An important hallmark in cancer cells is the increase in glucose uptake. GLUT1 is an important target in cancer treatment because cancer cells upregulate GLUT1, a membrane protein that facilitates ...the basal uptake of glucose in most cell types, to ensure the flux of sugar into metabolic pathways. The dysregulation of GLUT1 is associated with numerous disorders, including cancer and metabolic diseases. There are natural products emerging as a source for inhibitors of glucose uptake, and resveratrol is a molecule of natural origin with many properties that acts as antioxidant and antiproliferative in malignant cells. In the present review, we discuss how GLUT1 is involved in the general scheme of cancer cell metabolism, the mechanism of glucose transport, and the importance of GLUT1 structure to understand the inhibition process. Then, we review the current state-of-the-art of resveratrol and other natural products as GLUT1 inhibitors, focusing on those directed at treating different types of cancer. Targeting GLUT1 activity is a promising strategy for the development of drugs aimed at treating neoplastic growth.
Klebsiella pneumoniae carbapenemase
(KPC-2) is the most commonly encountered class A β-lactamase variant worldwide, which confer high-level resistance to most available antibiotics. In this article ...we address the issue by a combined approach involving molecular dynamics simulations and hybrid quantum mechanics/molecular mechanics calculations. The study contributes to improve the understanding, at molecular level, of the acylation and deacylation stages of avibactam involved in the inhibition of KPC-2. The results show that both mechanisms, acylation and deacylation, the reaction occur via the formation of a tetrahedral intermediate. The formation of this intermediate corresponds to the rate limiting stage. The activation barriers are 19.5 kcal/mol and 23.0 kcal/mol for the acylation and deacylation stages, respectively. The associated rate constants calculated, using the Eyring equation, are 1.2 × 10
−1
and 3.9 × 10
−4
(s
−1
). These values allow estimating a value of 3.3 × 10
−3
for the inhibition constant, in good agreement with the experimental value.
Resveratrol-a polyphenol of natural origin-has been the object of massive research in the past decade because of its potential use in cancer therapy. However, resveratrol has shown an extensive range ...of cellular targets and effects, which hinders the use of the molecule for medical applications including cancer and type 2 diabetes. Here, we review the latest advances in understanding how resveratrol modulates glucose uptake, regulates cellular metabolism, and how this may be useful to improve current therapies. We discuss challenges and findings regarding the inhibition of glucose uptake by resveratrol and other polyphenols of similar chemical structure. We review alternatives that can be exploited to improve cancer therapies, including the use of other polyphenols, or the combination of resveratrol with other molecules and their impact on glucose homeostasis in cancer and diabetes.
is a lepidopteran whose larval stage has shown the ability to degrade polystyrene (PS), one of the most recalcitrant plastics to biodegradation. In the present study, we fed
larvae with PS for 54 ...days and determined candidate enzymes for its degradation. We first confirmed the biodegradation of PS by Fourier transform infrared spectroscopy- Attenuated total reflectance (FTIR-ATR) and then identified candidate enzymes in the larval gut by proteomic analysis using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Two of these proteins have structural similarities to the styrene-degrading enzymes described so far. In addition, potential hydrolases, isomerases, dehydrogenases, and oxidases were identified that show little similarity to the bacterial enzymes that degrade styrene. However, their response to a diet based solely on polystyrene makes them interesting candidates as a potential new group of polystyrene-metabolizing enzymes in eukaryotes.
In recent years, the increase in blood pressure at high altitudes has become an interesting topic among high-altitude researchers. In our animal studies using Wistar rats, we observed the existence ...of two rat populations that exhibit differential physiological responses during hypoxic exposure. These rats were classified as hypoxia-induced hypertensive rats and nonhypertensive rats. A decrease in nitric oxide levels was reported in different hypertension models associated with increased concentrations of asymmetric dimethylarginine (ADMA) and homocysteine, and we recently described an increase in arginase type II expression under hypoxia. ADMA and homocysteine decrease nitric oxide (NO) bioavailability; however, whether ADMA and homocysteine have a regulatory effect on arginase activity and therefore regulate another NO synthesis pathway is unknown. Therefore, the aim of this study was to measure basal ADMA and homocysteine levels in hypoxia-induced hypertensive rats and evaluate their effect on arginase II activity. Our results indicate that hypoxia-induced hypertensive rats presented lower nitric oxide concentrations than nonhypertensive rats, associated with higher concentrations of homocysteine and ADMA. Hypoxia-induced hypertensive rats also presented lower dimethylarginine dimethylaminohydrolase-2 and cystathionine β-synthase levels, which could explain the high ADMA and homocysteine levels. In addition, we observed that both homocysteine and ADMA had a significant effect on arginase II activation in the hypertensive rats. Therefore, we suggest that ADMA and homocysteine have dual regulatory effects on NO synthesis. The former has an inhibitory effect on eNOS, and the latter has a secondary activating effect on arginase II. We propose that arginase II is activated by AMDA and homocysteine in hypoxia-induced hypertensive rats.
Stereotactic surgery is a widely used procedure in neuroscience research to study the brain's regulation of feeding behavior. In line with this notion, this study aims to assess how food consumption ...and feeding patterns are affected in response to the use of auditory bars that preserve or damage the tympanic membrane during stereotactic surgery. Our previous observations led us to hypothesize that the traumatic tympanic membrane rupture affects food intake and feeding patterns in rats undergoing stereotactic procedures. Thereby, female and male rats were cannulated in the third ventricle (3V) using both types of auditory bars. Post-surgical pain was assessed using the grimace scale. Food intake, meal patterns and weight gain or loss were analyzed for 5-7 consecutive days after surgery. Normal food intake, increased body weight and regular meal patterns were observed from postoperative day 2 when the stereotactic procedure was performed using auditory bars that maintain the integrity of the tympanic membrane. However, tympanic membrane rupture prevented the expected recovery of food intake and body weight. This effect was accompanied by an alteration in eating patterns, which was persistent over 7 days of recovery. Thus, tympanic membrane preservation during surgery is necessary to evaluate short-term feeding patterns. This study demonstrates auditory bars that do not damage the tympanic membrane should be used when performing stereotactic surgery for subsequent analysis of rat behavior.
A significant amount of Mandarin Wastewater is generated in the production of canned mandarin segments. To the best of our knowledge, the efficiency of membranes to recover phenolic compounds present ...in Mandarin Wastewater has never been studied before. The highest added value of polyphenols in cosmetic and pharmaceutical industries greatly encourages its purification as much as possible. In this study, different ultrafiltration and nanofiltration membranes were tested, and the best combination was a 5 kDa PES spiral-wound ultrafiltration membrane at 3 bar, followed by the NF270–2540 flat-sheet polypiperazine-amide nanofiltration membrane at 10 bar. Ultrafiltration was able to retain pigments (R = 90 %), pectins (R = 63 %), and sugars (R = 58 %). Then, phenolic compounds passed to the permeate (R = 5 %), which was used as the feed for nanofiltration. Finally, polyphenols were concentrated in the retentate of nanofiltration (R = 80 %), while sugars were partially separated in the permeate (R = 50 %). For a more detailed phenolic profile, liquid chromatography coupled to mass spectrometry was performed with the initial wastewater and the nanofiltration permeate. The results showed a significant rejection of most of the phenolic compounds (rejection >60 %) and the purity of the chemical family of flavonoids was doubled.
•The recovery of phenolic compounds from Mandarin Wastewater was achieved using membrane processes.•The best results were obtained by 5 kDa UF membrane (3 bar), followed by the NF270-2540 membrane (10 bar).•UF retains pigments (R = 90%), pectins (R = 63%), and sugars (R = 58%). Phenolic compounds passed to the permeate (R = 5%).•Polyphenols were concentrated in the NF retentate (R = 80%), while sugars were partially separated in the permeate (R = 50%).
Agmatine is the product of the decarboxylation of L-arginine by the enzyme arginine decarboxylase. This amine has been attributed to neurotransmitter functions, anticonvulsant, anti-neurotoxic, and ...antidepressant in mammals and is a potential therapeutic agent for diseases such as Alzheimer's, Parkinson's, and cancer. Agmatinase enzyme hydrolyze agmatine into urea and putrescine, which belong to one of the pathways producing polyamines, essential for cell proliferation. Agmatinase from
(EcAGM) has been widely studied and kinetically characterized, described as highly specific for agmatine. In this study, we analyze the amino acids involved in the high specificity of EcAGM, performing a series of mutations in two loops critical to the active-site entrance. Two structures in different space groups were solved by X-ray crystallography, one at low resolution (3.2 Å), including a guanidine group; and other at high resolution (1.8 Å) which presents urea and agmatine in the active site. These structures made it possible to understand the interface interactions between subunits that allow the hexameric state and postulate a catalytic mechanism according to the Mn
and urea/guanidine binding site. Molecular dynamics simulations evaluated the conformational dynamics of EcAGM and residues participating in non-binding interactions. Simulations showed the high dynamics of loops of the active site entrance and evidenced the relevance of Trp68, located in the adjacent subunit, to stabilize the amino group of agmatine by cation-pi interaction. These results allow to have a structural view of the best-kinetic characterized agmatinase in literature up to now.
Arginase catalyzes the hydrolysis of L-arginine into L-ornithine and urea. This enzyme has several analogies with agmatinase, which catalyzes the hydrolysis of agmatine into putrescine and urea. ...However, this contrasts with the highlighted specificity that each one presents for their respective substrate. A comparison of available crystal structures for arginases reveals an important difference in the extension of two loops located in the entrance of the active site. The first, denominated loop A (I129-L140) contains the residues that interact with the alpha carboxyl group or arginine of arginase, and the loop B (D181-P184) contains the residues that interact with the alpha amino group of arginine. In this work, to determine the importance of these loops in the specificity of arginase, single, double, and triple arginase mutants in these loops were constructed, as well as chimeras between type I human arginase and E. coli agmatinase. In previous studies, the substitution of N130D in arginase (in loop A) generated a species capable of hydrolyzing arginine and agmatine. Now, the specificity of arginase is completely altered, generating a chimeric species that is only active with agmatine as a substrate, by substituting I129T, N130Y, and T131A together with the elimination of residues P132, L133, and T134. In addition, Quantum Mechanic/Molecular Mechanic (QM/MM) calculations were carried out to study the accommodation of the substrates in in the active site of this chimera. With these results it is concluded that this loop is decisive to discriminate the type of substrate susceptible to be hydrolyzed by arginase. Evidence was also obtained to define the loop B as a structural determinant for substrate affinity. Concretely, the double mutation D181T and V182E generate an enzyme with an essentially unaltered kcat value, but with a significantly increased Km value for arginine and a significant decrease in affinity for its product ornithine.
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