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1.
Int J Mol Sci ; 22(19)2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34639029

RESUMO

Atherosclerosis and NAFLD are the leading causes of death worldwide. The hallmark of NAFLD is triglyceride accumulation caused by an imbalance between lipogenesis de novo and fatty acid oxidation. Agmatine, an endogenous metabolite of arginine, exerts a protective effect on mitochondria and can modulate fatty acid metabolism. In the present study, we investigate the influence of agmatine on the progression of atherosclerotic lesions and the development of hepatic steatosis in apoE-/- mice fed with a Western high-fat diet, with a particular focus on its effects on the DNL pathway in the liver. We have proved that treatment of agmatine inhibits the progression of atherosclerosis and attenuates hepatic steatosis in apoE-/- mice on a Western diet. Such effects are associated with decreased total macrophage content in atherosclerotic plaque as well as a decrease in the TG levels and the TG/HDL ratio in plasma. Agmatine also reduced TG accumulation in the liver and decreased the expression of hepatic genes and proteins involved in lipogenesis de novo such as SREBP-1c, FASN and SCD1. In conclusion, agmatine may present therapeutic potential for the treatment of atherosclerosis and fatty liver disease. However, an exact understanding of the mechanisms of the advantageous actions of agmatine requires further study.


Assuntos
Agmatina/efeitos adversos , Aterosclerose/etiologia , Aterosclerose/metabolismo , Dieta Ocidental , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Lipídeos/sangue , Lipogênese , Animais , Aterosclerose/sangue , Aterosclerose/patologia , Biomarcadores , HDL-Colesterol/sangue , Dieta Ocidental/efeitos adversos , Modelos Animais de Doenças , Suscetibilidade a Doenças , Fígado Gorduroso/sangue , Fígado Gorduroso/patologia , Feminino , Imuno-Histoquímica , Metabolismo dos Lipídeos , Camundongos , Camundongos Knockout para ApoE , Triglicerídeos/sangue
2.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(8): 889-893, 2021 Aug 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34565735

RESUMO

The prevalence of abnormal glucose and lipid metabolism and its relevant diseases has increased year by year, and it has become a problem that threatens human health. Therefore, finding a more effective way to prevent and treat diseases related to abnormal glucose and lipid metabolism has become an urgent public problem. Agmatine is a polyamine substance which widely presents in mammals.It is a metabolite produced by decarboxylation of L-arginine under the action of arginine decarboxylase, hence also known as decarboxylated arginine. Its biological effects have been confirmed. Previous studies have shown that agmatine possesses anti-diabetic effects in diabetic animals. Agmatine not only increases the insulin secretion form ß-pancreatic cells to inhibit the hyperglycemia, but also attenuates insulin resistance in rats. Agmatine also plays a positive role in lipid metabolism disorders and related diseases by modulating lipid metabolism and fatty acid oxidation.


Assuntos
Agmatina , Agmatina/farmacologia , Animais , Arginina/metabolismo , Glicolipídeos , Metabolismo dos Lipídeos , Ratos
3.
Adv Exp Med Biol ; 1332: 85-105, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34251640

RESUMO

Arginine is a key amino acid in pregnant females as it is the precursor for nitric oxide (NO) via nitric oxide synthase and for polyamines (putrescine, spermidine, and spermine) by either arginase II and ornithine decarboxylase to putrescine or via arginine decarboxylase to agmatine and agmatine to putrescine via agmatinase. Polyamines are critical for placental growth and vascularization. Polyamines stabilize DNA and mRNA for gene transcription and mRNA translation, stimulate proliferation of trophectoderm, and formation of multinucleated trophectoderm cells that give rise to giant cells in the placentae of species such as mice. Polyamines activate MTOR cell signaling to stimulate protein synthesis and they are important for motility through modification of beta-catenin phosphorylation, integrin signaling via focal adhesion kinases, cytoskeletal organization, and invasiveness or superficial implantation of blastocysts. Physiological levels of arginine, agmatine, and polyamines are critical to the secretion of interferon tau for pregnancy recognition in ruminants. Arginine, polyamines, and agmatine are very abundant in fetal fluids, fetal blood, and tissues of the conceptus during gestation. The polyamines are thus available to influence a multitude of events including activation of development of blastocysts, implantation, placentation, fetal growth, and development required for the successful establishment and maintenance of pregnancy in mammals.


Assuntos
Agmatina , Poliaminas , Animais , Arginina , Feminino , Mamíferos , Camundongos , Placenta , Gravidez
5.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946272

RESUMO

Agmatine is the product of the decarboxylation of L-arginine by the enzyme arginine decarboxylase. This amine has been attributed to neurotransmitter functions, anticonvulsant, anti-neurotoxic, and antidepressant in mammals and is a potential therapeutic agent for diseases such as Alzheimer's, Parkinson's, and cancer. Agmatinase enzyme hydrolyze agmatine into urea and putrescine, which belong to one of the pathways producing polyamines, essential for cell proliferation. Agmatinase from Escherichia coli (EcAGM) has been widely studied and kinetically characterized, described as highly specific for agmatine. In this study, we analyze the amino acids involved in the high specificity of EcAGM, performing a series of mutations in two loops critical to the active-site entrance. Two structures in different space groups were solved by X-ray crystallography, one at low resolution (3.2 Å), including a guanidine group; and other at high resolution (1.8 Å) which presents urea and agmatine in the active site. These structures made it possible to understand the interface interactions between subunits that allow the hexameric state and postulate a catalytic mechanism according to the Mn2+ and urea/guanidine binding site. Molecular dynamics simulations evaluated the conformational dynamics of EcAGM and residues participating in non-binding interactions. Simulations showed the high dynamics of loops of the active site entrance and evidenced the relevance of Trp68, located in the adjacent subunit, to stabilize the amino group of agmatine by cation-pi interaction. These results allow to have a structural view of the best-kinetic characterized agmatinase in literature up to now.


Assuntos
Proteínas de Escherichia coli/química , Escherichia coli/química , Ureo-Hidrolases/química , Agmatina/metabolismo , Domínio Catalítico , Cristalografia por Raios X , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Modelos Moleculares , Conformação Proteica , Multimerização Proteica , Especificidade por Substrato , Ureo-Hidrolases/metabolismo
6.
Neurosci Lett ; 753: 135881, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33838255

RESUMO

Essential tremor (ET) is one of the most prevalent movement disorders and the most common cause of abnormal tremors. However, it cannot be treated efficiently with the currently available pharmacotherapy options. The pathophysiology of harmaline-induced tremor, most commonly used model of ET, involves various neurotransmitter systems including glutamate as well as ion channels. Agmatine, an endogenous neuromodulator, interacts with various glutamate receptor subtypes and ion channels, which have been associated with its' beneficial effects on several neurological disorders. The current study aims to assess the effect of agmatine on the harmaline model of ET. Two separate groups of male rats were injected either with saline or agmatine (40 mg/kg) 30 min prior to single intraperitoneal injection of harmaline (20 mg/kg). The percent duration, intensity and frequency of tremor and locomotor activity were evaluated by a custom-built tremor and locomotion analysis system. Pretreatment with agmatine reduced the percent tremor duration and intensity of tremor induced by harmaline, without affecting the tremor frequency. However, it did not affect the decreased spontaneous locomotor activity due to harmaline. This pattern of ameliorating effects of agmatine on harmaline-induced tremor provide the first evidence for being considered as a treatment option for ET.


Assuntos
Agmatina/farmacologia , Tremor Essencial/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Agmatina/uso terapêutico , Animais , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/toxicidade , Modelos Animais de Doenças , Tremor Essencial/induzido quimicamente , Tremor Essencial/diagnóstico , Harmalina/administração & dosagem , Harmalina/toxicidade , Humanos , Masculino , Fármacos Neuroprotetores/uso terapêutico , Ratos , Índice de Gravidade de Doença
7.
Neurochem Res ; 46(8): 1933-1940, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33914233

RESUMO

Agmatine, an endogenous derivative of arginine, has been found to be effective in treating idiopathic pain, convulsion, stress-mediated behavior, and attenuate the withdrawal symptoms of drugs like morphine. In the early stages of ischemic brain injury in animals, exogenous agmatine treatment was found to be neuroprotective. Agmatine is also considered as a putative neurotransmitter and is still an experimental drug. Chemically, agmatine is called agmatine 1-(4-aminobutyl guanidine). Crystallographic study data show that positively-charged guanidine can bind to the protein containing Gly and Asp residues, and the amino group can interact with the complimentary sites of Glu and Ser. In this study, we blocked the amino end of the agmatine by conjugating it with FITC, but the guanidine end was unchanged. We compared the neuroprotective function of the agmatine and agmatine-FITC by treating them in neurons after excitotoxic stimulation. We found that even the amino end blocked neuronal viability in the excitotoxic condition, by NMDA treatment for 1 h, was increased by agmatine-FITC, which was similar to that of agmatine. We also found that the agmatine-FITC treatment reduced the expression of nitric oxide production in NMDA-treated cells. This study suggests that even if the amino end of agmatine is blocked, it can perform its neuroprotective function.


Assuntos
Agmatina/farmacologia , Neurônios/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Agmatina/química , Animais , Células Cultivadas , Córtex Cerebral/citologia , Feminino , Feto/citologia , Fluoresceína-5-Isotiocianato/química , Fluoresceína-5-Isotiocianato/farmacologia , Camundongos Endogâmicos ICR , N-Metilaspartato/toxicidade , Fármacos Neuroprotetores/química , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo
8.
J Physiol Biochem ; 77(2): 305-320, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33635523

RESUMO

Diabetic retinopathy (DR) is the most common diabetic neurovascular complication, and the leading cause of preventable blindness among working-age individuals. Recently, agmatine, the endogenous decarboxylated L-arginine, has gained attention as a pleiotropic agent that modulates the diabetes-associated decline in quality of life, and exhibited varied protective biological effects. Diabetes was induced by a single streptozotocin (STZ, 50 mg/kg, i.p.) injection. When diabetes was verified, the animals were randomly allocated into three groups (16 rat each); diabetic, agmatine-treated diabetic (1 mg/kg, daily, for 12 weeks), and control group. Blood glucose homeostasis, retinal redox status, apoptotic parameters, nitric oxide synthase (NOS), nitric oxide (NO), vascular endothelial growth factor (VEGF), glutamate, glutamine, glutamine synthase (GS) activity, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), and mitogen-activated protein kinase (MAPKs) pathways were assayed biochemically. Retinal vascular permeability was measured. Retinal morphology was evaluated by hematoxylin and eosin staining. Retinal N-methyl-D-aspartic acid receptor1 (NMDAR1) and glutamate aspartate transporter (GLAST) mRNA were quantified. Glucose transporter 1, pro-caspase3, and glial fibrillary acidic protein (GFAP) expression were quantified by immunohistochemistry. Chronic agmatine treatment abrogated STZ-induced retinal neurodegeneration features including gliosis, and neuronal apoptosis, restored retinal vascular permeability, mostly through antioxidant, anti-apoptotic capacity, abolishing glutamate excitotoxicity, modulating the activity of NMDARs, MAPKs/NFκB, and NOS/NO pathways. By restoring the molecular and functional background of retinal neurovascular homeostatic balance, agmatine would be appropriate therapeutic option acting upstream of the DR, impeding its progression.


Assuntos
Agmatina/farmacologia , Antioxidantes/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Hipoglicemiantes/farmacologia , Fármacos Neuroprotetores/farmacologia , Retina/efeitos dos fármacos , Animais , Glicemia/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/induzido quimicamente , Retinopatia Diabética/genética , Retinopatia Diabética/patologia , Transportador 1 de Aminoácido Excitatório/genética , Transportador 1 de Aminoácido Excitatório/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Glutamato-Amônia Ligase/genética , Glutamato-Amônia Ligase/metabolismo , Ácido Glutâmico/metabolismo , Masculino , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo I/metabolismo , Estresse Oxidativo , Ratos , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Retina/metabolismo , Retina/patologia , Estreptozocina/administração & dosagem , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
9.
Eur J Pharmacol ; 892: 173739, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33220274

RESUMO

3-Hydroxy-3-methyl-glutaryl-co-enzyme-A (HMG-CoA) reductase inhibitors (statins) are popularly used for the treatment of obesity and hypercholesterolemia with established safety profile. Statins exhibits a wide range of neurobehavioral effects in addition to their peripheral actions, and may be beneficial in treatment of psychiatric conditions. Present study investigated the role of agmatine and imidazoline receptors in antidepressant-like effect of statins in mouse forced swimming test (FST). The antidepressant-like effect of atorvastatin (5 mg/kg, p.o.) and simvastatin (10 mg/kg, p.o.) was potentiated by pretreatment with agmatine (5 mg/kg, i.p.) as well as the drugs known to increase endogenous agmatine levels in brain viz., L-arginine (40 µg/mouse, i.c.v.), an agmatine biosynthetic precursor; arcaine (50 µg/mouse, i.c.v), agmatinase inhibitor; and aminoguanidine (6.5 µg/mouse, i.c.v.), a diamine oxidase inhibitor. Further, both the statins increased agmatine levels within hippocampus and prefrontal cortex. Conversely, prior administration of I1 receptor antagonist, efaroxan (1 mg/kg, i.p.) and I2 receptor antagonist, idazoxan (0.25 mg/kg, i.p.) blocked the antidepressant-like effect of statins and their synergistic combination with agmatine. These results demonstrate the involvement of agmatine and imidazoline receptors in antidepressant-like effect of statins and suggest as a potential therapeutic target for the treatment of depressive disorders.


Assuntos
Agmatina/metabolismo , Antidepressivos/farmacologia , Atorvastatina/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Depressão/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Sinvastatina/farmacologia , Agmatina/farmacologia , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Depressão/metabolismo , Depressão/fisiopatologia , Depressão/psicologia , Modelos Animais de Doenças , Quimioterapia Combinada , Receptores de Imidazolinas/efeitos dos fármacos , Receptores de Imidazolinas/metabolismo , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Natação
10.
Neurosci Lett ; 740: 135447, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33127446

RESUMO

Alzheimer's disease is an age related progressive neurodegenerative disorder characterized by decline in cognitive functions, such as memory loss and behavioural abnormalities. The present study sought to assess alterations in agmatine metabolism in the beta-amyloid (Aß1-42) Alzheimer's disease mouse model. Aß1-42 injected mice showed impairment of cognitive functioning as evidenced by increased working and reference memory errors in radial arm maze (RAM). This cognitive impairment was associated with a reduction in the agmatine levels and elevation in its degrading enzyme, agmatinase, whereas reduced immunocontent was observed in its synthesizing enzyme arginine decarboxylase expression within hippocampus and prefrontal cortex. Chronic agmatine treatment and its endogenous modulation by l-arginine, or arcaine or aminoguanidine prevented the learning and memory impairment induced by single intracranial Aß1-42 peptide injection. In conclusion, the present study suggests the importance of the endogenous agmatinergic system in ß-amyloid induced memory impairment in mice.


Assuntos
Agmatina/metabolismo , Agmatina/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides , Transtornos da Memória/metabolismo , Fragmentos de Peptídeos , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/psicologia , Animais , Carboxiliases/biossíntese , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/psicologia , Hipocampo/enzimologia , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/psicologia , Camundongos , Córtex Pré-Frontal/enzimologia , Desempenho Psicomotor/efeitos dos fármacos , Ureo-Hidrolases/metabolismo
11.
J Neural Transm (Vienna) ; 127(12): 1675-1684, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33026491

RESUMO

In this study, we aimed to investigate the effects of agmatine, nitric oxide (NO), arginine, and glutamate, which are the metabolites in the polyamine pathway,  on the performance of executive functions (EF) in attention deficit hyperactivity disorder (ADHD). The ADHD group included 35 treatment-naive children (6-14 years old) who were ewly diagnosed with ADHD. The control group consisted of 35 healthy children with the same age and sex, having no previous psychiatric disorders. In the study groups, Stroop test (ST) and trail making test (TMT) were used to monitor EF, and blood samples were collected to measure agmatine with ultra-high-performance liquid chromatography and NO, glutamate, and arginine with enzyme-linked immunosorbent assay (ELISA). The EFs were significantly impaired in the ADHD group. The agmatine and arginine levels of the ADHD group were significantly higher than their peers. The NO and glutamate levels were also higher in the ADHD group compared to the control group, but these differences did not reach statistical significance. Children with ADHD had more difficulties during EF tasks compared to healthy children. The elevated NO and glutamate levels may be related with the impairment during EF tasks. Therefore, agmatine and arginine may increase to improve EF tasks through its inhibitory effect on the synthesis of NO and glutamate. Further studies are needed about polyamine pathway molecules to shed light on the pathophysiology of ADHD.


Assuntos
Agmatina , Transtorno do Deficit de Atenção com Hiperatividade , Arginina , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Criança , Função Executiva , Ácido Glutâmico , Humanos , Testes Neuropsicológicos , Óxido Nítrico
12.
Biol Pharm Bull ; 43(10): 1556-1561, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32999165

RESUMO

Renal insufficiency secondary to contrast administration remains a prevalent and debilitating complication of angiographic procedures. Contrast-induced nephropathy (CIN) is a common clinical problem for which there is no effective medical treatment. However, agmatine has been shown to be effective against ischemia/reperfusion-induced acute kidney injury in rats, a similar condition to CIN. Our aim was to examine the protective effects of agmatine in a rat model of CIN and, based on those results, in a rabbit model of CIN. CIN in the rat model was induced by intravenous administration of indomethacin (10 mg/kg), Nω-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg) and iopamidol (OYPALOMIN, 7.4 g iodine/kg) at 2 weeks after a unilateral nephrectomy. CIN in the rabbit model was induced by intrarenal arterial injection of only iopamidol (BYSTAGE, 4.8 g iodine/kg). Intravenous injection of agmatine (0.1 and 0.3 mmol/kg) did not attenuate the CIN-induced renal insufficiency in the rat model. Intravenous injection of agmatine (0.3 mmol/kg) attenuated the CIN-induced renal insufficiency in the rabbit model such as increases in blood urea nitrogen and plasma creatinine levels. Renal histological damage was also improved by the agmatine administration. The difference in effects of agmatine injection between CIN rats and CIN rabbits was caused by indomethacin and L-NAME administrations. These results indicate that agmatine prevents the development of CIN-induced renal insufficiency in rabbits, and the effect is accompanied by activation of nitric oxide synthase and subsequent increase of blood flow.


Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Agmatina/uso terapêutico , Meios de Contraste/toxicidade , Modelos Animais de Doenças , Injúria Renal Aguda/enzimologia , Animais , Relação Dose-Resposta a Droga , Masculino , Óxido Nítrico Sintase/metabolismo , Coelhos , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
13.
mBio ; 11(4)2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32788384

RESUMO

Amino acid metabolism is crucial for fungal growth and development. Ureohydrolases produce amines when acting on l-arginine, agmatine, and guanidinobutyrate (GB), and these enzymes generate ornithine (by arginase), putrescine (by agmatinase), or GABA (by 4-guanidinobutyrase or GBase). Candida albicans can metabolize and grow on arginine, agmatine, or guanidinobutyrate as the sole nitrogen source. Three related C. albicans genes whose sequences suggested that they were putative arginase or arginase-like genes were examined for their role in these metabolic pathways. Of these, Car1 encoded the only bona fide arginase, whereas we provide evidence that the other two open reading frames, orf19.5862 and orf19.3418, encode agmatinase and guanidinobutyrase (Gbase), respectively. Analysis of strains with single and multiple mutations suggested the presence of arginase-dependent and arginase-independent routes for polyamine production. CAR1 played a role in hyphal morphogenesis in response to arginine, and the virulence of a triple mutant was reduced in both Galleria mellonella and Mus musculus infection models. In the bloodstream, arginine is an essential amino acid that is required by phagocytes to synthesize nitric oxide (NO). However, none of the single or multiple mutants affected host NO production, suggesting that they did not influence the oxidative burst of phagocytes.IMPORTANCE We show that the C. albicans ureohydrolases arginase (Car1), agmatinase (Agt1), and guanidinobutyrase (Gbu1) can orchestrate an arginase-independent route for polyamine production and that this is important for C. albicans growth and survival in microenvironments of the mammalian host.


Assuntos
Agmatina/metabolismo , Arginina/metabolismo , Candida albicans/enzimologia , Candida albicans/patogenicidade , Proteínas Fúngicas/metabolismo , Ureo-Hidrolases/metabolismo , Aminoácidos/metabolismo , Animais , Arginase/genética , Arginase/metabolismo , Clonagem Molecular , Feminino , Larva/microbiologia , Redes e Vias Metabólicas , Camundongos , Camundongos Endogâmicos BALB C , Mariposas/microbiologia , Células RAW 264.7 , Ureo-Hidrolases/genética , Virulência
14.
Brain Res ; 1747: 147045, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-32758481

RESUMO

Epidemiological studies indicated that mood disorders like depression and anxiety are highly prevalent in type-II diabetes mellitus (T2DM). However, the neurobiological mechanisms underlying the relationship between T2DM and depression have yet to be identified. Thus, understanding the neural mechanisms that mediate the co-morbidity of depression and type-II diabetes mellitus may unlock new pharmacological treatments for this condition. The present study investigated the role of the agmatinergic system in T2DM induced depression using forced swim test (FST) and anxiety in the elevated plus-maze (EPM)in rats. T2DM was induced by the combination of high-fat diet (HFD) and streptozotocin (STZ) injection and confirmed by high blood glucose levels. After 12 weeks, HFD fed and STZ injected rats exhibited depression-like behaviors and anxiety. It was associated with increased expression of pro-inflammatory cytokines like IL-6 and TNF-α, and reduced BDNF immunocontent in the hippocampal tissues. The T2DM-induced depression, anxiety, and neuroinflammatory markers were significantly inhibited by agmatine (10-20 mg/kg, i.p.), by once-daily administration during 9th to 12th week of the protocol. Agmatine levels were significantly reduced in the hippocampus of T2DM rats as compared to the normal fed (NF) control animals. In conclusion, the present study suggests the importance of endogenous agmatine in T2DM induced anxiety and depressive-like behavior in rats. The data projects agmatine as a potential therapeutic target for T2DM-associated depression, anxiety, and comorbidities.


Assuntos
Agmatina/farmacologia , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Agmatina/uso terapêutico , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Ansiedade/etiologia , Ansiedade/metabolismo , Citocinas/metabolismo , Depressão/etiologia , Depressão/metabolismo , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
15.
Curr Genet ; 66(6): 1179-1190, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32812074

RESUMO

Fusarium graminearum produces trichothecene mycotoxins in infected grains and axenic liquid culture. A proposed regulatory model of trichothecene biosynthesis was examined in relation to nitrogen utilization. First, we showed that an important factor for the stimulation of trichothecene biosynthesis was not the occurrence of agmatine as a specific inducer molecule, but rather continuous acidification of the liquid culture medium arising from agmatine catabolism. When the pH of the L-Gln synthetic medium was frequently adjusted to the pH of the agmatine culture, trichothecene productivity of the L-Gln culture was equal to that of the agmatine culture. For efficient trichothecene biosynthesis, the culture pH should be lowered at an appropriate time point during the early growth stage. Second, we re-evaluated the role of the nitrogen regulatory GATA transcription factor AreA in trichothecene biosynthesis. Since Tri6 encodes a transcription factor indispensable for trichothecene biosynthesis, all fifteen AreA-binding consensus sequences in the Tri6 promoter were mutated. The mutant could catabolize L-Phe as the sole nitrogen source; furthermore, the pH profile of the synthetic L-Phe medium (initial pH 4.2) was the same as that of the wild-type (WT) strain. Under such conditions, the promoter mutant exhibited approximately 72% of the trichothecene productivity compared to the WT strain. Thus, F. graminearum AreA (FgAreAp) is dispensable for the functioning of the Tri6 promoter, but it contributes to the increased production of mycotoxin under mildly acidic conditions to some extent. Further investigations on the culture pH revealed that extremely low pH bypasses the function of FgAreAp.


Assuntos
Agmatina/metabolismo , Fusarium/genética , Fatores de Transcrição/genética , Tricotecenos/metabolismo , Meios de Cultura/química , Meios de Cultura/farmacologia , Fusarium/metabolismo , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Nitrogênio/metabolismo , Poliaminas/metabolismo , Fatores de Transcrição/metabolismo
16.
Exp Neurol ; 333: 113398, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32659382

RESUMO

We investigated the ability of agmatine to potentiate the antidepressant-like and synaptic effects of ketamine in mice. Agmatine (0.1 and 1 mg/kg, p.o.) and ketamine (1 and 10 mg/kg, i.p.) produced an antidepressant-like effect in the tail suspension test. The combination of agmatine (0.01 mg/kg, p.o.) and ketamine (0.1 mg/kg, i.p.), at subthreshold doses, produced an antidepressant-like effect 1 h, 24 h and 7d after treatment. Western blot analysis from prefrontal cortex tissue showed that the combined treatment, after 1 h, increased p70S6K and GluA1, and reduced synapsin 1 phosphorylation. Additionally, after 24 h, Akt, p70S6K, GluA1, and synapsin 1 phosphorylation; and PSD95 immunocontent increased (which persisted for up to 7d). Dendritic architecture analysis of the prefrontal cortex revealed that the combined treatment improved dendritic arbor complexity (after 24 h, up to 7d), and increased spine density (after 1 h, up to 24 h). Morphometric analysis revealed a filopodia-shaped dendrite spine upregulation after 1 h. A predominance of stubby, mushroom, branched and filopodia; and a reduction in thin protrusions were observed after 24 h. Finally, mushroom-shaped dendritic spines predominance increased after 7d. Agmatine potentiated ketamine's antidepressant, and dendritic arbors and spines remodeling effects in a time-dependent manner. Our data indicate Akt/p70S6K signaling as a likely target for these effects.


Assuntos
Agmatina/farmacologia , Antidepressivos/farmacologia , Dendritos/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Ketamina/farmacologia , Proteína Oncogênica v-akt/efeitos dos fármacos , Proteínas Quinases S6 Ribossômicas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Animais , Dendritos/ultraestrutura , Espinhas Dendríticas/ultraestrutura , Sinergismo Farmacológico , Elevação dos Membros Posteriores , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos
17.
Nat Commun ; 11(1): 3169, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576825

RESUMO

Understanding tumor metabolism holds the promise of new insights into cancer biology, diagnosis and treatment. To assess human cancer metabolism, here we report a method to collect intra-operative samples of blood from an artery directly upstream and a vein directly downstream of a brain tumor, as well as samples from dorsal pedal veins of the same patients. After performing targeted metabolomic analysis, we characterize the metabolites consumed and produced by gliomas in vivo by comparing the arterial supply and venous drainage. N-acetylornithine, D-glucose, putrescine, and L-acetylcarnitine are consumed in relatively large amounts by gliomas. Conversely, L-glutamine, agmatine, and uridine 5-monophosphate are produced in relatively large amounts by gliomas. Further we verify that D-2-hydroxyglutarate (D-2HG) is high in venous plasma from patients with isocitrate dehydrogenases1 (IDH1) mutations. Through these paired comparisons, we can exclude the interpatient variation that is present in plasma samples usually taken from the cubital vein.


Assuntos
Biomarcadores Tumorais/sangue , Vasos Sanguíneos/metabolismo , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/metabolismo , Glioma/sangue , Glioma/metabolismo , Metabolômica , Acetilcarnitina/sangue , Adulto , Idoso , Agmatina/sangue , Sangue , Análise Química do Sangue , Glicemia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Feminino , Glioma/diagnóstico por imagem , Glioma/genética , Glucose , Glutamina/sangue , Glutaratos/sangue , Humanos , Isocitrato Desidrogenase/sangue , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Masculino , Pessoa de Meia-Idade , Ornitina/análogos & derivados , Ornitina/sangue , Putrescina/sangue , Uridina Monofosfato/sangue , Adulto Jovem
18.
Neurotoxicology ; 80: 1-11, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32522471

RESUMO

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder characterized by abnormal accumulation of extracellular ß-amyloid (Aß) plaques and neuronal damage. The present study investigated the effect of chronic intra-hippocampal agmatine administration on ß-Amyloid (Aß) induced memory impairment in mice. Aß1-42 peptide injected mice demonstrated impairment of cognitive abilities evaluated as reference memory error and working memory error in radial arm maze (RAM) and decreased exploration time for novel object as well as recognition index in novel object recognition (NOR) test along with elevation in Aß1-42 peptide, ß-Site APP cleaving enzyme 1 (BACE 1), microtubule-associated protein tau (MAPt), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and reduction in neprilysin and brain derived neurotrophic factor (BDNF) immunocontent within hippocampus and prefrontal cortex. Importantly, this was associated with a reduction in the agmatine levels following Aß1-42 peptide administration. Chronic administration of agmatine from day 8-27, prevented the memory impairment in mice and normalized the neurochemical alteration within prefrontal cortex and hippocampus induced by Aß1-42 peptide administration. However, it did not modulate the amyloid precursor protein and BACE expression. This study suggests that agmatine improves learning and memory impairment possibly through the down regulation of neuroinflammatory pathways in AD.


Assuntos
Agmatina/farmacologia , Anti-Inflamatórios/farmacologia , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Transtornos da Memória/prevenção & controle , Memória/efeitos dos fármacos , Nootrópicos/farmacologia , Agmatina/metabolismo , Peptídeos beta-Amiloides , Animais , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Camundongos , Teste de Campo Aberto/efeitos dos fármacos , Fragmentos de Peptídeos , Transdução de Sinais
19.
Int J Mol Sci ; 21(11)2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32531922

RESUMO

Agmatine is a neurotransmitter with anticonvulsant, anti-neurotoxic and antidepressant-like effects, in addition it has hypoglycemic actions. Agmatine is converted to putrescine and urea by agmatinase (AGM) and by an agmatinase-like protein (ALP), a new type of enzyme which is present in human and rodent brain tissues. Recombinant rat brain ALP is the only mammalian protein that exhibits significant agmatinase activity in vitro and generates putrescine under in vivo conditions. ALP, despite differing in amino acid sequence from all members of the ureohydrolase family, is strictly dependent on Mn2+ for catalytic activity. However, the Mn2+ ligands have not yet been identified due to the lack of structural information coupled with the low sequence identity that ALPs display with known ureohydrolases. In this work, we generated a structural model of the Mn2+ binding site of the ALP and we propose new putative Mn2+ ligands. Then, we cloned and expressed a sequence of 210 amino acids, here called the "central-ALP", which include the putative ligands of Mn2+. The results suggest that the central-ALP is catalytically active, as agmatinase, with an unaltered Km for agmatine and a decreased kcat. Similar to wild-type ALP, central-ALP is activated by Mn2+ with a similar affinity. Besides, a simple mutant D217A, a double mutant E288A/K290A, and a triple mutant N213A/Q215A/D217A of these putative Mn2+ ligands result on the loss of ALP agmatinase activity. Our results indicate that the central-ALP contains the active site for agmatine hydrolysis, as well as that the residues identified are relevant for the ALP catalysis.


Assuntos
Agmatina/metabolismo , Manganês/metabolismo , Ureo-Hidrolases/química , Ureo-Hidrolases/metabolismo , Animais , Sítios de Ligação , Escherichia coli/genética , Cinética , Mamíferos , Modelos Moleculares , Mutagênese Sítio-Dirigida , Conformação Proteica , Temperatura , Ureo-Hidrolases/genética
20.
Int J Mycobacteriol ; 9(2): 138-143, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32474534

RESUMO

Background: Polyamines are widespread intracellular molecules able to influence antibiotic susceptibility, but almost nothing is known on their occurrence and physiological role in mycobacteria. Methods: here, we analyzed transcriptomic, proteomic and biochemical data and obtained the first evidence for the post-transcriptional expression of some genes attributed to polyamine metabolism and polyamine transport in Mycolicibacterium smegmatis (basionym Mycobacterium smegmatis). Results: in our experiments, exponentially growing cells demonstrated transcription of 21 polyamine-associated genes and possessed 7 enzymes of polyamine metabolism and 2 polyamine transport proteins. Conclusion: Mycolicibacterium smegmatis putrescine synthesizing enzyme agmatinase SpeB was originally shown to catalyze agmatine conversion to putrescine in vitro. Nevertheless, we have not found any polyamines in mycobacterial cells.


Assuntos
Mycobacterium smegmatis/química , Mycobacterium smegmatis/enzimologia , Poliaminas/análise , Ureo-Hidrolases/metabolismo , Agmatina/metabolismo , Perfilação da Expressão Gênica , Mycobacterium smegmatis/genética , Proteômica , Putrescina/metabolismo , Ureo-Hidrolases/genética
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