Wahroonga, Australia
Wahroonga, Australia

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Adams S.,University of Sfax | Adams S.,St Vincents Hospital | Braidy N.,University of New South Wales | Bessesde A.,University of New South Wales | And 7 more authors.
Cancer Research | Year: 2012

Brain tumors are among the most common and most chemoresistant tumors. Despite treatment with aggressive treatment strategies, the prognosis for patients harboring malignant gliomas remains dismal. The kynurenine pathway (KP) is the principal route of L-tryptophan catabolism leading to the formation of the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD +), and important neuroactive metabolites, including the neurotoxin, quinolinic acid (QUIN), the neuroprotective agent, picolinic acid (PIC), the TH17/Treg balance modulator, 3-hydroxyanthranilic acid (3-HAA), and the immunosuppressive agent, L-Kynurenine (KYN). This review provides a new perspective on KP dysregulation in defeating antitumor immune responses, specifically bringing light to the lower segment of the KP, particularly QUIN-induced neurotoxicity and downregulation of the enzyme α-amino- β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) as a potential mechanism of tumor progression. Given its immunosuppressive effects, 3-HAA produced from the KP may also play a role in suppressing antitumor immunity in human tumors. The enzyme indoleamine 2, 3-dioxygenase (IDO-1) initiates and regulates the first step of the KP in most cells. Mounting evidence directly implicates that the induction and overexpression of IDO-1 in various tumors is a crucial mechanism facilitating tumor immune evasion and persistence. Tryptophan 2, 3-dioxygenase (TDO-2), which initiates the same first step of the KP as IDO-1, has likewise recently been shown to be a mechanism of tumoral immune resistance. Further, it was also recently shown that TDO-2-dependent production of KYN by brain tumors might be a novel mechanism for suppressing antitumor immunity and supporting tumor growth through the activation of the Aryl hydrocarbon receptor (AhR). This newly identified TDO-2-KYN-AhR signaling pathway opens up exciting future research opportunities and may represent a novel therapeutic target in cancer therapy. Our discussion points to a number of KP components, namely TDO-2, IDO-1, and ACMSD, as important therapeutic targets for the treatment of brain cancer. Targeting the KP in brain tumors may represent a viable strategy likely to prevent QUIN-induced neurotoxicity and KYN and 3-HAA-mediated immune suppression. ©2012 AACR.


Grant R.,Australasian Research Institute | Gobble J.,Medical Nutrition Therapy Northwest | Diehl H.,Lifestyle Medicine Institute
Nutrition and Metabolism | Year: 2013

Background: Low levels of high-density lipoproteins (HDL) are considered an important risk factor for cardiovascular disease and constitute one of the criteria for the Metabolic Syndrome (MetS). Lifestyle interventions promoting a low-fat, plant-based eating pattern appear to paradoxically reduce cardiovascular risk but also HDL levels. This study examined the changes in MetS risk factors, in particular HDL, in a large cohort participating in a 30-day lifestyle intervention that promoted a low-fat, plant-based eating pattern. Methods. Individuals (n = 5,046; mean age = 57.3 ± 12.9 years; 33.5% men, 66.5% women) participating in a in a Complete Health Improvement Program (CHIP) lifestyle intervention within the United States were assessed at baseline and 30 days for changes in body mass index (BMI), blood pressure (BP), lipid profile and fasting plasma glucose (FPG). Results: HDL levels decreased by 8.7% (p<0.001) despite significant reductions (p<0.001) in BMI (-3.2%), systolic BP (-5.2%), diastolic BP (-5.2%), triglycerides (TG; -7.7%), FPG (-6.3%), LDL (-13.0%), total cholesterol (TC, -11.1%), TC: HDL ratio (-3.2%), and LDL: HDL ratio (-5.3%). While 323 participants classified as having MetS at program entry no longer had this status after the 30 days, 112 participants acquired the MetS classification as a result of reduction in their HDL levels. Conclusions: When people move towards a low-fat, plant-based diet, HDL levels decrease while other indicators of cardiovascular risk improve. This observation raises questions regarding the value of using HDL levels as a predictor of cardiovascular risk in populations who do not consume a typical western diet. As HDL is part of the assemblage of risk factors that constitute MetS, classifying individuals with MetS may not be appropriate in clinical practice or research when applying lifestyle interventions that promote a plant-based eating pattern. © 2013 Kent et al.; licensee BioMed Central Ltd.


PubMed | Australasian Research Institute
Type: | Journal: Advances in neurobiology | Year: 2016

The importance of the essential, dietary-derived, polyunsaturated fatty acids (PUFAs) omega-6 and omega-3 to human health was first reported over 85 years ago. Subsequent research has revealed many beneficial effects of the omega-3 PUFAs in particular. This has been linked to their involvement in multiple biochemical functions, including synthesis of inflammatory mediators, cell membrane fluidity, intracellular signalling and gene expression. Through these pathways, the omega-3 PUFAs help modulate aspects of inflammation and immunity, cell growth and tissue repair. While a detailed understanding of the mechanisms involved in the role of omega-3 PUFAs to health in the central nervous system (CNS) is still to be elucidated, a role for both inflammatory modulation and a direct impact on neuronal membrane fluidity and receptor function is apparent. At least partially through these mechanisms, low omega-3 levels have been associated with CNS-linked disorders such as poor cognition, depression, anxiety disorders, poor anger control, attention deficit hyperactivity disorder (ADHD) and accelerated neurodegeneration in the elderly.Following a brief introduction to the history and chemistry of the omega-3 family of PUFAs, this chapter will provide an overview of the omega-3 fatty acids and how various members of this PUFA family influence central nervous system function leading towards either health or disease.

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