scholarly journals Natural small molecule FMHM inhibits lipopolysaccharide-induced inflammatory response by promoting TRAF6 degradation via K48-linked polyubiquitination

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Ke-Wu Zeng ◽  
Li-Xi Liao ◽  
Hai-Ning Lv ◽  
Fang-Jiao Song ◽  
Qian Yu ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Small Molecule

scholarly journals INH14, a Small-Molecule Urea Derivative, Inhibits the IKKα/β-Dependent TLR Inflammatory Response

ChemBioChem ◽  
2019 ◽  
Vol 20 (5) ◽  
pp. 710-717 ◽  
Author(s):  
Meinrad Drexel ◽  
Johannes Kirchmair ◽  
Sandra Santos-Sierra
Keyword(s):  
Inflammatory Response ◽  
Small Molecule ◽  
Urea Derivative

Small-molecule selectin inhibitor protects against liver inflammatory response after ischemia and reperfusion

1997 ◽  
Vol 185 (4) ◽  
pp. 365-372 ◽  
Author(s):  
J PALMAVARGAS ◽  
L TOLEDOPEREYRA ◽  
R DEAN ◽  
J HARKEMA ◽  
R DIXON ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Small Molecule ◽  
Ischemia And Reperfusion

ALDH1A1 Dysfunction in FA-Deficient Macrophages Contributes to Aberrant Activation of the Innate Immune Response

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4107-4107 ◽  
Author(s):  
Michael R Garbati ◽  
R. K. Rathbun ◽  
Jane E. Yates ◽  
Wenjin Yang ◽  
Grover C. Bagby
Keyword(s):  
Stem Cell ◽  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Small Molecule ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Macrophage Phenotype ◽  
Aldh Activity ◽  
Hematopoietic Stem ◽  
Normal Production

Abstract Recent work has clarified a role for aldehyde dehydrogenases in protecting Fanconi anemia (FA) hematopoietic stem cells (HSC) and indicates that the increase in endogenous aldehydes that attends the genetic loss of ALDH function is sufficient to induce bone marrow failure in this disease. Studies in many laboratories have also documented that: (1) exposure of FA HSC to inflammatory cytokines suppresses stem cell self-replication and, in vivo, exhausts the stem cell pool and (2) FA macrophages exposed to specific toll-like receptor (TLR) ligands overproduce the very inflammatory cytokines that suppress the HSC pool. Given that aldehydes form adducts with and, in some cases, activate signaling proteins involved in cytokine production, we tested the hypothesis that overproduction of inflammatory cytokines by FA macrophages results from a loss of FA protein-dependent ALDH function. We treated THP-1 human monocytic leukemia cells expressing shRNA targeting FANCC (T-shFC) or a non-targeted shRNA (T-shNT) with the aldehyde 4-hydroxynonenal (4-HNE) before exposing them to the TLR-7/8 agonist R848. 4-HNE alone did not induce TNF production in either cell line but did enhance TLR-induced TNF overproduction by T-shFC cells (but not T-shNT cells), suggesting that FANCC-deficient macrophages lack factors (e.g., ALDH) that neutralize a signal-enhancing effect of this aldehyde. To directly test the effects of ALDH loss, we pretreated cells with the general ALDH inhibitor diethylaminobenzaldehyde and found that this agent enhanced R848-induced normal production of TNF by approximately 1.6-fold in control cells but did not enhance TNF production in T-shFC cells that were already overproducing TNF. Having determined that ALDH1A1 (but not ALDH2) was highly inducible in both THP-1 cells (by R848) and Lin-Sca-1+Kit+ (by TNF) murine marrow cells, we used siRNA to suppress expression of ALDH2 or ALDH1A1. Knockdown of ALDH1A1 (but not ALDH2) enhanced R848-induced normal production of TNF by approximately 1.8-fold in T-shNT but not TNF overproduction in T-shFC (fig 1) or T-shFA (FANCA knockdown) cells. Our results are consistent with the notion that ALDH1A1 is non-functional in FANCC-deficient macrophages and we confirmed that suspicion in gain-of-function analyses. Specifically, treatment of T-shNT and T-shFC cells with Alda-1 (a small molecule ALDH agonist known to enhance the activity of both ALDH1A1 and ALDH2) suppressed TLR-induced TNF production (fig 2), even in the presence of 4-HNE, by both T-shNT and T-shFC cells. In summary, (1) increasing the aldehyde load in normal macrophages has little influences on the inflammatory response induced by TLR activation but in FANCC-deficient cells aldehydes exacerbate the inflammatory response, (2) suppression of ALDH function with DEAB and specific suppression of ALDH1A1, (but not ALDH2) induces an FA-like phenotype in control macrophages, and (3) pharmacological enhancement of ALDH activity suppresses induced cytokine overproduction by FANCC-deficient macrophages. We conclude that: (1) optimal function of ALDH1A1 is FANCC-dependent in normal macrophages, (2) that the TLR-dependent overproduction of inflammatory cytokines by FANCC-deficient macrophages may result either from an increase in the aldehyde load or the loss of a non-canonical signal-suppressive function of ALDH1A1, and (3) enhancement of ALDH activity using small molecule agonists such as Alda-1 may alleviate the FA macrophage phenotype and may thereby protect HSC from inflammation-induced exhaustion. Disclosures No relevant conflicts of interest to declare.

scholarly journals MD-2 as the target of a novel small molecule, L6H21, in the attenuation of LPS-induced inflammatory response and sepsis

2015 ◽  
Vol 172 (17) ◽  
pp. 4391-4405 ◽  
Author(s):  
Yi Wang ◽  
Xiaoou Shan ◽  
Gaozhi Chen ◽  
Lili Jiang ◽  
Zhe Wang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Small Molecule

scholarly journals Anti-SARS-CoV-2 IgG from severely ill COVID-19 patients promotes macrophage hyper-inflammatory responses

2020 ◽  
Author(s):  
Willianne Hoepel ◽  
Hung-Jen Chen ◽  
Sona Allahverdiyeva ◽  
Xue Manz ◽  
Jurjan Aman ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Adaptive Immunity ◽  
Small Molecule ◽  
Active Component ◽  
Inflammatory Responses ◽  
Endothelial Barrier ◽  
Barrier Integrity ◽  
Human Macrophages ◽  
Molecule Inhibitor

AbstractFor yet unknown reasons, severely ill COVID-19 patients often become critically ill around the time of activation of adaptive immunity. Here, we show that anti-Spike IgG from serum of severely ill COVID-19 patients induces a hyper-inflammatory response by human macrophages, which subsequently breaks pulmonary endothelial barrier integrity and induces microvascular thrombosis. The excessive inflammatory capacity of this anti-Spike IgG is related to glycosylation changes in the IgG Fc tail. Moreover, the hyper-inflammatory response induced by anti-Spike IgG can be specifically counteracted in vitro by use of the active component of fostamatinib, an FDA- and EMA-approved therapeutic small molecule inhibitor of Syk.One sentence summaryAnti-Spike IgG promotes hyper-inflammation.

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