Motion-Compensated Predictive RAHT for Dynamic Point Clouds.

We study the use of predictive approaches alongside the region-adaptive hierarchical transform (RAHT) in attribute compression of dynamic point clouds. The use of intra-frame prediction with RAHT was shown to improve attribute compression performance over pure RAHT and represents the state-of-the-art in attribute compression of point clouds, being part of MPEG's geometry-based test model. We studied a combination of inter-frame and intra-frame prediction for RAHT for the compression of dynamic point clouds. An adaptive zero-motion-vector (ZMV) scheme and an adaptive motion-compensated scheme are developed. The simple adaptive ZMV approach is able to achieve sizable gains over pure RAHT and over the intra-frame predictive RAHT (I-RAHT) for point clouds with little or no motion while ensuring similar compression performance to I-RAHT for point clouds with intense motion. The motion-compensated approach, more complex and more powerful, is able to achieve large gains across all of the tested dynamic point clouds.

Zgli: A Pipeline for Clustering by Compression with Application to Patient Stratification in Spondyloarthritis.

The normalized compression distance (NCD) is a similarity measure between a pair of finite objects based on compression. Clustering methods usually use distances (e.g., Euclidean distance, Manhattan distance) to measure the similarity between objects. The NCD is yet another distance with particular characteristics that can be used to build the starting distance matrix for methods such as hierarchical clustering or K-medoids. In this work, we propose Zgli, a novel Python module that enables the user to compute the NCD between files inside a given folder. Inspired by the CompLearn Linux command line tool, this module iterates on it by providing new text file compressors, a new compression-by-column option for tabular data, such as CSV files, and an encoder for small files made up of categorical data. Our results demonstrate that compression by column can yield better results than previous methods in the literature when clustering tabular data. Additionally, the categorical encoder shows that it can augment categorical data, allowing the use of the NCD for new data types. One of the advantages is that using this new feature does not require knowledge or context of the data. Furthermore, the fact that the new proposed module is written in Python, one of the most popular programming languages for machine learning, potentiates its use by developers to tackle problems with a new approach based on compression. This pipeline was tested in clinical data and proved a promising computational strategy by providing patient stratification via clusters aiding in precision medicine.

Edible mechanical metamaterials with designed fracture for mouthfeel control.

Metamaterials can display unusual and superior properties that come from their carefully designed structure rather than their composition. Metamaterials have permeated large swatches of science, including electromagnetics and mechanics. Although metamaterials hold the promise for realizing technological advances, their potential to enhance interactions between humans and materials has largely remained unexplored. Here, we devise a class edible mechanical metamaterials with tailored fracture properties to control mouthfeel sensory experience. Using chocolate as a model material, we first demonstrate how to create and control the fracture anisotropy, and the number of cracks, and demonstrate that these properties are captured in mouthfeel experience. We further use topology optimization to rationally design edible metamaterials with maximally anisotropic fracture strength. Our work opens avenues for the use of metamaterials to control fracture and to enhance human-matter interactions.

On Conditional Tsallis Entropy.

There is no generally accepted definition for conditional Tsallis entropy. The standard definition of (unconditional) Tsallis entropy depends on a parameter α that converges to the Shannon entropy as α approaches 1. In this paper, we describe three proposed definitions of conditional Tsallis entropy suggested in the literature-their properties are studied and their values, as a function of α, are compared. We also consider another natural proposal for conditional Tsallis entropy and compare it with the existing ones. Lastly, we present an online tool to compute the four conditional Tsallis entropies, given the probability distributions and the value of the parameter α.

The Entropy Universe.

About 160 years ago, the concept of entropy was introduced in thermodynamics by Rudolf Clausius. Since then, it has been continually extended, interpreted, and applied by researchers in many scientific fields, such as general physics, information theory, chaos theory, data mining, and mathematical linguistics. This paper presents The Entropy Universe, which aims to review the many variants of entropies applied to time-series. The purpose is to answer research questions such as: How did each entropy emerge? What is the mathematical definition of each variant of entropy? How are entropies related to each other? What are the most applied scientific fields for each entropy? We describe in-depth the relationship between the most applied entropies in time-series for different scientific fields, establishing bases for researchers to properly choose the variant of entropy most suitable for their data. The number of citations over the past sixteen years of each paper proposing a new entropy was also accessed. The Shannon/differential, the Tsallis, the sample, the permutation, and the approximate entropies were the most cited ones. Based on the ten research areas with the most significant number of records obtained in the Web of Science and Scopus, the areas in which the entropies are more applied are computer science, physics, mathematics, and engineering. The universe of entropies is growing each day, either due to the introducing new variants either due to novel applications. Knowing each entropy's strengths and of limitations is essential to ensure the proper improvement of this research field.

A Private Quantum Bit String Commitment.

We propose an entanglement-based quantum bit string commitment protocol whose composability is proven in the random oracle model. This protocol has the additional property of preserving the privacy of the committed message. Even though this property is not resilient against man-in-the-middle attacks, this threat can be circumvented by considering that the parties communicate through an authenticated channel. The protocol remains secure and private (but not composable) if we realize the random oracles as physical unclonable functions (PUFs) in the so-called bad PUF model.

A new diagnostic strategy which uses a luminol-H2O2 system to detect helminth eggs in fecal sediments processed by the Helmintex method.

Schistosomiasis remains a serious public health problem in tropical regions, affecting more than 250 million people. Sensitive diagnostic methods represent key tools for disease elimination, in particular in areas with low endemicity. Advances in the use of luminol-based chemiluminescent techniques have enabled greater sensitivity and speed in obtaining results in different diagnostic settings. In this study, we developed a luminol-H2O2 chemiluminescence (CL) method to detect Schistosoma mansoni eggs in human fecal sediments processed by the Helmintex (HTX) method. After S. mansoni eggs were incubated with a solution of luminol-H2O2 the light emission was detected and measured by spectrophotometry at 431 nm for 5 min, using detection and counts of eggs by bright field optical microscopy as a reference. CL intensity was found to correlate with different sources and numbers of eggs. Furthermore, our results showed that the CL method can distinguish positive from negative samples with 100% sensitivity and 71% specificity. To our knowledge, this is the first study to report the use of CL for the diagnosis of helminths from fecal samples. The combination of the HTX method with CL represents an important advance in providing a reference method with the highest standards of sensitivity.

Improvement of Resveratrol Effects When Combined with Rice Oil in Rat Models of Inflammation.

This study investigated the effects of systemic treatment with a new formulation of resveratrol (RSV) vehicled in rice oil (RSVO) in experimental rat models of inflammation. Male Wistar rats were evaluated in the following in vivo models: carrageenan-induced acute edema, complete Freund's adjuvant (CFA)-evoked sub-chronic edema, and CFA-induced polyarthritis. The animals were treated orally with RSVO (10-15 mg/kg) or RSV (100-200 mg/kg), depending on the experimental protocol. RSV was more effective than RSVO in carrageenan-elicited acute edema when dosed in either prophylactic or therapeutic schemes of administration. However, the repeated RSVO administration, at 10-fold lower doses, exhibited superior anti-inflammatory actions in either the sub-chronic edema or the chronic polyarthritis model elicited by CFA, when compared with RSV. The novel formulation RSVO displayed a lower plasma biotransformation when compared with the RSV-treated group-46% versus 88% of metabolites, respectively. RSVO also prevented polyarthritis-related cartilage destruction, an effect that might rely on the inhibition of the pro-inflammatory cytokine interleukin-6 (IL-6), associated with an increase of the anti-inflammatory cytokine interleukin-10 (IL-10). Noteworthy, the long-term administration of RSVO did not elicit any gastrointestinal harm. Our study revealed that RSVO was notably effective in the long-term inflammatory and degenerative responses triggered by CFA. This innovative formulation might well represent a promising alternative for treating chronic inflammatory diseases, such as arthritis.

Effect of grape seed extract-containing phosphoric acid formulations on bonding to enamel and dentin.

The aim was to evaluate the effect of 2% grape seed extract (GSE) containing phosphoric acid (PhA) on the bond strength to enamel and dentin. The control group was 37% PhA. The following three PhA formulations with 2% GSE and 20% ethanol were obtained: GSE5 = 5% PhA; GSE10 = 10% PhA; and GSE20 = 20% PhA. The enamel and dentin surfaces of molars were etched with the acid solutions, followed by Scotchbond Multi-Purpose adhesive and composite resin application. The tensile bond strength (TBS) test evaluated the bond to enamel after 24 h, and the microtensile bond strength (µTBS) test evaluated the bond to dentin after 24 h and 12-month water storage. Etched enamel and dentin were observed by scanning electron microscopy (SEM) and atomic force microscopy (AFM), respectively. The TBS data were submitted to one-way ANOVA, while µTBS data were submitted to two-way ANOVA and Tukey's test (α = 0.05). The TBS (MPa) to enamel did not significantly differ among the control (48.1 ± 15.7), GSE5 (46.1 ± 9.6), GSE10 (49.8 ± 13.6) and GSE20 (44.1 ± 11.9) groups (p = 0.537). The µTBS (MPa) to dentin of the control (28.4 ± 14.4) and GSE20 (24.1 ± 8.1) groups were significantly higher than those of the GSE5 (16.8 ± 7.4) and GSE10 (17.5 ± 6.6) groups at 24 h (p < 0.006). After 12-month storage, only GSE5 (21.0 ± 7.8) and GSE10 (17.6 ± 8.0) did not show significantly decreased µTBS (p > 0.145). SEM micrographs showed a shallower enamel etching pattern for GSE5. AFM images showed the formation of collagenous globular structures for GSE5 and GSE10. The different acid solutions did not influence the TBS to enamel, and the µTBS to dentin was stable over time when dentin was etched with GSE5 and GSE10.

Cross Talk between Apical Periodontitis and Metabolic Disorders: Experimental Evidence on the Role of Intestinal Adipokines and Akkermansia muciniphila.

INTRODUCTION: Infection and dysbiosis present a close relationship with metabolic diseases although the influence of apical periodontitis (AP) in this context needs further investigation. This study evaluated the influence of AP in a rat model of metabolic syndrome induced by 10% fructose supplementation. METHODS: Male Wistar rats were used. Animals that received a high-fructose diet (HFD, n = 30) or filtered water (control, n = 30) were subdivided into the following groups: (1) without induction of AP (no AP, n = 10 each), (2) with AP induction 2 weeks before euthanasia (AP 14 days, n = 10 each), and (3) with AP induction 4 weeks before euthanasia (AP 28 days, n = 10 each). RESULTS: HFD triggered metabolic syndrome, as indicated by the induction of overweight and hyperglycemia, besides polydipsia, regardless of the AP induction. Serum or intestinal tumor necrosis factor, interleukin 1 beta, and interleukin 6 levels were undetectable, regardless of the experimental group. Serum leptin and adiponectin levels were significantly elevated in the HFD group without AP induction. The intestinal levels of leptin were significantly increased in the groups with 28 days of AP induction despite HFD. A significant elevation of liver glutathione levels was observed in animals submitted to HFD and AP for 14 days. AP induction (14 or 28 days) led to pulp and periapical tissue inflammation without any influence of HFD. Either HFD or AP induction led to dysbiosis, as indicated by a significant reduction of fecal A. muciniphila expression. CONCLUSIONS: We provide novel evidence that AP can have systemic impacts on metabolic disorders, likely by modulating intestinal metabolism and microbiota.

Cyclin-Dependent Kinase 2 in Cellular Senescence and Cancer. A Structural and Functional Review.

BACKGROUND: Cyclin-dependent kinase 2 (CDK2) has been studied due to its role in the cell-cycle progression. The elucidation of the CDK2 structure paved the way to investigate the molecular basis for inhibition of this enzyme, with the coordinated efforts combining crystallography with functional studies. OBJECTIVE: Our goal here is to review recent functional and structural studies directed to understanding the role of CDK2 in cancer and senescence. METHODS: There are over four hundreds of crystallographic structures available for CDK2, many of them with binding affinity information. We use this abundance of data to analyze the essential features responsible for the inhibition of CDK2 and its function in cancer and senescence. RESULTS: The structural and affinity data available CDK2 makes it possible to have a clear view of the vital CDK2 residues involved in molecular recognition. A detailed description of the structural basis for ligand binding is of pivotal importance in the design of CDK2 inhibitors. Our analysis shows the relevance of the residues Leu 83 and Asp 86 for binding affinity. The recent findings revealing the participation of CDK2 inhibition in senescence open the possibility to explore the richness of structural and affinity data for a new era in the development of CDK2 inhibitors, targeting cellular senescence. CONCLUSION: Here, we analyzed structural information for CDK2 in combination with inhibitors and mapped the molecular aspects behind the strongest CDK2 inhibitors for which structures and ligandbinding affinity data were available. From this analysis, we identified the significant intermolecular interactions responsible for binding affinity. This knowledge may guide the future development of CDK2 inhibitors targeting cancer and cellular senescence.

Effect of grape seed extract-containing phosphoric acid formulations on bonding to enamel and dentin

Abstract The aim was to evaluate the effect of 2% grape seed extract (GSE) containing phosphoric acid (PhA) on the bond strength to enamel and dentin. The control group was 37% PhA. The following three PhA formulations with 2% GSE and 20% ethanol were obtained: GSE5 = 5% PhA; GSE10 = 10% PhA; and GSE20 = 20% PhA. The enamel and dentin surfaces of molars were etched with the acid solutions, followed by Scotchbond Multi-Purpose adhesive and composite resin application. The tensile bond strength (TBS) test evaluated the bond to enamel after 24 h, and the microtensile bond strength (μTBS) test evaluated the bond to dentin after 24 h and 12-month water storage. Etched enamel and dentin were observed by scanning electron microscopy (SEM) and atomic force microscopy (AFM), respectively. The TBS data were submitted to one-way ANOVA, while µTBS data were submitted to two-way ANOVA and Tukey's test (α = 0.05). The TBS (MPa) to enamel did not significantly differ among the control (48.1 ± 15.7), GSE5 (46.1 ± 9.6), GSE10 (49.8 ± 13.6) and GSE20 (44.1 ± 11.9) groups (p = 0.537). The µTBS (MPa) to dentin of the control (28.4 ± 14.4) and GSE20 (24.1 ± 8.1) groups were significantly higher than those of the GSE5 (16.8 ± 7.4) and GSE10 (17.5 ± 6.6) groups at 24 h (p < 0.006). After 12-month storage, only GSE5 (21.0 ± 7.8) and GSE10 (17.6 ± 8.0) did not show significantly decreased μTBS (p > 0.145). SEM micrographs showed a shallower enamel etching pattern for GSE5. AFM images showed the formation of collagenous globular structures for GSE5 and GSE10. The different acid solutions did not influence the TBS to enamel, and the µTBS to dentin was stable over time when dentin was etched with GSE5 and GSE10.

Adenosine deaminase activity and gene expression patterns are altered after chronic ethanol exposure in zebrafish brain.

Ethanol alters the homeostasis between excitatory and inhibitory neurotransmitters and its intoxication reveals adenosine as responsible to modify several responses including signal transduction. Zebrafish has been recently investigated for knowledge the prolonged effect of ethanol on behavioral and biochemical parameters. The aim of this study was to evaluate the soluble and membrane adenosine deaminase activities and gene expression in zebrafish brain. Animals were exposed to 0.5% ethanol for 7, 14, and 28days. There were no significant changes in ADA activity from soluble fraction after all treatments. However, we verified a decrease of ADA activity in membrane fraction after 28days (44%) of ethanol exposure. ADA1 was not altered whereas mRNA transcript levels for ADAL presented an increase after 28days of ethanol exposure (34%). ADA2-1 showed a decrease (26%) followed by an increase (17%) of transcripts after 14 and 28days of ethanol exposure, respectively. However, ADA2-1 truncated alternative splice isoform (ADA2-1/T) demonstrated a reduction after 28days (20%). ADA2-2 was decreased (22%) followed by an increase (109%) of transcripts after 14 and 18days of ethanol exposure, respectively. Altogether, the purine catabolism promoted by ADA may be an important target of the chronic toxicity induced for ethanol.

Antitumor activity of resveratrol is independent of Cu(II) complex formation in MCF-7 cell line.

Resveratrol (Rsv) is widely reported to possess anticarcinogenic properties in a plethora of cellular and animal models having limited toxicity toward normal cells. In the molecular level, Rsv can act as a suppressive agent for several impaired signaling pathways on cancer cells. However, Fukuhara and Miyata have shown a non-proteic reaction of Rsv, which can act as a prooxidant agent in the presence of copper (Cu), causing cellular oxidative stress accompanied of DNA damage. After this discovery, the complex Rsv-Cu was broadly explored as an antitumor mechanism in multiples tumor cell lines. The aim of the study is to explore the anticarcinogenic behavior of resveratrol-Cu(II) complex in MCF-7 cell line. Selectivity of Rsv binding to Cu ions was analyzed by HPLC and UV-VIS. The cells were enriched with concentrations of 10 and 50µM CuSO4 solution and treated with 25µM of Rsv. Copper uptake after enrichment of cells, as its intracellular distribution in MCF-7 line, was scanned by ICP-MS and TEM-EDS. Cell death and intracellular ROS production were determined by flow cytometry. Different from the extracellular model, no relationship of synergy between Rsv-Cu(II) and reactive oxidative species (ROS) production was detected in vitro. ICP-MS revealed intracellular copper accumulation to both chosen concentrations (0.33±0.09 and 1.18±0.13ppb) but there is no promotion of cell death by Rsv-Cu(II) complex. In addition, significant attenuation of ROS production was detected when cells were exposed to CuSO4 after Rsv treatment, falling from 7.54% of ROS production when treated only with Rsv to 3.07 and 2.72% with CuSO4. Based on these findings antitumor activity of resveratrol when in copper ions presence, is not mediated by Rsv-Cu complex formation in MCF-7 human cell line, suggesting that the antitumoral reaction is dependent of a cancer cellular model.

An evaluation of aversive memory and hippocampal oxidative status in streptozotocin-induced diabetic rats treated with resveratrol.

The present study evaluated the effects of streptozotocin (STZ)-induced diabetes on aversive memory, free radical content and enzymatic antioxidant activity in the hippocampus of adult Wistar rats submitted to oral treatment with resveratrol. Animals were divided into eight groups: non-diabetic rats treated with saline (ND SAL), non-diabetic rats treated with resveratrol at a dose 5mg/kg (ND RSV 5), non-diabetic rats treated with resveratrol at a dose 10mg/kg (ND RSV 10), non-diabetic rats treated with resveratrol at a dose 20mg/kg (ND RSV 20), diabetic rats treated with saline (D SAL), diabetic rats treated with resveratrol at a dose 5mg/kg (D RSV 5), diabetic rats treated with resveratrol at a dose 10mg/kg (D RSV 10) and diabetic rats treated with resveratrol at a dose 20mg/kg (D RSV 20). The animals received oral gavage for 35days. The contextual fear conditioning task was performed to evaluate aversive-based learning and memory. The oxidative status was evaluated in the hippocampus, by measuring the free radical content - using a 2',7'-dichlorofluorescein diacetate probe - and enzymatic antioxidant activities, such as superoxide dismutase and glutathione peroxidase. Our main behavioral results demonstrated that rats from the D RSV 10 and D RSV 20 groups showed an increase in freezing behavior when compared, respectively, to the ND RSV 10 (p<0.01) and ND RSV 20 (p<0.05). Oxidative stress parameters remained unchanged in the hippocampus of all the experimental groups. In contrast to previous experimental findings, our study was unable to detect either cognitive impairments or oxidative stress in the hippocampus of the diabetic rats. We suggest additional long-term investigations be conducted into the temporal pattern of STZ-induced diabetic disruption in memory and hippocampal oxidative status, as well as the effects of resveratrol on these parameters, in a time and dose-dependent manner.

Modulatory potential of resveratrol during lung inflammatory disease.

Neutrophils are the first cells to achieve the sites of infection or inflammation in the lungs. The massive accumulation of these cells is associated with acute and chronic lung injury. Therefore, they have been implicated in the pathogenesis of many lung diseases through the release of reactive oxygen intermediates, proteolytic enzymes and Neutrophil Extracellular Traps (NETs). The excessive and continuous release of NETs, fibers composed by decondensed chromatin coated with neutrophil proteins, are associated to the impairment of lung function in different pathological settings. Flavonoids inhibit the respiratory burst of neutrophils in mammals. However, one of these flavonoids, resveratrol has a particular chemical property. It reduce Cu(II) to Cu(I) form with concomitant formation of reactive oxygen species, which can produce DNA breakage as reported in several in vitro models. We hypothesize that direct resveratrol administration in lungs can cleave DNA in NETs, improving lung function during acute airway infections or chronic inflammatory lung diseases. If the hypothesis is correct, the control of NET formation can be used to reduce the inflammatory environment in lung after neutrophil stimuli. Additionally, the production of proinflammatory cytokines by neutrophils could be also diminished by resveratrol administration. In this sense, this flavonoid provides a multifaceted opportunity for treatment of lung diseases with strong or chronic neutrophil activation.

Coadministration of Resveratrol and Rice Oil Mitigates Nociception and Oxidative State in a Mouse Fibromyalgia-Like Model.

The mechanism underlying pain symptoms in fibromyalgia (FM) is not fully understood. Oxidative stress has emerged as pathophysiological event occurring during the development of the disease. The present study aimed at investigating the efficacy of resveratrol associated with rice bran oil on fibromyalgia-like mice model. Subcutaneous injection of reserpine (0.25 mg/Kg) during 3 days produced fibromyalgia-like symptoms. Resveratrol and/or rice oil or pregabalin were administered through oral route in therapeutic (single dose) and preventive (four doses) schemes. In both schemes, treatment with resveratrol associated with rice bran oil and pregabalin significantly reduced mechanical allodynia and thermal hyperalgesia in animals. The preventive scheme displayed antidepressant effect which was demonstrated by the forced swimming test as well as reduced reactive species in the cerebrospinal fluid of reserpinized animals. Taken together, our data provide evidences that the intake of resveratrol associated with rice bran oil plays antinociceptive and antidepressant actions probably through reducing reactive species and suggests the involvement of oxidative stress in this model of FM as possible underlying mechanism of pathogenesis of the disease.

Resveratrol prevents akinesia and restores neuronal tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta of diabetic rats.

This study evaluated the effects of resveratrol on locomotor behaviors, neuronal and glial densities, and tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta of rats with streptozotocin-induced diabetes. Animals were divided into four groups: non-diabetic rats treated with saline (SAL), non-diabetic rats treated with resveratrol (RSV), diabetic rats treated with saline (DM) and diabetic rats treated with resveratrol (DM+RSV). The animals received oral gavage with resveratrol (20 mg/kg) for 35 days. The open field test and the bar test were performed to evaluate bradykinesia and akinesia, respectively. The Nissl-stained neuronal and glial densities and the dopaminergic neuronal density were estimated using planar morphometry. Tyrosine hydroxylase immunoreactivity was evaluated using regional and cellular optical densitometry. In relation to the locomotor behaviors, it was observed that the DM group developed akinesia, which was attenuated by resveratrol in the DM+RSV group, while the DM and DM+RSV groups showed bradykinesia. Our main morpho-physiological results demonstrated: a decrease in the cellular tyrosine hydroxylase immunoreactivity in the DM group, which was attenuated by resveratrol in the DM+RSV group; a higher neuronal density in the RSV group, when compared to the DM and DM+RSV groups; an increase in the glial density in the DM group, which was also reversed by resveratrol in the DM+RSV group. Resveratrol treatment prevents akinesia development and restores neuronal tyrosine hydroxylase immunoreactivity and glial density in the substantia nigra pars compacta of diabetic rats, suggesting that this polyphenol could be a potential therapeutic option against diabetes-induced nigrostriatal dysfunctions.

Protective effects of resveratrol on hepatotoxicity induced by isoniazid and rifampicin via SIRT1 modulation.

Acute liver injury was induced in male BALB/c mice by coadministering isoniazid and rifampicin. In this work, the effects of resveratrol (1) were investigated in the hepatotoxicity caused by isoniazid-rifampicin in mice. Compound 1 was administered 30 min prior to isoniazid-rifampicin. Serum biochemical tests, liver histopathological examination, oxidative stress, myeloperoxidase activity, cytokine production (TNF-α, IL-12p70, and IL-10), and mRNA expression of SIRT1-7 and PPAR-γ/PGC1-α were evaluated. The administration of 1 significantly decreased aspartate transaminase and alanine aminotransferase levels, myeloperoxidase activity, and cytokine levels. Furthermore, 1 reverted the decrease of catalase and glutathione activities and ameliorated the histopathological alterations associated with antituberculosis drugs. Modulation of SIRT1 and PPAR-γ/PGC1-α expression is likely involved in the protective effects of 1. The results presented herein show that 1 was able to largely prevent the hepatotoxicity induced by isoniazid and rifampicin in mice, mainly by modulating SIRT1 mRNA expression.

Design of novel potent inhibitors of human uridine phosphorylase-1: synthesis, inhibition studies, thermodynamics, and in vitro influence on 5-fluorouracil cytotoxicity.

Uridine (Urd) is a promising biochemical modulator to reduce host toxicity caused by 5-fluorouracil (5-FU) without impairing its antitumor activity. Elevated doses of Urd are required to achieve a protective effect against 5-FU toxicity, but exogenous administration of Urd is not well-tolerated. Selective inhibitors of human uridine phosphorylase (hUP) have been proposed as a strategy to increase Urd levels. We describe synthesis and characterization of a new class of ligands that inhibit hUP type 1 (hUP1). The design of ligands was based on a possible SN1 catalytic mechanism and as mimics of the carbocation in the transition state of hUP1. The kinetic and thermodynamic profiles showed that the ligands here presented are the most potent in vitro hUP1 inhibitors developed to date. In addition, a lead compound improved the antiproliferative effects of 5-FU on colon cancer cells, accompanied by a reduction of in vitro 5-FU cytotoxicity in aggressive SW-620 cancer cells.