-resolution mass spectrometry revealed changes in the chemical composition of raw Atractylodes (SG), bran-fried Atractylodes (FG), and honey-bran-fried Atractylodes (MFG). MFG was superior to SG and FG in improving the pathological structure of gastric tissue in rats with acute gastric ulcers, reducing inflammatory cell infiltration in gastric tissue, and significantly reducing malondialdehyde while increasing superoxide dismutase and glutathione peroxidase, and reducing the damage caused by free radical accumulation in the gastric mucosa. In addition, MFG reduced the expression of matrix metalloproteinase-9 (MMP-9), an inhibitor of metalloproteinase-1 (TIMP-1) and nuclear factor kappa-B (NF-κB)proteins, inhibited inflammatory response, and regulated the degradation and rebalancing of the extracellular matrix. Fecal microbiota analysis also revealed that MFG normalized the intestinal flora to some extent. Our study shows that AM had a protective effect on rats with alcohol-induced acute gastric ulcers before and after processing, and AM-processed products were more effective than raw ones. Compared with MF, MFG had a higher rate of ulcer inhibition and a stronger anti-inflammatory effect, and its mechanism of action was related to the NF-κB-MMP-9/TIMP-1 signaling pathway.

Tumor necrosis factor-α upregulates polymeric immunoglobulin receptor expression by NF-κB signaling pathways in grass carp (Ctenopharyngodon idellus) liver cells

The polymeric immunoglobulin receptor (pIgR) is essential for controlling polymeric immunoglobulin to defend species from invading pathogens. However, the modulation pathway of pIgR expression in teleosts remains unclear. In this paper, to define that the cytokine TNF-α impacted the expression of pIgR, the recombinant proteins of TNF-α of grass carp were first prepared after approving that natural pIgR was expressed in liver cells of grass carp (Ctenopharyngodon idellus) (L8824). L8824 cells were incubated with variable amounts of recombinant TNF-α at various times, the results revealed that pIgR expressions showed a significant dose-dependent elevation at the gene and proteins, and a similar alteration trend was detected for the pIgR protein (secretory component: SC) secreted by L8824 cells into the culture supernatant. Moreover, nuclear factor kappa-B (NF-κB) inhibitors PDTC was used to study whether TNF-α regulated pIgR expressions through the NF-κB signaling pathways. L8824 cells were treated with TNF-α, inhibitor PDTC, and TNF-α + PDTC mixtures, respectively, and the levels of pIgR genes and pIgR protein in cells and SC in the culture supernatant decreased in cells treated with PDTC contrasted to the control, and subjected to reduced expression of PDTC + TNF-α reduced expression contrasted to that treated just with TNF-α, demonstrating that suppression of NF-κB obstructed the ability of TNF-α to elevate pIgR gene and pIgR protein in cells and SC in the culture supernatant. These outcomes indicated that TNF-α raised pIgR gene expression, pIgR protein, and SC creation, and this pIgR expression induced by TNF-α was modulated by complicated pathways that included NF-κB signaling mechanism, confirming TNF-α as a pIgR expression modulator and enhancing a deeper insight of the regulatory pathway for pIgR expression in teleosts.

Anti-inflammatory potential of selective small compounds by targeting TNF-α & NF-kB signaling: a comprehensive molecular docking and simulation study

Tumor necrosis factor alpha (TNF-α) is the major cause of inflammation in autoimmune diseases like rheumatoid arthritis (RA). It’s mechanisms of signal transduction through nuclear factor kappa B (NF-kB) pathway via small molecules such as metabolite crosstalk are still elusive. In this study, we have targeted TNF-α and NF-kB through metabolites of RA, to inhibit TNF-α activity and deter NF-kB signaling pathways, thereby mitigating the disease severity of RA. TNF-α and NF-kB structure was obtained from PDB database and metabolites of RA were selected from literature survey. In-silico studies were carried out by molecular docking using AutoDock Vina software and further, known TNF-α and NF-kB inhibitors were compared and revealed metabolite’s capacity to targets the respective proteins. Most suitable metabolite was then validated by MD simulation to verify its efficiency against TNF-α. Total 56 known differential metabolites of RA were docked with TNF-α and NF-kB compared to their corresponding inhibitor compounds. Four metabolites such as Chenodeoxycholic acid, 2-Hydroxyestrone, 2-Hydroxyestradiol (2-OHE2), and 16-Hydroxyestradiol were identified as a common TNF-α inhibitor’s having binding energies ranging from −8.3 to −8.6 kcal/mol, followed by docking with NF-kB. Further, 2-OHE2 was selected because of having binding energy −8.5 kcal/mol, found to inhibit inflammation and the effectiveness was validated by root mean square fluctuation, radius of gyration and molecular mechanics with generalized born and surface area solvation against TNF-α. Thus 2-OHE2, an estrogen metabolite was identified as the potential inhibitor, attenuated inflammatory activation and can be utilized as a therapeutic target to disseminate severity of RA.

Exploration of bioactive compounds from Mangifera indica (Mango) as probable inhibitors of thymidylate synthase and nuclear factor kappa-B (NF-Κb) in colorectal cancer management

Abstract This research is aimed at investigating the anti-colorectal cancer activities of phytochemicals from Mangifera indica (Mango) via the inhibition of thymidylate synthase (TS) and Nuclear Factor kappa B (NF–κB) using computational chemistry tools. Ligands (141 phytochemicals previously isolated from mangoes) and reference drugs (Raltitrexed and Emetine), the drug inhibitors of TS and NF–κB, respectively) were subjected to screening via ADMET profiling, drug-likeness analysis, oral bioavailability, PASS profile, and molecular interactions. Ligands that passed the previously mentioned screening were docked in duplicate against the target receptors (TS and NF–κB) using PyRx software. The mean values were calculated to obtain suitable docking scores. The analysis showed that TS was strongly inhibited by Friedelan-3beta-Ol with its lower binding energy of −9.0 kcal/mol more than Raltitrexed with a binding energy of −8.7 kcal/mol. NF–κB was also inhibited by Friedelan-3beta-Ol and Friedelin with binding energies of −8.0 and −8.1 kcal/mol, respectively, more than Emetine with a binding energy of −6.4 kcal/mol. These two phytochemicals performed much better than the standard drugs, thus selected as the best hits compounds because of their ADMET profile, drug-likeness properties, bioactivity, oral bioavailability, PASS prediction, binding affinities, and their interactions with the amino acids in the active sites of the receptors. Therefore, further studies are necessary for the validation of these claims toward the development of new effective and safer anti-colorectal cancer drugs.

Activation of ROS-PERK-TFEB by filbertone ameliorates neurodegenerative diseases via enhancing the autophagy-lysosomal pathway

The molecular mechanisms underlying the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease (PD), and Huntington's disease remain enigmatic, resulting in an unmet need for therapeutics development. Here, we suggest that filbertone, a key flavor compound found in the fruits of hazel trees of the genus Corylus, can ameliorate PD via lowering the abundance of aggregated α-synuclein. We previously reported that inhibition of hypothalamic inflammation by filbertone is mediated by suppression of nuclear factor kappa-B. Here, we report that filbertone activates PERK through mitochondrial reactive oxygen species production, resulting in the increased nuclear translocation of transcription factor-EB in SH-SY5Y human neuroblastoma cells. TFEB activation by filbertone promotes the autophagy-lysosomal pathway, which in turn alleviates the accumulation of α-synuclein. We also demonstrate that filbertone prevented the loss of dopaminergic neurons in the substantia nigra and striatum of mice on high-fat diet. Filbertone treatment also reduced high-fat diet-induced α-synuclein accumulation through upregulation of the autophagy-lysosomal pathway. In addition, filbertone improved behavioral abnormalities (i.e., latency time to fall and decrease of running distance) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD murine model. In conclusion, filbertone may show promise as a potential therapeutic for neurodegenerative disease.

Identification of potential inhibitors of thymidylate synthase (TS) (PDB ID: 6QXH) and nuclear factor kappa-B (NF–κB) (PDB ID: 1A3Q) from Capsicum annuum (bell pepper) towards the development of new therapeutic drugs against colorectal cancer (CRC)

Abstract Colorectal cancer is the third most deadly cancer globally. Drug resistance and attendant side effects make the available standard anti-colorectal cancer drugs against target receptors inefficient. Phytochemicals from medicinal plants are safer, cheaper, effective, and heal diseases from the cellular level. This study is aimed at identifying potential inhibitors of thymidylate synthase (TS) and nuclear factor kappa-B (NF–κB) target receptors from Capsicum annuum towards the development of new therapeutic drugs against colorectal cancer via in silico approach. One hundred and fifty (150) ligands previously reported from Capsicum annuum were downloaded from the PubChem database and were subjected to chemo-informatics analyses such as ADMET, drug-likeness, oral bioavailability, bioactivity, and PASS prediction to ascertain their therapeutic and safety profile before docking. The ligands that passed the analyses were docked against TS and NF–κB in duplicate using a creditable docking tool (PyRx). Raltitrexed and emetine were used as the standard drug inhibitors for TS and NF–κB, respectively. The results obtained from this study showed that feruloyl-beta-D-glucose (8.45 kcal/mol), 5-O-caffeoylquinic acid (−8.40 kcal/mol), 5-O-caffeoylquinic acid methyl ester (−7.89 kcal/mol), feruloyl hexoside (−7.40 kcal/mol), O-glucopyranoside (−7.55 kcal/mol), and quercetin (−7.00 kcal/mol) shared the same binding pocket with TS while feruloyl-beta-D-glucose (−7.00 kcal/mol), chlorogenic acid (−6.90 kcal/mol), 5-O-caffeoylquinic acid (−6.90 kcal/mol) and feruloyl hexoside (−6.50 kcal/mol) shared the same pocket with NF–κB. These compounds were selected as best hits due to their excellent inhibitory efficiency and chemoinformatic profiles. Thus, the compounds may function as prospective lead compounds for developing a new anti-colorectal cancer drug.