Inhibition Of Cytokine Production Research Articles

Nicorandil antiallodynic activity in a model of neuropathic pain is associated with the activation of ATP-dependent potassium channels and opioidergic pathways, and reduced production of cytokines and neutrophils recruitment in paw, sciatic nerve, and dorsal root ganglia.

Recently, we demonstrated that nicorandil inhibits mechanical allodynia induced by paclitaxel. In the present study, we evaluated the effect induced by nicorandil in a model of neuropathic pain induced by chronic constriction injury (CCI) in mice. We also investigated putative mechanisms underlying such an effect. CCI was induced by three ligatures of the left sciatic nerve. Mechanical allodynia was evaluated by measuring the paw withdrawal threshold with an electronic von Frey apparatus. Concentrations of cytokines and myeloperoxidase activity were determined in the paw tissue, sciatic nerve, and dorsal root ganglia (DRG). Oral administration of two doses of nicorandil (150mg/kg po), but not equimolar doses of nicotinamide or nicotinic acid, attenuated mechanical allodynia induced by CCI. Nicorandil activity was reduced by previous administration of glibenclamide (40mg/kg) or naltrexone (5mg/kg or 10mg/kg). Two doses of nicorandil (150mg/kg, po) reduced tumor necrosis factor-α, interleukin-1β and interleukin-6, but not CXCL-1, concentrations in the paw tissue of CCI mice. Two doses of nicorandil (150mg/kg, po) reduced concentrations of all these mediators in the sciatic nerve and DRG. Two doses of nicorandil (150mg/kg, po) also reduced the myeloperoxidase activity in the paw tissue, sciatic nerve, and DRG. Nicorandil exhibits antiallodynic activity in a model of neuropathic pain induced by CCI. Inhibition of cytokines production and reduction of neutrophils recruitment in paw tissue, sciatic nerve, and DRG as well as activation of ATP-dependent potassium channels and opioidergic pathways, underlie nicorandil antiallodynic activity.

U2AF1 S34F enhances tumorigenic potential of lung cells by exhibiting synergy with KRAS mutation and altering response to environmental stress.

Although U2AF1 S34F is a recurrent splicing factor mutation in lung adenocarcinoma (ADC), U2AF1 S34F alone is insufficient for producing tumors in previous models. Because lung ADCs with U2AF1 S34F frequently have co-occurring KRAS mutations and smoking histories, we hypothesized that tumor-forming potential arises from U2AF1 S34F interacting with oncogenic KRAS and environmental stress. To elucidate the effect of U2AF1 S34F co-occurring with a second mutation, we generated human bronchial epithelial cells (HBEC3kt) with co-occurring U2AF1 S34F and KRAS G12V . Transcriptome analysis revealed that co-occurring U2AF1 S34F and KRAS G12V differentially impacts inflammatory, cell cycle, and KRAS pathways. Subsequent phenotyping found associated suppressed cytokine production, increased proliferation, anchorage-independent growth, and tumors in mouse xenografts. Interestingly, HBEC3kts harboring only U2AF1 S34F display increased splicing in stress granule protein genes and viability in cigarette smoke concentrate. Our results suggest that U2AF1 S34F may potentiate transformation by granting precancerous cells survival advantage in environmental stress, permitting accumulation of additional mutations like KRAS G12V , which synergize with U2AF1 S34F to transform the cell.

A randomized, placebo-controlled trial of purified anthocyanins on cognitive function in individuals at elevated risk for dementia: Analysis of inflammatory biomarkers toward personalized interventions

BackgroundDementia poses a significant global health challenge. Anthocyanins neutralize free radicals, modulate signaling pathways, inhibit pro-inflammatory genes, and suppress cytokine production and may thus have positive cognitive effects in people at increased risk of dementia. We aim to investigate the effects of purified anthocyanins on cognitive function in people at increased risk of dementia according to their inflammation status based on blood-based inflammatory biomarkers. MethodsThis is a secondary analysis of a 24-week randomized, double-blind, placebo-controlled trial. Cluster analysis was performed to categorize two groups based on their individual inflammatory biomarker profile using multiplex sandwich ELISA for the quantitative measurement of cytokines. Descriptive statistics and longitudinal models assessed cognitive outcomes. The primary comparison was the group difference at week 24 based on a modified intention-to-treat analysis. ResultsCluster analysis revealed two distinct inflammatory biomarker profiles. In Cluster 1 (high levels of inflammation biomarkers), anthocyanin treatment showed a statistically significant improvement on cognitive function compared to placebo at 24 weeks. No significant differences were observed in Cluster 2 (low levels of inflammation biomarkers). The demographic characteristics, cognitive scores, and biomarker distributions were similar between treatment groups at baseline. However, cluster 1 exhibited higher BMI, diabetes prevalence, medication usage, and lower HDL cholesterol levels. ConclusionIndividuals with elevated levels of inflammation markers benefited from anthocyanin treatment to enhance cognitive performance, whereas those with lower levels did not. The anti-inflammatory and antioxidant properties of anthocyanins make them a promising intervention, and future prospective trials in people with increased inflammation are warranted.

Phytoconstituents as modulator of inflammatory pathways for COVID-19: A comprehensive review and recommendations.

SARS-CoV-2 infection causes disruptions in inflammatory pathways, which fundamentally contribute to COVID-19 pathophysiology. The present review critically evaluates the gaps in scientific literature and presents the current status regarding the inflammatory signaling pathways in COVID-19. We propose that phytoconstituents can be used to treat COVID-19 associated inflammation, several already formulated in traditional medications. For this purpose, extensive literature analysis was conducted in the PubMed database to collect relevant in vitro, in vivo, and human patient studies where inflammation pathways were shown to be upregulated in COVID-19. Parallelly, scientific literature was screened for phytoconstituents with known cellular mechanisms implicated for inflammation or COVID-19 associated inflammation. Studies with insufficient evidence on cellular pathways for autophagy and mitophagy were considered out of scope and excluded from the study. The final analysis was visualized in figures and evaluated for accuracy. Our findings demonstrate the frequent participation of NF-κB, a transcription factor, in inflammatory signaling pathways linked to COVID-19. Moreover, the MAPK signaling pathway is also implicated in producing inflammatory molecules. Furthermore, it was also analyzed that the phytoconstituents with flavonoid and phenolic backbones could inhibit either the TLR4 receptor or its consecutive signaling molecules, thereby, decreasing NF-κB activity and suppressing cytokine production. Although, allopathy has treated the early phase of COVID-19, anti-inflammatory phytoconstituents and existing ayurvedic formulations may act on the COVID-19 associated inflammatory pathways and provide an additional treatment strategy. Therefore, we recommend the usage of flavonoids and phenolic phytoconstituents for the treatment of inflammation associated with COVID-19 infection and similar viral ailments.

Seminal plasma inhibits Chlamydia trachomatis infection in vitro, and may have consequences on mucosal immunity

Seminal plasma (SP) is the main vector of C. trachomatis (CT) during heterosexual transmission from male to female. It has immunomodulatory properties and impacts the susceptibility to HIV-1 infection, but its role has not been explored during CT infection. In the female reproductive tract (FRT), CT infection induces cytokine production and neutrophil recruitment. The role of neutrophils during CT infection is partially described, they could be at the origin of the pathology observed during CT infection. During this study, we developed an experimental in vitro model to characterize the impact of CT infection and SP on endocervical epithelial cell immune response in the FRT. We also studied the impact of the epithelial cell response on neutrophil phenotype and functions. We showed that the production by epithelial cells of pro-inflammatory cytokines increased during CT infection. Moreover, the pool of SP as well as individuals SP inhibited CT infection in a dose-dependent manner. The pool of SP inhibited cytokine production in a dose-dependent manner. The pool of SP altered gene expression profiles of infected cells. The culture supernatants of cells infected or not with CT, in presence or not of the pool of SP, had an impact on neutrophil phenotype and functions: they affected markers of neutrophil maturation, activation and adhesion capacity, as well as the survival, ROS production and phagocytosis ability. This study proposes a novel approach to study the impact of the environment on the phenotype and functions of neutrophils in the FRT. It highlights the impact of the factors of the FRT environment, in particular SP and CT infection, on the mucosal inflammation and the need to take into account the SP component while studying sexually transmitted infections during heterosexual transmission from male to female.

Bioguided Optimization of the Nutrition-Health, Antioxidant, and Immunomodulatory Properties of Manihot esculenta (Cassava) Flour Enriched with Cassava Leaves.

Manihot esculenta (cassava) roots is a major food crop for its energy content. Leaves contain nutrients and demonstrate biological properties but remain undervalorized. In order to develop a bioguided optimization of cassava nutrition-health properties, we compared the phytochemistry and bioactive potential of cassava root flour extract (CF) with cassava flour extract enriched with 30% leaves powder (CFL). Cassava flour supplementation impact was explored on flour composition (starch, fiber, carotenoids, phenolic compounds), in vivo glycemic index, and bioactivity potential using macrophage cells. We assessed the impact of cassava flour supplementation on free radicals scavenging and cellular production of pro-inflammatory mediators. CFL showed higher levels of fiber, carotenoids, phenolic compounds, and lower glycemic index. Significantly higher bioactive properties (anti-inflammatory and antioxidant) were recorded, and inhibition of cytokines production has been demonstrated as a function of extract concentration. Overall, our results indicate that enrichment of cassava flour with leaves significantly enhances its nutrition-health and bioactive potential. This bioguided matrix recombination approach may be of interest to provide prophylactic and therapeutic dietary strategy to manage malnutrition and associated chronic non-communicable diseases characterized by low-grade inflammation and unbalanced redox status. It would also promote a more efficient use of available food resources.

A water-soluble caveolin-1 peptide inhibits psoriasis-like skin inflammation by suppressing cytokine production and angiogenesis

The plasma membrane protein caveolin-1 (CAV-1) regulates signaling by inhibiting a wide range of kinases and other enzymes. Our previous study demonstrated that the downregulation of CAV-1 in psoriatic epidermal cells contributes to inflammation by enhancing JAK/STAT signaling, cell proliferation, and chemokine production. Administration of the CAV-1 scaffolding domain (CSD) peptide suppressed imiquimod (IMQ)-induced psoriasis-like dermatitis. To identify an optimal therapeutic peptide derived from CAV-1, we have compared the efficacy of CSD and subregions of CSD that have been modified to make them water soluble. We refer to these modified peptides as sCSD, sA, sB, and sC. In IMQ-induced psoriasis-like dermatitis, while all four peptides showed major beneficial effects, sB caused the most significant improvements of skin phenotype and number of infiltrating cells, comparable or superior to the effects of sCSD. Phosphorylation of STAT3 was also inhibited by sB. Furthermore, sB suppressed angiogenesis both in vivo in the dermis of IMQ-induced psoriasis mice and in vitro by blocking the ability of conditioned media derived from CAV-1-silenced keratinocytes to inhibit tube formation by HUVEC. In conclusion, sB had similar or greater beneficial effects than sCSD not only by cytokine suppression but by angiogenesis inhibition adding to its ability to target psoriatic inflammation.

A Review on Analytical Methods for Determination of Azithromycin

Azithromycin treatment has been associated with a decrease in ventilation time and death in several viral infections. It possesses immune-modulating properties, including the capacity to inhibit cytokine production, preserve the integrity of epithelial cells, and prevent lung fibrosis. Primary hepatic metabolism is the process by which drugs are broken down into inactive metabolites that keep their biological effects. These prompted numerous studies and publications that used a variety of analytical techniques to find, evaluate, and investigate azithromycin and its metabolites. This review aims to provide an overview of the various analytical techniques—such as voltammetry, flow injection, hyphenated mass spectrometry, and chromatography—that have been published for the years 1990 to 2020 in order to determine azithromycin. While azithromycin was most commonly quantified using high-performance liquid chromatography, the study's results indicate that when compared to alternative techniques, liquid chromatography-mass spectrometry had the highest sensitivity, with a limit of detection of 0.0005 µg/mL.

Circulating levels of galectin-9 are a potential biomarker of survival in advanced non-small-cell lung cancer.

The immune system is recognized to have therapeutic potential to destroy cancer cells. Soluble T-cell immunoglobulin mucin domain-3 (sTIM-3) and its ligand galectin 9 (Gal-9) cause suppression of cytokine production, cell cycle arrest and cell death. sTIM-3 and Gal-9 levels may have prognostic implications in non-small-cell lung cancer (NSCLC) patients. This prospective cohort study was performed at Instituto de Medicina Integral Prof. Fernando Figueira, Recife, Pernambuco, Brazil. Fifty-eight patients were diagnosed with advanced NSCLC from January 2019 to January 2020. The age median was of 64.0 years. Soluble galectin-9 (sGal-9) levels in the smokers compared to nonsmoker patients (p < 0.0001). By using the receiver operating characteristic curve, we found that a baseline of 1694 pg/mL (cutoff). sGAL9 with specificity (72.2%), sensitivity (83.2%) and area under the curve = 0.8497 (p < 0.0004). Until 18.2 months, 46.8% and 72.9% were alive in the sGAL9low and sGAL9high groups, respectively (log-rank test; p = 0.02). The median survival was 15.9 months for sGAL9low (≤1694 pg/mL). This study indicated an association of tobacco with the release of circulating sGal-9 levels and the accuracy of sGal-9 as a potential biomarker predictive of survival time in advanced NSCLC patients. Furthermore, sGal-9 has may be a potential therapeutic target in the advanced NSCLC.

Embelin mitigates hepatotoxicity induced by isoniazid and rifampicin in rats

Isoniazid and rifampicin are reliable drugs against tuberculosis, but while effective, their use is associated with the risk of drug-induced liver damage. Embelin, a natural parabenzoquinone derived from the Embelia ribes plant, has gained attention for its potential therapeutic properties, antioxidant and organ-protective effects. The study aimed to assess the hepatoprotective properties of embelin against liver dama­ge induced by isoniazid and rifampicin in rats. Wistar rats were used, and liver damage was induced by administration of isoniazid (100 mg/kg) and rifampicin (100 mg/kg). Embelin was given at doses of 50, 75, and 100 mg/kg for 21 days. All the drugs were given orally. Serum levels of the oxidative stress markers, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) activity measured by enzymatic assay kits (Elabscience, China), and the levels of tumour necrosis factor-α (TNF-α), interleukins IL-1β and IL-6 measured by ELISA kits (Randox, UK) were estimated. Embelin administration at varying doses effectively restored AST, ALT, ALP, SOD and catalase activity and notably decreased MDA and nitric oxide concentration as well as expression of inflammatory cytokines TNF-α, IL-1β and IL-6 in the serum of animals with drug-induced liver damage. These findings underscore embelin’s hepatoprotective effects, likely attributed to its radical scavenging properties and ability to suppress cytokine production. Keywords: antioxidant effect, cytokine suppression, embelin, hepatoprotection, isoniazid, rifampicin

A novel 12-membered ring non-antibiotic macrolide EM982 attenuates cytokine production by inhibiting IKKβ and IκBα phosphorylation

Antimicrobial resistance poses a serious threat to human health worldwide and its incidence continues to increase owing to the overuse of antibiotics and other factors. Macrolide antibiotics such as erythromycin (EM) have immunomodulatory effects in addition to their antibacterial activity. Long-term, low-dose administration of macrolides has shown clinical benefits in treating non-infectious inflammatory respiratory diseases. However, this practice may also increase the emergence of drug-resistant bacteria. In this study, we synthesized a series of EM derivatives, and screened them for two criteria: (i) lack of antibacterial activity and (ii) ability to suppress tumor necrosis factor-α (TNF-α) production in THP-1cells stimulated with lipopolysaccharide. Among the 37 synthesized derivatives, we identified a novel 12-membered ring macrolide EM982 that lacked antibacterial activity against Staphylococcus aureus and suppressed the production of TNF-α and other cytokines. The effects of EM982 on Toll-like receptor 4 (TLR4) signaling were analyzed using a reporter assay and Western blotting. The reporter assay showed that EM982 suppressed the activation of transcription factors, NF-κB and/or activator protein 1 (AP-1), in HEK293cells expressing human TLR4. Western blotting showed that EM982 inhibited the phosphorylation of both IκB kinase (IKK) β and IκBα, which function upstream of NF-κB, whereas it did not affect the phosphorylation of p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, and c-Jun N-terminal kinase, which act upstream of AP-1. These results suggest that EM982 suppresses cytokine production by inhibiting phosphorylation of IKKβ and IκBα, resulting in the inactivation of NF-κB.

The IRE1α/XBP1 pathway sustains cytokine responses of group 3 innate lymphoid cells in inflammatory bowel disease.

Group 3 innate lymphoid cells (ILC3s) are key players in intestinal homeostasis. ER stress is linked to inflammatory bowel disease (IBD). Here, we used cell culture, mouse models, and human specimens to determine whether ER stress in ILC3s affects IBD pathophysiology. We show that mouse intestinal ILC3s exhibited a 24-hour rhythmic expression pattern of the master ER stress response regulator inositol-requiring kinase 1α/X-box-binding protein 1 (IRE1α/XBP1). Proinflammatory cytokine IL-23 selectively stimulated IRE1α/XBP1 in mouse ILC3s through mitochondrial ROS (mtROS). IRE1α/XBP1 was activated in ILC3s from mice exposed to experimental colitis and in inflamed human IBD specimens. Mice with Ire1α deletion in ILC3s (Ire1αΔRorc) showed reduced expression of the ER stress response and cytokine genes including Il22 in ILC3s and were highly vulnerable to infections and colitis. Administration of IL-22 counteracted their colitis susceptibility. In human ILC3s, IRE1 inhibitors suppressed cytokine production, which was upregulated by an IRE1 activator. Moreover, the frequencies of intestinal XBP1s+ ILC3s in patients with Crohn's disease before administration of ustekinumab, an anti-IL-12/IL-23 antibody, positively correlated with the response to treatment. We demonstrate that a noncanonical mtROS-IRE1α/XBP1 pathway augmented cytokine production by ILC3s and identify XBP1s+ ILC3s as a potential biomarker for predicting the response to anti-IL-23 therapies in IBD.

Blocking the MIR155HG/miR-155 axis reduces CTGF-induced inflammatory cytokine production and α-SMA expression via upregulating AZGP1 in hypertrophic scar fibroblasts

Hypertrophic scarring (HS) is a pathological condition characterized by excessive fibrosis and inflammation, resulting in excessive extracellular matrix formation in the skin. MIR155HG, a long non-coding RNA, is abnormally upregulated in fibrotic tissues; however, its underlying mechanism is poorly understood. Using single-cell sequencing data, we analyzed connective tissue growth factor (CTGF) expression in various cell types in HS and normal skin tissues and MIR155HG expression in clinical samples. To investigate the mechanism of fibrosis, an in vitro model using CTGF-treated hypertrophic scar fibroblasts (HSFBs) was established and qRT-PCR, western blotting and ELISA assays were performed to investigate the expression of interleukin (IL)-1β, IL-6, and mesenchymal markers α-smooth muscle actin (α-SMA). CTGF stimulates MIR155HG level through phosphorylated STAT3 binding to the MIR155HG promoter. We analyzed the methylation of MIR155HG, assessed the levels of miR-155-5p/−3p in CTGF-treated HSFBs and identified differentially expressed genes among HS and NS samples using the Gene Expression Omnibus RNA sequencing data. The binding between miR-155-5p/−3p and AZGP1 was confirmed using a dual-luciferase assay and inflammatory cytokine production and α-SMA expression were investigated in rescue experiments. The findings revealed that CTGF elevated inflammatory cytokine production, α-SMA and MIR155HG expression in HSFBs. MIR155HG is upregulated in HS tissues due to low DNA methylation. Mechanistically, miR-155-5p/−3p was directly bound to MIR155HG 3’UTR. MIR155HG silencing inhibited cytokine production and α-SMA expression by repressing the generation of miR-155-5p/−3p in CTGF-treated HSFBs. Bioinformatics analysis and luciferase reporter assays revealed that miR-155-5p/−3p targets AZGP1. In addition, transfection with plasmids carrying AZGP1 cDNA significantly inhibited the signaling activity of miR-155-5p/−3 p-overexpressing HSFBs. Our findings highlight the importance of the MIR155HG/miR-155/AZGP1 axis in regulating cytokine production and α-SMA in HS.

N4BP1 coordinates ubiquitin-dependent crosstalk within the IκB kinase family to limit Toll-like receptor signaling and inflammation

The ubiquitin-binding endoribonuclease N4BP1 potently suppresses cytokine production by Toll-like receptors (TLRs) that signal through the adaptor MyD88 but is inactivated via caspase-8-mediated cleavage downstream of death receptors, TLR3, or TLR4. Here, we examined the mechanism whereby N4BP1 limits inflammatory responses. In macrophages, deletion of N4BP1 prolonged activation of inflammatory gene transcription at late time points after TRIF-independent TLR activation. Optimal suppression of inflammatory cytokines by N4BP1 depended on its ability to bind polyubiquitin chains, as macrophages and mice-bearing inactivating mutations in a ubiquitin-binding motif in N4BP1 displayed increased TLR-induced cytokine production. Deletion of the noncanonical IκB kinases (ncIKKs), Tbk1 and Ikke, or their adaptor Tank phenocopied N4bp1 deficiency and enhanced macrophage responses to TLR1/2, TLR7, or TLR9 stimulation. Mechanistically, N4BP1 acted in concert with the ncIKKs to limit the duration of canonical IκB kinase (IKKα/β) signaling. Thus, N4BP1 and the ncIKKs serve as an important checkpoint against over-exuberant innate immune responses.

Active Hexose Correlated Compound Feeding to Stress Mice Induces Differential Cytokine Production during Chlamydia muridarum Genital Infection

Oral supplementation of Active Hexose Correlated Compound (AHCC) mushroom extract is reported to enhance resistance to infection. However, AHCC feeding to stressed mice during Chlamydia muridarum. genital infection and host immune response remain unexplored. This study aimed to explore cytokine production profiles of immune cells of AHCC-fed stressed mice. Wildtype C57BL/6J mice that were stressed and infected with C. muridarum intravaginally. After seven days, splenic T cells and bone marrow-derived dendritic cells (DCs), and macrophages (MØs) were proliferated, and culture supernatants were collected to determine cytokine production by ELISA. Phenotyping of surface markers of immune cells using flow cytometry is underway. ELISA results show that AHCC increases the production of Th1 (IL-12 and IFN-g) and Th2 (IL-10, IL-13, IL.23) cytokines compared to PBS-fed stressed mice. Increased production of TNF-α in LPS-treated DCs and MØs of WT was observed. Overall, AHCC-feeding increases the production of protective and suppressive cytokines.

Abstract 2021: The RXR agonist MSU-42011 and the MEK inhibitor selumetinib reduce pERK levels in NF1-deficient cells and inhibit cytokine production in macrophages

Abstract Neurofibromatosis type 1 (NF1) is a common genetic disease that predisposes approximately 50% of affected individuals to develop plexiform neurofibromas (PNFs), which can progress to highly aggressive malignant peripheral nerve sheath tumors (MPNSTs) in approximately 10% of patients. NF1 is caused by mutations in the tumor suppressor gene NF1, which encodes for neurofibromin, a negative regulator of RAS activity. Selumetinib, a specific inhibitor of MEK1/2, is the only FDA-approved drug for NF1-associated PNFs. However, the anti-tumor effects of selumetinib are limited in MPNSTs and have dose-limiting side effects. Deficiency of the NF1 gene not only promotes tumorigenesis but also has broad effects on the immune cells and cytokine signaling driven by hyperactive RAS signaling. Because macrophages account for almost half of cells in NF1 lesions and their infiltration correlates with disease progression, we hypothesized that targeting tumor-promoting immune cells could be an alternative approach for treating NF1. The novel retinoid X receptor (RXR) agonist MSU-42011 reduces tumor growth in experimental Kras-driven cancers by decreasing pERK expression, reducing tumor-promoting immune cells like CD206+ macrophages and regulatory T cells, and increasing activated cytotoxic T cells. Here, we treated NF1-deficient cells and macrophages with MSU-42011 and selumetinib, either alone or in combination, using monoculture and conditioned media (CM) conditions. In human PNF cells and mouse MPNSTs, treatment with 200 nM MSU-40211 or 50 nM selumetinib for 3 hours reduced pERK protein levels compared with untreated controls, and the combination treatment enhanced this reduction in pERK protein levels. Additionally, there was a trend toward reduction in cell viability with increasing drug concentrations after 72 hours of the combination treatment. Moreover, CM from human and mouse PNF cells increased the mRNA expression of monocyte chemoattractant CCL2 (C-C motif chemokine ligand 2) and the secretion of IL-6 and TNFα in human THP1 monocytes/macrophages and bone marrow derived macrophages (BMDM). Notably, MSU-42011 and selumetinib alone inhibited CCL2 mRNA expression in THP1 macrophages and BMDM stimulated with CM from human and mouse PNF cells, respectively, and the inhibition of CCL2 mRNA expression was greatest with combination treatment. The combination of MSU42011 and selumetinib also significantly reduced tumor burden in a LL2 model of lung cancer driven by an activating Kras mutation. Based on the similarities in RAS activation and immune cell infiltration in NF1 and lung cancer, our next step is to confirm the immunomodulatory and anti-tumor effects of MSU-42011 and selumetinib in a syngeneic model of PNF and MPNST. Citation Format: Pei-Yu Hung, Jessica A. Moerland, Karen T. Liby. The RXR agonist MSU-42011 and the MEK inhibitor selumetinib reduce pERK levels in NF1-deficient cells and inhibit cytokine production in macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2021.

Neuroprotective roles of flavonoid "hispidulin" in the central nervous system: A review.

Interest in naturally occurring phytochemicals has been on the increase, they are believed to reduce the risk of brain disorders. Hispidulin (HN) is a phenolic flavonoid compound with various pharmacological and biological effects on the central nervous system. It belongs to the flavone class of flavonoids. It can be found in different plant materials, especially fruits and vegetables. The literature used in this review was collected from credible scientific databases including ScienceDirect, Scopus, PubMed, Google Scholar, and Hindawi without time restriction, using relevant keywords, such as HN, brain, central nervous system, flavonoids, and flavones. HN was discovered to possess pro-apoptotic properties, act as an antioxidant, inhibit cytokine production and toll-like receptor 4 expression, as well as impede nuclear factor kappa beta and mitogen-activated protein kinase B. HN was also found to inhibit lipid peroxidation in vitro and reduce brain edema in mice. These pharmacological potentials suggest that HN is a promising candidate for neuroprotection in CNS disorders like depression and epilepsy. This review provides an update on the scientific literature concerning how these activities could help provide various forms of neuroprotection in the CNS. Additional experimental data on the effects of HN in models of neurological disorders and neuroprotection should be explored further. Based on the current study, HN is a promising candidate for neuroprotection of the CNS.

The role of dopamine receptors in the modulation of mononuclear phagocytes in multiple sclerosis

To investigate the role of dopamine receptor D1DR and D2DR in the production of cytokines interleukin-6 (IL-6) and IL-1β by monocytes and macrophages in patients with relapsing-remitting multiple sclerosis (MS). Ten patients with relapsing-remitting MS and 10 healthy subjects were examined. The level of IL-6 and IL-1β production was assessed in culture supernatants obtained from CD14+ monocytes or macrophages stimulated with interferon-γ (IFN-γ) and lipopolysaccharide (LPS). To study the role of dopamine receptors in the regulation of CD14+ monocytes or macrophages, samples of cells were incubated in the presence of specific D1DR or D2DR antagonists, after which IFN-γ/LPS were added to the cultures. Levels of cytokines in culture supernatants were measured by enzyme-linked immunosorbent assay. The production of IL-6 and IL-1β by CD14+ monocytes and macrophages was comparable between the groups. Blockade of D1DR suppressed cytokine production by CD14+ monocytes and macrophages in both groups. In contrast, blockade of D2DR increased the production of cytokines by CD14+ monocytes and did not affect cytokine production by macrophages in both groups. Targeting of dopaminergic receptors could be considered as an additional mechanism of immunomodulation in MS with both pro- and anti-inflammatory effects on cells of the innate immune system.

Dietary Fiber-Derived Microbial Butyrate Suppresses ILC2-Dependent Airway Inflammation in COPD.

Group 2 innate lymphoid cells (ILC2) strongly modulate COPD pathogenesis. However, the significance of microbiota in ILC2s remains unelucidated. Herein, we investigated the immunomodulatory role of short-chain fatty acids (SCFAs) in regulating ILC2-associated airway inflammation and explores its associated mechanism in COPD. In particular, we assessed the SCFA-mediated regulation of survival, proliferation, and cytokine production in lung sorted ILC2s. To elucidate butyrate action in ILC2-driven inflammatory response in COPD models, we administered butyrate to BALB/c mice via drinking water. We revealed that SCFAs, especially butyrate, derived from dietary fiber fermentation by gut microbiota inhibited pulmonary ILC2 functions and suppressed both IL-13 and IL-5 synthesis by murine ILC2s. Using in vivo and in vitro experimentation, we validated that butyrate significantly ameliorated ILC2-induced inflammation. We further demonstrated that butyrate suppressed ILC2 proliferation and GATA3 expression. Additionally, butyrate potentially utilized histone deacetylase (HDAC) inhibition to enhance NFIL3 promoter acetylation, thereby augmenting its expression, which eventually inhibited cytokine production in ILC2s. Taken together, the aforementioned evidences demonstrated a previously unrecognized role of microbial-derived SCFAs on pulmonary ILC2s in COPD. Moreover, our evidences suggest that metabolomics and gut microbiota modulation may prevent lung inflammation of COPD.

Resveratrol inhibits cytokine production in LPS-stimulated RAW264.7 cells potentially through TLR4/MyD88/NF-κB pathway

Resveratrol is a naturally occurring compound with anti-inflammatory properties. However, the protective molecular mechanisms of resveratrol against LPS-induced inflammation have not been thoroughly known. In the present study, we examined the anti-inflammatory effect of resveratrol in inflammatory model using murine macrophage-like cell RAW264.7 stimulated with LPS. Resveratrol suppressed the production of inflammatory cytokines in LPS-stimulated RAW264.7 cells with the IC50 value as 17.5 ± 0.7 μM for IL-6, 14.2 ± 1.9 μM for IL-10, and 18.9 ± 0.6 μM for TNF-α. Gene expression of TLR4, MyD88 and NF-κB were significantly suppressed by resveratrol treatment in LPS-stimulated RAW264.7 cells. In conclusion, the anti-inflammatory property of resveratrol is potentially related to its inhibitory effecton TLR4/MyD88/NF-κB signaling pathway in macrophages.