Featured Articles

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited genetic disease that is estimated to affect around 1 in 400 – 1,000 people (NIDDK, NIH). Most people with ADPKD can be attributed to defects in either PKD1, or to lesser extent, PKD2 genes. Of interest, metabolites of the kynurenine pathway (KP) have been associated with the cause of chronic kidney disease (Grams et al., 2017). Nguyen, Kleczko and colleagues studied the role of the KP underlying polycystic kidney disease (PKD) model, published in JCI insight. In this study, the authors investigated KP activation in a PKD mouse model (C57Bl/6J PKD1... read more

Over 17 million yearly fatalities are attributed to cardiovascular diseases and the majority are due to myocardial infarctions (MI). Having just one MI event increases the yearly mortality risk by 5% for the remaining lifetime. Adult cardiac myocytes have a limited capacity to regenerate and instead, scarring occurs at the site of damage. Whereas in neonates, damaged cardiac myocytes regenerate, healing the damaged tissue. Understanding the difference between adult and neonatal cardiomyocytes regenerative mechanisms could help promote tissue repair following MI. Previous research has demonstrated that MI induces an inflammatory response to stimulate regeneration. It is well known that the... read more

Neuropathic pain can occur due to trauma to the central or peripheral nervous system. However, neuropathy is also associated with diseases such as diabetes, accounting for nearly 30% of cases. The underlying cause of neuropathic pain is diverse and for some patients, it remains to be elucidated. Due to the widespread symptoms and causes of neuropathy, effective treatment has been challenging. Depression is common in individuals suffering from chronic pain and the kynurenine pathway (KP) has been shown to be altered in both of these states. In a recent study by Dr. Alexandre Maganin and colleagues, they investigated the potential role... read more

Schizophrenia (SCZ) is a chronic mental disorder that affects around 1 in 300 people. The exact cause of SCZ remains to be elucidated; however, it is likely a combination of events that contributes to the pathogenesis of this disease. Some genetic risk factors for SCZ are pro-inflammatory factors. In fact, research has demonstrated an increased inflammatory state in individuals with SCZ. Additionally, schizophrenia has been associated with a reduction in gray matter volume. Inflammatory states can alter kynurenine pathway (KP) activity. Therefore, in a recent study published by Dr. Sumiao Zhou and colleagues in Frontiers in Psychiatry, they investigated KP... read more

Over a year ago, in our first issue Newsletter, we highlighted the importance of the kynurenine pathway (KP) in COVID-19 and asked if KP alteration in people with COVID-19 may lead to neurodegeneration (see our Newsletter issue 1 to recap). Fast track to the present, some interesting insights into that question have emerged and are covered in this month’s feature article. Giron et al focus on a subset of individuals who experience persistent, recurrent, or new symptoms following COVID-19 acute infection, commonly referred to as long COVID (see WHO) in comparison to those without long COVID. They examined the symptoms,... read more

Exactly a year ago in our featured article (see Jun/July 2021), we highlighted the importance of IDO-1 interaction with AhR and PD-1 in overcoming immune tolerance within the tumour microenvironment. This has implications for improving the efficacy of future immunotherapies in cancer or at least in ovarian cancer. However, limiting IDO-1 activity may not inhibit kynurenine (KYN) production completely since there are other enzymes, such as TDO-2 that also convert tryptophan to KYN. Further, small-molecule inhibitors via systemic administration can have a short half-life, lack localized effect, and may result in unexpected adverse effects. To overcome these issues, B. Wang et... read more

Alzheimer’s disease (AD) is the most common form of dementia worldwide affecting nearly 40 million individuals. While the exact pathophysiology of AD remains to be elucidated it is known that the risk of AD increases with aging. It is appreciated that aging results in changes that can include neuronal atrophy, increased neuroinflammation, and vascular damage. However, it is unknown what factors exacerbate the natural aging process driving disease progression. Kynurenine metabolites have been shown to be either neuroprotective or neurotoxic, as such the pathway has been investigated in AD. A recent study published by Dr. Marcela Cespedes et al. in... read more

Germ-free mice have offered a model to investigate the roles that the gut microbiota play during development and disease. It is appreciated that the commensal microbes help to educate the immune system and without their presence the immune system is under developed. Furthermore, gut microbes contribute to the hosts metabolism. For example, microbes generate indolic compounds from tryptophan and these microbial-derived metabolites have been shown to be either protective or risk-factors for type 2 diabetes, as was shown in our feature article in September 2021. With the gut-brain axis these metabolites can also impact the brain. As such, a recent... read more

Many pharmacological treatments for psychiatric disorders are thought to target serotonin, either its neurotransmission or bioavailability. Lithium has been used since the mid-19th century to treat psychiatric disorders however, its underlying mechanisms have yet to be fully elucidated. Lithium treatment has been shown to increase serotonin neurotransmission in animal studies. Since tryptophan underpins both serotonin and the kynurenine pathway it is critical to understand how therapeutics impact the balance of these biological pathways. A recent study published by Dr. Ria Göttert et al. in Glia investigated the impact lithium treatment has on the inflammation-induced kynurenine pathway. Microglia cells stimulated with... read more

In our recent newsletter (issue 2), we talked about the importance of tryptophan (Trp) starvation in cancer immunobiology, owing much of its initial discovery as a physiological phenomenon in maternal-fetal rejection. We now know that Trp depletion via IDO upregulation leads to IDO-AhR mediated suppression of immune activity. From an immune cell perspective, this mechanism is highly undesirable but presents a new insight that perhaps targeting immune cells to overcome Trp depletion may improve cancer prognosis. Recently, published in Nature, Abhijeet Pataskar and colleagues present a new mechanistic function of Trp depletion – tryptophan-to-phenylalanine (Trp-to-Phe) ‘substitutants.’ What is Trp-to-Phe substitutant?... read more

It is appreciated that metabolites generated by the metabolism of tryptophan via the kynurenine pathway (KP) play a role in neurobiological diseases and processes (R Schwarcz and TW Stone, 2017). However, there is a need to better understand the cellular expression of key enzymes of the KP, the ability of metabolites to cross the blood-brain barrier, and the biological effects of these metabolites in the brain. A recent study published by Dr. Korrapati V. Sathyasaikumar et al. in Antioxidants investigated the expression of kynurenine 3-monooxygenase (KMO) in the brain of mice. Previously microglia were considered to be the predominate cell... read more

Tryptophan metabolism has been demonstrated to play a role in many disease states and changes in the kynurenine pathway metabolites are being linked to depression, cancer, and neurodegenerative disorders. Like other metabolic pathways, diet can affect the observed levels of downstream metabolites. Therefore, it is critical to understand how common laboratory diets can alter levels of these metabolites in experimental animals. A recent study published by Dr. Yuhei Yajima et al. in the International Journal of Tryptophan Research investigated how common laboratory diets can alter kynurenine metabolite levels. In this study three experimental laboratory diets (MF, AIN-93G, and AIN-93M) were fed... read more