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Figure 1. Stress, pro-inflammatory cytokines and O&NS can all increase IDO and/or TDO, leading to an increase in kynurenine and kynurenic acid, which are AhR ligands. AhR activation can drive significant changes in GBM/GSC, including an increase in CYP1B1 within mitochondria. Mitochondria CYP1B1 “backward” convert melatonin to NAS. NAS activates TrkB directly as well as via BDNF induction, leading to GBM/GSC proliferation and survival. A number of other factors and processes can increase the NAS/melatonin ratio, including CYP2C19, P2Y1 receptor, mGluR5 receptor and O-demethylation. These also provide trophic support to GSC and contribute to chemoresistance. The mitochondrial melatonergic pathway can also be regulated by miR-7, miR-375 and miR-451, which inhibit 14-3-3, thereby decreasing the 14-3-3 stabilization of AANAT, and inhibit both NAS and melatonin production. TrkB can also be released in the GBM/GSC exosomes, leading to an increase in aggressiveness of neighbouring cells. The upregulation of YY1 in GBM/GSC can increase melatonergic pathway activation. Stress, inflammation and O&NS can also induce gut dysbiosis and increase gut permeability, with the resultant decrease in butyrate contributing to GBM/GSC pathoaetiology and pathophysiology. Evolution has provided a number of ways to regulate the initiation and products of the melatonergic pathway. AANAT: aralkylamine N-acetyltransferase; AhR: aryl hydrocarbon receptor; ASMT: acetylserotonin methyltransferase; BDNF: brain derived neurotrophic factor; CYP: cytochrome P450; GBM: glioblastoma multiforme; GSC: glioblastoma stem-like cells; IDO: indoleamine 2,3-dioxygenase; KAT: kynurenine aminotransferase; mGluR: metabotropic glutamate receptor; NAS: N-acetylserotonin; O&NS: oxidative and nitrosative stress; P2Y1: purinergic receptor; TDO: tryptophan 2,3-dioxygenase; TrkB: tyrosine receptor kinase B