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Abstract Background (R)-Ketamine exhibits rapid and sustained antidepressant effects in animal models of depression. It is stereoselectively metabolized to (R)-norketamine and subsequently to (2R,6R)-hydroxynorketamine in the liver. The metabolism of ketamine to hydroxynorketamine was recently demonstrated to be essential for ketamine’s antidepressant actions. However, no study has compared the antidepressant effects of these 3 compounds in animal models of depression. Methods The effects of a single i.p. injection of (R)-ketamine, (R)-norketamine, and (2R,6R)-hydroxynorketamine in a rat learned helplessness model were examined. Results A single dose of (R)-ketamine (20 mg/kg) showed an antidepressant effect in the rat learned helplessness model. In contrast, neither (R)-norketamine (20 mg/kg) nor (2R,6R)-hydroxynorketamine (20 and 40 mg/kg) did so. Conclusions Unlike (R)-ketamine, its metabolite (2R,6R)-hydroxynorketamine did not show antidepressant actions in the rat learned helplessness model. Therefore, it is unlikely that the metabolism of ketamine to hydroxynorketamine is essential for ketamine’s antidepressant actions.

Phenolamines and flavonoids are two important components in bee pollen. There are many reports on the bioactivity of flavonoids in bee pollen, but few on phenolamines. This study aims to separate and characterize the flavonoids and phenolamines from rape bee pollen, and compare their antioxidant activities and protective effects against oxidative stress. The rape bee pollen was separated to obtain 35% and 50% fractions, which were characterized by HPLC-ESI-QTOF-MS/MS. The results showed that the compounds in 35% fraction were quercetin and kaempferol glycosides, while the compounds in 50% fraction were phenolamines, including di-p-coumaroyl spermidine, p-coumaroyl caffeoyl hydroxyferuloyl spermine, di-p-coumaroyl hydroxyferuloyl spermine, and tri-p-coumaroyl spermidine. The antioxidant activities of phenolamines and flavonoids were evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2’-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid (ABTS), and ferric reducing antioxidant power (FRAP) assays. It was found that the antioxidant activity of phenolamines was significantly higher than that of flavonoids. Moreover, phenolamines showed better protective effects than flavonoids on HepG2 cells injured by AAPH. Furthermore, phenolamines could significantly reduce the reactive oxygen species (ROS), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and increase the superoxide dismutase (SOD) and glutathione (GSH) levels. This study lays a foundation for the further understanding of phenolamines in rape bee pollen.

In response to infestation by herbivores, rice plants rapidly biosynthesize defense compounds by activating a series of defense-related pathways. However, which defensive compounds in rice are effective against herbivores remains largely unknown. We found that the infestation of white-backed planthopper (WBPH) Sogatella furcifera gravid females significantly increased levels of jasmonic acid (JA), jasmonoyl-isoleucine (JA-Ile) and H 2 O 2 , and reduced the level of ethylene in rice; levels of 11 of the tested 12 phenolamides (PAs) were subsequently enhanced. In contrast, WBPH nymph infestation had no effect on levels of JA, JA-Ile, ethylene and H 2 O 2 in rice, and enhanced levels of only 2 of 12 PAs. Moreover, infestation by brown planthopper Nilaparvata lugens gravid females also affected the production of these PAs differently. Bioassays revealed that 4 PAs – N-feruloylputrescine, N-feruloyltyramine, feruloylagmatine and N1,N10-diferuloylspermidine – were toxic to newly emerged WBPH female adults. Our results suggest that WBPH- or BPH-induced biosynthesis of PAs in rice seems to be shaped primarily by the specific profile of defense-related signals elicited by the herbivore and that PAs play a role in conferring the resistance to WBPH on rice.

Branched-chain polyamines (BCPAs), exemplified by N ⁴-bis(aminopropyl)spermidine, are distinctive polycations that occur predominantly in thermophilic bacteria and euryarchaeal archaea. Their dedicated aminopropyltransferase, BpsA (EC 2.5.1.128), extends spermidine into branched architectures via sequential decarboxylated S -adenosylmethionine (dcSAM)-dependent reactions. Accumulated evidence demonstrates that BCPAs engage nucleic acids with substantially higher affinity than linear polyamines such as spermidine, and they uniquely induce strong DNA compaction accompanied by B→A→C structural transitions. These interactions greatly enhance the resistance of DNA to thermal, chemical, and physical damage. Genetic and physiological analyses in Thermococcus kodakarensis further show that loss of BCPA biosynthesis compromises growth at very high temperatures, disrupts temperature- and membrane-associated stress responses, and alters transcriptional and translational regulation; intriguingly, the linear tetraamine thermospermine can partially substitute for BCPA in several of these functions. Beyond cellular physiology, immobilized BCPAs enable sensitive nucleic-acid capture and direct PCR and isothermal DNA amplification from highly dilute solutions, demonstrating their potential utility in molecular diagnostics and environmental DNA workflows. This review synthesizes current knowledge of BCPA distribution, biosynthesis, structure–function relationships, cellular roles, and emerging biotechnological applications, and highlights key open questions in the field.

Infectious diseases caused by trypanosomatids, including African trypanosomiasis (sleeping sickness), Chagas disease, and different forms of leishmaniasis, are Neglected Tropical Diseases affecting millions of people worldwide, mainly in vulnerable territories of tropical and subtropical areas. In general, current treatments against these diseases are old-fashioned, showing adverse effects and loss of efficacy due to misuse or overuse, thus leading to the emergence of resistance. For these reasons, searching for new antitrypanosomatid drugs has become an urgent necessity, and different metabolic pathways have been studied as potential drug targets against these parasites. Considering that trypanosomatids possess a unique redox pathway based on the trypanothione molecule absent in the mammalian host, the key enzymes involved in trypanothione metabolism, trypanothione reductase and trypanothione synthetase, have been studied in detail as druggable targets. In this review, we summarize some of the recent findings on the molecules inhibiting these two essential enzymes for Trypanosoma and Leishmania viability.

Most cases of breast cancer (BrCa) mortality are due to vascular metastasis. BrCa cells must intravasate through endothelial cells (ECs) to enter a blood vessel in the primary tumor and then adhere to ECs and extravasate at the metastatic site. In this study we demonstrate that inhibition of hypoxia-inducible factor (HIF) activity in BrCa cells by RNA interference or digoxin treatment inhibits primary tumor growth and also inhibits the metastasis of BrCa cells to the lungs by blocking the expression of angiopoietin-like 4 (ANGPTL4) and L1 cell adhesion molecule (L1CAM). ANGPTL4 is a secreted factor that inhibits EC-EC interaction, whereas L1CAM increases the adherence of BrCa cells to ECs. Interference with HIF, ANGPTL4 or L1CAM expression inhibits vascular metastasis of BrCa cells to the lungs.

A large number of plants accumulate N-acylated polyamines (phenolamides [PAs]) in response to biotic and/or abiotic stress conditions. In the native tobacco (Nicotiana attenuata), the accumulation of two major PAs, caffeoylputrescine and dicaffeoylspermidine (DCS), after herbivore attack is known to be controlled by a key transcription factor, MYB8. Using a broadly targeted metabolomics approach, we show that a much larger spectrum of PAs composed of hydroxycinnamic acids and two polyamines, putrescine and spermidine, is regulated by this transcription factor. We cloned several novel MYB8-regulated genes, annotated as putative acyltransferases, and analyzed their function. One of the novel acyltransferases (ATI) is shown to encode a hydroxycinnamoyl-coenzyme A: putrescine acyltransferase responsible for caffeoylputrescine biosynthesis in tobacco. Another gene (acyltransferase DH29), specific for spermidine conjugation, mediates the initial acylation step in DCS formation. Although this enzyme was not able to perform the second acylation toward DCS biosynthesis, another acyltransferase gene, CV86, proposed to act on monoacylated spermidines, was isolated and partially characterized. The activation of MYB8 in response to herbivore attack and associated signals required the activity of LIPOXYGENASE3, a gene involved in jasmonic acid (JA) biosynthesis in N. attenuata. These new results allow us to reconstruct a complete branch in JA signaling that defends N. attenuata plants against herbivores: JA via MYB8' s transcriptional control of ATI and DH29 genes controls the entire branch of PA biosynthesis, which allows N.attenuata to mount a chemically diverse (and likely efficient) defense shield against herbivores.

Migraine is a very common, multifactorial, and recurrent central nervous system disorder that causes throbbing headache, photophobia, phonophobia, nausea, and disability. Migraine occurs more often in females, and its complex physiopathology is not yet fully understood. An increasing number of gastrointestinal disorders have been linked to the occurrence of migraine suggesting that gut microbiota might play a pivotal role in migraine through the gut-brain axis. In the present work, we performed a metagenome-wide association study (MWAS) to determine the relationship between gut microbiota and migraine by analyzing 108 shotgun-sequenced fecal samples obtained from elderly women who suffer from migraine and matched healthy controls. Notably, the alpha diversity was significantly decreased in the migraine group at species, genus, and Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologous levels. Firmicutes, especially the \"unfriendly\" spp., were significantly enriched in the migraine group. Conversely, the healthy controls held more beneficial microorganisms, such as , and . For functional modules, the migraine group was enriched in gut-brain modules (GBMs) including kynurenine degradation and γ-aminobutyric acid (GABA) synthesis. However, the healthy controls held higher gut metabolic modules (GMMs) including glycolysis, homoacetogenesis, and GBMs including quinolinic acid degradation and -adenosyl methionine (SAM) synthesis. The differences in gut microbiota composition and function between the migraine and healthy groups provided new information as well as novel therapeutic targets and strategies for migraine treatment, which could help to improve the early diagnosis of the disease, as well as the long-term prognosis and the life quality of patients suffering from migraine.

African trypanosomes cause human sleeping sickness and livestock trypanosomiasis in sub-Saharan Africa. We present the sequence and analysis of the 11 megabase-sized chromosomes of Trypanosoma brucei. The 26-megabase genome contains 9068 predicted genes, including [approximately]900 pseudogenes and [approximately]1700 T. brucei-specific genes. Large subtelomeric arrays contain an archive of 806 variant surface glycoprotein (VSG) genes used by the parasite to evade the mammalian immune system. Most VSG genes are pseudogenes, which may be used to generate expressed mosaic genes by ectopic recombination. Comparisons of the cytoskeleton and endocytic trafficking systems with those of humans and other eukaryotic organisms reveal major differences. A comparison of metabolic pathways encoded by the genomes of T. brucei, T. cruzi, and Leishmania major reveals the least overall metabolic capability in T. brucei and the greatest in L. major. Horizontal transfer of genes of bacterial origin has contributed to some of the metabolic differences in these parasites, and a number of novel potential drug targets have been identified.

Polyamines (PAs) are essential metabolites in eukaryotes, participating in a variety of proliferative processes, and in trypanosomatid protozoa play an additional role in the synthesis of the critical thiol trypanothione. The PAs are synthesized by a metabolic process which involves arginase (ARG), which catalyzes the enzymatic hydrolysis of l-arginine (l-Arg) to l-ornithine and urea, and ornithine decarboxylase (ODC), which catalyzes the enzymatic decarboxylation of l-ornithine in putrescine. The S-adenosylmethionine decarboxylase (AdoMetDC) catalyzes the irreversible decarboxylation of S-adenosylmethionine (AdoMet), generating the decarboxylated S-adenosylmethionine (dAdoMet), which is a substrate, together with putrescine, for spermidine synthase (SpdS). Leishmania parasites and all the other members of the trypanosomatid family depend on spermidine for growth and survival. They can synthesize PAs and polyamine precursors, and also scavenge them from the microenvironment, using specific transporters. In addition, Trypanosomatids have a unique thiol-based metabolism, in which trypanothione (N1-N8-bis(glutathionyl)spermidine, T(SH)₂) and trypanothione reductase (TR) replace many of the antioxidant and metabolic functions of the glutathione/glutathione reductase (GR) and thioredoxin/thioredoxin reductase (TrxR) systems present in the host. Trypanothione synthetase (TryS) and TR are necessary for the protozoa survival. Consequently, enzymes involved in spermidine synthesis and its utilization, i.e. ARG, ODC, AdoMetDC, SpdS and, in particular, TryS and TR, are promising targets for drug development.