Tumors have evolved a variety
of methods to reprogram conventional
metabolic pathways to favor their own nutritional needs, including
glutaminolysis, the first step of which is the hydrolysis of glutamine
to glutamate by the amidohydrolase glutaminase 1 (GLS1). A GLS1 inhibitor
could potentially target certain cancers by blocking the tumor cell’s
ability to produce glutamine-derived nutrients. Starting from the
known GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl
sulfide, we describe the medicinal chemistry evolution of a series
from lipophilic inhibitors with suboptimal physicochemical and pharmacokinetic
properties to cell potent examples with reduced molecular weight and
lipophilicity, leading to compounds with greatly improved oral exposure
that demonstrate in vivo target engagement accompanied by activity
in relevant disease models.
Accumulating evidence suggests that microglial cells have altered morphology and proliferation in different brain regions of methamphetamine (Meth) abusers and Meth-abusing animal models. However, the possible mechanisms underlying Meth-induced microglial activation remain poorly understood. Meanwhile, Toll-like receptor4 (TLR4) is closely associated with inflammation. Therefore the aim of the present study was to assess whether Meth treatment affects TLR4 expression; in addition, we evaluated the effects of ginkgolide B (GB), a diterpene lactone extracted from Ginkgo biloba, on Meth-mediated inflammation. BV2 cells were treated with Meth. Interestingly, Meth treatment significantly increased TLR4 expression, activated the NF-κB signaling pathway, and promoted TNF-α, IL-6 and IL-1β excretion. These effects, however, were partially attenuated by GB pre-treatment. To further confirm the role of TLR4 in Meth-mediated inflammation, the siRNA technology was applied to knock down TLR4, which resulted in hampered Meth-mediated inflammatory responses, confirming the important role of TLR4 in this process. Taken together, our findings suggested that Meth exposure results in BV2 cell activation, in association with TLR4 upregulation. GB could attenuate Meth-induced inflammation, at least partially through TLR4-NF-κB signaling pathway, therefore, targeting TLR4 may constitute a potential intervention strategy for Meth mediated neuroinflammation.
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