The FDA-approved small-molecule drug dasatinib is currently used as a treatment for chronic myeloid leukemia (CML). However, the effects of dasatinib on microglial and/or astrocytic neuroinflammatory responses and its mechanism of action have not been studied in detail. BV2 microglial cells, primary astrocytes, or primary microglial cells were treated with dasatinib (100 or 250 nM) or vehicle (1% DMSO) for 30 min or 2 h followed by lipopolysaccharide (LPS; 200 ng/ml or 1 μg/ml) or PBS for 5.5 h. RT-PCR, real-time PCR; immunocytochemistry; subcellular fractionation; and immunohistochemistry were subsequently conducted to determine the effects of dasatinib on LPS-induced neuroinflammation. In addition, wild-type mice were injected with dasatinib (20 mg/kg, intraperitoneally (i.p.) daily for 4 days or 20 mg/kg, orally administered (p.o.) daily for 4 days or 2 weeks) or vehicle (4% DMSO + 30% polyethylene glycol (PEG) + 5% Tween 80), followed by injection with LPS (10 mg/kg, i.p.) or PBS. Then, immunohistochemistry was performed, and plasma IL-6, IL-1β, and TNF-α levels were analyzed by ELISA. Dasatinib regulates LPS-induced proinflammatory cytokine and anti-inflammatory cytokine levels in BV2 microglial cells, primary microglial cells, and primary astrocytes. In BV2 microglial cells, dasatinib regulates LPS-induced proinflammatory cytokine levels by regulating TLR4/AKT and/or TLR4/ERK signaling. In addition, intraperitoneal injection and oral administration of dasatinib suppress LPS-induced microglial/astrocyte activation, proinflammatory cytokine levels (including brain and plasma levels), and neutrophil rolling in the brains of wild-type mice. Our results suggest that dasatinib modulates LPS-induced microglial and astrocytic activation, proinflammatory cytokine levels, and neutrophil rolling in the brain.

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Dasatinib regulates LPS-induced microglial and astrocytic neuroinflammatory responses by inhibiting AKT/STAT3 signaling.

The present invention relates to compounds of formula (I): in which Y, Y, R, R 2, R 3 and R 4 are defined in the Summary of the Invention; capable of inhibiting the activity of BCR-ABL1 and mutants thereof. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds in the treatment of cancers.

Benzamide derivatives for inhibiting the activity of abl1, abl2 and bcr-abl1

Compounds and compositions for inhibiting the activity of abl1, abl2 and bcr-abl1

https://pubs.rsc.org/en/content/articlepdf/2022/gc/d2gc00302c

Pyrolytic lignin: a promising biorefinery feedstock for the production of fuels and valuable chemicals

Journey of lignin from a roadblock to bridge for lignocellulose biorefineries: A comprehensive review.

Lignin depolymerization and biotransformation to industrially important chemicals/biofuels

Chronic myeloid leukaemia is a chronic myeloproliferative disorder characterised by a reciprocal translocation between chromosomes 9 and 22 and thereby formation of the Philadelphia chromosome. Imatinib mesylate (STI-571) is a potent and selective inhibitor of BCR-ABL tyrosine kinase and has emerged as a treatment of choice in chronic myeloid leukaemia (CML) patients in chronic phase. It has shown activity in CML patients in the chronic phase or blastic phase. However there is poor penetration of the central nervous system (CNS) by the drug or its active metabolites. Therefore the CNS acts as a sanctuary site for malignant cells for CML patients treated with Imatinib. We report cases of two CML patients on Imatinib therapy, who were in haematological remission but developed CNS disease.

/pdf/central-nervous-system-blast-crisis-in-chronic-myeloid-467g3h3q5u.pdf

Narayan Radhika

Papers

Lignin depolymerization and biotransformation to industrially important chemicals/biofuels

Central Nervous System Blast Crisis in Chronic Myeloid Leukemia on Imatinib Mesylate Therapy: Report of Two Cases

Development of potential consortia for biotransformation of lignin and polyaromatic hydrocarbons (PAHs)