Search Results (9)

Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising therapeutic target for treating various cancers (such as breast cancer, liver cancer, etc.) and other diseases (blood diseases, cardiovascular diseases, etc.), owing to its observed overexpression, thereby presenting significant opportunities in drug development. Since its discovery in 2004, extensive research has been conducted on LSD1 inhibitors, with notable contributions from computational approaches. This review systematically summarizes LSD1 inhibitors investigated through computer-aided drug design (CADD) technologies since 2010, showcasing a diverse range of chemical scaffolds, including phenelzine derivatives, tranylcypromine (abbreviated as TCP or 2-PCPA) derivatives, nitrogen-containing heterocyclic (pyridine, pyrimidine, azole, thieno[3,2-b]pyrrole, indole, quinoline and benzoxazole) derivatives, natural products (including sanguinarine, phenolic compounds and resveratrol derivatives, flavonoids and other natural products) and others (including thiourea compounds, Fenoldopam and Raloxifene, (4-cyanophenyl)glycine derivatives, propargylamine and benzohydrazide derivatives and inhibitors discovered through AI techniques). Computational techniques, such as virtual screening, molecular docking and 3D-QSAR models, have played a pivotal role in elucidating the interactions between these inhibitors and LSD1. Moreover, the integration of cutting-edge technologies such as artificial intelligence holds promise in facilitating the discovery of novel LSD1 inhibitors. The comprehensive insights presented in this review aim to provide valuable information for advancing further research on LSD1 inhibitors. Full article

Methamphetamine (meth) is a neurotoxic psychostimulant that increases monoamine oxidase (MAO)-dependent mitochondrial oxidant stress in axonal but not somatic compartments of substantia nigra pars compacta (SNc) and locus coeruleus (LC) neurons. Chronic meth administration results in the degeneration of SNc and LC neurons in male mice, and MAO inhibition is neuroprotective, suggesting that the deleterious effects of chronic meth begin in axons before advancing to the soma of SNc and LC neurons. To test this hypothesis, mice were administered meth (5 mg/kg) for 14, 21, or 28 days, and SNc and LC axonal lengths and numbers of neurons were quantified. In male mice, the SNc and LC axon lengths decreased with 14, 21, and 28 days of meth, whereas somatic loss was only observed after 28 days of meth; MAO inhibition (phenelzine; 20 mg/kg) prevented axonal and somatic loss of SNc and LC neurons. In contrast, chronic (28-day) meth had no effect on the axon length or numbers of SNc or LC neurons in female mice. The results demonstrate that repeated exposure to meth produces SNc and LC axonal deficits prior to somatic loss in male subjects, consistent with a dying-back pattern of degeneration, whereas female mice are resistant to chronic meth-induced degeneration. Full article

Dysregulated brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signalling is implicated in several neurodegenerative diseases, including Alzheimer’s disease. A failure of neurotrophic support may participate in neurodegenerative mechanisms, such as ferroptosis, which has likewise been implicated in this disease class. The current study investigated whether modulators of TrkB signalling affect ferroptosis. Cell viability, C11 BODIPY, and cell-free oxidation assays were used to observe the impact of TrkB modulators, and an immunoblot assay was used to detect TrkB expression. TrkB modulators such as agonist BDNF, antagonist ANA-12, and inhibitor K252a did not affect RSL3-induced ferroptosis sensitivity in primary cortical neurons expressing detectable TrkB receptors. Several other modulators of the TrkB receptor, including agonist 7,8-DHF, activator phenelzine sulphate, and inhibitor GNF-5837, conferred protection against a range of ferroptosis inducers in several immortalised neuronal and non-neuronal cell lines, such as N27 and HT-1080 cells. We found these immortalised cell lines lack detectable TrkB receptor expression, so the anti-ferroptotic activity of these TrkB modulators was most likely due to their inherent radical-trapping antioxidant properties, which should be considered when interpreting their experimental findings. These modulators or their variants could be potential anti-ferroptotic therapeutics for various diseases. Full article

Non-typhoidal Salmonella ingeniously scavenges energy for growth from tyramine (TYR) and d-glucuronic acid (DGA), both of which occur in the host as the metabolic byproducts of the gut microbial metabolism. A critical first step in energy scavenging from TYR and DGA in Salmonella involves TYR-oxidation via TYR-oxidoreductase and production of free-DGA via β-glucuronidase (GUS)-mediated hydrolysis of d-glucuronides (conjugated form of DGA), respectively. Here, we report that Salmonella utilizes TYR and DGA as sole sources of energy in a serotype-independent manner. Using colorimetric and radiometric approaches, we report that genes SEN2971, SEN3065, and SEN2426 encode TYR-oxidoreductases. Some Salmonella serotypes produce GUS, thus can also scavenge energy from d-glucuronides. We repurposed phenelzine (monoaminoxidase-inhibitor) and amoxapine (GUS-inhibitor) to inhibit the TYR-oxidoreductases and GUS encoded by Salmonella, respectively. We show that phenelzine significantly inhibits the growth of Salmonella by inhibiting TYR-oxidoreductases SEN2971, SEN3065, and SEN2426. Similarly, amoxapine significantly inhibits the growth of Salmonella by inhibiting GUS-mediated hydrolysis of d-glucuronides. Because TYR and DGA serve as potential energy sources for Salmonella growth in vivo, the data and the novel approaches used here provides a better understanding of the role of TYR and DGA in Salmonella pathogenesis and nutritional virulence. Full article

Cycas pectinata Buch.-Ham. is commonly used in folk medicine against various disorders. The present study investigated the antidepressant and cytotoxicity activity of methanol extract of C. pectinata (MECP) along with quantitative phytochemical analysis by GC-MS method. Here, the GC-MS study of MECP presented 41 compounds, among which most were fatty acids, esters, terpenoids and oximes. The antidepressant activity was assessed by the forced swimming test (FST) and tail suspension test (TST) models. In contrast, MECP (200 and 400 mg/kg) exhibited a significant and dose-dependent manner reduction in immobility comparable with fluoxetine (10 mg/kg) and phenelzine (20 mg/kg). MECP showed a weak toxicity level in the brine shrimp lethality bioassay (ED₅₀: 358.65 µg/mL) comparable to the standard drug vincristine sulfate (ED₅₀: 2.39 µg/mL). Three compounds from the GC-MS study were subjected to density functional theory (DFT) calculations, where only cyclopentadecanone oxime showed positive and negative active binding sites. Cyclopentadecanone oxime also showed a good binding interaction in suppressing depression disorders by blocking monoamine oxidase and serotonin receptors with better pharmacokinetic and toxicological properties. Overall, the MECP exhibited a significant antidepressant activity with moderate toxicity, which required further advance studies to identify the mechanism. Full article

Treatment with several antipsychotic drugs exhibits a tendency to induce weight gain and diabetic complications. The proposed mechanisms by which the atypical antipsychotic drug olanzapine increases body weight include central dysregulations leading to hyperphagia and direct peripheral impairment of fat cell lipolysis. Several investigations have reproduced in vitro direct actions of antipsychotics on rodent adipocytes, cultured preadipocytes, or human adipose tissue-derived stem cells. However, to our knowledge, no such direct action has been described in human mature adipocytes. The aim of the present study was to compare in human adipocytes the putative direct alterations of lipolysis by antipsychotics (haloperidol, olanzapine, ziprazidone, risperidone), antidepressants (pargyline, phenelzine), or anxiolytics (opipramol). Lipolytic responses to the tested drugs, and to recognized lipolytic (e.g., isoprenaline) or antilipolytic agents (e.g., insulin) were determined, together with glucose transport and amine oxidase activities in abdominal subcutaneous adipocytes from individuals undergoing plastic surgery. None of the tested drugs were lipolytic. Surprisingly, only opipramol exhibited substantial antilipolytic properties in the micromolar to millimolar range. An opipramol antilipolytic effect was evident against isoprenaline-, forskolin-, or atrial natriuretic peptide-stimulated lipolysis. Opipramol did not impair insulin activation of glucose transport but inhibited monoamine oxidase (MAO) activity to the same extent as antidepressants recognized as MAO inhibitors (pargyline, harmine, or phenelzine), whereas antipsychotics were inefficient. Considering its unique properties, opipramol, which is not associated with weight gain in treated patients, is a good candidate for drug repurposing because it limits exaggerated lipolysis, prevents hydrogen peroxide release by amine oxidases in adipocytes, and is thereby of potential use to limit lipotoxicity and oxidative stress, two deleterious complications of diabetes and obesity. Full article

Acute kidney injury (AKI) refers to an abrupt decrease in kidney function. It affects approximately 7% of all hospitalized patients and almost 35% of intensive care patients. Mortality from acute kidney injury remains high, particularly in critically ill patients, where it can be more than 50%. The primary causes of AKI include ischemia/reperfusion (I/R), sepsis, or nephrotoxicity; however, AKI patients may present with a complicated etiology where many of the aforementioned conditions co-exist. Multiple bio-markers associated with renal damage, as well as metabolic and signal transduction pathways that are involved in the mediation of renal dysfunction have been identified as a result of the examination of models, patient samples, and clinical data of AKI of disparate etiologies. These discoveries have enhanced our ability to diagnose AKIs and to begin to elucidate the mechanisms involved in their pathogenesis. Studies in our laboratory revealed that the expression and activity of spermine/spermidine N¹-acetyltransferase (SAT1), the rate-limiting enzyme in polyamine back conversion, were enhanced in kidneys of rats after I/R injury. Additional studies revealed that the expression of spermine oxidase (SMOX), another critical enzyme in polyamine catabolism, is also elevated in the kidney and other organs subjected to I/R, septic, toxic, and traumatic injuries. The maladaptive role of polyamine catabolism in the mediation of AKI and other injuries has been clearly demonstrated. This review will examine the biochemical and mechanistic basis of tissue damage brought about by enhanced polyamine degradation and discuss the potential of therapeutic interventions that target polyamine catabolic enzymes or their byproducts for the treatment of AKI. Full article

Background: Two classes of amine oxidases are found in mammals: those with a flavin adenine dinucleotide as a cofactor, such as monoamine oxidases (MAO) and lysine-specific demethylases (LSD), and those with copper as a cofactor, including copper-containing amine oxidases (AOC) and lysyl oxidases (LOX). All are expressed in adipose tissue, including a semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1) strongly present on the adipocyte surface. Methods: Previously, irreversible MAO inhibitors have been reported to limit food intake and/or fat extension in rodents; however, their use for the treatment of depressed patients has not revealed a clear anti-obesity action. Semicarbazide and other molecules inhibiting SSAO/VAP-1 also reduce adiposity in obese rodents. Results: Recently, a LOX inhibitor and a subtype-selective MAO inhibitor have been shown to limit fattening in high-fat diet-fed rats. Phenelzine, which inhibits MAO and AOC, limits adipogenesis in cultured preadipocytes and impairs lipogenesis in mature adipocytes. When tested in rats or mice, phenelzine reduces food intake and/or fat accumulation without cardiac adverse effects. Novel amine oxidase inhibitors have been recently characterized in a quest for promising anti-inflammatory or anti-cancer approaches; however, their capacity to mitigate obesity has not been studied so far. Conclusions: The present review of the diverse effects of amine oxidase inhibitors impairing adipocyte differentiation or limiting excessive fat accumulation indicates that further studies are needed to reveal their potential anti-obesity properties. Full article

Phenelzine has been suggested to have an antiobesity effect by inhibiting de novo lipogenesis, which led us to investigate the metabolic effects of oral chronic phenelzine treatment in high-sucrose-drinking mice. Sucrose-drinking mice presented higher body weight gain and adiposity versus controls. Phenelzine addition did not decrease such parameters, even though fat pad lipid content and weights were not different from controls. In visceral adipocytes, phenelzine did not impair insulin-stimulated de novo lipogenesis and had no effect on lipolysis. However, phenelzine reduced the mRNA levels of glucose transporters 1 and 4 and phosphoenolpyruvate carboxykinase in inguinal white adipose tissue (iWAT), and altered circulating levels of free fatty acids (FFA) and glycerol. Interestingly, glycemia was restored in phenelzine-treated mice, which also had higher insulinaemia. Phenelzine-treated mice presented higher rectal temperature, which was associated to reduced mRNA levels of uncoupling protein 1 in brown adipose tissue. Furthermore, unlike sucrose-drinking mice, hepatic malondialdehyde levels were not altered. In conclusion, although de novo lipogenesis was not inhibited by phenelzine, the data suggest that the ability to re-esterify FFA is impaired in iWAT. Moreover, the effects on glucose homeostasis and oxidative stress suggest that phenelzine could alleviate obesity-related alterations and deserves further investigation in obesity models. Full article