Microbiota, Tryptophan and Aryl Hydrocarbon Receptors as the Target Triad in Parkinson’s Disease—A Narrative Review

In the era of a steadily increasing lifespan, neurodegenerative diseases among the elderly present a significant therapeutic and socio-economic challenge. A properly balanced diet and microbiome diversity have been receiving increasing attention as targets for therapeutic interventions in neurodegeneration. Microbiota may affect cognitive function, neuronal survival and death, and gut dysbiosis was identified in Parkinson’s disease (PD). Tryptophan (Trp), an essential amino acid, is degraded by microbiota and hosts numerous compounds with immune- and neuromodulating properties. This broad narrative review presents data supporting the concept that microbiota, the Trp-kynurenine (KYN) pathway and aryl hydrocarbon receptors (AhRs) form a triad involved in PD. A disturbed gut–brain axis allows the bidirectional spread of pro-inflammatory molecules and α-synuclein, which may contribute to the development/progression of the disease. We suggest that the peripheral levels of kynurenines and AhR ligands are strongly linked to the Trp metabolism in the gut and should be studied together with the composition of the microbiota. Such an approach can clearly delineate the sub-populations of PD patients manifesting with a disturbed microbiota–Trp-KYN–brain triad, who would benefit from modifications in the Trp metabolism. Analyses of the microbiome, Trp-KYN pathway metabolites and AhR signaling may shed light on the mechanisms of intestinal distress and identify new targets for the diagnosis and treatment in early-stage PD. Therapeutic interventions based on the combination of a well-defined food regimen, Trp and probiotics seem of potential benefit and require further experimental and clinical research

Fractalkine, sICAM-1 and Kynurenine Pathway in Restrictive Anorexia Nervosa–Exploratory Study

The link between the kynurenine pathway and immunomodulatory molecules—fractalkine and soluble intercellular adhesion molecule-1 (sICAM-1)—in anorexia nervosa (AN) remains unknown. Fractalkine, sICAM-1, tryptophan (TRP), kynurenine (KYN), neuroprotective kynurenic acid (KYNA), neurotoxic 3-OH-kynurenine (3-OH-KYN), and the expression of mRNA for kynurenine aminotransferases (KAT1-3) were studied in 20 female patients with restrictive AN (mostly drug-free, all during first episode of the disease) and in 24 controls. In AN, serum fractalkine, but not sICAM-1, KYNA, KYN, TRP or 3-OH-KYN, was higher; ratios TRP/KYN, KYN/KYNA, KYN/3-OH-KYN and KYNA/3-OH-KYN were unaltered. The expression of the gene encoding KAT3, but not of genes encoding KAT1 and KAT2 (measured in blood mononuclear cells), was higher in patients with AN. In AN, fractalkine positively correlated with TRP, while sICAM-1 was negatively associated with 3-OH-KYN and positively linked with the ratio KYN/3-OH-KYN. Furthermore, TRP and fractalkine were negatively associated with the body mass index (BMI) in AN. Expression of KAT1, KAT2 and KAT3 did not correlate with fractalkine, sICAM-1 or BMI, either in AN or control. Increased fractalkine may be an independent factor associated with the restrictive type of AN. Excessive physical activity probably underlies increased expression of KAT3 observed among enrolled patients. Further, longitudinal studies on a larger cohort of patients should be aimed to clarify the contribution of fractalkine and KAT3 to the pathogenesis of AN

Transplantable Melanomas in Hamsters and Gerbils as Models for Human Melanoma. Sensitization in Melanoma Radiotherapy—From Animal Models to Clinical Trials

The focus of the present review is to investigate the role of melanin in the radioprotection of melanoma and attempts to sensitize tumors to radiation by inhibiting melanogenesis. Early studies showed radical scavenging, oxygen consumption and adsorption as mechanisms of melanin radioprotection. Experimental models of melanoma in hamsters and in gerbils are described as well as their use in biochemical and radiobiological studies, including a spontaneously metastasizing ocular model. Some results from in vitro studies on the inhibition of melanogenesis are presented as well as radio-chelation therapy in experimental and clinical settings. In contrast to cutaneous melanoma, uveal melanoma is very successfully treated with radiation, both using photon and proton beams. We point out that the presence or lack of melanin pigmentation should be considered, when choosing therapeutic options, and that both the experimental and clinical data suggest that melanin could be a target for radiosensitizing melanoma cells to increase efficacy of radiotherapy against melanoma