Self-assembled dipeptide confined in covalent organic polymers for fluorescence sensing of tryptamine in fermented meat products.

Diphenylalanine(FF)-Zn self-assembly (FS) confined in covalent organic polymers (FS@COPs) with efficient fluorescence was synthesized for fluorescence sensing of biogenic amines, which was one of the most important indicators for monitoring food freshness. FS@COPs combined excellent biodegradability of self-assembled dipeptide with chemical stability, porosity and targeted site recognition of COPs. With an optimal excitation wavelength of 360 nm and an optimal emission wavelength of 450 nm, FS@COPs could be used as fluorescence probes to rapidly visualize and highly sensitive determination of tryptamine (Try) within 15 min, and the linear range was from 40 to 900 µg L-1 with a detection limit of 63.08 µg kg-1. Importantly, the FS@COPs showed a high fluorescence quantum yield of 11.28%, and good stability, solubility, and selectivity, which could successfully achieve the rapid, accurate and highly sensitive identification of Try. Furthermore, we revealed the mechanism of FS@COPs for fluorescence sensing of targets. The FS@COPs system was applied to the fluorescence sensing of Try in real samples and showed satisfactory accuracy of 93.02%-105.25%.

Identification of technological/metabolic/environmental profiles associated with cheeses accumulating the neuroactive compound tryptamine.

Tryptamine is a neuromodulator of the central nervous system. It is also a biogenic amine, formed by the microbial decarboxylation of L-tryptophan. Tryptamine accumulation in cheese has been scarcely examined. No studies are available regarding the factors that could influence its accumulation. Determining the tryptamine content and identifying the factors that influence its accumulation could help in the design of functional tryptamine-enriched cheeses without potentially toxic concentrations being reached. We report the tryptamine concentration of 300 cheese samples representing 201 varieties. 16% of the samples accumulated tryptamine, at between 3.20 mg kg-1 and 3012.14 mg kg-1 (mean of 29.21 mg kg-1). 4.7% of cheeses accumulated tryptamine at higher levels than those described as potentially toxic. Moreover, three technological/metabolic/environmental profiles associated with tryptamine-containing cheese were identified, as well as the hallmark varieties reflecting each. Such knowledge could be useful for the dairy industry to control the tryptamine content of their products.

Risk factors for nausea and vomiting requiring the daily administration of 5-HT3 receptor antagonists in radiotherapy combined with temozolomide for high-grade glioma.

Radiotherapy combined with temozolomide (TMZ+RT) is the primary treatment for high-grade glioma. TMZ is classified as a moderate emetic risk agent and, thus, supportive care for nausea and vomiting is important. In Nagoya University Hospital, all patients are treated with a 5-hydroxy-tryptamine 3 receptor antagonist (5-HT3RA) for the first 3 days. The daily administration of 5-HT3RA is resumed after the 4th day based on the condition of patients during TMZ+RT. Therefore, the present study investigated risk factors for nausea and vomiting in patients requiring the daily administration of 5-HT3RA. Patients with high-grade glioma who received TMZ+RT between January 2014 and December 2019 at our hospital were included. Patients were divided into two groups: a control group (patients who did not resume 5-HT3RA) and resuming 5-HT3RA group (patients who resumed 5-HT3RA after the 4th day), and both groups were compared to identify risk factors for nausea and vomiting during TMZ+RT. There were 78 patients in the control group (68%) and 36 in the resuming 5-HT3RA group (32%). A multivariate analysis of patient backgrounds in the two groups identified age <18 years, PS 2 or more, and occipital lobe tumors as risk factors for nausea and vomiting. Nausea and vomiting were attenuated in 30 patients (83%) in the resuming 5-HT3RA group following the resumption of 5-HT3RA. The results obtained highlight the importance of extracting patients with these risk factors before the initiation of therapy and the early resumption or daily administration of 5-HT3RA according to the condition of each patient.

Biogenic amine tryptamine in human vaginal probiotic isolates mediates matrix inhibition and thwarts uropathogenic E. coli biofilm.

Probiotics offer a promising prophylactic approach against various pathogens and represent an alternative strategy to combat biofilm-related infections. In this study, we isolated vaginal commensal microbiota from 54 healthy Indian women to investigate their probiotic traits. We primarily explored the ability of cell-free supernatant (CFS) from Lactobacilli to prevent Uropathogenic Escherichia coli (UPEC) colonization and biofilm formation. Our findings revealed that CFS effectively reduced UPEC's swimming and swarming motility, decreased cell surface hydrophobicity, and hindered matrix production by downregulating specific genes (fimA, fimH, papG, and csgA). Subsequent GC-MS analysis identified Tryptamine, a monoamine compound, as the potent bioactive substance from Lactobacilli CFS, inhibiting UPEC biofilms with an MBIC of 4 µg/ml and an MBEC of 8 µg/ml. Tryptamine induced significant changes in E. coli colony biofilm morphology, transitioning from the Red, Dry, and Rough (RDAR) to the Smooth and White phenotype, indicating reduced extracellular matrix production. Biofilm time-kill assays demonstrated a four-log reduction in UPEC viability when treated with Tryptamine, highlighting its potent antibacterial properties, comparable to CFS treatment. Biofilm ROS assays indicated a significant elevation in ROS generation within UPEC biofilms, suggesting a potential antibacterial mechanism. Gene expression studies with Tryptamine-treated samples showed a reduction in expression of curli gene (csgA), consistent with CFS treatment. This study underscores the potential of Tryptamine from probiotic Lactobacilli CFS as a promising antibiofilm agent against UPEC biofilms.

N-Salicyloyl Tryptamine Derivatives as Potent Neuroinflammation Inhibitors by Constraining Microglia Activation via a STAT3 Pathway.

Neuroinflammation is an important factor that exacerbates neuronal death and abnormal synaptic function in neurodegenerative diseases (NDDs). Due to the complex pathogenesis and the presence of blood-brain barrier (BBB), no effective clinical drugs are currently available. Previous results showed that N-salicyloyl tryptamine derivatives had the potential to constrain the neuroinflammatory process. In this study, 30 new N-salicyloyl tryptamine derivatives were designed and synthesized to investigate a structure-activity relationship (SAR) for the indole ring of tryptamine in order to enhance their antineuroinflammatory effects. Among them, both in vitro and in vivo compound 18 exerted the best antineuroinflammatory effects by suppressing the activation of microglia, which is the culprit of neuroinflammation. The underlying mechanism of its antineuroinflammatory effect may be related to the inhibition of transcription, expression and phosphorylation of signal transducer and activator of transcription 3 (STAT3) that subsequently regulated downstream cyclooxygenase-2 (COX-2) expression and activity. With its excellent BBB permeability and pharmacokinetic properties, compound 18 exhibited significant neuroprotective effects in the hippocampal region of lipopolysaccharides (LPS)-induced mice than former N-salicyloyl tryptamine derivative L7. In conclusion, compound 18 has provided a new approach for the development of highly effective antineuroinflammatory therapeutic drugs targeting microglia activation.

Enhanced In Vitro Plant Morphogenesis of Tobacco: Unveiling Indoleamine-Modulated Adaptogenic Properties of Tulsi (Ocimum sanctum L.).

The medicinal plant tulsi (Ocimum sanctum L.) is acknowledged for its invigorating and healing properties that enhance resilience to stress in various human and animal models by modulating antioxidant compounds. While extensive research has documented these effects in humans, the adaptogenic potential of tulsi in stressful in vitro plant systems has not been explored. This study aimed to elucidate the adaptogenic properties of tulsi leaf extract on the in vitro regeneration of tobacco leaf explants through an investigation of the indoleamines at different developmental stages. Shoot regeneration from leaf explants on the medium supplemented with tulsi extract (20%) was compared to the control, and the differences in indoleamine compounds were analyzed using ultra-performance liquid chromatography. Treatment of the explants with the extract resulted in an almost two-fold increase in the number of regenerants after four weeks of culture, and 9% of the regenerants resembled somatic embryo-like structures. The occurrence of browning in the extract-treated explants stopped on day 10, shoots began to develop, and a significant concentration of tryptamine and N-acetyl-serotonin accumulated. A comparative analysis of indoleamine compounds in intact and cut tobacco leaves also revealed the pivotal role of melatonin and 2-hydroxymelatonin functioning as antioxidants during stress adaptation. This study demonstrates that tulsi is a potent adaptogen that is capable of modulating plant morphogenesis in vitro, paving the way for further investigations into the role of adaptogens in plant stress biology.

RE104: Synthesis and Activity of a Novel Serotonergic Psychedelic Prodrug of 4-Hydroxy-N,N-diisopropyltryptamine.

Results from randomized clinical trials of psilocybin in depressive disorders highlight the therapeutic potential of serotonergic psychedelic compounds in mental health disorders. The synthetic 5-hydroxytryptamine 2A receptor agonist 4-hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT) is structurally similar to psilocin but is reported to have a shorter duration (2-3 h) of psychedelic effects, suggesting the potential for psilocybin-like therapeutic activity with reduced clinical resource burden. Here, we describe the preclinical and translational characterization of RE104, a 4-OH-DiPT prodrug comprising a glutarate moiety designed to cleave rapidly in situ and thus provide reasonable bioavailability of the active drug. Plasma concentration of 4-HO-DiPT over time in PK experiments in rats was correlated with head-twitch intensity. The half-life of 4-OH-DiPT was 40 min after subcutaneous administration of RE104 in rats. In a forced swim test, a single dose of RE104 (1 mg/kg) significantly reduced mean immobility time at 1 week compared with vehicle (P < 0.001), confirming translational antidepressant potential. Taken together, these data with RE104 show that the glutarate ester can act as an efficient prodrug strategy for 4-HO-DiPT, a unique short-duration psychedelic with potential in depressive disorders.

Comparative genomics of N-acetyl-5-methoxytryptamine members in four Prunus species with insights into bud dormancy and abiotic stress responses in Prunus avium.

KEY MESSAGE: This study provides novel insights into the evolution, diversification, and functions of melatonin biosynthesis genes in Prunus species, highlighting their potential role in regulating bud dormancy and abiotic stresses. The biosynthesis of melatonin (MEL) in plants is primarily governed by enzymatic reactions involving key enzymes such as serotonin N-acetyltransferase (SNAT), tryptamine 5-hydroxylase (T5H), N-acetylserotonin methyltransferase (ASMT) and tryptophan decarboxylase (TDC). In this study, we analyzed Melatonin genes in four Prunus species such as Prunus avium (Pavi), Prunus pusilliflora (Ppus), Prunus serulata (Pser), and Prunus persica (Pper) based on comparative genomics approach. Among the four Prunus species, a total of 29 TDCs, 998 T5Hs, 16 SNATs, and 115 ASMTs within the genome of four Prunus genomes. A thorough investigation of melatonin-related genes was carried out using systematic biological methods and comparative genomics. Through phylogenetic analysis, orthologous clusters, Go enrichment, syntenic relationship, and gene duplication analysis, we discovered both similarities and variations in Melatonin genes among these Prunus species. Additionally, our study revealed the existence of unique subgroup members in the Melatonin genes of these species, which were distinct from those found in Arabidopsis genes. Furthermore, the transcriptomic expression analysis revealed the potential significance of melatonin genes in bud dormancy regulation and abiotic stresses. Our extensive results offer valuable perspectives on the evolutionary patterns, intricate expansion, and functions of PavMEL genes. Given their promising attributes, PavTDCs, PavT5H, PavNAT, and three PavASMT genes warrant in-depth exploration as prime candidates for manipulating dormancy in sweet cherry. This was done to lay the foundation for future explorations into the structural and functional aspects of these factors in Prunus species. This study offers significant insights into the functions of ASMT, SNAT, T5H, and TDC genes and sheds light on their roles in Prunus avium. Moreover, it established a robust foundation for further exploration functional characterization of melatonin genes in fruit species.

Oxidative tryptamine dimers from Corynebacterium durum directly target survivin to induce AIF-mediated apoptosis in cancer cells.

Accumulating evidence indicates that microbial communities in the human body crucially affect health through the production of chemical messengers. However, the relationship between human microbiota and cancer has been underexplored. As a result of a biochemical investigation of the commensal oral microbe, Corynebacterium durum, we identified the non-enzymatic transformation of tryptamine into an anticancer compound, durumamide A (1). The structure of 1 was determined using LC-MS and NMR data analysis as bis(indolyl)glyoxylamide, which was confirmed using one-pot synthesis and X-ray crystallographic analysis, suggesting that 1 is an oxidative dimer of tryptamine. Compound 1 displayed cytotoxic activity against various cancer cell lines with IC50 values ranging from 25 to 35 µM. A drug affinity responsive target stability assay revealed that survivin is the direct target protein responsible for the anticancer effect of 1, which subsequently induces apoptosis-inducing factor (AIF)-mediated apoptosis. Inspired by the chemical structure and bioactivity of 1, a new derivative, durumamide B (2), was synthesized using another indole-based neurotransmitter, serotonin. The anticancer properties of 2 were similar to those of 1; however, it was less active. These findings reinforce the notion of human microbiota-host interplay by showing that 1 is naturally produced from the human microbial metabolite, tryptamine, which protects the host against cancer.

Determination of psilocybin and psilocin content in multiple Psilocybe cubensis mushroom strains using liquid chromatography - tandem mass spectrometry.

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.

Potential of Tryptamine Derivatives as Multi-Target Directed Ligands for Alzheimer's Disease: AChE, MAO-B, and COX-2 as Molecular Targets.

Extensive research has been dedicated to develop compounds that can target multiple aspects of Alzheimer's disease (AD) treatment due to a growing understanding of AD's complex multifaceted nature and various interconnected pathological pathways. In the present study, a series of biological assays were performed to evaluate the potential of the tryptamine analogues synthesized earlier in our lab as multi-target-directed ligands (MTDLs) for AD. To assess the inhibitory effects of the compounds, various in vitro assays were employed. Three compounds, SR42, SR25, and SR10, displayed significant AChE inhibitory activity, with IC50 values of 0.70 µM, 0.17 µM, and 1.00 µM, respectively. These values superseded the standard drug donepezil (1.96 µM). In the MAO-B inhibition assay, SR42 (IC50 = 43.21 µM) demonstrated superior inhibitory effects as compared to tryptamine and other derivatives. Moreover, SR22 (84.08%), SR24 (79.30%), and SR42 (75.16%) exhibited notable percent inhibition against the COX-2 enzyme at a tested concentration of 100 µM. To gain insights into their binding mode and to validate the biological results, molecular docking studies were conducted. Overall, the results suggest that SR42, a 4,5 nitro-benzoyl derivative of tryptamine, exhibited significant potential as a MTDL and warrants further investigation for the development of anti-Alzheimer agents.

Phenylethylamine sensing at the electrified liquid-liquid interface. Can electrochemistry be used to follow the UHT milk spoilage process?

This study involved an investigation into the electrochemical characteristic of a few biogenic amines (BAs) occurring at the polarized interface between two immiscible electrolyte solutions (ITIES) with ion transfer voltammetry (ITV). The main focus of this research was the comprehensive electroanalytical and physicochemical analysis of phenylethylamine (PEA), allowing the determined of the formal Galvani potential of the ion transfer reaction (ΔorgaqΦ'), diffusion coefficients (D), formal free Gibbs energy of the ion transfer reaction (ΔG'aq→org) and water-1,2-dichloroethane partition coefficient (logPwater/DCEPEA). Furthermore, the collected data were employed to calculate analytical parameters, including voltametric detection sensitivity, limits of detection and the target analyte quantification. Moreover, the influence of the presence of 7 other BAs (histamine, spermine, spermidine, putrescine, cadaverine, tyramine and tryptamine) on the recorded signals originating from the PEA ion transfer was checked. The feasibility of the developed method was corroborated through experimentation with milk samples. Additionally, utilizing the devised methodology, an electrochemical assessment of the spoilage progression in milk samples was undertaken.

Synergistic effect of tryptamine-urea derivatives to overcome the chromosomally-mediated colistin resistance in Klebsiella pneumoniae.

Colistin is considered as the last-resort antibiotics to treat multi-drug resistant Gram-negative bacterial infections in humans. However, the clinical use of colistin was limited because of the apparition of chromosomal mutations and mobile colistin resistance genes in bacterial isolates. One promising strategy is to combine existing antibiotics with promising non-antibiotics to overcome the widespread emergence of antibiotic-resistant pathogens. Moreover, colistin resistance would be regulated by two component systems PhoP/PhoQ which leads to permanent synthesis of cationic groups compensating for Mg2+ deficiency. In this study, the synthesis of a small library of tryptamine urea derivatives was carried out. In addition, antibiotic susceptibility, antibiotic adjuvant screening and checkerboard assays were used to investigate the antibacterial activity of these synthesized compounds and the potential synergistic activity of their combination with colistin. Conformational analysis of the docked binding modes of the active compound in the predicted binding pocket of bacterial response regulator PhoP were carried out, to see if the active compound inhibits PhoP which is involved in colistin resistance. Finally, hemolytic activity studies have been conducted on the most active compound.

A fatal case of aspiration due to consumption of the hallucinogenic tryptamine derivative dipropyltryptamine (DPT).

BACKGROUND AND AIM: This case involves a 20-year-old man with prior hallucinogen-use experience, who sniffed an unknown amount of dipropyltryptamine in an apartment. Dipropyltryptamine, a hallucinogenic compound belonging to the tryptamine class is recognized for inducing effects similar to dimethyltryptamine (DMT) but with a longer duration. Ten to fifteen minutes later he experienced visual hallucinations, followed by increasing apathy. Two hours post consumption he developed abdominal pain, leading to collapse, seizure, and vomiting. Despite emergency medical resuscitation on site, transport to hospital 2.5 hours post consumption and extracorporeal life support he died 21 hours later. Relevant toxicological and morphological findings are presented. METHODS: A serum sample was collected four hours post consumption. Autopsy was performed six days after death. Antemortem serum, as well as postmortem cardiac blood and urine were analyzed for alcohol and psychoactive drugs by systematic toxicological analyses employing gas chromatography-mass spectrometry (Maurer/Pfleger/Weber library among others), liquid chromatography-ion trap mass spectrometry (LC-MSn, Toxtyper™), and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Dipropyltryptamine was quantified by LC-MS/MS after solid-phase extraction. RESULTS: Autopsy revealed a state after deep aspiration of gastric contents with consecutive brain edema due to oxygen deprivation. Dipropyltryptamine concentrations were approximately 210 ng/ml, 110 ng/ml and 180 ng/ml in antemortem serum, postmortem cardiac blood and urine, respectively. To the best of our knowledge, these are the first reported concentrations of dipropyltryptamine in a fatal case. CONCLUSION: Unlike typical tryptamine overdose reports, this case did not present with agitation, hyperthermia, or tachycardia. Despite the individual's prior experience with tryptamines and the generally low toxicity associated with this class of hallucinogens, death in this case was an indirect consequence of the nasal consumption of a high dose of dipropyltryptamine.

Rare Ophiuroid-Type Steroid 3ß,21-, 3ß,22-, and 3α,22-Disulfates from the Slime Sea Star Pteraster marsippus and Their Colony-Inhibiting Effects against Human Breast Cancer Cells.

Two new steroid 3ß,21-disulfates (1, 2) and two new steroid 3ß,22- and 3α,22-disulfates (3, 4), along with the previously known monoamine alkaloid tryptamine (5) were found in the ethanolic extract of the Far Eastern slime sea star Pteraster marsippus. Their structures were determined on the basis of detailed analysis of one-dimensional and two-dimensional NMR, HRESIMS, and HRESIMS/MS data. Compounds 1 and 2 have a Δ22-21-sulfoxy-24-norcholestane side chain. Compounds 3 and 4 contain a Δ24(28)-22-sulfoxy-24-methylcholestane side chain, which was first discovered in the polar steroids of starfish and brittle stars. The influence of substances 1-4 on cell viability, colony formation, and growth of human breast cancer T-47D, MCF-7, and MDA-MB-231 cells was investigated. It was shown that compounds 1 and 2 possess significant colony-inhibiting activity against T-47D cells, while compounds 3 and 4 were more effective against MDA-MB-231 cells.

Hypothetical biosynthetic pathways of pharmaceutically potential hallucinogenic metabolites in Myristicaceae, mechanistic convergence and co-evolutionary trends in plants and humans.

The family Myristicaceae harbour mind-altering phenylpropanoids like myristicin, elemicin, safrole, tryptamine derivatives such as N,N-dimethyltryptamine (DMT) and 5-methoxy N,N-dimethyltryptamine (5-MeO-DMT) and ß-carbolines such as 1-methyl-6-methoxy-dihydro-ß-carboline and 2-methyl-6-methoxy-1,2,3,4-tetrahydro-ß-carboline. This study aimed to systematically review and propose the hypothetical biosynthetic pathways of hallucinogenic metabolites of Myristicaceae which have the potential to be used pharmaceutically. Relevant publications were retrieved from online databases, including Google Scholar, PubMed Central, Science Direct and the distribution of the hallucinogens among the family was compiled. The review revealed that the biosynthesis of serotonin in plants was catalysed by tryptamine 5-hydroxylase (T5H) and tryptophan 5-hydroxylase (TPH), whereas in invertebrates and vertebrates only by tryptophan 5-hydroxylase (TPH). Indolethylamine-N-methyltransferase catalyses the biosynthesis of DMT in plants and the brains of humans and other mammals. Caffeic acid 3-O-methyltransferase catalyses the biosynthesis of both phenylpropanoids and tryptamines in plants. All the hallucinogenic markers exhibited neuropsychiatric effects in humans as mechanistic convergence. The review noted that DMT, 5-MeO-DMT, and ß-carbolines were natural protectants against both plant stress and neurodegenerative human ailments. The protein sequence data of tryptophan 5-hydroxylase and tryptamine 5-hydroxylase retrieved from NCBI showed a co-evolutionary relationship in between animals and plants on the phylogenetic framework of a Maximum Parsimony tree. The review also demonstrates that the biosynthesis of serotonin, DMT, 5-MeO-DMT, 5-hydroxy dimethyltryptamine, and ß-carbolines in plants, as well as endogenous secretion of these compounds in the brain and blood of humans and rodents, reflects co-evolutionary mutualism in plants and humans.

Effect of Zhengan Xifengtang on Blood Pressure and Fecal Microflora of Spontaneously Hypertensive Rats / 中国实验方剂学杂志

ObjectiveTo observe the effect of Zhengan Xifengtang on blood pressure and fecal microflora of spontaneously hypertensive rats （SHRs）. MethodA total of 75 male SHRs aged nine weeks were randomly divided into SHR group， Benazepril group （1.00 mg·kg-1·d-1）， high-dose Zhengan Xifengtang group （34.5 g·kg-1·d-1）， medium-dose Zhengan Xifengtang group （17.25 g·kg-1·d-1）， and low-dose Zhengan Xifengtang group （8.625 g·kg-1·d-1）. A total of 15 male Wistar-Kyoto （WKY） rats aged nine weeks were selected as the normal group. The normal group and SHR group were administrated with an equal volume of distilled water for eight weeks. During the administration， the blood pressure of the rats was measured regularly. After the intervention， fresh feces were collected with a sterile frozen storage tube， and 16S amplicon information was collected and analyzed. Plasma， hippocampus， and ileum of rats were collected for ultra-high performance liquid chromatography-tandem mass spectrometry（UPLC-MS/MS） detection. ResultZhengan Xifengtang decreased the systolic blood pressure and diastolic blood pressure of SHRs. Compared with the SHR group， Zhengan Xifengtang decreased the diversity of fecal microflora of SHRs. At the phylum level， Zhengan Xifengtang increased the relative abundance of SHR Verrucomicrobia and Actinobacteria and decreased the relative abundance of Synergistetes， Tenericutes， and Candidatus Saccharibacteria. Compared with the SHR group， Zhengan Xifengtang increased the relative abundance of Blautia wexlerae， Fusicatenibacter saccharivorans， and Akkermansia muciniphila and decreased the relative abundance of Clostridium lavalense， Intestinimonas butyriciproducens， Acetatifactor muris， Alloprevotella rava， and Oscillibacter valericigenes. Spearman correlation analysis showed that the systolic blood pressure of rats was negatively correlated with the relative abundance of Ethanoligenens， Aerococcus， Butyrivibrio， Olsenella， Bifidobacterium， Clostridium XIVb， Allobaculum， and Fusicatenibacter and positively correlated with the relative abundance of Alloprevotella. Zhengan Xifengtang increased the contents of plasma， hippocampal 5-hydroxy tryptamine（5-HT）， and 5-hydroxyindole acetic acid（5-HIAA） in SHRs and decreased the contents of 5-HT and 5-HIAA in the ileum， and the content of 5-HT in the hippocampus was negatively correlated with that in the ileum. ConclusionZhengan Xifengtang can reduce the blood pressure of SHRs， which may be related to reducing the diversity of SHR microflora， regulating the structure of the microflora， increasing the relative abundance of 5-HT and short-chain fatty acids bacteria， and lowering the relative abundance of pathogenic bacteria related to intestinal inflammation.

Microbiota-derived tryptophan metabolism: Impacts on health, aging, and disease.

The intricate interplay between gut microbiota and the host is pivotal in maintaining homeostasis and health. Dietary tryptophan (TRP) metabolism initiates a cascade of essential endogenous metabolites, including kynurenine, kynurenic acid, serotonin, and melatonin, as well as microbiota-derived Trp metabolites like tryptamine, indole propionic acid (IPA), and other indole derivatives. Notably, tryptamine and IPA, among the indole metabolites, exert crucial roles in modulating immune, metabolic, and neuronal responses at both local and distant sites. Additionally, these metabolites demonstrate potent antioxidant and anti-inflammatory activities. The levels of microbiota-derived TRP metabolites are intricately linked to the gut microbiota's health, which, in turn, can be influenced by age-related changes. This review aims to comprehensively summarize the cellular and molecular impacts of tryptamine and IPA on health and aging-related complications. Furthermore, we explore the levels of tryptamine and IPA and their corresponding bacteria in select diseased conditions, shedding light on their potential significance as biomarkers and therapeutic targets.

Switching on/off aryl hydrocarbon receptor and pregnane X receptor activities by chemically modified tryptamines.

Microbial indoles have been demonstrated as selective or dual agonists and ligands of the pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR). However, structural determinants of microbial indoles selectivity towards both receptors remain elusive. Here, we studied the effects of existing and newly synthesized derivatives of indole microbial metabolite tryptamine on the activity of AhR and PXR receptors. We show that the elongation of indolyl-3-alkaneamine chain, indole N-methylation and conversion of indolyl-3-alkaneamines to oleamides resulted in a major increase of PXR activity and in parallel loss of AhR activity. Using reporter gene assays, RT-PCR and TR-FRET techniques, we have characterized in detail the activation of PXR by novel indolyl-3-alkanyl-oleamides, 1-methyltryptamine and 1-methyltryptamine-acetamide. As a proof of concept, we demonstrated anti-inflammatory and epithelial barrier-protective activity of lead derivatives in intestinal Caco-2 cells, employing the measurement of expression of pro-inflammatory chemokines, tight junction genes, trans-epithelial electric resistance TEER, and dextran-FITC permeability assay. In conclusion, we show that a subtle chemical modifications of simple microbial indole metabolite tryptamine, leads to substantial changes in AhR and PXR agonist activities.

Ability of Latilactobacillus curvatus FAM25164 to produce tryptamine: Identification of a novel tryptophan decarboxylase.

Screenings of cheese isolates revealed that the Latilactobacillus curvatus strain FAM25164 formed tryptamine and tyramine. In the present study, it was studied whether a tryptophan decarboxylase, which has rarely been described in bacteria, could be involved in the production of tryptamine. The genome of strain FAM25164 was sequenced and two amino acid decarboxylase genes of interest were identified by sequence comparisons and gene context analyses. One of the two genes, named tdc1, showed 99% identity to the tdcA gene that has recently been demonstrated by knockout studies to play a role in tyramine formation in L. curvatus. The second gene, named tdc2, was predicted to have an amino acid decarboxylase function, but could not be assigned to a metabolic function. Its protein sequence has 51% identity with Tdc1 and the tdc2 gene is part of a gene cluster not often found in publicly available genome sequences of L. curvatus. Among others, the gene cluster includes a tryptophan-tRNA ligase, indicating that tdc2 plays a role in tryptophan metabolism. To study decarboxylase activity, tdc1 and tdc2 were cloned and expressed as His6-tagged proteins in Escherichia coli. The recombinant E. coli expressing tdc1 produced tyramine, whereas E. coli expressing tdc2 produced tryptamine. The purified recombinant Tdc1 protein decarboxylated tyrosine and 2,3-dihydroxy-l-phenylalanine (l-DOPA), but not tryptophan and phenylalanine. In contrast, the purified Tdc2 was capable of decarboxylating tryptophan but not l-DOPA, tyrosine, or phenylalanine. This study describes a novel bacterial tryptophan decarboxylase (EC 4.1.1.105) that may be responsible for tryptamine formation in cheese.