Synthesis and Anti-neuroinflammatory Activity of Lactone Benzoyl Hydrazine and 2-nitro-1-phenyl-1H -Indole Derivatives as p38α MAPK Inhibitors

2015 ◽  
Vol 86 (5) ◽  
pp. 1121-1130 ◽  
Author(s):  
Bao Cheng ◽  
Yongsheng Lin ◽  
Ming Kuang ◽  
Sai Fang ◽  
Qiong Gu ◽  
...  
Keyword(s):  
Indole Derivatives ◽  
P38α Mapk ◽  
Mapk Inhibitors ◽  
Benzoyl Hydrazine

Discovery of naphthyl-N -acylhydrazone p38α MAPK inhibitors with in vivo anti-inflammatory and anti-TNF-α activity

2017 ◽  
Vol 91 (2) ◽  
pp. 391-397 ◽  
Author(s):  
Rosana H. C. N. Freitas ◽  
Natália M. Cordeiro ◽  
Patrícia R. Carvalho ◽  
Marina A. Alves ◽  
Isabella A. Guedes ◽  
...  
Keyword(s):  
Tnf Α ◽  
P38α Mapk ◽  
Anti Inflammatory ◽  
Mapk Inhibitors ◽  
Α Activity

scholarly journals LY6G6D is Epigenetically Activated in Classical Colorectal Adenocarcinoma and Hyper-Methylated in Mucinous Subtypes Determining Resistance to FOLFOX Therapeutic Regimens.

2021 ◽  
Author(s):  
Francesca Pia Caruso ◽  
Mario Rosario D'andrea ◽  
Luigi Coppola ◽  
Matteo Landriscina ◽  
Valentina Condelli ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Dna Methyltransferase ◽  
Mek Inhibitor ◽  
Proteomic Data ◽  
First Line Therapy ◽  
P38α Mapk ◽  
P38 Mapk Inhibitors ◽  
Chemical Inhibition ◽  
Mapk Inhibitors

Abstract Background: Colorectal cancer (CRC) represents a significant and ever-increasing societal threat and burden. Activation of Lymphocyte antigen 6G6D could induce anti-tumor specific immunity unique to CRC, but factors regulating its activation remain obscure.Methods: Transcriptome, epigenome and proteomic data from TCGA and independent database were investigated using in silico approaches. Expression of candidate genes was independently validated by immunohistochemistry in CRC tissues. In vitro RNA mediated gene silencing of putative regulators, treatment with MEK and p38 MAPK inhibitors and Bioinformatic prediction were carried out to unveil LY6G6D regulation.Results: LY6G6D is down-regulated in mucinous CRC regardless its anatomic location, while its activation progresses through the classical adenoma-carcinoma sequence. The lack of LY6G6D expression in mucinous CRC involves alterations of secretome-based immune responses. DNA methylation changes in LY6G6D promoter are intimately related to its transcript regulation, epigenomic and different histological subtypes. RNA-mediated gene silencing and chemical inhibition of p38α MAPK as well as DNA methyltransferase DNMT1 knock-down lead to a decrease in LY6G6D expression, supporting that p38a MAPK and DNA methylases mediated LY6G6D regulation. Cancer cells with an intact p38α MAPK stabilize LY6G6D expression allowing effective responses to trametinib, a MEK inhibitor able to exert anti-inflammatory effects. In a metastatic CRC subset, LY6G6D hypermethylation predicts resistance to FOLFOX first-line therapy, supporting the idea that its cancer-specific hypomethylation and consequent activation may be a tissue-specific mechanism of anti-tumor immunity. Conclusions: LY6G6D has the potentiality to be used as a biomarker for patient stratification and immune therapeutic intervention of mucinous versus non-mucinous CRC.

scholarly journals p38α MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse

2018 ◽  
Vol 115 (43) ◽  
pp. E10245-E10254 ◽  
Author(s):  
Matthew J. Robson ◽  
Meagan A. Quinlan ◽  
Kara Gross Margolis ◽  
Paula A. Gajewski-Kurdziel ◽  
Jeremy Veenstra-VanderWeele ◽  
...  
Keyword(s):  
Social Interactions ◽  
P38 Mapk ◽  
Treatment Options ◽  
Colonic Motility ◽  
Mapk Signaling ◽  
Autism Spectrum ◽  
Mapk Activity ◽  
P38α Mapk ◽  
P38 Mapk Inhibitors ◽  
Mapk Inhibitors

Autism spectrum disorder (ASD) is a common neurobehavioral disorder with limited treatment options. Activation of p38 MAPK signaling networks has been identified in ASD, and p38 MAPK signaling elevates serotonin (5-HT) transporter (SERT) activity, effects mimicked by multiple, hyperfunctional SERT coding variants identified in ASD subjects. Mice expressing the most common of these variants (SERT Ala56) exhibit hyperserotonemia, a biomarker observed in ASD subjects, as well as p38 MAPK-dependent SERT hyperphosphorylation, elevated hippocampal 5-HT clearance, hypersensitivity of CNS 5-HT1A and 5-HT2A/2C receptors, and behavioral and gastrointestinal perturbations reminiscent of ASD. As the α-isoform of p38 MAPK drives SERT activation, we tested the hypothesis that CNS-penetrant, α-isoform–specific p38 MAPK inhibitors might normalize SERT Ala56 phenotypes. Strikingly, 1-week treatment of adult SERT Ala56 mice with MW150, a selective p38α MAPK inhibitor, normalized hippocampal 5-HT clearance, CNS 5-HT1A and 5-HT2A/2C receptor sensitivities, social interactions, and colonic motility. Conditional elimination of p38α MAPK in 5-HT neurons of SERT Ala56 mice restored 5-HT1A and 5-HT2A/2C receptor sensitivities as well as social interactions, mirroring effects of MW150. Our findings support ongoing p38α MAPK activity as an important determinant of the physiological and behavioral perturbations of SERT Ala56 mice and, more broadly, supports consideration of p38α MAPK inhibition as a potential treatment for core and comorbid phenotypes present in ASD subjects.

Design and molecular modeling of novel P38α MAPK inhibitors targeting breast cancer, synthesized from oxygen heterocyclic natural compounds

2019 ◽  
Vol 27 (7) ◽  
pp. 1308-1319 ◽  
Author(s):  
Omaima M. Abdelhafez ◽  
Eman Y. Ahmed ◽  
Nehad A. Abdel Latif ◽  
Reem K. Arafa ◽  
Zakaria Y. Abd Elmageed ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Modeling ◽  
Natural Compounds ◽  
P38α Mapk ◽  
Mapk Inhibitors

Discovery of potent p38α MAPK inhibitors through a funnel like workflow combining in silico screening and in vitro validation

2019 ◽  
Vol 182 ◽  
pp. 111624 ◽  
Author(s):  
Andrea Astolfi ◽  
Mark Kudolo ◽  
Jose Brea ◽  
Giorgia Manni ◽  
Giuseppe Manfroni ◽  
...  
Keyword(s):  
In Silico ◽  
In Silico Screening ◽  
P38α Mapk ◽  
Mapk Inhibitors

Co-crystal structure determination and cellular evaluation of 1,4-dihydropyrazolo[4,3-c] [1,2] benzothiazine 5,5-dioxide p38α MAPK inhibitors

2019 ◽  
Vol 511 (3) ◽  
pp. 579-586
Author(s):  
Desirée Bartolini ◽  
Mike Bührmann ◽  
Maria Letizia Barreca ◽  
Giuseppe Manfroni ◽  
Violetta Cecchetti ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Structure Determination ◽  
Crystal Structure Determination ◽  
P38α Mapk ◽  
Mapk Inhibitors

Synthesis and molecular docking studies of new furochromone derivatives as p38α MAPK inhibitors targeting human breast cancer MCF-7 cells

2017 ◽  
Vol 25 (8) ◽  
pp. 2423-2436 ◽  
Author(s):  
Kamelia M. Amin ◽  
Yasmin M. Syam ◽  
Manal M. Anwar ◽  
Hamed I. Ali ◽  
Tamer M. Abdel-Ghani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Docking ◽  
Human Breast Cancer ◽  
Docking Studies ◽  
Human Breast ◽  
Molecular Docking Studies ◽  
P38α Mapk ◽  
Mapk Inhibitors ◽  
Mcf 7

scholarly journals Ablation of p38α MAPK Signaling in Osteoblast Lineage Cells Protects Mice From Bone Loss Induced by Estrogen Deficiency

Endocrinology ◽  
2015 ◽  
Vol 156 (12) ◽  
pp. 4377-4387 ◽  
Author(s):  
Cyril Thouverey ◽  
Joseph Caverzasio
Keyword(s):  
Bone Loss ◽  
Nuclear Factor Κb ◽  
Mapk Signaling ◽  
Osteoclast Formation ◽  
Estrogen Deficiency ◽  
Nuclear Factor ◽  
Receptor Activator ◽  
P38α Mapk ◽  
Mapk Inhibitors ◽  
Osteoblast Lineage

Estrogen deficiency causes bone loss by increasing the number of bone-resorbing osteoclasts. Selective p38α MAPK inhibitors prevent bone-wasting effects of estrogen withdrawal but implicated mechanisms remain to be identified. Here, we show that inactivation of the p38α-encoding gene in osteoblast lineage cells with the use of an osteocalcin-cre transgene protects mice from ovariectomy-induced bone loss (a murine model of postmenopausal osteoporosis). Ovariectomy fails to induce bone loss, increase bone resorption, and stimulate receptor activator of nuclear factor κB ligand and IL-6 expression in mice lacking p38α in osteoblasts and osteocytes. Finally, TNFα or IL-1, which are osteoclastogenic cytokines overproduced in the bone marrow under estrogen deficiency, can activate p38α signaling in osteoblasts, but those cytokines cannot enhance Rankl and Il6 expressions or increase osteoclast formation in p38a-deficient osteoblast cultures. These findings demonstrate that p38α MAPK signaling in osteoblast lineage cells mediates ovariectomy-induced bone loss by up-regulating receptor activator of nuclear factor κB ligand and IL-6 production.

Syntheses and structure–activity relationships for some triazolyl p38α MAPK inhibitors

2014 ◽  
Vol 24 (5) ◽  
pp. 1352-1357 ◽  
Author(s):  
Jean-Paul G. Seerden ◽  
Gabriela Leusink-Ionescu ◽  
Robin Leguijt ◽  
Catherine Saccavini ◽  
Edith Gelens ◽  
...  
Keyword(s):  
Structure Activity Relationships ◽  
Structure Activity ◽  
P38α Mapk ◽  
Mapk Inhibitors

scholarly journals Target Engagement Analysis and Link to Pharmacodynamic Endpoint for a Novel Class of CNS-penetrant and Efficacious p38α MAPK Inhibitors

2014 ◽  
Vol 9 (4) ◽  
pp. 454-460 ◽  
Author(s):  
Adam D. Bachstetter ◽  
D. Martin Watterson ◽  
Linda J. Van Eldik
Keyword(s):  
Target Engagement ◽  
P38α Mapk ◽  
Mapk Inhibitors
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