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1.
Microbiology (Reading) ; 168(8)2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35920804

RESUMO

Polyamines bind to various cellular components, such as nucleic acids, phospholipids, proteins and nucleotides. They are involved in the virulence and protection against physiological stresses of several bacterial species. Streptococcus agalactiae is able to colonize the vaginal tract of asymptomatic pregnant women and to resist, by an as yet poorly characterized mechanism, pH 4.0, the low physiological pH of this environment. We identified a transporter of the amino acid/polyamine antiporter family (SAK_1604 in strain A909) that shares 39.8 % similar amino acids with CadB and 34.7 % with PotE, two transporters implicated in acid resistance in Escherichia coli. We found that sak_1604 is overexpressed in the presence of spermidine and during citric acid stress at the vaginal pH, but not during lactic acid or HCl stresses at the same pH or during a sodium citrate stress at pH 7.4. Dihydrogen citrate is the predominant form of citric acid at pH 4.0. Using a deletion mutant, we proved that SAK_1604 is involved in the survival of S. agalactiae during citric acid stress at pH 4.0 in the presence of spermidine, and we showed by TLC analysis that it is involved in spermidine transport in these conditions. Our data open new perspectives on the comprehension of the molecular mechanisms allowing S. agalactiae to survive at the physiological pH of the vagina and on the unsuspected role of an ionic form of citric acid.


Assuntos
Antiporters , Espermidina , Aminoácidos/metabolismo , Antiporters/genética , Antiporters/metabolismo , Ácido Cítrico/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Feminino , Humanos , Concentração de Íons de Hidrogênio , Proteínas de Membrana Transportadoras/metabolismo , Poliaminas/metabolismo , Gravidez , Espermidina/metabolismo , Streptococcus agalactiae/genética , Streptococcus agalactiae/metabolismo
2.
Microbiology (Reading) ; 168(8)2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35917154

RESUMO

Streptococcus pyogenes are Gram-positive opportunistic pathogens residing in the human nasopharynx and skin. Changes in environmental conditions, such as pH, temperature and availability of essential ions, can stimulate the expression of S. pyogenes virulence factors. One such factor could be the availability of an extracellular pool of polyamines. Polyamines are synthesized from amino acids, and are universally present in the environment. Polyamines have been implicated in the ecology of pathogenesis by modulating quorum sensing, host adaptation and virulence. Polyamines mediate pathogenesis and help the pathogen resist environmental stress. In this study, we investigated the ability of the polyamine, spermidine, to promote acid stress survival of S. pyogenes. S. pyogenes does not synthesize spermidine, but the extracellular pool of spermidine constituted by the host and microbiome could be utilized as a signalling molecule. We report that spermidine promotes acid stress resistance in S. pyogenes. Moreover, spermidine affects the morphology of S. pyogenes by decreasing the cell size and increasing the dltA gene expression. Along with dltA, spermidine upregulated the gene expression of cell wall-modifying genes such as mur, pgdA, pepO and srtA, which might help the bacteria to resist acidic stress.


Assuntos
Espermidina , Streptococcus pyogenes , Ácidos/metabolismo , Humanos , Muramidase , Poliaminas/metabolismo , Espermidina/metabolismo , Streptococcus pyogenes/genética , Virulência/genética
3.
JCI Insight ; 7(13)2022 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-35801587

RESUMO

Polyamine dysregulation plays key roles in a broad range of human diseases from cancer to neurodegeneration. Snyder-Robinson syndrome (SRS) is the first known genetic disorder of the polyamine pathway, caused by X-linked recessive loss-of-function mutations in spermine synthase. In the Drosophila SRS model, altered spermidine/spermine balance has been associated with increased generation of ROS and aldehydes, consistent with elevated spermidine catabolism. These toxic byproducts cause mitochondrial and lysosomal dysfunction, which are also observed in cells from SRS patients. No efficient therapy is available. We explored the biochemical mechanism and discovered acetyl-CoA reduction and altered protein acetylation as potentially novel pathomechanisms of SRS. We repurposed the FDA-approved drug phenylbutyrate (PBA) to treat SRS using an in vivo Drosophila model and patient fibroblast cell models. PBA treatment significantly restored the function of mitochondria and autolysosomes and extended life span in vivo in the Drosophila SRS model. Treating fibroblasts of patients with SRS with PBA ameliorated autolysosome dysfunction. We further explored the mechanism of drug action and found that PBA downregulates the first and rate-limiting spermidine catabolic enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1), reduces the production of toxic metabolites, and inhibits the reduction of the substrate acetyl-CoA. Taken together, we revealed PBA as a potential modulator of SAT1 and acetyl-CoA levels and propose PBA as a therapy for SRS and potentially other polyamine dysregulation-related diseases.


Assuntos
Poliaminas , Espermidina , Acetilcoenzima A/metabolismo , Acetilesterase , Acetiltransferases/genética , Acetiltransferases/metabolismo , Animais , Drosophila/metabolismo , Retardo Mental Ligado ao Cromossomo X , Fenilbutiratos/farmacologia , Poliaminas/metabolismo , Espermidina/metabolismo , Espermina/metabolismo
4.
Anal Chim Acta ; 1220: 340077, 2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35868706

RESUMO

Primary liver cancer, mostly hepatocellular carcinoma (HCC) is the most common cause of cancer-related deaths around the world. Hepatitis B virus (HBV) DNA is the dominant factor that influences the progression of HCC. In this work, a novel electrochemical sensor triggered by a sandwich hybridization reaction has been developed for the ultrasensitive detection of HBV DNA. The multi-walled carbon nanotubes (MWCNTs) and hydroxylatopillar [5]arene (HP5) stabilized Au nanoparticles are used to modify the electrode to immobilize Rhodamine B-labeled DNA probes and improve the electron transfer efficiency. A supramolecular aggregate was synthesized based on pentaethylenehexamine (PEHA) induced self-assembly behavior of water-soluble pillar [5]arene (WP5) stabilized Ag nanoparticles through host-guest interaction, which serves as signal materials. The sensitivity of the sensor has enhanced on account of the electrochemical oxidation from Ag to Ag+ to yield an electrochemical response greater than that of the single silver nanoparticle. Linear sweep voltammetry (LSV) curves illustrate that the response has a good linear relationship with the logarithm of HBV-DNA concentration in a wide range from 0.1 fmol/L to 0.1 nmol/L, and the detection limit is 0.19 fmol/L according to the 3σ rule. Besides, the sensor shows good reproducibility, stability and selectivity, providing a promising prospect for application in disease diagnosis and prognosis.


Assuntos
Técnicas Biossensoriais , Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas Metálicas , Nanotubos de Carbono , Técnicas Biossensoriais/métodos , DNA , Técnicas Eletroquímicas/métodos , Eletrodos , Ouro/química , Humanos , Limite de Detecção , Nanopartículas Metálicas/química , Nanotubos de Carbono/química , Poliaminas , Reprodutibilidade dos Testes , Prata/química
5.
Mil Med Res ; 9(1): 33, 2022 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-35786219

RESUMO

The literature is full of claims regarding the consumption of polyphenol or polyamine-rich foods that offer some protection from developing cardiovascular disease (CVD). This is achieved by preventing cardiac hypertrophy and protecting blood vessels through improving the function of endothelium. However, do these interventions work in the aged human hearts? Cardiac aging is accompanied by an increase in left ventricular hypertrophy, along with diastolic and systolic dysfunction. It also confers significant cardiovascular risks for both sexes. The incidence and prevalence of CVD increase sharply at an earlier age in men than women. Furthermore, the patterns of heart failure differ between sexes, as do the lifetime risk factors. Do caloric restriction (CR)-mimetics, rich in polyphenol or polyamine, delay or reverse cardiac aging equally in both men and women? This review will discuss three areas: (1) mechanisms underlying age-related cardiac remodeling; (2) gender-related differences and potential mechanisms underlying diminished cardiac response in older men and women; (3) we select a few polyphenol or polyamine rich compounds as the CR-mimetics, such as resveratrol, quercetin, curcumin, epigallocatechin gallate and spermidine, due to their capability to extend health-span and induce autophagy. We outline their abilities and issues on retarding aging in animal hearts and preventing CVD in humans. We discuss the confounding factors that should be considered for developing therapeutic strategies against cardiac aging in humans.


Assuntos
Doenças Cardiovasculares , Insuficiência Cardíaca , Idoso , Envelhecimento/fisiologia , Animais , Restrição Calórica , Doenças Cardiovasculares/prevenção & controle , Feminino , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/prevenção & controle , Humanos , Poliaminas , Polifenóis
6.
Int J Mol Sci ; 23(14)2022 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-35886868

RESUMO

Polyamine levels decrease with menopause; however, little is known about the mechanisms regulated by menopause. In this study, we found that among the genes involved in the polyamine pathway, polyamine oxidase (PAOX) mRNA levels were the most significantly reduced by treatment with 17ß-estradiol in estrogen receptor (ESR)-positive MCF-7 breast cancer cells. Treatment with 17ß-estradiol also reduced the PAOX protein levels. Treatment with selective ESR antagonists and knockdown of ESR members revealed that estrogen receptor 2 (ESR2; also known as ERß) was responsible for the repression of PAOX by 17ß-estradiol. A luciferase reporter assay showed that 17ß-estradiol downregulates PAOX promoter activity and that 17ß-estradiol-dependent PAOX repression disappeared after deletions (-3126/-2730 and -1271/-1099 regions) or mutations of activator protein 1 (AP-1) binding sites in the PAOX promoter. Chromatin immunoprecipitation analysis showed that ESR2 interacts with AP-1 bound to each of the two AP-1 binding sites. These results demonstrate that 17ß-estradiol represses PAOX transcription by the interaction of ESR2 with AP-1 bound to the PAOX promoter. This suggests that estrogen deficiency may upregulate PAOX expression and decrease polyamine levels.


Assuntos
Neoplasias da Mama , Receptor beta de Estrogênio , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Estradiol/metabolismo , Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Células MCF-7 , Oxirredutases atuantes sobre Doadores de Grupo CH-NH , Poliaminas , Fator de Transcrição AP-1/genética
7.
Cells ; 11(15)2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35892565

RESUMO

Magnesium ions (Mg2+) have favorable effects such as the improvement of barrier function and the reduction of inflammation reaction in inflammatory skin diseases. However, its mechanisms have not been fully understood. Microarray analysis has shown that the gene expressions of polyamine synthases are upregulated by MgCl2 supplementation in human HaCaT keratinocytes. Here, we investigated the mechanism and function of polyamine production. The mRNA and protein levels of polyamine synthases were dose-dependently increased by MgCl2 supplementation, which were inhibited by U0126, a MEK inhibitor; CHIR-99021, a glycogen synthase kinase-3 (GSK3) inhibitor; and Naphthol AS-E, a cyclic AMP-response-element-binding protein (CREB) inhibitor. Similarly, reporter activities of polyamine synthases were suppressed by these inhibitors, suggesting that MEK, GSK3, and CREB are involved in the transcriptional regulation of polyamine synthases. Cell viability was reduced by ultraviolet B (UVB) exposure, which was rescued by MgCl2 supplementation. The UVB-induced elevation of reactive oxygen species was attenuated by MgCl2 supplementation, which was inhibited by cysteamine, a polyamine synthase inhibitor. Our data indicate that the expression levels of polyamine synthases are upregulated by MgCl2 supplementation mediated through the activation of the MEK/GSK3/CREB pathway. MgCl2 supplementation may be useful in reducing the UVB-induced oxidative stress in the skin.


Assuntos
Magnésio , Raios Ultravioleta , Linhagem Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Suplementos Nutricionais , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Queratinócitos/metabolismo , Magnésio/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Poliaminas/metabolismo
8.
Viruses ; 14(7)2022 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-35891396

RESUMO

Zika virus (ZIKV) and dengue virus (DENV) are members of the Flaviviridae family of RNA viruses and cause severe disease in humans. ZIKV and DENV share over 90% of their genome sequences, however, the clinical features of Zika and dengue infections are very different reflecting tropism and cellular effects. Here, we used simultaneous RNA sequencing and ribosome footprinting to define the transcriptional and translational dynamics of ZIKV and DENV infection in human neuronal progenitor cells (hNPCs). The gene expression data showed induction of aminoacyl tRNA synthetases (ARS) and the translation activating PIM1 kinase, indicating an increase in RNA translation capacity. The data also reveal activation of different cell stress responses, with ZIKV triggering a BACH1/2 redox program, and DENV activating the ATF/CHOP endoplasmic reticulum (ER) stress program. The RNA translation data highlight activation of polyamine metabolism through changes in key enzymes and their regulators. This pathway is needed for eIF5A hypusination and has been implicated in viral translation and replication. Concerning the viral RNA genomes, ribosome occupancy readily identified highly translated open reading frames and a novel upstream ORF (uORF) in the DENV genome. Together, our data highlight both the cellular stress response and the activation of RNA translation and polyamine metabolism during DENV and ZIKV infection.


Assuntos
Vírus da Dengue , Dengue , Infecção por Zika virus , Zika virus , Vírus da Dengue/genética , Humanos , Poliaminas , RNA Viral/genética , Zika virus/genética
9.
Biophys J ; 121(15): 2873-2881, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35791875

RESUMO

Molecular interactions and reactions in living cells occur with high background concentrations of organic compounds including proteins. Uncharged water-soluble polymers are commonly used cosolutes in studies on molecular crowding, and most studies argue about the effects of intracellular crowding based on results obtained using polymer cosolutes. Further investigations using protein crowders and organic cations are important in understanding the effects of cellular environments on nucleic acids with negatively charged surfaces. We assessed the effects of using model globular proteins, serum proteins, histone proteins, structurally flexible polypeptides, di- and polyamines, and uncharged polymers. Thermal stability analysis of DNA oligonucleotide structures revealed that unlike conventional polymer cosolutes, basic globular proteins (lysozyme and cytochrome c) at high concentrations stabilized long internal and bulge loop structures but not fully matched duplexes. The selective stabilization of long loop structures suggests preferential binding to unpaired nucleotides in loops through weak electrostatic interactions. Furthermore, the ability of the proteins to stabilize the loop structures was enhanced under macromolecular crowding conditions. Remarkably, the effects of basic proteins on the stability of fully matched duplexes were dissimilar to those of basic amino-acid-rich polypeptides and polyamines. This study provides new insights into the interaction of nucleic acid structures with organic cations.


Assuntos
DNA , Ácidos Nucleicos , Cátions/química , DNA/química , Conformação de Ácido Nucleico , Poliaminas , Polímeros , Termodinâmica
10.
Sci Rep ; 12(1): 11804, 2022 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-35821246

RESUMO

Polyamines are small cationic molecules that have been linked to various cellular processes including replication, translation, stress response and recently, capsule regulation in Streptococcus pneumoniae (Spn, pneumococcus). Pneumococcal-associated diseases such as pneumonia, meningitis, and sepsis are some of the leading causes of death worldwide and capsule remains the principal virulence factor of this versatile pathogen. α-Difluoromethyl-ornithine (DFMO) is an irreversible inhibitor of the polyamine biosynthesis pathway catalyzed by ornithine decarboxylase and has a long history in modulating cell growth, polyamine levels, and disease outcomes in eukaryotic systems. Recent evidence shows that DFMO can also target arginine decarboxylation. Interestingly, DFMO-treated cells often escape polyamine depletion via increased polyamine uptake from extracellular sources. Here, we examined the potential capsule-crippling ability of DFMO and the possible synergistic effects of the polyamine transport inhibitor, AMXT 1501, on pneumococci. We characterized the changes in pneumococcal metabolites in response to DFMO and AMXT 1501, and also measured the impact of DFMO on amino acid decarboxylase activities. Our findings show that DFMO inhibited pneumococcal polyamine and capsule biosynthesis as well as decarboxylase activities, albeit, at a high concentration. AMXT 1501 at physiologically relevant concentration could inhibit both polyamine and capsule biosynthesis, however, in a serotype-dependent manner. In summary, this study demonstrates the utility of targeting polyamine biosynthesis and transport for pneumococcal capsule inhibition. Since targeting capsule biosynthesis is a promising way for the eradication of the diverse and pathogenic pneumococcal strains, future work will identify small molecules similar to DFMO/AMXT 1501, which act in a serotype-independent manner.


Assuntos
Antineoplásicos , Eflornitina , Eflornitina/farmacologia , Ornitina Descarboxilase/metabolismo , Inibidores da Ornitina Descarboxilase , Poliaminas/metabolismo , Streptococcus pneumoniae/metabolismo
11.
World J Microbiol Biotechnol ; 38(9): 159, 2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35834138

RESUMO

The most dominant arbuscular mycorrhizal (AM) symbiont can be established on roots of most terrestrial plants by beneficial AM fungi. A type of polycationic and aliphatic compounds, polyamines (PAs), are involved in plant physiological activities including stress responses. Interestingly, small amounts of PAs such as putrescine (Put) and spermidine (Spd) were found in AM fungal spores, and they are considered to be a component involved in mycorrhizal development, including mycorrhizal colonization, appressoria formation, spore germination and mycelial growth. Thus, PAs are regulatory factors in plant-AM symbiosis. Inoculation of AM fungi also affects the metabolism of endogenous PAs in host plants, including PAs synthesis and catabolism, thus, regulating various physiological events of the host. As a result, there seems to be a dialogue between PAs and AM fungi. Existing knowledge makes us understand that endogenous or exogenous PAs are an important regulator factor in the growth of AM fungi, as well as a key substance to colonize roots, which further enhances mycorrhizal benefits in plant growth responses and root architecture. The presence of AM symbiosis in roots alters the dynamic balance of endogenous PAs, triggering osmotic adjustment and antioxidant defense systems, maintaining charge balance and acting as a stress signalling molecule, which affects various physiological activities, such as plant growth, nutrient acquisition, stress tolerance and improvement of root architecture. This review mainly elucidated (i) what is the role of fungal endogenous PAs in fungal growth and colonization of roots in host plants? (ii) how AM fungi and PAs interact with each other to alter the growth of fungi and plants and subsequent activities, providing the reference for the future combined use of AM fungi and PAs in agricultural production, although there are still many unknown events in the dialogue.


Assuntos
Micorrizas , Fungos , Micorrizas/fisiologia , Raízes de Plantas/microbiologia , Plantas , Poliaminas/metabolismo , Simbiose
12.
Med Sci (Basel) ; 10(3)2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35893120

RESUMO

The polyamines spermidine and spermine are positively charged aliphatic molecules. They are critical in the regulation of nucleic acid and protein structures, protein synthesis, protein and nucleic acid interactions, oxidative balance, and cell proliferation. Cellular polyamine levels are tightly controlled through their import, export, de novo synthesis, and catabolism. Enzymes and enzymatic cascades involved in polyamine metabolism have been well characterized. This knowledge has been used for the development of novel compounds for research and medical applications. Furthermore, studies have shown that disturbances in polyamine levels and their metabolic pathways, as a result of spontaneous mutations in patients, genetic engineering in mice or experimentally induced injuries in rodents, are associated with multiple maladaptive changes. The adverse effects of altered polyamine metabolism have also been demonstrated in in vitro models. These observations highlight the important role these molecules and their metabolism play in the maintenance of physiological normalcy and the mediation of injury. This review will attempt to cover the extensive and diverse knowledge of the biological role of polyamines and their metabolism in the maintenance of physiological homeostasis and the mediation of tissue injury.


Assuntos
Ácidos Nucleicos , Poliaminas , Animais , Homeostase , Camundongos , Poliaminas/metabolismo , Espermidina/metabolismo , Espermina/metabolismo
13.
Talanta ; 247: 123600, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35659686

RESUMO

Monitoring the level of matrix metalloproteinase-9 (MMP-9) and inhibiting its expression is important for the diagnosis and treatment of various diseases. However, the analysis of MMP-9 is challenging owing to its very low content in the blood, especially at the early stages of diseases. Therefore, we developed an ultrasensitive and easy-to-use immunosensor based on a three-dimensional (3D) bioplatform for the determination of the total MMP-9 concentration in plasma. The used 3D bioplatform (G2 poly(amidoamine) dendrimer; PAMAM) improved the sensitivity of the determination by significantly expanding the surface area of the receptor layer. The antigen-antibody recognition process was controlled by quartz crystal microbalance with dissipation (QCM-D) and electrochemical impedance spectroscopy (EIS). The effect of the orientation of antibody molecules in the sensing layer on the work parameters of the immunosensor was analyzed using unmodified PAMAM (PAMAM-NH2) and PAMAM functionalized with -COOH groups (PAMAM-COOH). The developed immunosensor based on PAMAM-NH2 was characterized by a lower detection limit (LOD = 2.0 pg⋅mL-1) and wider analytical range (1·10-4 - 5 µg⋅mL-1 for EIS and QCM-D) compared to PAMAM-COOH immunosensor (EIS: 1·10-4 - 0.5 µg⋅mL-1; QCM-D: 5·10-4 - 0.5 µg⋅mL-1). The functionality of the proposed device was verified in spiked plasma. The recoveries determined in commercial human and rat plasma and noncommercial rat plasma were very close to the value of 100% and in the range of 96-120% for Au/PAMAM-NH2/Ab and Au/PAMAM-COOH/Ab immunosensors, respectively. The designed analytical devices showed high selectivity and sensitivity without the use of any amplifiers such as metal nanoparticles or enzymes.


Assuntos
Técnicas Biossensoriais , Dendrímeros , Nanopartículas Metálicas , Animais , Técnicas Biossensoriais/métodos , Dendrímeros/química , Técnicas Eletroquímicas/métodos , Ouro/química , Imunoensaio/métodos , Limite de Detecção , Metaloproteinase 9 da Matriz , Nanopartículas Metálicas/química , Poli A , Poliaminas , Ratos
14.
Exp Cell Res ; 417(2): 113235, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-35671837

RESUMO

Adenosylmethionine decarboxylase 1 (AMD1) has been implicated in carcinogenesis and tumor progression. However, the potential biomechanism and biological implications of AMD1 in breast cancer (BC) remain unclear. The purpose of this study was to investigate the effect of abnormal expression of AMD1 in BC. The expression of AMD1 in different human BC cell lines was studied by using western blotting and qRT-PCR. In vitro cell proliferation, clone formation, cell cycle and apoptosis assays were performed to explore the effect of AMD1 on cellular proliferation. Xenograft mouse models were established to elucidate the role of AMD1 in BC growth. The expression profiles of AMD1 in 28 pairs of BC tissues and adjacent noncancerous tissues (ANTs) were investigated by using western blotting and immunohistochemistry. The clinical implication and prognostic evaluation of AMD1 in BC were examined by excavating the online database. We found that the expression levels of AMD1 in BC cell lines were significantly higher than those in the normal human breast epithelial cell line MCF-10A. In addition, AMD1 potentiated proliferation, induced cell cycle progression and inhibited apoptosis in BC cells. Subcutaneous tumor xenografts also supported the promotive role of AMD1 in BC growth. We discovered that the level of AMD1 in BC tissues was significantly higher than that in ANTs. Using the online database, increased AMD1 was found to be associated with clinical indicators and predicted a poor prognosis in patients with BC. Our findings indicate that AMD1 elicits potent oncogenic effects on the malignant progression of BC. AMD1 might serve as a promising diagnostic biomarker and therapeutic target for patients with BC.


Assuntos
Neoplasias da Mama , MicroRNAs , Adenosilmetionina Descarboxilase/genética , Adenosilmetionina Descarboxilase/metabolismo , Animais , Neoplasias da Mama/metabolismo , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Poliaminas
15.
Food Res Int ; 157: 111204, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35761526

RESUMO

Glycine betaine (GB) has been reported to mitigate chilling injury of peach fruit during postharvest cold storage, but the effects of GB treatment on changes of fruit flavor and amino acid metabolism remain unclear. In this study, the changes of organic acids and amino acids in peach fruit treated with GB were analyzed through physiological and metabolomic methods. The results manifested that GB treatment reduced internal browning index and maintained higher contents of total soluble solids, titratable acidity, organic acids and total free amino acids. Electronic tongue analysis exhibited separation between GB-treated and control fruit. Additionally, GB treatment increased proline, polyamines and γ-aminobutyric acid (GABA) contents by higher enzyme activities and upregulated gene expressions of arginine metabolism, GABA shunt pathway and lower enzyme activities and downregulated gene expressions of polyamine degradation pathway. Thus, GB treatment could enhance flavor quality and cold tolerance of peach fruit during low temperature storage.


Assuntos
Prunus persica , Aminoácidos/análise , Betaína/análise , Betaína/metabolismo , Betaína/farmacologia , Frutas/química , Poliaminas/metabolismo , Prunus persica/química , Ácido gama-Aminobutírico/análise
16.
Med Sci (Basel) ; 10(2)2022 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-35645240

RESUMO

Parasites of the genus Leishmania cause a variety of devastating and often fatal diseases in humans and domestic animals worldwide. The need for new therapeutic strategies is urgent because no vaccine is available, and treatment options are limited due to a lack of specificity and the emergence of drug resistance. Polyamines are metabolites that play a central role in rapidly proliferating cells, and recent studies have highlighted their critical nature in Leishmania. Numerous studies using a variety of inhibitors as well as gene deletion mutants have elucidated the pathway and routes of transport, revealing unique aspects of polyamine metabolism in Leishmania parasites. These studies have also shed light on the significance of polyamines for parasite proliferation, infectivity, and host-parasite interactions. This comprehensive review article focuses on the main polyamine biosynthetic enzymes: ornithine decarboxylase, S-adenosylmethionine decarboxylase, and spermidine synthase, and it emphasizes recent discoveries that advance these enzymes as potential therapeutic targets against Leishmania parasites.


Assuntos
Leishmania , Parasitos , Animais , Leishmania/genética , Leishmania/metabolismo , Ornitina Descarboxilase/genética , Ornitina Descarboxilase/metabolismo , Parasitos/metabolismo , Poliaminas/metabolismo , Espermidina Sintase/metabolismo
17.
World J Gastroenterol ; 28(20): 2214-2226, 2022 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-35721884

RESUMO

BACKGROUND: Direct acting antiviral (DAA) therapy has enabled hepatitis C virus infection to become curable, while histological changes remain uncontained. Few valid non-invasive methods can be confirmed for use in surveillance. Gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) is a liver-specific magnetic resonance imaging (MRI) contrast, related to liver function in the hepatobiliary phase (HBP). Whether Gd-EOB-DTPA-enhanced MRI can be used in the diagnosis and follow up of hepatic fibrosis in patients with chronic hepatitis C (CHC) has not been investigated. AIM: To investigate the diagnostic and follow-up values of Gd-EOB-DTPA-enhanced MRI for hepatic histology in patients with CHC. METHODS: Patients with CHC were invited to undergo Gd-EOB-DTPA-enhanced MRI and liver biopsy before treatment, and those with paired qualified MRI and liver biopsy specimens were included. Transient elastography (TE) and blood tests were also arranged. Patients treated with DAAs who achieved 24-wk sustained virological response (SVR) underwent Gd-EOB-DTPA-enhanced MRI and liver biopsy again. The signal intensity (SI) of the liver and muscle were measured in the unenhanced phase (UEP) (SIUEP-liver, SIUEP-muscle) and HBP (SIHBP-liver, SIHBP-muscle) via MRI. The contrast enhancement index (CEI) was calculated as [(SIHBP-liver/SIHBP-muscle)]/[(SIUEP-liver/SIUEP-muscle)]. Liver stiffness measurement (LSM) was confirmed with TE. Serologic markers, aspartate aminotransferase-to-platelet ratio index (APRI) and Fibrosis-4 (FIB-4), were also calculated according to blood tests. The grade of inflammation and stage of fibrosis were evaluated with the modified histology activity index (mHAI) and Ishak fibrosis score, respectively. Fibrosis regression was defined as a ≥ 1-point decrease in the Ishak fibrosis score. The correlation between the CEI and liver pathology was evaluated. The diagnostic and follow-up values of the CEI, LSM, and serologic markers were compared. RESULTS: Thirty-nine patients with CHC were enrolled [average age, 42.3 ± 14.4 years; 20/39 (51.3%) male]. Twenty-one enrolled patients had eligible paired Gd-EOB-DTPA-enhanced MRI and liver tissues after achieving SVR. The mHAI median significantly decreased after SVR [baseline 6.0 (4.5-13.5) vs SVR 2.0 (1.5-5.5), Z = 3.322, P = 0.017], but the median stage of fibrosis did not notably change (P > 0.05). Sixty pairs of qualified MRI and liver tissue samples were available for use to analyze the relationship between the CEI and hepatic pathology. The CEI was negatively correlated with the mHAI (r = -0.56, P < 0.001) and Ishak score (r = -0.69, P < 0.001). Further stratified analysis showed that the value of the CEI decreased with the progression of the stage of fibrosis rather than with the grade of necroinflammation. For patients with Ishak score ≥ 5, the areas under receiver operating characteristics curve of the CEI, LSM, APRI, and FIB-4 were approximately at baseline, 0.87-0.93, and after achieving SVR, 0.83-0.91. The CEI cut-off value was stable (baseline 1.58 and SVR 1.59), but those of the APRI (from 1.05 to 0.24), FIB-4 (from 1.78 to 1.28), and LSM (from 10.8 kpa to 7.1 kpa) decreased dramatically. The APRI and FIB-4 cannot be used as diagnostic means for SVR in patients with Ishak score ≥ 3 (P > 0.05). Seven patients achieved fibrosis regression after achieving SVR. In these patients, the CEI median increased (from 1.71 to 1.83, Z = -1.981, P = 0.048) and those of the APRI (from 1.71 to 1.83, Z = -2.878, P = 0.004) and LSM (from 6.6 to 4.8, Z = -2.366, P = 0.018) decreased. However, in patients without fibrosis regression, the medians of the APRI, FIB-4, and LSM also changed significantly (P < 0.05). CONCLUSION: Gd-EOB-DTPA-enhanced MRI has good diagnostic value for staging fibrosis in patients with CHC. It can be used for fibrotic-change monitoring post SVR in patients with CHC treated with DAAs.


Assuntos
Hepatite C Crônica , Rubiaceae , Ácido Acético , Adulto , Antivirais/uso terapêutico , Biomarcadores , Meios de Contraste , Feminino , Gadolínio/uso terapêutico , Gadolínio DTPA , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico por imagem , Hepatite C Crônica/tratamento farmacológico , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/tratamento farmacológico , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Poliaminas , Estudos Retrospectivos
18.
Molecules ; 27(12)2022 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-35744819

RESUMO

Poly(o-methoxyaniline) emeraldine-salt form (ES-POMA) was chemically synthesized using hydrochloric acid and subjected to a heat treatment (HT) process for 1 h at 100 °C (TT100) and 200 °C (TT200). The HT process promoted a progressive decrease in crystallinity. The Le Bail method revealed a decomposition from tetrameric to trimeric-folded chains after the HT process. The unheated POMA-ES presented a globular vesicular morphology with varied micrometric sizes. The heat treatment promoted a reduction in these globular structures, increasing the non-crystalline phase. The boundary length (S) and connectivity/Euler feature (χ) parameters were calculated from the SEM images, revealing that ES-POMA presented a wide distribution of heights. The TT100 and TT200 presented a narrow boundary distribution, suggesting smoother surfaces with smaller height variations. The UV-VIS analysis revealed that the transition at 343 nm (nonlocal π → π*) was more intense in the TT200 due to the electronic delocalization, which resulted from the reduced polymer chain caused by the HT process. In addition to the loss of conjugation, counter ion withdrawal reduced the ion-chain interaction, decreasing the local electron density. This result shows the influence of the chlorine counter ions on the peaks position related to the HOMO → LUMO transition, since the π → polaron transition occurs due to the creation of the energy states due to the presence of counter ions. Finally, the electrical conductivity decreased after the HT process from 1.4 × 10-4 S.cm-1 to 2.4 × 10-6 S.cm-1 as result of the polymer deprotonation/degradation. Thus, this paper proposed a systematic evaluation of the POMA molecular structure and crystallite size and shape after heat treatment.


Assuntos
Temperatura Alta , Poliaminas , Compostos de Anilina , Condutividade Elétrica , Poli A , Poliaminas/química , Polímeros/química
19.
Molecules ; 27(12)2022 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-35744995

RESUMO

Polyamine (PA) catabolism is often reduced in cancer cells. The activation of this metabolic pathway produces cytotoxic substances that might cause apoptosis in cancer cells. Chemical compounds able to restore the level of PA catabolism in tumors could become potential antineoplastic agents. The search for activators of PA catabolism among bicyclononan-9-ones is a promising strategy for drug development. The aim of the study was to evaluate the biological activity of new 3,7-diazabicyclo[3.3.1]nonan-9-one derivatives that have antiproliferative properties by accelerating PA catabolism. Eight bispidine derivatives were synthetized and demonstrated the ability to activate PA catabolism in regenerating rat liver homogenates. However, only three of them demonstrated a potent ability to decrease the viability of cancer cells in the MTT assay. Compounds 4c and 4e could induce apoptosis more effectively in cancer HepG2 cells rather than in normal WI-38 fibroblasts. The lead compound 4e could significantly enhance cancer cell death, but not the death of normal cells if PAs were added to the cell culture media. Thus, the bispidine derivative 4e 3-(3-methoxypropyl)-7-[3-(1H-piperazin-1-yl)ethyl]-3,7-diazabicyclo[3.3.1]nonane could become a potential anticancer drug substance whose mechanism relies on the induction of PA catabolism in cancer cells.


Assuntos
Antineoplásicos , Neoplasias , Animais , Antineoplásicos/química , Apoptose , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias/tratamento farmacológico , Poliaminas/química , Ratos , Relação Estrutura-Atividade
20.
Commun Biol ; 5(1): 586, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35705689

RESUMO

Placental function and dysfunction differ by sex but the mechanisms are unknown. Here we show that sex differences in polyamine metabolism are associated with escape from X chromosome inactivation of the gene encoding spermine synthase (SMS). Female placental trophoblasts demonstrate biallelic SMS expression, associated with increased SMS mRNA and enzyme activity. Polyamine depletion in primary trophoblasts reduced glycolysis and oxidative phosphorylation resulting in decreased acetyl-coA availability and global histone hypoacetylation in a sex-dependent manner. Chromatin-immunoprecipitation sequencing and RNA-sequencing identifies progesterone biosynthesis as a target of polyamine regulated gene expression, and polyamine depletion reduced progesterone release in male trophoblasts. The effects of polyamine depletion can be attributed to spermine as SMS-silencing recapitulated the effects on energy metabolism, histone acetylation, and progesterone release. In summary, spermine metabolism alters trophoblast gene expression through acetyl-coA biosynthesis and histone acetylation, and SMS escape from X inactivation explains some features of human placental sex differences.


Assuntos
Histonas , Trofoblastos , Acetilcoenzima A/metabolismo , Acetilação , Feminino , Expressão Gênica , Histonas/genética , Histonas/metabolismo , Humanos , Masculino , Placenta/metabolismo , Poliaminas/metabolismo , Gravidez , Progesterona/metabolismo , Espermina , Trofoblastos/metabolismo
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