In the decades since their discovery in plants in the mid-to-late 1900s, melatonin (N-acetyl-5-methoxytryptamine) and serotonin (5-methoxytryptamine) have been established as their own class of phytohormone and have become popular targets for examination and study as stress ameliorating compounds. The indoleamines play roles across the plant life cycle from reproduction to morphogenesis and plant environmental perception. There is growing interest in harnessing the power of these plant neurotransmitters in applied and agricultural settings, particularly as we face increasingly volatile climates for food production; however, there is still a lot to learn about the mechanisms of indoleamine action in plants. A recent explosion of interest in these compounds has led to exponential growth in the field of melatonin research in particular. This concept paper aims to summarize the current status of indoleamine research and highlight some emerging trends.

A method for clinical potency determination of psilocybin and psilocin in hallucinogenic mushroom species Psilocybe cubensis was developed using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Five strains of dried, intact mushrooms were obtained and analyzed: Blue Meanie, Creeper, B-Plus, Texas Yellow, and Thai Cubensis. An extraction protocol was developed; this included an evaluation of sample milling technique, extraction solvents, and recovery/stability. Reversed phase chromatography on fused-core particle phases was developed for the determination of the two analytes using internal standard calibration with deuterated isotopologues of each analyte. The separation takes less than 5 min. Matrix effects were investigated by comparing signal response of calibration samples in neat solution and several mushroom matrices; no significant matrix effects were observed. The limit of detection for psilocybin was 1.5 ng/mL (1.5 pg on-column; 300 ng/g mushroom) and for psilocin was 0.15 ng/mL (0.15 pg on-column; 30 ng/g mushroom) using a Shimadzu LCMS-8050 triple quadrupole mass spectrometer. Assessment of the accuracy and precision of the method indicated percent error and RSD were <6 % at all concentration levels. Three whole, intact mushrooms from each strain were analyzed individually to obtain average content differences both between strains and between mushrooms of the same strain. From most to least potent, the study found that the average total psilocybin and psilocin concentrations for the Creeper, Blue Meanie, B+, Texas Yellow, and Thai Cubensis strains were 1.36, 1.221, 1.134, 1.103, and 0.879 % (w/w), respectively. A subset of these mushrooms was also tested in a separate non-affiliated laboratory, and the results were comparable between the two laboratories. Results from the secondary laboratory showed improved precision when multiple mushrooms were homogenized together, prior to extraction.

Melatonin (N-acetyl-5-methoxy-tryptamine) is a mammalian neurohormone, antioxidant and signaling molecule that was first discovered in plants in 1995. The first studies investigated plant melatonin from a human perspective quantifying melatonin in foods and medicinal plants and questioning whether its presence could explain the activity of some plants as medicines. Starting with these first handful of studies in the late 1990s, plant melatonin research has blossomed into a vibrant and active area of investigation and melatonin has been found to play critical roles in mediating plant responses and development at every stage of the plant life cycle from pollen and embryo development through seed germination, vegetative growth and stress response. Here we have utilized a systematic approach in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) protocols to reduce bias in our assessment of the literature and provide an overview of the current state of melatonin research in plants, covering 1995-2021. This review provides an overview of the biosynthesis and metabolism of melatonin as well as identifying key themes including: abiotic stress responses, root development, light responses, interkingdom communication, phytohormone and plant signaling. Additionally, potential biases in the literature are investigated and a birefringence in the literature between researchers from plant and medical based which has helped to shape the current state of melatonin research. Several exciting new opportunities for future areas of melatonin research are also identified including investigation of non-crop and non-medicinal species as well as characterization of melatonin signaling networks in plants.

During the past decades, tryptophan metabolism disorder was discovered to play a vital and complex role in the development of cancer. Indoleamine 2,3-dioxygenase 2 (IDO2) is one of the initial and rate-limiting enzymes of the kynurenine pathway of tryptophan catabolism. Increasing evidence indicates that IDO2 is upregulated in some tumors and plays a role in the development of cancer. In spite of the growing body of research, few reviews focused on the role of IDO2 in cancer. Here, we review the emerging knowledge on the roles of IDO2 in cancer and its potential as a therapeutic target. Firstly, the main biological features and regulatory mechanisms are reviewed, after which we focus on the expression and roles of IDO2 in cancer. Finally, we discuss the potential of IDO2 as a therapeutic target for cancer treatment.

Plants respond to changes in their environments through hormonal activation of a physiological cascade that redirects metabolic resources and growth. In filberts (Corylus sp.), chelated iron promotes the growth of new shoots but the mechanism(s) are not understood.
To use untargeted metabolomics and hormonomics approaches to generate novel hypotheses for the morphoregulatory role of ferric ethylenediamine-N,N\'-di-(ortho-hydroxyphenyl) acetic acid (Fe-EDDHA) in filbert shoot organogenesis in vitro.
Data were generated using previously optimized standardized untargeted metabolomics protocols with time of flight mass spectrometry. Multivariate statistical tools (principal component and partial least squares discriminant analysis) did not detect significant differences. Discovery tools Significance Analysis of Microarrays (SAM), multiple linear regression analysis, Bayesian analysis, logical algorithms, machine learning, synthetic biotransformations, targeted hormonomics, and online resources including MetaboAnalyst were used.
Starch/sucrose metabolism and shikimate pathway metabolites were increased. Dose dependent decreases were found in polyphenol metabolism, specifically ellagic acid and its methylated derivative 3,4,3\'-tri-O-methylellagic acid. Hormonomics analysis revealed significant differences in phytohormones and their conjugates. FeEDDHA treatment reduced indole-3-acetic acid, abscisic acid, salicylic acid, jasmonic acid conjugates (JA-Trp, JA-Ile, OH-JA) and dihydrozeatinglucoside in regenerating explants. Serotonin (5HT) was decreased in FeEDDHA-treated regenerating tissues while the related metabolite melatonin was increased. Eight phenolic conjugates of 5HT and eight catabolites were affected by FeEDDHA indicating that metabolism to sequester, deactivate and metabolize 5HT was induced by Fe(III). Tryptophan was metabolized through kynurenine but not anthranilate.
Seven novel hypotheses were generated to guide future studies to understand the regulatory control(s) of shoot organogenesis.

Sarcomas are heterogeneous malignant mesenchymal neoplasms with limited sensitivity to immunotherapy. We recently demonstrated an increase in Kynurenine Pathway (KP) activity in the plasma of sarcoma patients treated with pembrolizumab. While the KP has already been described to favor immune escape through the degradation of L-Tryptophan and production of metabolites including L-Kynurenine, Indoleamine 2,3 dioxygenase (IDO1), a first rate-limiting enzyme of the KP, still represents an attractive therapeutic target, and its blockade had not yet been investigated in sarcomas. Using immunohistochemistry, IDO1 and CD8, expression profiles were addressed within 203 cases of human sarcomas. At a preclinical level, we investigated the modulation of the KP upon PDL1 blockade in a syngeneic model of sarcoma through mRNA quantification of key KP enzymes within the tumor. Furthermore, in order to evaluate the possible anti-tumor effect of IDO blockade in combination with PDL1 blockade, an innovative IDO inhibitor (GDC-0919) was used. Its effect was first assessed on Kynurenine to Tryptophan ratio at plasmatic level and also within the tumor. Following GDC-0919 treatment, alone or in combination with anti-PDL1 antibody, tumor growth, immune cell infiltration, and gene expression profiling were measured. IDO1 expression was observed in 39.1% of human sarcoma cases and was significantly higher in tumors with high CD8 infiltration. In the pre-clinical setting, blockade of PDL1 led to a strong anti-tumor effect and was associated with an intratumoral inflammatory cytokines signature driven by Ifng but also with a modulation of the KP enzymes including Ido1 and Ido2. IDO1 inhibition using GDC-0919 resulted in (i) a significant decrease of plasmatic Kynurenine to Tryptophan ratio and in (ii) a decrease of tumoral Kynurenine. However, GDC-0919 used alone or combined with anti-PDL1, did not show anti-tumoral activity and did not affect the tumor immune cell infiltrate. In order to elucidate the mechanism(s) underlying the lack of effect of GDC-0919, we analyzed the gene expression profile of intratumoral biopsies. Interestingly, we have found that GDC-0919 induced a downregulation of the expression of pvr and granzymes, and an upregulation of inhba and Dtx4 suggesting a potential role of the IDO pathway in the control of NK function.

Until recently, metabotropic glutamate receptor 4 (mGlu4) has not received adequate attention in terms of drug targeting when compared to other members of the same mGlu receptor family, possibly because of the difficulties encountered in developing highly selective, either orthosteric or allosteric, ligands for this receptor. Areas covered: This review gives to discussion to the past and recent advances (between 2012-2017) in targeting the mGlu4 receptor for the treatment of disorders of the central nervous system (CNS) as well as immunological (neuroinflammation) and metabolic diseases (diabetes). Chemical structures, properties, and pharmacological properties discussed herein were retrieved from the scientific literature databases, PubMed and Google Scholar. Expert opinion: The fertile field of mGlu receptor positive allosteric modulators (PAMs) has recently led to the discovery of foliglurax, a highly selective mGlu4 receptor PAM with optimal bioavailability after oral administration and excellent brain distribution. However, further elucidation of the biological properties of the mGlu4 receptor, including expression and its signalling profile in distinct tissues and cells are still awaited in order to establish the mGlu4 receptor as a definite drug target in several CNS and non-CNS diseases.

Melatonin is a neurohormone that controls many relevant physiological processes beyond the control of circadian rhythms. Melatonin\'s actions are carried out by two main types of melatonin receptors; MT1 and MT2. These receptors are important, and not just because of the biological actions of its natural agonist; but also, because melatonin analogues can improve or antagonize their biological effect. Area covered: The following article describes the importance of melatonin as a biologically relevant molecule. It also defines the receptors for this substance, as well as the second messengers coupled to these receptors. Lastly, the article describes the amino acid residues involved in the docking process in both MT1 and MT2 melatonin receptors. Expert opinion: The biological actions of melatonin and their interpretations are becoming more relevant and therefore require the development of new pharmacological tools. Understanding the second messenger mechanisms involved in melatonin actions, as well as the characteristics of the docking of this molecule to MT1 and MT2 melatonin receptors, will permit the development of more selective agonists and antagonists which will help us to better understand this molecule as well to develop new therapeutic compounds.

We aimed to investigate the expression of suppressors cytokine signaling (SOCS)-3, transforming growth factor (TGF)-β and indoleamine 2,3-dioxygense (IDO) and to analyse the relationship of SOCS3 and TGF-β with IDO expression in early pregnancy chorionic villi and decidua in the maternal-fetal interface. Western blot analysis and immunohistochemical method were used to detect the expression of TGF-β, SOCS3 and IDO in chorionic villi and decidua tissues of normal pregnant women. SOCS3, TGF-β and IDO protein was identified in chorionic villi and decidua tissues of normal pregnant women and there was a negative correlation between the expression of IDO and SOCS3, but TGF-β expression was positively correlated with IDO expression. The levels of IDO expression in the decidua from normal pregnancies were significantly higher than those in chorionic villi, while the expression of SOCS3 was no significant difference between decidua and chorionic villi. In normal physiological state of pregnancy, SOCS3 and TGF-β may be involved in the regulation of immune tolerance by positive or negative regulation of IDO expression at maternal fetal interface.

Diabetes mellitus type 1 (DM1) is an autoimmune disease in which β-cells of the pancreas islet are destroyed by T lymphocytes. Specific T cells are activated by antigen-presenting cells, mainly dendritic cells (DCs). It is already known that the regulation of tryptophan pathway in DC can be a mechanism of immunomodulation. The enzyme indoleamine 2,3-dioxygenase (IDO) is present in many cells, including DC, and participates in the metabolism of the amino acid tryptophan. Recent studies suggest the involvement of IDO in the modulation of immune response, which became more evident after the in vitro demonstration of IDO production by DC and of the ability of these cells to inhibit lymphocyte function through the control of tryptophan metabolism. Current studies on immunotherapies describe the use of DC and IDO to control the progression of the immune response that triggers DM1. The initial results obtained are promising and indicate the possibility of developing therapies for the treatment or prevention of the DM1. Clinical trials using these cells in DM1 patients represent an interesting alternative treatment. However, clinical trials are still in the initial phase and a robust group of assays is necessary.