Inhibition Of Cytokine Production Research Articles

Transcutaneous auricular vagus nerve stimulation reduces cytokine production in sepsis: An open double-blind, sham-controlled, pilot study

BackgroundStudies have shown that vagus nerve-mediated inflammatory reflex could inhibit cytokine production and inflammation in sepsis animals. ObjectivesThis study aimed to explore the efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) on inflammation and disease severity of sepsis patients. MethodsA randomized, double-blind, sham-controlled pilot study was performed. Twenty sepsis patients were randomly assigned to receive taVNS or sham stimulation for five consecutive days. Stimulation effect was assessed with serum cytokine levels, Acute Physiology and Chronic Health Evaluation (APACHE) Ⅱ score, and Sequential Organ Failure Assessment (SOFA) score at baseline and on Day 3, Day 5, and Day 7. ResultsTaVNS was well tolerated in the study population. Patients receiving taVNS experienced significant reductions in serum TNF-α and IL-1β levels and increases in IL-4 and IL-10 levels. SOFA scores decreased on Day 5 and Day 7 compared with baseline in the taVNS group. However, no changes were found in sham stimulation group. The changes of cytokine from Day 7 to Day 1 were greater with taVNS than sham stimulation. No differences in the APACHE Ⅱ score and SOFA score were observed between the two groups. ConclusionsTaVNS resulted in significantly lower serum pro-inflammatory cytokines and higher serum anti-inflammatory cytokines in sepsis patients.

Severe fever with thrombocytopenia syndrome virus replicates in platelets and enhances platelet activation

BackgroundSevere fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) infection causes an emerging hemorrhagic fever in East Asia with a high mortality rate. Thrombocytopenia is a consistent feature of SFTS illness, but the mechanism remains elusive. ObjectivesWe aimed to better understand the role of platelets in the pathophysiology of SFTSV infection, including the development of thrombocytopenia. MethodsUsing platelets from healthy volunteers and patients with SFTS, we evaluated the functional changes in platelets against SFTSV infection. We investigated the direct effect of glycoprotein VI on platelet-SFTSV interaction by quantitative real-time PCR, molecular docking, surface plasmon resonance spectrometry, flow cytometry, western blot, and platelet functional studies in vitro. Interactions of SFTSV and platelet-SFTSV complexes with macrophages were also determined by scanning electron microscope, quantitative real-time PCR, and flow cytometry. ResultsThis study is the first to demonstrate that platelets are capable of harboring and producing SFTSV particles. Structural and functional studies found that SFTSVs bind platelet glycoprotein VI to potentiate platelet activation, including platelet aggregation, adenosine triphosphate release, spreading, clot retraction, coagulation, phosphatidylserine exposure, thrombus formation, and adherence. In vitro mechanistic studies highlighted that the interaction of platelets with human THP-1 cells promoted SFTSV clearance and suppressed cytokine production in macrophages. However, unwanted SFTSV replication in macrophages reciprocally aggravated SFTSV persistence in the circulation, which may contribute to thrombocytopenia and other complications during SFTSV infection. ConclusionThese findings together highlighted the pathophysiological role of platelets in initial intrinsic defense against SFTSV infections, as well as intertwined processes with host immunity, which can also lead to thrombocytopenia and poor prognosis.

The Molecular Mechanisms underlying the Therapeutic Effect of Berberine in Inflammatory Skin Diseases

Clinical therapy of chronic inflammatory skin diseases such as atopic dermatitis is extremely difficult. Recently, the use of a number of traditional herbal medicines has been attempted to treat these skin diseases. Orengedokuto is a traditional herbal medicine consisting of four crude natural medicines, and in the field of dermatology, it is used to treat skin diseases accompanied by inflammation and pruritus. Our recent animal study showed that berberine, a major component of Orengedokuto, improves skin inflammation and itching in mice with atopy-like dermatitis. Furthermore, we identified EIF3F and MALT1 as factors involved in the suppression of cytokine production by berberine. In addition, berberine also activates AMP-activated protein kinase, which is involved in the expression of inflammatory and anti-inflammatory cytokines. In addition, berberine also attenuates epidermal hyperplasia though the inhibition of CDC6 expression. Taken together, these findings indicate that berberine improves inflammatory skin diseases by controlling gene expression related to both inflammation, anti-inflammation and keratinocyte hyperproliferation.

Procyanidin B2 3,3″-di-O-gallate suppresses IFN-γ production in murine CD4+ T cells through the regulation of glutamine influx via direct interaction with ASCT2.

Excessive activation of CD4+ T cells increases cytokine production substantially and induces immune-mediated diseases. Procyanidins are polyphenols with anti-inflammatory properties. Procyanidin B2 (PCB2) gallate [specifically, PCB2 3,3''-di-O-gallate (PCB2DG)] inhibits cytokine production through the suppression of glycolysis via mammalian target of rapamycin (mTOR) in T cells. Several amino acids play critical roles in T cell activation, especially glutamine, which is important in mTOR signaling and interferon-γ (IFN-γ) production in CD4+ T cells. However, the mechanisms underlying the effects of PCB2DG, including its interaction partners, have yet to be clarified. In the present study, the mechanisms underlying the inhibitory effect of PCB2DG on IFN-γ through glutamine metabolism regulation were investigated. We found that PCB2DG treatment reduced intracellular glutamine levels in CD4+ T cells, whereas the addition of glutamine abrogated the inhibitory effects of PCB2DG on IFN-γ production. The PCB2DG-induced reduction in intracellular glutamine accumulation led to the upregulated expression of activating transcription factor 4, which was induced by the cytoprotective signaling pathway in the amino acid response. In addition, the mRNA and protein expression levels of alanine serine cysteine transporter 2 (ASCT2), a major glutamine transporter in CD4+ T cells, were not altered by PCB2DG treatment. Further analysis using a target identification strategy revealed that PCB2DG binds to ASCT2, suggesting that PCB2DG interacts directly with this major glutamine transporter to inhibit glutamine influx. Overall, this study indicates that ASCT2 is a novel target protein of a dietary polyphenol and provides new insights into the mechanism underlying the immunomodulatory effects of polyphenols.

Ly-6A-Induced Growth Inhibition and Cell Death in a Transformed CD4+ T Cell Line: Role of Tumor Necrosis Factor-α.

Ly-6A, a member of the Ly-6/uPAR supergene family of proteins, is a cell adhesion and cell signaling protein. Signaling through Ly-6A activates the cell-intrinsic apoptotic cell death pathway in CD4+ T cell lines, as indicated by the release of cytochrome C, and activation of caspases 9 and 3. In addition, Ly-6A induces cytokine production and growth inhibition. The mechanism underlying the distinct cellular responses that are triggered by engaging Ly-6A protein has remained unknown. To examine the relatedness of these distinct responses, we have quantified the production of pro-apoptotic, growth inhibitory and tumor suppressive cytokines, such as TNF-α, TGF-β and a related protein GDF-10, in response to Ly-6A signaling. Anti-Ly-6A monoclonal antibody-induced activation of YH16.33 CD4+ T cell line generated low levels of TGF-β and GDF-10 but elevated levels of TNF-α. Blocking the biological activity of TNF-α resulted in reduced Ly-6A-induced apoptosis in T cells. The Ly-6A-induced response in the T cell line was distinct, as signaling through the antigen receptor complex did not cause growth inhibition and apoptosis despite high levels of TGF-β and GDF-10 that were detected in these cultures. Additionally, in response to antigen receptor complex signaling, lower amount of TNF-α was detected. These results indicate the contribution of TNF-α in the observed Ly-6A-induced growth inhibition and apoptosis and provide a mechanistic explanation for the biologically distinct responses observed in CD4+ T cells after engaging Ly-6A protein. Additionally, the findings reported here will aid in the understanding of inhibitory signaling initiated by Ly-6A protein, especially in the context of its potential immune checkpoint inhibitory role in T cells.

Abstract TP216: Suppression Of Macrophage Activation By Myelin

Introduction: In intracerebral hemorrhage, blood-derived macrophages contribute to a neurotoxic inflammatory response. The endogenous signals that are able to suppress this response are poorly understood. Macrophages likely phagocytose myelin in the CNS during intracerebral hemorrhage and uptake of myelin limits macrophage cytokine production in response to LPS. The components of myelin responsible for its suppressive effects are not well understood, although cholesterol is a likely candidate. Additionally, the broader effects of myelin on macrophage phenotype have not been investigated. Methods and Results: Murine bone marrow-derived macrophages were treated with cholesterol before stimulation with S100A9 or LPS. The inflammatory response was measured by production of TNF, IL-6, CCL2, and IL-10 by ELISA. Cholesterol limited inflammatory cytokine production in response to LPS but not to S100A9. The LXR antagonist GSK2033 partially blocked the suppressive effects of cholesterol but activation of LXR with T0901317 was not sufficient to suppress cytokine production. An RNA-Seq screen was performed to examine broader effects of myelin and cholesterol uptake. BMDMs were pretreated with cholesterol, myelin, or the LXR agonist T0901317 before stimulation with S100A9, LPS, TNF, IFNg, IL-4, IL-10, TGFb, Poly(I:C), or Pam3CSK4. Myelin suppressed responses to all of these stimulations, as did T0901317 but to a lesser extent. Cholesterol suppressed the macrophage response to LPS but not the other stimulations. Conclusions: Myelin broadly limits macrophage responses to pro-inflammatory signals. Cholesterol alone limits the response to LPS, partially through activation of LXR, but LXR-independent mechanisms appear to be involved as well. Cholesterol does not limit the response to other stimulations, suggesting that other components of myelin or activation of phagocytic receptors contribute to suppression of the macrophage response.

Correlation of high serum interleukin-6 with clinical outcome and T cell response in patients with unresectable hepatocellular carcinoma treated with atezolizumab and bevacizumab.

596 Background: We elucidated the clinical and immunologic implications of serum interleukin (IL)-6 levels in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Ate/Bev). Methods: We prospectively enrolled 165 patients with unresectable HCC (Discovery cohort: 84 patients from three centers; Validation cohort: 81 patients from one center). Baseline blood samples were analyzed using a flow cytometric bead array. The tumor immune microenvironment was analyzed using RNA sequencing. Results: In the Discovery cohort, clinical benefit (CB) was defined as a complete or partial response or stable disease for ≥ 6 months. Among various blood-based biomarkers, the serum IL-6 level was significantly higher in patients without CB than in those with CB (mean 11.56 vs. 5.05 pg/mL, P=0.02). The optimal cutoff value for high IL-6 was determined as 18.49 pg/mL using maximally selected rank statistics, and 15.2% of patients were identified to have high IL-6 levels at baseline. In both the Discovery and Validation cohorts, patients with high baseline IL-6 levels had a reduced response rate and worse progression-free and overall survival after Ate/Bev compared with that of patients with low IL-6 levels. In the multivariable Cox regression analysis, the clinical implication of high IL-6 levels persisted even after adjustment for various confounding factors. Patients with high IL-6 levels showed reduced interferon-γ and tumor necrosis factor-α secretion from CD8+ T cells. Moreover, excess IL-6 suppressed cytokine production and CD8+ T-cell proliferation. Finally, patients with high IL-6 levels exhibited a non-T-cell-inflamed immunosuppressive tumor microenvironment. Conclusions: High baseline IL-6 levels can be associated with poor clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment.

T Cell Energy Metabolism Is a Target of Glucocorticoids in Mice, Healthy Humans, and MS Patients.

Glucocorticoids (GCs) are used to treat inflammatory disorders such as multiple sclerosis (MS) by exerting prominent activities in T cells including apoptosis induction and suppression of cytokine production. However, little is known about their impact on energy metabolism, although it is widely accepted that this process is a critical rheostat of T cell activity. We thus tested the hypothesis that GCs control genes and processes involved in nutrient transport and glycolysis. Our experiments revealed that escalating doses of dexamethasone (Dex) repressed energy metabolism in murine and human primary T cells. This effect was mediated by the GC receptor and unrelated to both apoptosis induction and Stat1 activity. In contrast, treatment of human T cells with rapamycin abolished the repression of metabolic gene expression by Dex, unveiling mTOR as a critical target of GC action. A similar phenomenon was observed in MS patients after intravenous methylprednisolon (IVMP) pulse therapy. The expression of metabolic genes was reduced in the peripheral blood T cells of most patients 24 h after GC treatment, an effect that correlated with disease activity. Collectively, our results establish the regulation of T cell energy metabolism by GCs as a new immunomodulatory principle.

High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma

We elucidated the clinical and immunologic implications of serum IL-6 levels in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Ate/Bev). We prospectively enrolled 165 patients with unresectable HCC (discovery cohort: 84 patients from three centres; validation cohort: 81 patients from one centre). Baseline blood samples were analysed using a flow cytometric bead array. The tumour immune microenvironment was analysed using RNA sequencing. In the discovery cohort, clinical benefit 6 months (CB6m) was defined as complete or partial response, or stable disease for ≥6 months. Among various blood-based biomarkers, serum IL-6 levels were significantly higher in participants without CB6m than in those with CB6m (mean 11.56 vs. 5.05pg/ml, p= 0.02). Using maximally selected rank statistics, the optimal cut-off value for high IL-6 was determined as 18.49pg/ml, and 15.2% of participants were found to have high IL-6 levels at baseline. In both the discovery and validation cohorts, participants with high baseline IL-6 levels had a reduced response rate and worse progression-free and overall survival after Ate/Bev treatment compared with those with low baseline IL-6 levels. In multivariable Cox regression analysis, the clinical implications of high IL-6 levels persisted, even after adjusting for various confounding factors. Participants with high IL-6 levels showed reduced interferon-γ and tumour necrosis factor-α secretion from CD8+ T cells. Moreover, excess IL-6 suppressed cytokine production and proliferation of CD8+ T cells. Finally, participants with high IL-6 levels exhibited a non-T-cell-inflamed immunosuppressive tumour microenvironment. High baseline IL-6 levels can be associated with poor clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment. Although patients with hepatocellular carcinoma who respond to treatment with atezolizumab and bevacizumab exhibit favourable clinical outcomes, a fraction of these still experience primary resistance. We found that high baseline serum levels of IL-6 correlate with poor clinical outcomes and impaired T-cell response in patients with hepatocellular carcinoma treated with atezolizumab and bevacizumab.

Pharmacokinetic/Pharmacodynamic Modeling of Dexamethasone Anti-Inflammatory and Immunomodulatory Effects in LPS-Challenged Rats: A Model for Cytokine Release Syndrome.

Dexamethasone (DEX) is a potent synthetic glucocorticoid used for the treatment of variety of inflammatory and immune-mediated disorders. The RECOVERY clinical trial revealed benefits of DEX therapy in COVID-19 patients. Severe SARS-CoV-2 infection leads to an excessive inflammatory reaction commonly known as a cytokine release syndrome that is associated with activation of the toll like receptor 4 (TLR4) signaling pathway. The possible mechanism of action of DEX in the treatment of COVID-19 is related to its anti-inflammatory activity arising from inhibition of cytokine production but may be also attributed to its influence on immune cell trafficking and turnover. This study, by means of pharmacokinetic/pharmacodynamic modeling, aimed at the comprehensive quantitative assessment of DEX effects in lipopolysaccharide-challenged rats and to describe interrelations among relevant signaling molecules in this animal model of cytokine release syndrome induced by activation of TLR4 pathway. DEX was administered in a range of doses from 0.005 to 2.25 mg·kg-1 in LPS-challenged rats. Serum DEX, corticosterone (CST), tumor necrosis factor α, interleukin-6, and nitric oxide as well as lymphocyte and granulocyte counts in peripheral blood were quantified at different time points. A minimal physiologically based pharmacokinetic/pharmacodynamic (mPBPK/PD) model was proposed characterizing the time courses of plasma DEX and the investigated biomarkers. A high but not complete inhibition of production of inflammatory mediators and CST was produced in vivo by DEX. The mPBPK/PD model, upon translation to humans, may help to optimize DEX therapy in patients with diseases associated with excessive production of inflammatory mediators, such as COVID-19. SIGNIFICANCE STATEMENT: A mPBPK/PD model was developed to describe concentration-time profiles of plasma DEX, mediators of inflammation, and immune cell trafficking and turnover in LPS-challenged rats. Interrelations among DEX and relevant biomarkers were reflected in the mechanistic model structure. The mPBPK/PD model enabled quantitative assessment of in vivo potency of DEX and, upon translation to humans, may help optimize dosing regimens of DEX for the treatment of immune-related conditions associated with exaggerated immune response.

2-carba-cyclic phosphatidic acid modulates astrocyte-to-microglia communication and influences microglial polarization towards an anti-inflammatory phenotype

2-carba-cyclic phosphatidic acid (2ccPA) suppresses microglial and astrocyte inflammation for neuronal survival following traumatic brain injury. However, it remains unknown how 2ccPA regulates microglial activation. In this study, to elucidate the 2ccPA behavior in glial communication, we collected the astrocyte conditioned media (ACM) from primary astrocyte cultures that were treated by lipopolysaccharide (LPS) and 2ccPA and analyzed the alteration of microglial inflammation caused by the ACM treatment. The addition of the ACM derived from LPS- and 2ccPA-double treated astrocytes to microglia decreased the CD86+ pro-inflammatory M1 microglia, which were upregulated with the ACM collected from astrocytes treated by LPS without 2ccPA, while the direct addition of LPS and 2ccPA to microglia failed to decrease the CD86+ microglia to the basal level. We confirmed that the ACM from LPS- and 2ccPA-treated astrocytes increased the ratio of CD206+ anti-inflammatory M2 microglia to total microglia, whereas direct treatment of microglia with LPS and 2ccPA had no effect on the CD206+ microglia ratio, demonstrating the importance of astrocyte intervention in microglial polarization. In addition, we examined whether astrocytes modulate the 2ccPA-regulated proinflammatory cytokine production derived from microglia. The addition of the ACM from LPS- and 2ccPA-treated astrocytes to microglia remarkably canceled the LPS-induced upregulation of IL-1β, IL-6, and TNF-α secreted from microglia, while the direct addition of LPS and 2ccPA to microglia showed no affect. Therefore, our results indicate that astrocytes mediate the 2ccPA function to shift microglia towards the M2 phenotype by interfering with the polarization of M1 microglia and to suppress cytokine production.

Recent Advancement and Novel Application of Natural Polyphenols for the Treatment of Allergy Asthma: From Phytochemistry to Biological Implications.

Allergic diseases, primarily IgE-mediated, exert a substantial global health burden. A pivotal role in allergic reactions is played by mast cells, with histamine serving as a central mediator. Within this context, plant-based polyphenols, abundantly present in vegetables and fruits, show promising potential for allergy prevention. These natural compounds, particularly flavonoids, possess anti-inflammatory and anti-allergic properties, influencing dendritic cells, modulating macrophages, and fostering the proliferation of B cells and T cells. The potent anti-allergic effects of flavonoids are attributed to their ability to reduce the production of signaling factors, suppress cytokine production, and regulate signal transduction and gene expression in mast cells, basophils, and T cells. Notably, their benefits extend beyond allergy prevention, as they hold promise in the prevention and treatment of autoimmune illnesses such as diabetes, rheumatoid arthritis, and multiple sclerosis. In the context of allergic reactions and autoimmune diseases, polyphenols exhibit immunomodulatory effects by inhibiting autoimmune T cell proliferation and downregulating pro-inflammatory cytokines. In recent times, flavonoids, being the most prevalent polyphenols in food, have garnered significant attention from researchers due to their potential health advantages. This review compiles the latest scientific research to highlight the impact of flavonoids on allergic illnesses and their potential as a beneficial dietary component.

Neudesin, A Secretory Protein, Suppresses Cytokine Production in Bone Marrow-Derived Dendritic Cells Stimulated by Lipopolysaccharide

Neudesin, A Secretory Protein, Suppresses Cytokine Production in Bone Marrow-Derived Dendritic Cells Stimulated by Lipopolysaccharide

Immunomodulatory Effects of Modified Bovine Colostrum, Whey, and Their Combination with Other Natural Products: Effects on Human Peripheral Blood Mononuclear Cells

Many natural products have immunomodulatory properties. However, the mechanism of immunomodulatory activities are poorly understood. This study evaluated the influence of bovine colostrum products, a whey product, or their combinations with other natural products on human peripheral blood mononuclear cells' (PBMC) ability to produce cytokines upon activation. PBMCs were pretreated with ultrafiltered colostrum, nano-filtered bovine colostrum, egg yolk extract, a botanical blend, colostrum + egg yolk extract, colostrum + egg yolk + botanical blend, and fermented whey and then stimulated with lipopolysaccharide or phytohemagglutinin. Cytokine production was measured by the Luminex assay. All study products demonstrated immunomodulatory properties by regulating cytokines production by activated PBMCs. Ultrafiltered colostrum alone displayed the highest immune stimulatory activity. It stimulated proinflammatory cytokine production by lipopolysaccharide-activated PBMCs and suppressed cytokine production by phytohemagglutinin-activated cells. Other study products mainly suppressed cytokine release by both cell types. The immunomodulatory properties depended upon the dose of the products used in the study. All tested products modulated innate and adaptive immune cell activities. Most of the products demonstrated anti-inflammatory properties, except ultrafiltered colostrum, which stimulated the lipopolysaccharide-activated PBMC production of inflammatory cytokines. These products can be potentially used to support overall immune health.

RAMP1 signaling attenuates acute lung injury by inhibiting cytokine production and neutrophil recruitment.

RAMP1 signaling attenuates acute lung injury by inhibiting cytokine production and neutrophil recruitment.

Hybrid molecules based on an emodin scaffold. Synthesis and activity against SARS-CoV-2 and Plasmodium.

Since the Covid-19 epidemic, it has been clear that the availability of small and affordable drugs that are able to efficiently control viral infections in humans is still a challenge in medicinal chemistry. The synthesis and biological activities of a series of hybrid molecules that combine an emodin moiety and other structural moieties expected to act as possible synergistic pharmacophores in a single molecule were studied. Emodin has been reported to block the entry of the SARS-CoV-2 virus into human cells and might also inhibit cytokine production, resulting in the reduction of pulmonary injury induced by SARS-CoV-2. The pharmacophore associated with emodin was either a polyamine residue (emodin-PA series), a choice driven by the fact that a natural alkyl PA like spermine and spermidine play regulatory roles in immune cell functions, or a diphenylmethylpiperazine derivative of the norchlorcyclizine series (emoxyzine series). In fact, diphenylmethylpiperazine antagonists of the H1 histamine receptor display activity against several viruses by multiple interrelated mechanisms. In the emoxyzine series, the most potent drug against SARS-CoV-2 was (R)-emoxyzine-2, with an EC50 value = 1.9 μM, which is in the same range as that of the reference drug remdesivir. However, the selectivity index was rather low, indicating that the dissociation of antiviral potency and cytotoxicity remains a challenge. In addition, since emodin was also reported to be a relatively high-affinity inhibitor of the virulence regulator FIKK kinase from the malaria parasite Plasmodium vivax, the antimalarial activity of the synthesized hybrid compounds has been evaluated. However, these molecules cannot efficiently compete with the currently used antimalarial drugs.

Ropinirole inhibits inflammatory cytokine production in gingival epithelial cells and suppresses alveolar bone loss in an experimental rat model of periodontitis.

The present study explored whether the dopamine 2-like receptor agonist, ropinirole, a drug used for treating Parkinson's disease, suppresses neutrophilic inflammation and alveolar bone loss in an experimental rat model of periodontitis. Periodontitis is a neutrophilic inflammatory disease caused by periodontal pathogens. An excessive T helper (Th)17 immune response is involved in the progression of periodontitis, and interleukin (IL)-17 promotes the exacerbation of inflammation and alveolar bone destruction. Recent evidence has suggested that dopamine signaling plays a key role in Th17 cell differentiation, and that dopamine 2-like receptor agonists suppress cytokine production from Th17 cells. We previously demonstrated that tannic acid, which is a dopamine 2-like receptor agonist, inhibits alveolar bone resorption in an experimental model of periodontitis. The present study used a carrageenan-induced rat model of periodontitis with or without ropinirole. Micro-computed tomography analysis was performed. Cells of the murine gingival epithelial cell line GE1 were stimulated with carrageenan and IL-17A in the presence or absence of ropinirole. The anti-inflammatory effect of ropinirole was analyzed using reverse transcription- quantitative PCR and enzyme-linked immunosorbent assay. Subsequently, in the carrageenan-induced rat model of periodontitis, alveolar bone resorption was observed in the maxillary second molar by micro-computed tomography analysis. Intriguingly, ropinirole suppressed the alveolar bone destruction. The expression levels of C-X-C motif chemokine ligand 1 (CXCL1) and IL-17 receptor A (IL-17RA) in GE1 cells were increased by carrageenan, and CXCL1 expression in GE1 cells was upregulated under IL-17A stimulation. Moreover, ropinirole inhibited CXCL1 and IL-17RA expression in GE1 cells in the presence of IL-17A and carrageenan. Finally, haloperidol promoted CXCL1 expression in GE1 cells in the presence of carrageenan. Overall, these findings suggested that ropinirole suppressed neutrophilic inflammation and alveolar bone destruction in periodontitis by inhibiting CXCL1 expression in gingival epithelial cells through the dopamine 2-like receptor. Thus, ropinirole shows promise as a drug for the treatment of periodontitis.

Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.

Expression of PD-L1 in Lung Carcinoma and Its Correlation with Histopathological Grade, Stage, and Survival of Patients.

Objective PD-L1, a 40 kDa type 1 transmembrane protein, suppresses the adaptive arm of the immune system. The interaction of PD-1 with the ligand PD-L1 inhibits cytokine production and plays a role in the progression of lung cancer. The present study was performed to observe the expression of PD-L1 in lung carcinoma patients and its correlation with histopathological grade, stage, and survival of patients. Materials and Methods This prospective study included all new cases of lung carcinoma diagnosed on histopathological or cytopathological examination over a period of 1 year. PD-L1 immunoexpression was statistically analyzed and graded according to the Tumor Proportion Score in all cases and correlated with histopathological grade, stage, and survival of patients. Results This study included 56 cases of lung carcinoma with 64.2% cases showing PD-L1 positivity, out of which 44.6% were non-small cell and 19.6% were small cell lung carcinoma. In all, 32.1% cases with lymphovascular invasion, 53.5% with necrosis, and 37.5% cases with greater than 5/10 HPF mitotic figures showed positive PD-L1 expression. Paired cell blocks and histopathology showed 70% concordance for PD-L1 expression. 16.1% cT3N1M0 cases and 25% stage IIIA cases showed PD-L1 positivity. In all, 60.7% patients with positive PD-L1 expression did not survive for 12 months following diagnosis. Conclusion PD-L1 immunoexpression was increased in lung carcinoma cases and was associated with poor histomorphological features including lymphovascular invasion, necrosis, and increased mitotic activity. PD-L1 correlated with cases having decreased 12-month survival and stage IIIA carcinoma. Thus, it may be useful in the stratification of patients who benefit from the PD-L1 targeted therapy.

Design, synthesis, and bioactivity evaluation of novel 1-(4-(benzylsulfonyl)-2-nitrophenyl) derivatives as potential anti-inflammatory agents against LPS-induced acute lung injury

Acute lung injury (ALI) is a devastating disease with a high mortality rate of 30%–40%. There is an unmet clinical need owing to limited treatment strategies and little clinical benefit. The pathology of ALI indicates that reducing the inflammatory response could be a highly desirable strategy to treat ALI. In this study, we designed and synthesized 36 novel 1-(4-(benzylsulfonyl)-2-nitrophenyl) derivatives and evaluated their anti-inflammatory activities by measuring the release of cytokines in lipopolysaccharide (LPS)-challenged J774A.1 cells. Compounds 19, 20, and 39 potently reduced the release of IL-6 and TNF-α in J774A.1 cells. Additionally, 39 improved LPS-induced ALI in vivo and inhibited cytokine production in lung tissues. Furthermore, 39 reduced inflammatory infiltration and downregulated p-p65 levels in lung tissues. Thus, compound 39 could serve as a new lead structure for the development of anti-inflammatory drugs to treat ALI.