Trace amines are endogenous molecules distributed in the central nervous system and peripheral tissues that resemble common biogenic amines in terms of subcellular localization, chemical structure, and metabolism. Trace amine-associated receptor (TAAR) is a kind of evolutionarily conserved G-protein-coupled receptors in vertebrates, in which TAAR1 is a functional regulator of monoamine transmitters such as dopamine and serotonin. TAAR1 is widely considered as a potential therapeutic target for schizophrenia, depression and drug addiction. Moreover, TAAR1 is also expressed in peripheral tissues. The homeostasis imbalance of trace aminergic system can induce over-activation of peripheral immune system and central immune inflammatory response. TAAR1 modulators are becoming potential emerging drugs for the treatment of immune-related illnesses, because they may play a major role in the activation or modulation of immune response.
Animals ; Humans ; Receptors, G-Protein-Coupled/metabolism* ; Biogenic Amines ; Dopamine ; Substance-Related Disorders

ω-transaminase (ω-TA) is a natural biocatalyst that has good application potential in the synthesis of chiral amines. However, the poor stability and low activity of ω-TA in the process of catalyzing unnatural substrates greatly hampers its application. To overcome these shortcomings, the thermostability of (R)-ω-TA (AtTA) from Aspergillus terreus was engineered by combining molecular dynamics simulation assisted computer-aided design with random and combinatorial mutation. An optimal mutant AtTA-E104D/A246V/R266Q (M3) with synchronously enhanced thermostability and activity was obtained. Compared with the wild- type (WT) enzyme, the half-life t_1/2 (35 ℃) of M3 was prolonged by 4.8-time (from 17.8 min to 102.7 min), and the half deactivation temperature (T¹⁰₅₀) was increased from 38.1 ℃ to 40.3 ℃. The catalytic efficiencies toward pyruvate and 1-(R)-phenylethylamine of M3 were 1.59- and 1.56-fold that of WT. Molecular dynamics simulation and molecular docking showed that the reinforced stability of α-helix caused by the increase of hydrogen bond and hydrophobic interaction in molecules was the main reason for the improvement of enzyme thermostability. The enhanced hydrogen bond of substrate with surrounding amino acid residues and the enlarged substrate binding pocket contributed to the increased catalytic efficiency of M3. Substrate spectrum analysis revealed that the catalytic performance of M3 on 11 aromatic ketones were higher than that of WT, which further showed the application potential of M3 in the synthesis of chiral amines.
Transaminases/chemistry* ; Molecular Docking Simulation ; Amines/chemistry* ; Pyruvic Acid/metabolism* ; Enzyme Stability

Metastasis is one of the main reasons causing death in cancer patients. It was reported that chemotherapy might induce metastasis. In order to uncover the mechanism of chemotherapy-induced metastasis and find solutions to inhibit treatment-induced metastasis, the relationship between epithelial-mesenchymal transition (EMT) and doxorubicin (DOX) treatment was investigated and a redox-sensitive small interfering RNA (siRNA) delivery system was designed. DOX-related reactive oxygen species (ROS) were found to be responsible for the invasiveness of tumor cells in vitro, causing enhanced EMT and cytoskeleton reconstruction regulated by Ras-related C3 botulinum toxin substrate 1 (RAC1). In order to decrease RAC1, a redox-sensitive glycolipid drug delivery system (chitosan-ss-stearylamine conjugate (CSO-ss-SA)) was designed to carry siRNA, forming a gene delivery system (CSO-ss-SA/siRNA) downregulating RAC1. CSO-ss-SA/siRNA exhibited an enhanced redox sensitivity compared to nonresponsive complexes in 10 mmol/L glutathione (GSH) and showed a significant safety. CSO-ss-SA/siRNA could effectively transmit siRNA into tumor cells, reducing the expression of RAC1 protein by 38.2% and decreasing the number of tumor-induced invasion cells by 42.5%. When combined with DOX, CSO-ss-SA/siRNA remarkably inhibited the chemotherapy-induced EMT in vivo and enhanced therapeutic efficiency. The present study indicates that RAC1 protein is a key regulator of chemotherapy-induced EMT and CSO-ss-SA/siRNA silencing RAC1 could efficiently decrease the tumor metastasis risk after chemotherapy.
Amines/chemistry* ; Antineoplastic Agents/adverse effects* ; Breast Neoplasms/pathology* ; Chitosan/chemistry* ; Doxorubicin/adverse effects* ; Drug Delivery Systems ; Epithelial-Mesenchymal Transition/drug effects* ; Female ; Humans ; MCF-7 Cells ; Neoplasm Metastasis/prevention & control* ; Oxidation-Reduction ; RNA, Small Interfering/administration & dosage* ; Reactive Oxygen Species/metabolism* ; rac1 GTP-Binding Protein/physiology*

Animals always seek rewards and the related neural basis has been well studied. However, what happens when animals fail to get a reward is largely unknown, although this is commonly seen in behaviors such as predation. Here, we set up a behavioral model of repeated failure in reward pursuit (RFRP) in Drosophila larvae. In this model, the larvae were repeatedly prevented from reaching attractants such as yeast and butyl acetate, before finally abandoning further attempts. After giving up, they usually showed a decreased locomotor speed and impaired performance in light avoidance and sugar preference, which were named as phenotypes of RFRP states. In larvae that had developed RFRP phenotypes, the octopamine concentration was greatly elevated, while tβh mutants devoid of octopamine were less likely to develop RFRP phenotypes, and octopamine feeding efficiently restored such defects. By down-regulating tβh in different groups of neurons and imaging neuronal activity, neurons that regulated the development of RFRP states and the behavioral exhibition of RFRP phenotypes were mapped to a small subgroup of non-glutamatergic and glutamatergic octopaminergic neurons in the central larval brain. Our results establish a model for investigating the effect of depriving an expected reward in Drosophila and provide a simplified framework for the associated neural basis.
Acetates ; pharmacology ; Animals ; Animals, Genetically Modified ; Avoidance Learning ; physiology ; Biogenic Amines ; metabolism ; Conditioning, Operant ; physiology ; Drosophila ; physiology ; Drosophila Proteins ; genetics ; metabolism ; Feeding Behavior ; drug effects ; physiology ; Instinct ; Larva ; physiology ; Locomotion ; drug effects ; genetics ; Nervous System ; cytology ; Neurons ; physiology ; Octopamine ; metabolism ; RNA Interference ; physiology ; Reward ; Statistics, Nonparametric ; Transcription Factors ; genetics ; metabolism

N-Acyl-4-phenylthiazole-2-amines were designed and synthesized, moreover their effects on acetylcholinesterase activities were tested. N-Acyl-4-phenylthiazole-2-amines were prepared from substituted 2-bromo-1-acetophenones by three steps reaction, and their AChE inhibitory activities were measured by Ellman method in vitro. The results showed that the target compounds had a certain inhibitory activity on AChE in vitro. Among them, 8c was the best, and IC50 of 8c was 0.51 micromol x L(-1), better than that of rivastigmine and Huperzine-A. The inhibitory activities of N-acyl-4-phenylthiazole-2-amines on acetylcholinesterase are worth while to be further studied.
Acetylcholinesterase ; metabolism ; Alkaloids ; pharmacology ; Amines ; chemical synthesis ; pharmacology ; Cholinesterase Inhibitors ; chemical synthesis ; pharmacology ; Drug Design ; Rivastigmine ; pharmacology ; Sesquiterpenes ; pharmacology ; Structure-Activity Relationship ; Thiazoles ; pharmacology

A series of novel N-acyl-thiochromenothiazol-2-amine derivatives were designed and synthesized, furthermore, their inhibition effect on acetylcholinesterase was investigated. N-Acyl-thiochromenothiazol-2-amines were prepared from thiophenol by Hantzsch reaction, acylation reaction and substitution reaction. Moreover, their bioactivities as AChE inhibitors in vitro were measured with Ellman spectrophotometry. The results showed that most of them had a certain inhibition activity on AChE, and the compound 10a was the best in them. The IC50 of 10a to AChE is 7.92 μmol x L(-1), and the value is better than that of rivastigmine. N-Acyl-thiochromenothiazol-2-amine derivatives showed a certain bioactivity in vitro, which were worth further investigation.
Acetylcholinesterase ; metabolism ; Amines ; chemical synthesis ; pharmacology ; Benzopyrans ; chemical synthesis ; pharmacology ; Cholinesterase Inhibitors ; chemical synthesis ; pharmacology ; Rivastigmine ; Structure-Activity Relationship ; Thiazoles ; chemical synthesis ; pharmacology

We examined the possible anti-inflammatory mechanisms of gabapentin in the attenuation of neuropathic pain and the interaction between the anti-allodynic effects of gabapentin and interleukin-10 (IL-10) expression in a rat model of neuropathic pain. The anti-allodynic effect of intrathecal gabapentin was examined over a 7-day period. The anti-allodynic effects of IL-10 was measured, and the effects of anti-IL-10 antibody on the gabapentin were assessed. On day 7, the concentrations of pro-inflammatory cytokines and IL-10 were measured. Gabapentin produced an anti-allodynic effect over the 7-day period, reducing the expression of pro-inflammatory cytokines but increasing the expression of IL-10 (TNF-alpha, 316.0 +/- 69.7 pg/mL vs 88.8 +/- 24.4 pg/mL; IL-1beta, 1,212.9 +/- 104.5 vs 577.4 +/- 97.1 pg/mL; IL-6, 254.0 +/- 64.8 pg/mL vs 125.5 +/- 44.1 pg/mL; IL-10, 532.1 +/- 78.7 pg/mL vs 918.9 +/- 63.1 pg/mL). The suppressive effect of gabapentin on pro-inflammatory cytokine expression was partially blocked by the anti-IL-10 antibody. Expression of pro-inflammatory cytokines was significantly attenuated by daily injections of IL-10. The anti-allodynic effects of gabapentin may be caused by upregulation of IL-10 expression in the spinal cord, which leads to inhibition of the expression of pro-inflammatory cytokines in the spinal cords.
Amines/pharmacology/*therapeutic use ; Analgesics/pharmacology/*therapeutic use ; Animals ; Antibodies/immunology/pharmacology ; Behavior, Animal/drug effects ; Cyclohexanecarboxylic Acids/pharmacology/*therapeutic use ; Cytokines/*metabolism ; Disease Models, Animal ; Injections, Spinal ; Interleukin-10/genetics/immunology/*metabolism ; Male ; Neuralgia/*drug therapy/metabolism/pathology ; Rats ; Rats, Sprague-Dawley ; Recombinant Proteins/biosynthesis/genetics/pharmacology ; Spinal Cord/metabolism ; Up-Regulation ; gamma-Aminobutyric Acid/pharmacology/*therapeutic use

Liver X receptor (LXR), a member of the superfamily of nuclear receptors, plays an important role in the activation of transcription factors involved in cholesterol metabolism, glucose homeostasis inflammation and lipogenesis. It is shown that LXR agnoists have the potentiality to be used as drugs for the prevention and treatment of atherosclerosis, which is its best investigated therapeutic indication. There are many compounds being studied in preclinical evaluation and biological assay. This paper will review briefly the LXR agonists in recent years.
ATP-Binding Cassette Transporters ; metabolism ; Amines ; chemical synthesis ; chemistry ; pharmacology ; Animals ; Atherosclerosis ; drug therapy ; metabolism ; Benzimidazoles ; chemical synthesis ; chemistry ; pharmacology ; Cholesterol ; analogs & derivatives ; pharmacology ; Glucose ; analogs & derivatives ; pharmacology ; Humans ; Lipid Metabolism ; Lipogenesis ; Liver X Receptors ; Orphan Nuclear Receptors ; agonists ; physiology ; Quinolines ; chemical synthesis ; chemistry ; pharmacology ; Sterol Regulatory Element Binding Protein 1 ; metabolism

BACKGROUNDGabapentin has been widely and successfully used in the clinic for many neuropathic pain syndromes since last decade, however its analgesic mechanisms are still elusive. Our study was to investigate whether Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) contributes to the analgesic effect of gabapentin on a chronic constriction injury (CCI) model.

METHODSGabapentin (2%, 100 mg/kg) or saline (0.5 ml/100 g) was injected intraperitoneally 15 minutes prior to surgery and then every 12 hours from postoperative day 0 - 4 to all rats in control, sham and CCI groups. The analgesic effect of gabapentin was assessed by measuring mechanical allodynia and thermal hyperalgesia of rats. Expression and activation of CaMKII were quantified by reverse-transcriptional polymerase chain reaction and Western blotting.

RESULTSThe analgesic effect of gabapentin on mechanical allodynia and thermal hyperalgesia was significant in the CCI model, with maximal reduction reached on postoperative day 8. Gabapentin decreased the expression of the total CaMKII and phosphorylated CaMKII in CCI rats.

CONCLUSIONThe analgesic effect of gabapentin on CCI rats may be related to the decreased expression and phosphorylation of CaMKII in the spinal cord.

Amines ; therapeutic use ; Analgesics ; therapeutic use ; Animals ; Blotting, Western ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 ; metabolism ; Cyclohexanecarboxylic Acids ; therapeutic use ; Male ; Neuralgia ; drug therapy ; metabolism ; Rats ; Rats, Sprague-Dawley ; gamma-Aminobutyric Acid ; therapeutic use

This study was designed to determine whether early gabapentin treatment has a protective analgesic effect on neuropathic pain and compared its effect to the late treatment in a rat neuropathic model, and as the potential mechanism of protective action, the alpha2delta1-subunit of the voltage-dependent calcium channel (alpha2delta1-subunit) was evaluated in both sides of the L5 dorsal root ganglia (DRG). Neuropathic pain was induced in male Sprague-Dawley rats by a surgical ligation of left L5 nerve. For the early treatment group, rats were injected with gabapentin (100 mg/kg) intraperitoneally 15 min prior to surgery and then every 24 hr during postoperative day (POD) 1-4. For the late treatment group, the same dose of gabapentin was injected every 24 hr during POD 8-12. For the control group, L5 nerve was ligated but no gabapentin was administered. In the early treatment group, the development of allodynia was delayed up to POD 10, whereas allodynia was developed on POD 2 in the control and the late treatment group (p<0.05). The alpha2delta1-subunit was up-regulated in all groups, however, there was no difference in the level of the alpha2delta1-subunit among the three groups. These results suggest that early treatment with gabapentin offers some protection against neuropathic pain but it is unlikely that this action is mediated through modulation of the alpha2delta1-subunit in DRG.
Amines/administration & dosage/*therapeutic use ; Analgesics/administration & dosage/*therapeutic use ; Animals ; Calcium Channels/genetics/*metabolism ; Cyclohexanecarboxylic Acids/administration & dosage/*therapeutic use ; Disease Models, Animal ; Injections, Intraperitoneal ; Ligation ; Male ; Neuralgia/*drug therapy/metabolism ; Pain Measurement ; Protein Subunits/genetics/metabolism ; Rats ; Rats, Sprague-Dawley ; Spinal Nerves/surgery ; Up-Regulation ; gamma-Aminobutyric Acid/administration & dosage/*therapeutic use