Intestinal toxicity induced by chemotherapeutics has become an important reason for the interruption of therapy and withdrawal of approved agents. In this study, we demonstrated that chemotherapeutics-induced intestin...Intestinal toxicity induced by chemotherapeutics has become an important reason for the interruption of therapy and withdrawal of approved agents. In this study, we demonstrated that chemotherapeutics-induced intestinal damage were commonly characterized by the sharp upregulation of tryptophan(Trp)àkynurenine(KYN)àkynurenic acid(KA) axis metabolism. Mechanistically,chemotherapy-induced intestinal damage triggered the formation of an interleukin-6(IL-6)àindoleamine2,3-dioxygenase 1(IDO1)àaryl hydrocarbon receptor(AHR) positive feedback loop, which accelerated kynurenine pathway metabolism in gut. Besides, AHR and G protein-coupled receptor 35(GPR35) negative feedback regulates intestinal damage and inflammation to maintain intestinal integrity and homeostasis through gradually sensing kynurenic acid level in gut and macrophage, respectively. Moreover, based on virtual screening and biological verification, vardenafil and linagliptin as GPR35 and AHR agonists respectively were discovered from 2388 approved drugs. Importantly, the results that vardenafil and linagliptin significantly alleviated chemotherapy-induced intestinal toxicity in vivo suggests that chemotherapeutics combined with the two could be a promising therapeutic strategy for cancer patients in clinic.This work highlights GPR35 and AHR as the guardian of kynurenine pathway metabolism and core component of defense responses against intestinal damage.展开更多
Chronic induction of the kynurenine pathway（KP） contributes to neuroinflammation by producing the excitotoxin quinolinic acid（QUIN）. This has led to significant interest in the development of inhibitors of this pa...Chronic induction of the kynurenine pathway（KP） contributes to neuroinflammation by producing the excitotoxin quinolinic acid（QUIN）. This has led to significant interest in the development of inhibitors of this pathway, particularly in the context of neurodegenerative disease. However, acute spinal cord injury（SCI） also results in deleterious increases in QUIN, as secondary inflammatory processes mediated largely by infiltrating macrophages, become predominant. QUIN mediates significant neurotoxicity primarily by excitotoxic stimulation of the N-methyl-D-aspartate receptor, but other mechanisms of QUIN toxicity are known. More recent focus has assessed the contribution that neuroinflammation and modulations in the KP make in mood and psychiatric disorders with recent studies linking inflammation and modulations in the KP, to impaired cognitive performance and depressed mood in SCI patients. We hypothesize that these findings suggest that in SCI, inhibition of QUIN production and other metabolites, may have multiple therapeutic modalities and further studies investigating this are warranted. However, for central nervous system-based conditions, achieving good blood-brain-barrier permeability continues to be a limitation of current KP inhibitors.展开更多
Unlike relapsing remitting multiple sclerosis, there are very few therapeutic options for patients with progressive forms of multiple sclerosis. While immune mechanisms are key participants in the pathogenesis of rela...Unlike relapsing remitting multiple sclerosis, there are very few therapeutic options for patients with progressive forms of multiple sclerosis. While immune mechanisms are key participants in the pathogenesis of relapsing remitting multiple sclerosis, the mechanisms underlying the development of progressive multiple sclerosis are less well understood. Putative mechanisms behind progressive multiple sclerosis have been put forth： insufficient energy production via mitochondrial dysfunction, activated microglia, iron accumulation, oxidative stress, activated astrocytes, Wallerian degeneration, apoptosis, etc. Furthermore, repair processes such as remyelination are incomplete. Experimental therapies that strive to improve metabolism within neurons and glia, e.g., oligodendrocytes, could act to counter inadequate energy supplies and/or support remyelination. Most experimental approaches have been examined as standalone interventions; however, it is apparent that the biochemical steps being targeted are part of larger pathways, which are further intertwined with other metabolic pathways. Thus, the potential benefits of a tested intervention, or of an established therapy, e.g., ocrelizumab, could be undermined by constraints on upstream and/or downstream steps. If correct, then this argues for a more comprehensive, multifaceted approach to therapy. Here we review experimental approaches to support neuronal and glial metabolism, and/or promote remyelination, which may have potential to lessen or delay progressive multiple sclerosis.展开更多
基金supported by the National Nature Science Foundation of China (NSFC Nos.81773861 and 81773682)National Science and Technology Major Project (2017ZX09101001, China)+3 种基金Jiangsu Provincial National Science Foundation for Distinguished Young Scholars(No. BK20180027, China)Double First-Class University Projectthe Program for Jiangsu province Innovative Research Teamfunded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD, China)。
文摘Intestinal toxicity induced by chemotherapeutics has become an important reason for the interruption of therapy and withdrawal of approved agents. In this study, we demonstrated that chemotherapeutics-induced intestinal damage were commonly characterized by the sharp upregulation of tryptophan(Trp)àkynurenine(KYN)àkynurenic acid(KA) axis metabolism. Mechanistically,chemotherapy-induced intestinal damage triggered the formation of an interleukin-6(IL-6)àindoleamine2,3-dioxygenase 1(IDO1)àaryl hydrocarbon receptor(AHR) positive feedback loop, which accelerated kynurenine pathway metabolism in gut. Besides, AHR and G protein-coupled receptor 35(GPR35) negative feedback regulates intestinal damage and inflammation to maintain intestinal integrity and homeostasis through gradually sensing kynurenic acid level in gut and macrophage, respectively. Moreover, based on virtual screening and biological verification, vardenafil and linagliptin as GPR35 and AHR agonists respectively were discovered from 2388 approved drugs. Importantly, the results that vardenafil and linagliptin significantly alleviated chemotherapy-induced intestinal toxicity in vivo suggests that chemotherapeutics combined with the two could be a promising therapeutic strategy for cancer patients in clinic.This work highlights GPR35 and AHR as the guardian of kynurenine pathway metabolism and core component of defense responses against intestinal damage.
文摘Chronic induction of the kynurenine pathway（KP） contributes to neuroinflammation by producing the excitotoxin quinolinic acid（QUIN）. This has led to significant interest in the development of inhibitors of this pathway, particularly in the context of neurodegenerative disease. However, acute spinal cord injury（SCI） also results in deleterious increases in QUIN, as secondary inflammatory processes mediated largely by infiltrating macrophages, become predominant. QUIN mediates significant neurotoxicity primarily by excitotoxic stimulation of the N-methyl-D-aspartate receptor, but other mechanisms of QUIN toxicity are known. More recent focus has assessed the contribution that neuroinflammation and modulations in the KP make in mood and psychiatric disorders with recent studies linking inflammation and modulations in the KP, to impaired cognitive performance and depressed mood in SCI patients. We hypothesize that these findings suggest that in SCI, inhibition of QUIN production and other metabolites, may have multiple therapeutic modalities and further studies investigating this are warranted. However, for central nervous system-based conditions, achieving good blood-brain-barrier permeability continues to be a limitation of current KP inhibitors.
文摘Unlike relapsing remitting multiple sclerosis, there are very few therapeutic options for patients with progressive forms of multiple sclerosis. While immune mechanisms are key participants in the pathogenesis of relapsing remitting multiple sclerosis, the mechanisms underlying the development of progressive multiple sclerosis are less well understood. Putative mechanisms behind progressive multiple sclerosis have been put forth： insufficient energy production via mitochondrial dysfunction, activated microglia, iron accumulation, oxidative stress, activated astrocytes, Wallerian degeneration, apoptosis, etc. Furthermore, repair processes such as remyelination are incomplete. Experimental therapies that strive to improve metabolism within neurons and glia, e.g., oligodendrocytes, could act to counter inadequate energy supplies and/or support remyelination. Most experimental approaches have been examined as standalone interventions; however, it is apparent that the biochemical steps being targeted are part of larger pathways, which are further intertwined with other metabolic pathways. Thus, the potential benefits of a tested intervention, or of an established therapy, e.g., ocrelizumab, could be undermined by constraints on upstream and/or downstream steps. If correct, then this argues for a more comprehensive, multifaceted approach to therapy. Here we review experimental approaches to support neuronal and glial metabolism, and/or promote remyelination, which may have potential to lessen or delay progressive multiple sclerosis.
