A novel chrysin thiazole derivative polarizes macrophages to an M1 phenotype via targeting TLR4

2020 ◽  
Vol 88 ◽  
pp. 106986
Author(s):  
Xiujing Feng ◽  
Wen Yu ◽  
Lingsen Cao ◽  
Fanda Meng ◽  
Mulin Cong
Keyword(s):  
Thiazole Derivative ◽  
M1 Phenotype

A Thiazole Compound with Potential Antithrombotic Activity

1982 ◽  
Vol 47 (02) ◽  
pp. 173-176 ◽  
Author(s):  
E E Nishizawa ◽  
A R Mendoza ◽  
T Honohan ◽  
K A Annis
Keyword(s):  
Platelet Aggregation ◽  
Potent Inhibitor ◽  
Platelet Rich Plasma ◽  
Development Program ◽  
Antithrombotic Agent ◽  
Antithrombotic Activity ◽  
Thiazole Derivative ◽  
Cyclooxygenase Activity ◽  
Drug Development Program

SummaryA thiazole derivative, 4,5-bis(p-methoxyphenyl)-2-(trifluoromethyl)-thiazole was found to be a potent inhibitor of collagen-induced platelet aggregation, in vitro, using platelets from at least six species, including man. It was active in human platelet-rich plasma at a concentration of 1 ng/ml. While its antiplatelet activity was greater than that of flurbiprofen, its cyclooxygenase activity was equivalent to that of flurbiprofen. Also, compared to flurbiprofen, the thiazole had less anti-inflammatory activity in the hind-paw edema test. The thiazole derivative inhibited platelet aggregation following oral administration in five laboratory species. In the guinea pig it was active at 0.5 mg/kg. The LD50 in mice was greater than 1000 mg/kg (i.p.). This compound, which was designed through a systematic drug development program, may have high potential as an antithrombotic agent.

128 Development of an M1-polarized, non-viral chimeric antigen receptor macrophage (CAR-M) platform for cancer immunotherapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A141-A141
Author(s):  
Yumi Ohtani ◽  
Kayleigh Ross ◽  
Aditya Dandekar ◽  
Rashid Gabbasov ◽  
Michael Klichinsky
Keyword(s):  
Cancer Immunotherapy ◽  
Chimeric Antigen Receptor ◽  
Scale Up ◽  
Antigen Receptor ◽  
Innate Immune ◽  
List Type ◽  
M1 Phenotype ◽  
The Impact ◽  
Anti Tumor Activity ◽  
Immunosuppressive Factors

BackgroundWe have previously developed CAR-M as a novel cell therapy approach for the treatment of solid tumors.1 CAR-M have the potential to overcome key challenges that cell therapies face in the solid tumor setting – tumor infiltration, immunosuppression, lymphocyte exclusion – and can induce epitope spreading to overcome target antigen heterogeneity. While macrophages transduced with the adenoviral vector Ad5f35 (Ad CAR-M) traffic to tumors, provide robust anti-tumor activity, and recruit and activate T cells, we sought to identify a robust non-viral method of macrophage engineering in order to reduce the cost of goods, manufacturing complexity, and potential immunogenicity associated with viral vectors.MethodsAs innate immune cells, macrophages detect exogenous nucleic acids and respond with inflammatory and apoptotic programs. Thus, we sought to identify a means of mRNA delivery that avoids recognition by innate immune sensors. We screened a broad panel of mRNA encoding an anti-HER2 CAR comprising multiplexed 5’Cap and base modifications using an optimized and scalable electroporation approach and evaluated the impact of interferon-β priming on CAR-M phenotype and function.ResultsWe identified the optimal multiplexed mRNA modifications that led to maximal macrophage viability, transfection efficiency, intensity of CAR expression, and duration of expression. Non-viral HER2 CAR-M phagocytosed and killed human HER2+ tumor cells. Unlike Ad CAR-M, mRNA CAR-M were not skewed toward an M1 state by mRNA electroporation. Priming non-viral CAR-M with IFN-β induced a durable M1 phenotype, as shown by stable upregulation of numerous M1 markers and pathways. IFN-β priming significantly enhanced the anti-tumor activity of CAR but not control macrophages. IFN-β primed mRNA CAR-M were resistant to M2 conversion, maintaining an M1 phenotype despite challenge with various immunosuppressive factors, and converted bystander M2 macrophages toward M1. Interestingly, priming mRNA CAR-M with IFN-β significantly enhanced the persistence of CAR expression, overcoming the known issue of rapid mRNA turnover. RNA-seq analysis revealed that IFN-β priming affected pathways involved in increasing translation and decreasing RNA degradation in human macrophages.ConclusionsWe have established a novel, optimized non-viral CAR-M platform based on chemically modified mRNA and IFN-β priming. IFN-β priming induced a durable M1 phenotype, improved CAR expression, improved CAR persistence, led to enhanced anti-tumor function, and rendered resistance to immunosuppressive factors. This novel platform is amenable to scale-up, GMP manufacturing, and represents an advance in the development of CAR-M.ReferenceKlichinsky M, Ruella M, Shestova O, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat Biotechnol 2020;38(8):947–953.

Microwave assisted synthesis of novel imidazo [2,1-b]thiazole derivative attached to quinoxalinones

2012 ◽  
Vol 53 (45) ◽  
pp. 6008-6014 ◽  
Author(s):  
Chandrani Mukherjee ◽  
Kenneth T. Watanabe ◽  
Edward R. Biehl
Keyword(s):  
Microwave Assisted Synthesis ◽  
Thiazole Derivative ◽  
Microwave Assisted

scholarly journals TNF and Increased Intracellular Iron Alter Macrophage Polarization to a Detrimental M1 Phenotype in the Injured Spinal Cord

Neuron ◽  
2014 ◽  
Vol 83 (5) ◽  
pp. 1098-1116 ◽  
Author(s):  
Antje Kroner ◽  
Andrew D. Greenhalgh ◽  
Juan G. Zarruk ◽  
Rosmarini Passos dos Santos ◽  
Matthias Gaestel ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Macrophage Polarization ◽  
Injured Spinal Cord ◽  
Intracellular Iron ◽  
M1 Phenotype

scholarly journals Phenylmethimazole and a thiazole derivative of phenylmethimazole inhibit IL-6 expression by triple negative breast cancer cells

2017 ◽  
Vol 803 ◽  
pp. 130-137 ◽  
Author(s):  
Mahboubeh S. Noori ◽  
John D. O’Brien ◽  
Zachary J. Champa ◽  
Sudhir P. Deosarkar ◽  
Olivia L. Lanier ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Thiazole Derivative

Abstract 520: High-density Lipoprotein Inhibits Human M1 Macrophage Polarisation through the Redistribution of Caveolin-1

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Man K Lee ◽  
Xiao-Lei Moore ◽  
Yi Fu ◽  
Annas Al-sharea ◽  
Dragana Dragoljeic ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cholesterol Efflux ◽  
Human Macrophage ◽  
Ros Production ◽  
Oxygen Species ◽  
M1 Macrophages ◽  
Macrophage Polarisation ◽  
Caveolin 1 ◽  
M1 Phenotype ◽  
M2 Phenotype

Macrophages play a critical role in the development and progression of atherosclerosis. Depending on their surrounding milieu, macrophages can adopt a wide range of functional phenotypes; pro-inflammatory (M1) and pro-resolving (M2). HDL has many cardio-protective properties including potent anti-inflammatory effects, largely through the removal of cholesterol from cells. It is currently not known if this extends to influencing human macrophage phenotypes. Thus, we aimed to investigate the effect of HDL on human macrophage polarisation. Human blood monocyte-derived macrophages were induced to either an M1-phenotype by incubation with LPS and IFN-γ or to an M2-phenotype with IL-4. Macrophages were differentiated in the presence or absence of human HDL and their phenotypes were characterised using cell surface markers, reactive oxygen species (ROS) production by flow cytometry, and mRNA expression by real-time PCR. Downstream signalling pathways were also explored. We discovered that HDL inhibited the induction to M1 as evidenced by a decrease in cell surface marker expression; CD192 and CD64. This was accompanied by a decreased expression of M1-associated inflammatory genes TNF-α, IL-6 and MCP-1. However, HDL had no effect on induction to the M2 phenotype. Similarly, methyl-beta-cyclodextrin (MβCD), a non-specific cholesterol acceptor was also able to suppress M1 induction suggesting cholesterol efflux is important in this process. Further we found that HDL decreased membrane caveolin-1 in M1 macrophages and redistributed it intracellularly. The requirement of caveolin-1 was revealed as bone marrow-derived macrophages from Cav-1-/- mice continued to differentiate into M1 despite the addition of HDL. Moreover, we demonstrated a decrease in STAT3 and ERK1/2 phosphorylation in M1 macrophages treated with HDL, suggesting cholesterol efflux inhibits the STAT3s and MAPKs during induction to the M1 phenotype. Finally, we found that HDL also inhibited M1 function; with reduced reactive oxygen species (ROS) production. We provide evidence that HDL reduces macrophage induction to the inflammatory M1 phenotype, but not M2, via cellular redistribution of caveolin-1 and inactivation of STAT3 and ERK1/2 signalling pathway.

Abstract T P80: Inhibition of Ezh2 Leads to Decreased M1 and Enhanced M2 Microglia Phenotypes

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Edward Koellhoffer ◽  
Jeremy Grenier ◽  
Rodney Ritzel ◽  
Louise McCullough
Keyword(s):  
Ischemic Stroke ◽  
Pcr Analysis ◽  
M2 Polarization ◽  
M2 Microglia ◽  
M1 Polarization ◽  
Glial Cultures ◽  
M2 Response ◽  
M1 Phenotype ◽  
Cayman Chemical ◽  
M2 Phenotype

Background: Ischemic stroke results in the activation of microglia, which may polarize toward a pro-inflammatory (M1) phenotype or an anti-inflammatory, neuroprotective (M2) phenotype. Thus, simultaneously suppressing the M1 response and promoting the M2 response could be beneficial in the treatment of stroke. Recently, the epigenetic modulator Jmjd3 has been shown to be essential for M2 polarization. However, Jmjd3 is antagonized by Ezh2 which is associated with M1 polarization. Thus, we hypothesized that inhibition of Ezh2 tilts the balance between Jmjd3 and Ezh2, thereby enhancing polarization toward an M2 phenotype and improved outcome in ischemic stroke. Methods: Mixed glial cultures were isolated from P0.5-P2 C57BL/6J mice and cultured for 14 days before microglial isolation. Microglia were rested for 24 hours before treatment every other day with 6uM GSK343 (Cayman Chemical) or DMSO vehicle control. After 7 days, microglia were stimulated with LPS or IL-4 and RNA was isolated at 4hr and 24hr post-stimulation for qRT-PCR analysis. Results: LPS-induced IL6 and IL1B expression was significantly abrogated by 71% and 53%, respectively (p<0.05), at 24hr when Ezh2 was inhibited. Additionally, Ezh2 inhibition both increased baseline expression of M2-associated genes ARG1, CD206, and IRF4 by 196%, 257%, and 395%, respectively (p<0.05), and rescued their expression in the presence of LPS at 24hr (p<0.05) in which they were otherwise significantly down-regulated. Conclusion: Pharmacological inhibition of Ezh2 limits microglial M1 polarization and enhances M2 polarization.

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