scholarly journals A Novel Small-Molecule Inhibitor of Endosomal TLRs Reduces Inflammation and Alleviates Autoimmune Disease Symptoms in Murine Models

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1648
Author(s):  
Mahesh Chandra Patra ◽  
Asma Achek ◽  
Gi-Young Kim ◽  
Suresh Panneerselvam ◽  
Hyeon-Jun Shin ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Small Molecule ◽  
Lupus Erythematosus ◽  
Inflammatory Diseases ◽  
Poly I:C ◽  
Cpg Oligodeoxynucleotide ◽  
Molecule Inhibitor ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Factor Α

Toll-like receptors (TLRs) play a fundamental role in the inflammatory response against invading pathogens. However, the dysregulation of TLR-signaling pathways is implicated in several autoimmune/inflammatory diseases. Here, we show that a novel small molecule TLR-inhibitor (TAC5) and its derivatives TAC5-a, TAC5-c, TAC5-d, and TAC5-e predominantly antagonized poly(I:C) (TLR3)-, imiquimod (TLR7)-, TL8-506 (TLR8)-, and CpG-oligodeoxynucleotide (TLR9)-induced signaling pathways. TAC5 and TAC5-a significantly hindered the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), reduced the phosphorylation of mitogen-activated protein kinases, and inhibited the secretion of tumor necrosis factor-α (TNF-α) and interleukin-6. Besides, TAC5-a prevented the progression of psoriasis and systemic lupus erythematosus (SLE) in mice. Interestingly, TAC5 and TAC5-a did not affect Pam3CSK4 (TLR1/2)-, FSL-1 (TLR2/6)-, or lipopolysaccharide (TLR4)-induced TNF-α secretion, indicating their specificity towards endosomal TLRs (TLR3/7/8/9). Collectively, our data suggest that the TAC5 series of compounds are potential candidates for treating autoimmune diseases such as psoriasis or SLE.

scholarly journals Ononin induces cell apoptosis and reduces inflammation in rheumatoid arthritis fibroblast-like synoviocytes by alleviating MAPK and NF-κB signaling pathways

2021 ◽  
Author(s):  
Yue Meng ◽  
Jian Ji ◽  
Xiao Xiao ◽  
Minghan Li ◽  
Shangbo Niu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Signaling Pathways ◽  
Cell Apoptosis ◽  
Cell Model ◽  
Inflammatory Diseases ◽  
Mitogen Activated Protein Kinase ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Factor Α ◽  
Fibroblast Like Synoviocytes

As a kind of chronic inflammatory diseases, Rheumatoid arthritis (RA) has a low cure rate and easy recurrence. It has widely reported that abnormal activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling pathways are associated with the development of RA inflammation. Blocking the inflammatory signaling pathways of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) can delay the development of RA. Ononin is a natural isoflavone glycoside and plays a key role in modulating inflammation related signaling pathways. However, whether Ononin exerts anti-inflammatory effects on RA inflammation remains unknown. In this study, we evaluated the therapeutic effect of Ononin on RA by establishing a tumor necrosis factor α (TNF-α)-induced RA-FLS cell model. Our data confirmed that Ononin could alleviate TNF-α-induced RA-FLS and MH7A cells viability, increase cell apoptosis, decrease the production of pro-inflammatory cytokines like interleukin-1β (IL-1β) and interleukin 6 (IL-6), and further inhibit the abnormal activation of NF-κB and MAPK pathways. Our results suggested that Ononin could be a potential therapeutic agent for RA.

scholarly journals Could Polyphenols Help in the Control of Rheumatoid Arthritis?

Molecules ◽  
2019 ◽  
Vol 24 (8) ◽  
pp. 1589 ◽  
Author(s):  
Sung ◽  
Kwon ◽  
Um ◽  
Kim
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Diseases ◽  
Mitogen Activated Protein Kinase ◽  
Bone Damage ◽  
Autoimmune Inflammatory Disease ◽  
Novel Drugs ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Factor Α ◽  
Therapeutic Alternatives

Rheumatoid arthritis (RA) is a chronic, systemic, joint-invading, autoimmune inflammatory disease, which causes joint cartilage breakdown and bone damage, resulting in functional impairment and deformation of the joints. The percentage of RA patients has been rising and RA represents a substantial burden for patients around the world. Despite the development of many RA therapies, because of the side effects and low effectiveness of conventional drugs, patients still need and researchers are seeking new therapeutic alternatives. Polyphenols extracted from natural products are effective on several inflammatory diseases, including RA. In this review polyphenols are classified into four types: flavonoids, phenolic acids, stilbenes and others, among which mainly flavonoids are discussed. Researchers have reported that anti-RA efficacies of polyphenols are based mainly on three mechanisms: their anti-inflammatory, antioxidant and apoptotic properties. The main RA factors modified by polyphenols are mitogen-activated protein kinase (MAPK), interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), nuclear factor κ light chain enhancer of activated B cells (NF-κB) and c-Jun N-terminal kinases (JNK). Polyphenols could be potent alternative RA therapies and sources for novel drugs for RA by affecting its key mechanisms.

Transcriptional profiling of IKK2/NF-κB— and p38 MAP kinasedependent gene expression in TNF-α—stimulated primary human endothelial cells

Blood ◽  
2004 ◽  
Vol 103 (9) ◽  
pp. 3365-3373 ◽  
Author(s):  
Dorothee Viemann ◽  
Matthias Goebeler ◽  
Sybille Schmid ◽  
Kerstin Klimmek ◽  
Clemens Sorg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Signaling Pathways ◽  
Transcriptional Profiling ◽  
Nuclear Factor Κb ◽  
Iκb Kinase ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
A Minor ◽  
Factor Α

Abstract Inflammatory stimulation of endothelial cells by tumor necrosis factor α (TNF-α) involves activation of nuclear factor κB (NF-κB) and p38 mitogen-activated protein (MAP) kinase signaling pathways. A reliable analysis of the gene expression program elicited by TNF-α and its assignment to distinct signaling pathways is not available. A sophisticated analysis of oligonucleotide microarrays covering more than 13 000 genes allowed definition of the TNF-α-regulated endothelial gene expression profile and novel TNF-α-induced genes. Virtually all TNF-α-inducible genes were dependent on IκB kinase 2 (IKK2)/NF-κB activation, whereas a minor number was additionally modulated by p38. Furthermore, genes suppressed by IKK2/NF-κB were newly identified. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometry confirmed reliability of data. Thus, these results define a list of primary candidates for targeted modulation of endothelial functions during inflammation. (Blood. 2004;103:3365-3373)

Candida tropicalis induces pro-inflammatory cytokine production, NF-κB and MAPKs pathways regulation, and dectin-1 activation

2018 ◽  
Vol 64 (12) ◽  
pp. 937-944 ◽  
Author(s):  
Zhimin Duan ◽  
Qing Chen ◽  
Rong Zeng ◽  
Leilei Du ◽  
Caixia Liu ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Inflammatory Cytokine ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
Peripheral Blood Mononuclear ◽  
Downstream Signaling ◽  
Tnf Α ◽  
Mitogen Activated Protein

The prevalence of Candida infection induced by non-albicans Candida (NAC) species is increasing. However, as a common NAC species, C. tropicalis has received much less study in terms of host immunity than C. albicans has. In this study, we evaluated the pro-inflammatory cytokine responses evoked by C. tropicalis and determined whether dectin-1 and downstream NF-κB and mitogen-activated protein kinases (MAPKs) signaling pathways played roles in inflammation in human peripheral blood mononuclear cells (PBMCs) and THP-1 macrophage-like cells. Exposure of PBMCs and THP-1 macrophage-like cells to C. tropicalis led to the enhanced gene expression and secretion of TNF-α and IL-6 in a time- and dose-dependent manner. THP-1 macrophage-like cells being challenged by C. tropicalis resulted in the activation of the NF-κB, p38, and ERK1/2 MAPK signaling pathways. We also found that the expression of dectin-1 was increased with C. tropicalis treatment. These data reveal that dectin-1 may play a role in sensing the inflammation response induced by C. tropicalis and that NF-κB and MAPK are involved in the downstream signaling pathways in macrophages.

scholarly journals Alpha-Lipoic Acid Suppresses Extracellular Histone-Induced Release of the Infammatory Mediator Tumor Necrosis Factor-α by Macrophages

2017 ◽  
Vol 42 (6) ◽  
pp. 2559-2568 ◽  
Author(s):  
Ping Chang ◽  
Juan Liu ◽  
Ying Yu ◽  
Shao-Ye Cui ◽  
Zhen-Hui Guo ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Signaling Pathways ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Raw 264.7 ◽  
Alpha Lipoic Acid ◽  
Tnf Α ◽  
Extracellular Histones ◽  
Factor Α ◽  
Necrosis Factor

Background/Aims: This study investigated signaling pathways via which extracellular histones induce the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) release from the macrophage cell line RAW 264.7 and the anti-inflammatory efficacy of the antioxidant alpha-lipoic acid (ALA). Methods: ELISA and western blotting analyses were conducted to detect the release of TNF-α from histone-stimulated RAW 264.7 macrophages and the associated phospho-activation of MAPKs (ERK and p38) and NF-κB p65. The effects of ALA on the release of TNF-α and phospho-activation of the MAPKs and NF-κB p65 were studied. P < 0.05 was considered statistically significant. Results: Extracellular histones dose-dependently induced TNF-α release from RAW 264.7 cells and increased the phosphorylation of p38, ERK, and NF-κB p65. TNF-α release was markedly suppressed by p38, ERK, and NF-kB inhibitors. ALA reduced histone-induced TNF-α release, ERK/p38 MAPK activation, and NF-kB activation without affecting macrophage viability. Conclusion: Histones induce TNF-α release from macrophages by activating the MAPK and NF-kB signaling pathways, while ALA suppresses this response by inhibiting ERK, p38 and NF-kB. These findings identify potentially critical inflammatory signaling pathways in sepsis and molecular targets for sepsis treatment.

Abstract 035: Cholinergic Agonists Protect from the Development of Hypertension during Chronic Inflammatory Disease

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Keisa W Mathis
Keyword(s):  
Protein Expression ◽  
Lupus Erythematosus ◽  
Inflammatory Diseases ◽  
Autoimmune Disorder ◽  
Chronic Inflammatory Disease ◽  
Cholinergic Agonists ◽  
Inflammatory Pathway ◽  
Genetic Mouse Model ◽  
Tnf Α ◽  
Anti Inflammatory

Systemic lupus erythematosus (SLE) is an autoimmune disorder with prevalent hypertension. Previous studies using a genetic mouse model of SLE (NZBWF1) suggest chronic inflammation is an important contributor to SLE hypertension. A novel neuroimmune pathway involving the α7 subunit of the nicotinic acetylcholine receptor (α7nAChR) suppresses splenic cytokine release and reduces systemic inflammation upon stimulation. To test whether activation of this ‘cholinergic anti-inflammatory pathway’ at the level of the α7nAChR attenuates the development of hypertension during SLE, female SLE and control (NZW) mice were infused with nicotine hydrogen tartrate salt (2 mg/kg/day, SC) or saline for 7 days. Nicotine-treated SLE mice had lower splenic protein expression of TNF-α and IL-6 (normalized to β-actin) relative to saline-treated SLE mice (1.09±0.06 vs. 1.37±0.06 and 0.36±0.04 vs. 0.55±0.10; all p<0.05), suggesting efficacy of the therapy. Mean arterial pressure (MAP; mmHg) was increased in SLE mice compared to controls (140±4 vs. 114±2; p<0.001). Nicotine prevented the rise in MAP in SLE mice (129±4; p=0.022), but not controls (121±3). This protection from hypertension coincided with a 46±5% lower renal cortical TNF-α in nicotine-treated SLE mice compared to saline-treated SLE mice (0.39±0.04 vs. 0.73±0.18), which is important because it has been previously shown that renal TNF-α plays a mechanistic role in the development of hypertension during SLE. Because nicotine acts on both ganglionic and peripheral cholinergic receptors, in a subsequent study mice were administered the selective α7nAChR agonist, PNU-282987 (0.38 mg/kg/day, IP), or vehicle for 28 days. PNU-282987-treated SLE mice had lower splenic protein expression of TNF-α and IL-6 relative to saline-treated SLE mice (0.33±0.01 vs. 0.54±0.03 and 0.40±0.08 vs. 0.86±0.05; all p<0.05). MAP was increased in SLE mice compared to controls (138±2 vs. 122±5). PNU-282987 prevented the rise in MAP in SLE mice (128±4), but not controls (125±5). These data suggest the anti-inflammatory effects of cholinergic agonists may protect from SLE hypertension and that the cholinergic anti-inflammatory pathway may be an important target in hypertensive patients with chronic inflammatory diseases.

The Role of Oxidative Stress, Inflammation, and Advanced Glycation End Product in Skin Manifestations of Diabetes Mellitus

2021 ◽  
Vol 17 ◽  
Author(s):  
Lili Legiawati
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Adhesion Molecule ◽  
Intercellular Adhesion Molecule ◽  
Skin Disorders ◽  
Intercellular Adhesion Molecule 1 ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
High Level ◽  
Factor Α

: Diabetes mellitus is a metabolic disorder caused by an increase in insulin resistance, a decrease in insulin production, or both of them, resulting in a high level of blood glucose or hyperglycemia. An uncontrolled state of DM may cause complications, namely skin disorder. One or more skin disorders are found amongst 74% of T2DM patients, with the highest percentage is dry skin (47%), followed by infection (10%), diabetic hand (5%), hair loss and diabetic dermopathy (each 4%). In DM, the state of hyperglycemia and production of advanced glycaemic end-products (AGEs) profoundly impact skin changes. In the pathological pathway, AGEs induce oxidative stress and inflammation. Nonetheless, AGEs level is higher in T2DM patients compared to non-T2DM people. This is caused by hyperglycemia and oxidative stress. Binding between AGEs and receptor of AGEs (RAGE) promotes pathway of oxidative stress and inflammation cascade via mitogen-activated protein kinases (MAPK), nuclear factor-k-light-chain-enhancer of activated β cells (NF-kβ), interleukin- 6 (IL-6), tumor necrosis factor-α (TNF-α), expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 2 (VCAM-2) pathway which furtherly effectuates DM complication including skin disorders.

The Augmented Productions of Neopterin and Cytokines from Macrophages/monocytes in vitro

Pteridines ◽  
1996 ◽  
Vol 7 (3) ◽  
pp. 72-76
Author(s):  
Tadashi Lizuka ◽  
Mitsuyo Sasaki ◽  
Hitomi Kamisako ◽  
Ko Oishi ◽  
Shigeru Uemura ◽  
...  
Keyword(s):  
Kawasaki Disease ◽  
Interleukin 1 ◽  
Poly I:C ◽  
Recombinant Interferon ◽  
Preliminary Examination ◽  
Tnf Α ◽  
Ifn Γ ◽  
Factor Α ◽  
Necrosis Factor

Summary In Kawasaki disease patients, increases in excretion of urinary neopterin coincided with fever and monocytosis in peripheral blood. We examined the products of neopterin, tumor necrosis factor-α (TNFα) and Interleukin-1 β (1L-1β) from healthy adult macrophages/monocytes (Mφ>/M), after stimulation with several activators to obtain some understanding of Kawasaki disease. Upon stimulation with either lipopolysaccharide (LPS) or polyinosinate-polycytidylate (Poly I:C), the Mφ/M released neopterin and pyogenic products (TNF-α or 1L-1β). The release of neopterin was eliminated by the addition of the anti-interferon-y antibody. The production of both TNF-α, 1L-1β and neopterin from Mφ/M upon stimulation of LPS was augmented in a co-culture with low dose recombinant interferon-y (rIFN-γ). Upon stimulation with rIFN-γ alone, however, the Mφ/M released neopterin but not the pyogenic products. A preliminary examination failed to detect. any difference in the response of the Mφ/M in adults annd children after stimulation with LPS. We concluded that some endotoxins could trigger the onset of Kawasaki disease and that endogenous IFN-γ can play an important role in the abnormality of Kawasaki disease patients

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