Plant Copper Amine Oxidases: Key Players in Hormone Signaling Leading to Stress-Induced Phenotypic Plasticity

Polyamines are ubiquitous, low-molecular-weight aliphatic compounds, present in living organisms and essential for cell growth and differentiation. Copper amine oxidases (CuAOs) oxidize polyamines to aminoaldehydes releasing ammonium and hydrogen peroxide, which participates in the complex network of reactive oxygen species acting as signaling molecules involved in responses to biotic and abiotic stresses. CuAOs have been identified and characterized in different plant species, but the most extensive study on a CuAO gene family has been carried out in Arabidopsis thaliana. Growing attention has been devoted in the last years to the investigation of the CuAO expression pattern during development and in response to an array of stress and stress-related hormones, events in which recent studies have highlighted CuAOs to play a key role by modulation of a multilevel phenotypic plasticity expression. In this review, the attention will be focused on the involvement of different AtCuAOs in the IAA/JA/ABA signal transduction pathways which mediate stress-induced phenotypic plasticity events.     

2-Phenyloxazole-4-carboxamide as a Scaffold for Selective Inhibition of Human Monoamine Oxidase B

A series of 2-phenyloxazoles bearing an amide group at position 4 were designed and synthesized for evaluation as potential inhibitors of human recombinant monoamine oxidases (hrMAOs). Results of kinetics experiments demonstrated that all compounds behave as competitive MAO inhibitors, with good selectivity toward the MAO-B isoform. The most potent and selective derivatives are characterized by inhibition constant (K_i) values in the sub-micromolar range and a good selectivity index (K_{i MAO-A}/K_{i MAO-B}>50). Some derivatives were also found to be able to inhibit MAO activity in nerve growth factor (NGF)-differentiated PC12 cells, taken as a model of neuronal cells. In particular, 2-(2-hydroxyphenyl)-N-phenyloxazole-4-carboxamide (compound 4 a ) may be a promising new scaffold, exerting the highest selectivity and inhibitory effect toward MAOs in NGF-differentiated PC12 cell lysates, without compromising cell viability. Molecular docking analysis allowed a rationalization of the experimentally observed binding affinity and selectivity.     

Flavin-Dependent Enzymes in Cancer Prevention

Statistical studies have demonstrated that various agents may reduce the risk of cancer’s development. One of them is activity of flavin-dependent enzymes such as flavin-containing monooxygenase (FMO)_GS-OX1, FAD-dependent 5,10-methylenetetrahydrofolate reductase and flavin-dependent monoamine oxidase. In the last decade, many papers concerning their structure, reaction mechanism and role in the cancer prevention were published. In our work, we provide a more in-depth analysis of flavin-dependent enzymes and their contribution to the cancer prevention. We present the actual knowledge about the glucosinolate synthesized by flavin-containing monooxygenase (FMO)_GS-OX1 and its role in cancer prevention, discuss the influence of mutations in FAD-dependent 5,10-methylenetetrahydrofolate reductase on the cancer risk, and describe FAD as an important cofactor for the demethylation of histons. We also present our views on the role of riboflavin supplements in the prevention against cancer.     

Synthesis,Biochemistry, and Computational Studies of Brominated Thienyl Chalcones: A New Class of Reversible MAO‐B Inhibitors

A series of (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐(para‐substituted phenyl)prop‐2‐en‐1‐ones ( TB1 – TB11 ) was synthesized and tested for inhibitory activity toward human monoamine oxidase (hMAO). All compounds were found to be competitive, selective, and reversible toward hMAO‐B except (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐(4‐nitrophenyl)prop‐2‐en‐1‐one ( TB7 ) and (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐(4‐chlorophenyl)prop‐2‐en‐1‐one ( TB8 ), which were selective inhibitors of hMAO‐A. The most potent compound, (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐[4‐(dimethylamino)phenyl]prop‐2‐en‐1‐one ( TB5 ), showed the best inhibitory activity and higher selectivity toward hMAO‐B, with K_i and SI values of 0.11±0.01 μm and 13.18, respectively. PAMPA assays for all compounds were carried out in order to evaluate the capacity of the compounds to cross the blood–brain barrier. Moreover, the most potent MAO‐B inhibitor, TB5 , was found to be nontoxic at 5 and 25 μm , with 95.75 and 84.59 % viability among cells, respectively. Molecular docking simulations were carried out to understand the crucial interactions responsible for selectivity and potency.     

Exploration of a Library of 3,4‐(Methylenedioxy)aniline‐Derived Semicarbazones as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase: Design,Synthesis, and Evaluation

A library of 3,4‐(methylenedioxy)aniline‐derived semicarbazones was designed, synthesized, and evaluated as monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitors for the treatment of neurodegenerative diseases. Most of the new compounds selectively inhibited MAO‐B and AChE, with IC₅₀ values in the micro‐ or nanomolar ranges. Compound 16 , 1‐(2,6‐dichlorobenzylidene)‐4‐(benzo[1,3]dioxol‐5‐yl)semicarbazide presented a balanced multifunctional profile of MAO‐A (IC₅₀=4.52±0.032 μm ), MAO‐B (IC₅₀=0.059±0.002 μm ), and AChE (IC₅₀=0.0087±0.0002 μm ) inhibition without neurotoxicity. Kinetic studies revealed that compound 16 exhibits competitive and reversible inhibition against MAO‐A and MAO‐B, and mixed‐type inhibition against AChE. Molecular docking studies further revealed insight into the possible interactions within the enzyme–inhibitor complexes. The most active compounds were found to interact with the enzymes through hydrogen bonding and hydrophobic interactions. Additionally, in silico molecular properties and ADME properties of the synthesized compounds were calculated to explore their drug‐like characteristics.     

Adolescent male rats exposed to social defeat exhibit altered anxiety behavior and limbic monoamines as adults.

Social stress in adolescence is correlated with emergence of psychopathologies during early adulthood. In this study, the authors investigated the impact of social defeat stress during mid-adolescence on adult male brain and behavior. Adolescent male Sprague–Dawley rats were exposed to repeated social defeat for 5 days while controls were placed in a novel empty cage. When exposed to defeat-associated cues as adults, previously defeated rats showed increased risk assessment and behavioral inhibition, demonstrating long-term memory for the defeat context. However, previously defeated rats exhibited increased locomotion in both elevated plus-maze and open field tests, suggesting heightened novelty-induced behavior. Adolescent defeat also affected adult monoamine levels in stress-responsive limbic regions, causing decreased medial prefrontal cortex dopamine, increased norepinephrine and serotonin in the ventral dentate gyrus, and decreased norepinephrine in the dorsal raphe. Our results suggest that adolescent social defeat produces both deficits in anxiety responses and altered monoaminergic function in adulthood. This model offers potential for identifying specific mechanisms induced by severe adolescent social stress that may contribute to increased adult male vulnerability to psychopathology. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pressure Induced Inactivation of Selected Food Enzymes

Pectinesterase, lipase, polyphenol oxidase, lipoxygenase, peroxidase, lactoperoxidase, phosphatase and catalase have been examined at distinct conditions within a pressure range of 0.1 to 900 MPa, temperatures from 25°C to 60°C, pH 3 to 7, and time of treatment of 2 min to 45 min. Results in model buffers made it possible to rank the enzymes according to their pressure induced inactivation in the following order: lipoxygenase, lactoperoxidase, pectinesterase, lipase, phosphatase, catalase, polyphenol oxidase, peroxidase. A combination of pressure with moderate temperature increased the degree of enzyme inactivation. Pressure treatment of real food systems showed a protective effect of food ingredients on the pressure inactivation of most enzymes evaluated. For example sucrose protected pectinesterase from inactivation by pressure while lactoperoxidase and lipoxigenase were as stable in milk as in buffer.     

Indanones As High‐Potency Reversible Inhibitors of Monoamine Oxidase

Recent reports document that α‐tetralone (3,4‐dihydro‐2H‐naphthalen‐1‐one) is an appropriate scaffold for the design of high‐potency monoamine oxidase (MAO) inhibitors. Based on the structural similarity between α‐tetralone and 1‐indanone, the present study involved synthesis of 34 1‐indanone and related indane derivatives as potential inhibitors of recombinant human MAO‐A and MAO‐B. The results show that C6‐substituted indanones are particularly potent and selective MAO‐B inhibitors, with IC₅₀ values ranging from 0.001 to 0.030 μM . C5‐Substituted indanone and indane derivatives are comparatively weaker MAO‐B inhibitors. Although the 1‐indanone and indane derivatives are selective inhibitors of the MAO‐B isoform, a number of homologues are also potent MAO‐A inhibitors, with three homologues possessing IC₅₀ values <0.1 μM . Dialysis of enzyme–inhibitor mixtures further established a selected 1‐indanone as a reversible MAO inhibitor with a competitive mode of inhibition. It may be concluded that 1‐indanones are promising leads for the design of therapies for neurodegenerative and neuropsychiatric disorders such as Parkinson’s disease and depression.