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1.
Antivir Ther ; 28(1): 13596535231155263, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36724136

RESUMO

BACKGROUND: Polyamines are involved in several cellular processes and inhibiting their synthesis affects chikungunya virus (CHIKV) replication and translation, and, therefore, reduces the quantity of infectious viral particles produced. In this study, we evaluated the inhibition of CHIKV replication by N-ω-chloroacetyl-L-ornithine (NCAO), a competitive inhibitor of ornithine decarboxylase, an enzyme which is key in the biosynthesis of polyamines (PAs). METHODS: The cytotoxicity of NCAO was evaluated by MTT in cell culture. The inhibitory effect of CHIKV replication by NCAO was evaluated in Vero and C6/36 cells. The intracellular polyamines were quantified by HPLC in CHIKV-infected cells. We evaluated the yield of CHIKV in titres via the addition of PAs in Vero, C6/36 cells and human fibroblast BJ treated with NCAO. RESULTS: We found that NCAO inhibits the replication of CHIKV in Vero and C6/36 cells in a dose-dependent manner, causing a decrease in the PFU/mL of at least 4 logarithms (p < 0.01) in both cell lines. Viral yields were restored by the addition of exogenous polyamines, mainly putrescine. The HPLC analyses showed that NCAO decreases the content of intracellular PAs, even though it is predominantly spermidines and spermines which are present in infected cells. Inhibition of CHIKV replication was observed in human fibroblast BJ treated with 100 µM NCAO 24 h before and 48 h after the infection at a MOI 1. CONCLUSIONS: NCAO inhibits CHIKV replication by depleting the intracellular polyamines in Vero, C6/36 cells and human fibroblast BJ, suggesting that this compound is a possible antiviral agent for CHIKV.


Assuntos
Febre de Chikungunya , Vírus Chikungunya , Animais , Chlorocebus aethiops , Humanos , Células Vero , Replicação Viral , Fibroblastos , Poliaminas/farmacologia
2.
Molecules ; 28(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36677873

RESUMO

When the expression of NOS2 in M1-polarized macrophages is induced, huge amounts of nitric oxide (•NO) are produced from arginine and molecular oxygen as the substrates. While anti-microbial action is the primary function of M1 macrophages, excessive activation may result in inflammation being aggravated. The reaction of •NO with superoxide produces peroxynitrite, which is highly toxic to cells. Alternatively, however, this reaction eliminates radial electrons and may occasionally alleviate subsequent radical-mediated damage. Reactions of •NO with lipid radicals terminates the radical chain reaction in lipid peroxidation, which leads to the suppression of ferroptosis. •NO is involved in the metabolic remodeling of M1 macrophages. Enzymes in the tricarboxylic acid (TCA) cycle, notably aconitase 2, as well as respiratory chain enzymes, are preferential targets of •NO derivatives. Ornithine, an alternate compound produced from arginine instead of citrulline and •NO, is recruited to synthesize polyamines. Itaconate, which is produced from the remodeled TCA cycle, and polyamines function as defense systems against overresponses of M1 macrophages in a feedback manner. Herein, we overview the protective aspects of •NO against radical species and the autoregulatory systems that are enabled by metabolic remodeling in M9-polarized macrophages.


Assuntos
Macrófagos , Óxido Nítrico , Óxido Nítrico/metabolismo , Macrófagos/metabolismo , Arginina/metabolismo , Poliaminas/metabolismo , Homeostase
3.
Anal Chim Acta ; 1241: 340807, 2023 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-36657877

RESUMO

The metabolome and lipidome are critical components in illustrating biological processes and pathological mechanisms. Generally, two or more independent methods are required to analyze the two compound panels due to their distinct chemical properties and polarity differences. Here, a novel strategy integrating stepwise solid-phase extraction (SPE) and dansyl chemical derivatization was proposed for all-in-one injection LC-MS/MS analysis of serum metabolome and lipidome. In this workflow, a stepwise elution procedure was firstly optimized to separate the metabolome and lipidome fractions using an Ostro plate. Dansyl chemical derivatization was then applied to label amine/phenol, carboxyl, and carbonyl-containing sub-metabolomes. Our results demonstrated that the dansyl labeling could significantly improve chromatographic separation, enhance the MS response, and overcome the matrix effect of co-eluting lipids. Ultimately, an all-in-one injection LC-MS/MS method measuring 256 lipids (covering 20 subclasses) and 212 metabolites (including amino acids, bile acids, fatty acids, acylcarnitines, indole derivatives, ketones and aldehydes, nucleic acid metabolism, polyamines, etc.) was established. This method was applied to investigate the metabolic changes in cisplatin-induced nephrotoxicity in rats and the results were compared with previous untargeted metabolomics. The presented strategy could predominantly improve the analytical coverage and throughput and can be of great use in discovering reliable potential biomarkers in various applications.


Assuntos
Lipidômica , Espectrometria de Massas em Tandem , Animais , Ratos , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Metaboloma , Metabolômica/métodos , Poliaminas/metabolismo , Lipídeos , Extração em Fase Sólida/métodos
4.
Biochem Biophys Res Commun ; 644: 55-61, 2023 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-36630735

RESUMO

RNA structure plays an important role in regulating cellular function and there is a significant emerging interest in targeting RNA for drug discovery. Here we report the identification of 4-aminoquinolines as modulators of RNA structure and function. Aminoquinolines have a broad range of pharmacological activities, but their specific mechanism of action is often not fully understood. Using electrophoretic mobility shift assays and enzymatic probing we identified 4-aminoquinolines that bind the stem-loop II motif (s2m) of SARS-CoV-2 RNA site-specifically and induce dimerization. Using fluorescence-based RNA binding and T-box riboswitch functional assays we identified that hydroxychloroquine binds the T-box riboswitch antiterminator RNA element and inhibits riboswitch function. Based on its structure and riboswitch dose-response activity we identified that the antagonist activity of hydroxychloroquine is consistent with it being a conformationally restricted analog of the polyamine spermidine. Given the known role that polyamines play in RNA function, the identification of an RNA binding ligand with the pharmacophore of a conformationally restricted polyamine has significant implications for further elucidation of RNA structure-function relationships and RNA-targeted drug discovery.


Assuntos
COVID-19 , Riboswitch , Humanos , Poliaminas , Hidroxicloroquina , RNA Viral , SARS-CoV-2/genética , Aminoquinolinas/farmacologia , RNA Bacteriano/genética , Conformação de Ácido Nucleico
5.
FEMS Microbiol Lett ; 3702023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36690345

RESUMO

Azospirillum baldaniorum Sp 245 is a model plant growth-promoting rhizobacterium. The first cross-talk with plants takes place within the roots. Roots cells growth is constrained by the primary cell wall (CW). Also, neighboring CW form the apoplast that should affect cells signaling and biochemical messages. Studies on CW phenolic composition ferulate (FA), diferulates (DFA) and p-coumarate and polyamines (PA) metabolisms of A. baldaniorum Sp 245- inoculated roots and on bacterial PA production in culture media should help to understand more about the mechanisms involved in Azospirillum-root association. For this purpose, CW-bound FA, DFA and p-coumarate contents, putrescine (put) and spermidine contents, diamine and polyamine oxidases activities, and H2O2 content of Cucumis sativus roots from dark grown seedlings inoculated with A. baldaniorum Sp 245 were determined. Also, bacterial PA production under constant agitation or static conditions was evaluated. Results showed lesser contents of all phenolics, and higher FA/DFA ratio in CW of inoculated roots that should be responsible for roots growth promotion. Also, the increased put content, DAO activity, and H2O2 production in the roots should be associated to A. baldaniorum Sp 245 growth promotion in early stages. Finally, the participation of both PA in A. baldaniorum Sp 245 biofilm formation was demonstrated.


Assuntos
Cucumis sativus , Cucumis sativus/metabolismo , Poliaminas/metabolismo , Plântula , Peróxido de Hidrogênio/metabolismo , Raízes de Plantas/metabolismo , Putrescina/metabolismo , Parede Celular/metabolismo
6.
Plant Physiol Biochem ; 195: 193-205, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36641943

RESUMO

Beneficial rhizobacteria in the soil are important drivers of plant health and growth. In this study, we provide the draft genome of a root colonizing and auxin-producing Pseudomonas sp. strain GBPI_506. The bacterium was investigated for its contribution in the growth of Nicotiana benthamiana (Nb) and biosynthesis of nicotine. The bacterium showed chemotaxis towards root exudates potentially mediated by putrescine, a polyamine compound, to colonize the roots of Nb. Application of the bacterium with the roots of Nb, increased plant biomass and total soluble sugars in the leaves, and promoted lateral root (LR) development as compared to the un-inoculated plants. Confocal analysis using transgenic (DR5:GFP) Arabidopsis showed increased auxin trafficking in the LR of inoculated plants. Upregulation of nicotine biosynthesis genes and genes involved in salicylic acid (SA) and jasmonic acid (JA) signaling in the roots of inoculated plants suggested increased nicotine biosynthesis as a result of bacterial application. An increased JA content in roots and nicotine accumulation in leaves provided evidence on JA-mediated upregulation of nicotine biosynthesis in the bacterized plants. The findings suggested that the bacterial root colonization triggered networking between auxin, SA, and JA to facilitate LR development leading to enhanced plant growth and nicotine biosynthesis in Nb.


Assuntos
Arabidopsis , Tabaco , Tabaco/genética , Nicotina , Pseudomonas , Poliaminas , Ácidos Indolacéticos , Arabidopsis/genética , Ácido Salicílico , Hormônios , Raízes de Plantas/genética , Ciclopentanos , Oxilipinas
7.
Nat Commun ; 14(1): 399, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36693889

RESUMO

Metabolic changes in immune cells contribute to both physiological and pathophysiological outcomes of immune reactions. Here, by comparing protein expression, transcriptome, and salivary metabolome profiles of uninfected and HIV+ individuals, we found perturbations of polyamine metabolism in the oral mucosa of HIV+ patients. Mechanistic studies using an in vitro human tonsil organoid infection model revealed that HIV infection of T cells also resulted in increased polyamine synthesis, which was dependent on the activities of caspase-1, IL-1ß, and ornithine decarboxylase-1. HIV-1 also led to a heightened expression of polyamine synthesis intermediates including ornithine decarboxylase-1 as well as an elevated dysfunctional regulatory T cell (TregDys)/T helper 17 (Th17) cell ratios. Blockade of caspase-1 and polyamine synthesis intermediates reversed the TregDys phenotype showing the direct role of polyamine pathway in altering T cell functions during HIV-1 infection. Lastly, oral mucosal TregDys/Th17 ratios and CD4 hyperactivation positively correlated with salivary putrescine levels, which were found to be elevated in the saliva of HIV+ patients. Thus, by revealing the role of aberrantly increased polyamine synthesis during HIV infection, our study unveils a mechanism by which chronic viral infections could drive distinct T cell effector programs and Treg dysfunction.


Assuntos
Infecções por HIV , Mucosa Bucal , Poliaminas , Humanos , Caspases/imunologia , Infecções por HIV/imunologia , Mucosa Bucal/imunologia , Ornitina Descarboxilase/imunologia , Poliaminas/imunologia , Linfócitos T/imunologia
8.
Theranostics ; 13(2): 611-620, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36632232

RESUMO

Inspired by the attractions of fruit flies to polyamines of rotten food, we developed a facile, bio-orthogonal, supramolecular homing and hunting strategy, relying on the elevated levels of polyamines in tumor as the natural guest cues to attract cucurbit [7] uril (CB[7]) functionalized liposomes to the tumor site, owing to the strong, bio-orthogonal host-guest interactions between CB[7] and polyamines. This supramolecular homing enabled a high targeting efficiency of CB[7] functionalized liposomes, and allowed better tissue penetration and retention in breast tumor. The employment of a receptor functionalized nanomedicine for direct tropism towards endogenous biomarkers as guest cues, reminiscent of natural chemotaxis but in a bio-orthogonal manner, has not been previously reported, offering new sights to the design and development of new nanoformulations that rely on bio-orthogonal interactions for chemotaxis-guided targeting.


Assuntos
Neoplasias , Poliaminas , Humanos , Lipossomos , Sinais (Psicologia) , Caça
9.
Immunohorizons ; 7(1): 41-48, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36637514

RESUMO

Group 3 innate lymphocytes (ILC3s) rapidly respond to invading pathogens or inflammatory signals, which requires shifting cellular metabolic demands. Metabolic adaptations regulating ILC3 function are not completely understood. Polyamines are polycationic metabolites that have diverse roles in cellular functions and in immunity regulate immune cell biology, including Th17 cells. Whether polyamines play a role in ILC3 activation is unknown. In this article, we report that the polyamine synthesis pathway is important for ILC3 activation. IL-23-activated mouse ILC3s upregulate ornithine decarboxylase, the enzyme catalyzing the rate-limiting step of the conversion of ornithine to putrescine in polyamine synthesis, with a subsequent increase in putrescine levels. Inhibition of ornithine decarboxylase via a specific inhibitor, α-difluoromethylornithine, reduced levels of IL-22 produced by steady-state or IL-23-activated ILC3s in a putrescine-dependent manner. Thus, the polyamine putrescine is a positive regulator of ILC3 activation. Our results suggest that polyamines represent a potential target for therapeutic modulation of ILC3 activation during infection or inflammatory disorders.


Assuntos
Poliaminas , Putrescina , Camundongos , Animais , Poliaminas/metabolismo , Poliaminas/farmacologia , Putrescina/farmacologia , Ornitina Descarboxilase/metabolismo , Ativação Linfocitária , Interleucina-23
10.
Neurobiol Dis ; 177: 105962, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36563791

RESUMO

BACKGROUND: Reliable and sensitive biomarkers are needed for enhancing and predicting Parkinson's disease (PD) diagnosis. OBJECTIVE: To investigate comprehensive metabolomic profiling of biochemicals in CSF and serum for determining diagnostic biomarkers of PD. METHODS: Fifty subjects, symptomatic with PD for ≥5 years, were matched to 50 healthy controls (HCs). We used ultrahigh-performance liquid chromatography linked to tandem mass spectrometry (UHPLC-MS/MS) for measuring relative concentrations of ≤1.5 kDalton biochemicals. A reference library created from authentic standards facilitated chemical identifications. Analytes underwent univariate analysis for PD association, with false discovery rate-adjusted p-value (≤0.05) determinations. Multivariate analysis (for identifying a panel of biochemicals discriminating PD from HCs) used several biostatistical methods, including logistic LASSO regression. RESULTS: Comparing PD and HCs, strong differentiation was achieved from CSF but not serum specimens. With univariate analysis, 21 CSF compounds exhibited significant differential concentrations. Logistic LASSO regression led to selection of 23 biochemicals (11 shared with those determined by the univariate analysis). The selected compounds, as a group, distinguished PD from HCs, with Area-Under-the-Receiver-Operating-Characteristic (ROC) curve of 0.897. With optimal cutoff, logistic LASSO achieved 100% sensitivity and 96% specificity (and positive and negative predictive values of 96% and 100%). Ten-fold cross-validation gave 84% sensitivity and 82% specificity (and 82% positive and 84% negative predictive values). From the logistic LASSO-chosen regression model, 2 polyamine metabolites (N-acetylcadaverine and N-acetylputrescine) were chosen and had the highest fold-changes in comparing PD to HCs. Another chosen biochemical, acisoga (N-(3-acetamidopropyl)pyrrolidine-2-one), also is a polyamine metabolism derivative. CONCLUSIONS: UHPLC-MS/MS assays provided a metabolomic signature highly predictive of PD. These findings provide further evidence for involvement of polyamine pathways in the neurodegeneration of PD.


Assuntos
Doença de Parkinson , Espectrometria de Massas em Tandem , Humanos , Doença de Parkinson/diagnóstico , Metabolômica/métodos , Biomarcadores , Poliaminas
11.
Langmuir ; 39(1): 495-506, 2023 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-36529944

RESUMO

New antimicrobial agents are needed to address the ever-growing risk of bacterial resistance, particularly for methicillin- and vancomycin-resistant Staphylococcus aureus (S. aureus). Here, we report a class of bile acid oligomers as facial amphiphilic antimicrobials, which are noncovalently fabricated by cholic acid (CA) and deoxycholic acid (DCA) with polyamines (e.g., diamines, diethylenetriamine, spermidine, and spermine). The antibacterial activities of these bile acid oligomers (CA/polyamines and DCA/polyamines) against S. aureus become stronger with increasing the amine group numbers of polyamines without obviously enhanced cytotoxicity and skin irritation. DCA/spermine, entirely composed of natural products, exhibits the best antibacterial activity but the lowest cytotoxicity and the weakest skin irritation. All CA/polyamines and DCA/polyamines form well-ordered ribbon-like aggregates, collecting numerous facial amphiphilic structures to significantly enhance the interactions with bacterial membranes. In particular, the biogenic polyamines with more than two amine groups provide extra positively charged sites, hence facilitating the binding of bile acid oligomers to the negatively charged outer membrane of the bacteria via electrostatic interaction. This in turn promotes more oligomeric bile acid units that can be inserted into the membrane through hydrophobic interaction between bile acids and lipid domains. The noncovalently constructed and separable amphiphilic antimicrobials can avoid the long-term coexistence of microorganisms and antibacterial molecules in different acting modes. Therefore, the noncovalent bile acid oligomers, especially those with higher oligomerization degrees, can be a potential approach to effectively enhance antibacterial activity, improve environmental friendliness, and reduce bacterial drug resistance.


Assuntos
Anti-Infecciosos , Staphylococcus aureus Resistente à Meticilina , Ácidos e Sais Biliares/farmacologia , Espermina , Staphylococcus aureus , Anti-Infecciosos/farmacologia , Ácido Cólico/farmacologia , Ácido Cólico/química , Antibacterianos/toxicidade , Antibacterianos/química , Poliaminas/farmacologia , Bactérias
12.
J Gen Physiol ; 155(2)2023 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-36524992

RESUMO

Inwardly rectifier potassium (Kir) channels are a major potassium channel sub-class whose function is regulated by ligand-dependent gating and highly voltage-dependent block by polyamines. With molecular dynamics simulations over previously unattainable timescales, Jogini et al. (J. Gen. Physiol. https://doi.org/10.1085/jgp.202213085) provide unprecedented visualization of K+ conduction through open Kir2.2 channels and of the molecular details of channel block by spermine.


Assuntos
Ativação do Canal Iônico , Espermina , Espermina/farmacologia , Poliaminas/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Potássio/farmacologia
13.
J Gen Physiol ; 155(2)2023 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-36524993

RESUMO

Inward-rectifier potassium channels (Kirs) are lipid-gated ion channels that differ from other K+ channels in that they allow K+ ions to flow more easily into, rather than out of, the cell. Inward rectification is known to result from endogenous magnesium ions or polyamines (e.g., spermine) binding to Kirs, resulting in a block of outward potassium currents, but questions remain regarding the structural and dynamic basis of the rectification process and lipid-dependent channel activation. Here, we present the results of long-timescale molecular dynamics simulations starting from a crystal structure of phosphatidylinositol 4,5-bisphosphate (PIP2)-bound chicken Kir2.2 with a non-conducting pore. After introducing a mutation (G178R) that is known to increase the open probability of a homologous channel, we were able to observe transitions to a stably open, ion-conducting pore, during which key conformational changes occurred in the main activation gate and the cytoplasmic domain. PIP2 binding appeared to increase stability of the pore in its open and conducting state, as PIP2 removal resulted in pore closure, with a median closure time about half of that with PIP2 present. To investigate structural details of inward rectification, we simulated spermine binding to and unbinding from the open pore conformation at positive and negative voltages, respectively, and identified a spermine-binding site located near a previously hypothesized site between the pore cavity and the selectivity filter. We also studied the effects of long-range electrostatics on conduction and spermine binding by mutating charged residues in the cytoplasmic domain and found that a finely tuned charge density, arising from basic and acidic residues within the cytoplasmic domain, modulated conduction and rectification.


Assuntos
Canais de Potássio Corretores do Fluxo de Internalização , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Espermina/metabolismo , Poliaminas/metabolismo , Potássio/metabolismo , Lipídeos , Oócitos/metabolismo
14.
Methods Mol Biol ; 2610: 67-73, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36534282

RESUMO

White spot syndrome virus (WSSV), an enveloped double-stranded DNA virus, is the causative agent of white spot syndrome (WSS), which has been linked to cultured shrimp mass mortality in many countries. Therefore, the development of anti-WSSV agents is among the top priorities of the aquaculture sector. Here, we describe the preparation of polyamine-modified carbon quantum dots (polyamine CQDs) for the treatment of WSSV. Moreover, in vivo experiments were conducted in shrimp to confirm the anti-WSSV effect of the proposed CQD-based strategy.


Assuntos
Penaeidae , Pontos Quânticos , Vírus da Síndrome da Mancha Branca 1 , Animais , Vírus da Síndrome da Mancha Branca 1/genética , Carbono , Poliaminas/farmacologia
15.
J Org Chem ; 88(1): 285-299, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36480555

RESUMO

The introduction of urea or thiourea functionality to the macrocycle skeleton represents an alternative way to control conformational dynamics of chiral, polyamines of a figure-shaped periodical structure. Formally highly symmetrical, these macrocycles may adapt diverse conformations, depending on the nature of an amide linker and on a substitution pattern within the aromatic units. The type of heteroatom X in the N-C(═X)-N units present in each vertex of the macrocycle core constitutes the main factor determining the chiroptical properties. In contrast to the urea-containing derivatives, the electronic circular dichroism of thioureas is controlled by the chiral neighborhood closest to the chromophore. The dynamically induced exciton couplet is observed when the biphenyl chromophores are present in the macrocycle core. In the solid state, the seemingly disordered molecules may create ordered networks stabilized by intermolecular S···halogen, H···halogen, and S···H interactions. The presence of two bromine substituents in each aromatic unit in thiourea-derived trianglamine gives rise to a self-sorting phenomenon in the crystal. In solution, this particular macrocycle exists as a dynamic equimolar mixture of two conformational diastereoisomers, differing in the spatial (clockwise and counter clockwise) arrangement of the C-Br bonds. In the crystal lattice, macrocycles of a given handedness assemble into homohelical layers.


Assuntos
Tioureia , Ureia , Estrutura Molecular , Conformação Molecular , Poliaminas
16.
J Comput Aided Mol Des ; 37(2): 75-90, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36494599

RESUMO

Chagas disease, also known as American trypanosomiasis, is a neglected tropical disease caused by the protozoa Trypanosoma cruzi, affecting nearly 7 million people only in the Americas. Polyamines are essential compounds for parasite growth, survival, and differentiation. However, because trypanosomatids are auxotrophic for polyamines, they must be obtained from the host by specific transporters. In this investigation, an ensemble of QSAR classifiers able to identify polyamine analogs with trypanocidal activity was developed. Then, a multi-template homology model of the dimeric polyamine transporter of T. cruzi, TcPAT12, was created with Rosetta, and then refined by enhanced sampling molecular dynamics simulations. Using representative snapshots extracted from the trajectory, a docking model able to discriminate between active and inactive compounds was developed and validated. Both models were applied in a parallel virtual screening campaign to repurpose known drugs as anti-trypanosomal compounds inhibiting polyamine transport in T. cruzi. Montelukast, Quinestrol, Danazol, and Dutasteride were selected for in vitro testing, and all of them inhibited putrescine uptake in biochemical assays, confirming the predictive ability of the computational models. Furthermore, all the confirmed hits proved to inhibit epimastigote proliferation, and Quinestrol and Danazol were able to inhibit, in the low micromolar range, the viability of trypomastigotes and the intracellular growth of amastigotes.


Assuntos
Doença de Chagas , Tripanossomicidas , Trypanosoma cruzi , Humanos , Putrescina/uso terapêutico , Ligantes , Danazol/uso terapêutico , Quinestrol/uso terapêutico , Poliaminas/química , Poliaminas/uso terapêutico , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Proteínas de Membrana Transportadoras/uso terapêutico , Tripanossomicidas/farmacologia , Tripanossomicidas/química
17.
J Biomater Sci Polym Ed ; 33(2): 212-228, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34547218

RESUMO

We evaluate the effects of the new Dentine matrix protein 1 (DMP-1) biomimetic system composed of phosphorylated polyamidoamine dendrimer (PAMAM-PO3H2) and carboxylated polyamidoamine dendrimer (PAMAM-COOH) on the mineralization of type I collagen fibrils. PAMAM-PO3H2 and PAMAM-COOH were observed to have the ability to induce internal and external mineralization of type I collagen fibrils in vitro through non-classical mineralization crystallization pathway, which has become a hopeful biomimetic system of biomimetic remineralization and demineralization of dentin type I collagen fibrils and has great potential in inducing biomimetic remineralization of demineralized dentin.


Assuntos
Biomimética , Dendrímeros , Colágeno Tipo I , Dentina , Poliaminas
18.
J Therm Biol ; 110: 103353, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36462880

RESUMO

Silkworms have limited ability to regulate their body temperature upon exposure to varying atmospheric temperatures. Environmental changes, such as global warming, adversely affect silkworm viability. Spermidine, a polyamine, protects various organisms against heat stress. This study aimed to evaluate the effect of spermidine on the thermotolerance of Bombyx mori larvae. 5th instar Bombyx mori larvae were divided into the control and spermidine groups and reared at 28 ± 1 °C and 80%-85% relative humidity. To induce heat stress, the larvae were exposed to various temperatures 32 °C, 36 °C, and 40 °C for 1 h on day 5 and subsequently allowed to recover at 28 ± 1 °C. Growth characteristics were evaluated by examining larval viability and quantifying proteins and carbohydrates. The thermotolerance of the spermidine group was higher than that of the control group at 40 °C heat stress conditions. The spermidine feeding increased the protein content and reduced the carbohydrate content significantly under heat stress condition. For the first time, this study demonstrated that spermidine alleviated thermal stress by enhancing the nutritional indices and antioxidant potential of the Bombyx mori larvae. A significant increase in economic properties was observed in spermidine fed groups. Thus, foliar feeding of spermidine to B. mori larvae markedly improved silkworm thermotolerance.


Assuntos
Bombyx , Termotolerância , Animais , Espermidina/farmacologia , Resposta ao Choque Térmico , Poliaminas , Larva
19.
Front Immunol ; 13: 1048204, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36505496

RESUMO

Backgrounds: Polyamine metabolism (PM) is closely related to the tumor microenvironment (TME) and is involved in antitumor immunity. Clear cell renal cell carcinoma (ccRCC) not only has high immunogenicity but also has significant metabolic changes. However, the role of PM in the immune microenvironment of ccRCC remains unclear. This study aimed to reveal the prognostic value of PM-related genes (PMRGs) expression in ccRCC and their correlation with the TME. Methods: The expression levels PMRGs in different cells were characterized with single-cell sequencing analysis. The PMRG expression pattern of 777 ccRCC patients was evaluated based on PMRGs. Unsupervised clustering analysis was used in identifying PMRG expression subtypes, and Lasso regression analysis was used in developing polyamine gene expression score (PGES), which was validated in external and internal data sets. The predictive value of PGES for immunotherapy was validated in the IMvigor210 cohort. Multiple algorithms were used in analyzing the correlation between PGES and immune cells. The sensitivity of PGES to chemotherapeutic drugs was analyzed with the "pRRophetic" package. We validated the genes that develop PGES in tissue samples. Finally, weighted gene co-expression network analysis was used in identifying the key PMRGs closely related to ccRCC, and cell function experiments were carried out. Results: PMRGs were abundantly expressed on tumor cells, and PMRG expression was active in CD8+ T cells and fibroblasts. We identified three PMRG expression subtypes. Cancer and immune related pathways were active in PMRG expression cluster A, which had better prognosis. PGES exhibited excellent predictive value. The high-PGES group was characterized by high immune cell infiltration, high expression of T cell depletion markers, high tumor mutation burden and tumor immune dysfunction and exclusion, was insensitive to immunotherapy but sensitive to sunitinib, temsirolimus, and rapamycin, and had poor prognosis. Spermidine synthetase (SRM) has been identified as a key gene and is highly expressed in ccRCC at RNA and protein levels. SRM knockdown can inhibit ccRCC cell proliferation, migration, and invasion. Conclusions: We revealed the biological characteristics of PMRG expression subtypes and developed PGES to accurately predict the prognosis of patients and response to immunotherapy.


Assuntos
Carcinoma de Células Renais , Carcinoma , Neoplasias Renais , Humanos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/terapia , Poliaminas , Linfócitos T CD8-Positivos , Neoplasias Renais/genética , Neoplasias Renais/terapia , Expressão Gênica , Microambiente Tumoral/genética
20.
Langmuir ; 38(51): 16144-16155, 2022 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-36516233

RESUMO

In the nanomedicine field, there is a need to widen the availability of nanovectors to compensate for the increasingly reported side effects of poly(ethene glycol). Nanovectors enabling cross-linking can further optimize drug delivery. Cross-linkable polyoxazolines are therefore relevant candidates to address these two points. Here we present the synthesis of coumarin-functionalized poly(2-alkyl-2-oxazoline) block copolymers, namely, poly(2-methyl-2-oxazoline)-block-poly(2-phenyl-2-oxazoline) and poly(2-methyl-2-oxazoline)-block-poly(2-butyl-2-oxazoline). The hydrophilic ratio and molecular weights were varied in order to obtain a range of possible behaviors. Their self-assembly after nanoprecipitation or film rehydration was examined. The resulting nano-objects were fully characterized by transmission electron microscopy (TEM), cryo-TEM, multiple-angle dynamic and static light scattering. In most cases, the formation of polymer micelles was observed, as well as, in some cases, aggregates, which made characterization more difficult. Cross-linking was performed under UV illumination in the presence of a coumarin-bearing cross-linker based on polymethacrylate derivatives. Addition of the photo-cross-linker and cross-linking resulted in better-defined objects with improved stability in most cases.


Assuntos
Poliaminas , Polímeros , Sistemas de Liberação de Medicamentos , Micelas
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