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1.
J Clin Exp Hematop ; 61(3): 145-151, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34334531

RESUMO

We established an IL-2 and IL-4 (IL2/4) - dependent adult T-cell leukemia/lymphoma (ATLL) cell line (YG-PLL) by adding poly-L-lysine (PLL) to the culture medium. YG-PLL originates from lymphoma cells and contains a defective HTLV-I proviral genome. Although YG-PLL cannot survive without IL-2/4, the follicular dendritic cell (FDC)-like cell line HK expressing OX40-ligand gene (OX40L+HK) inhibited their death in the presence of soluble neutral polymers. After the prevention of cell death, YG-PLL proliferated on OX40L+HK without IL2/4 in the presence of two kinds of positively or negatively charged polymers. In particular, dermatan sulfate and poly-L-histidine supported growth for more than 4 months. Therefore, the original lymphoma cells proliferated transiently in the presence of IL2/4, and their growth arrest was inhibited by the addition of PLL. Furthermore, YG-PLL lost IL2/4 dependency by the following 3-step procedure: preculture with IL2/4 and neutral polymers, 3-day culture with neutral polymer on OX40L+HK to inhibit cell death, and co-culture with OX40L+HK in the presence of the positively and negatively charged polymers. The extracellular environment made by soluble polymers plays a role in the growth of ATLL in vitro.


Assuntos
Linhagem Celular Tumoral , Dermatan Sulfato/farmacologia , Histidina/farmacologia , Interleucina-2/metabolismo , Interleucina-4/metabolismo , Leucemia-Linfoma de Células T do Adulto/etiologia , Leucemia-Linfoma de Células T do Adulto/metabolismo , Ligante OX40/metabolismo , Células Dendríticas Foliculares/imunologia , Células Dendríticas Foliculares/metabolismo , Expressão Gênica , Humanos , Leucemia-Linfoma de Células T do Adulto/patologia , Ligante OX40/genética
2.
Life Sci ; 282: 119816, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34273376

RESUMO

BACKGROUND: Combined exercise training (CET) has been associated with positive responses in the clinical status of patients with heart failure (HF). Other nonpharmacological tools, such as amino acid supplementation, may further enhance its adaptation. The aim was to test whether CET associated with supplementing carnosine precursors could present better responses in the functional capacity and biochemical variables of rats with HF. METHODS: Twenty-one male Wistar rats were subjected to myocardial infarction and allocated to three groups: sedentary (SED, n = 7), CET supplemented with placebo (CETP, n = 7), and CET with HF supplemented with ß-alanine and L-histidine (CETS, n = 7). The trained animals were submitted to a strength protocol three times per week. Aerobic training was conducted twice per week. The supplemented group received ß-alanine and L-histidine orally (250 mg/kg per day). RESULTS: Maximum oxygen uptake, running distance, time to exhaustion and maximum strength were higher in the CET-P group than that in the SED group and even higher in the CET-S group than that in the CET-P group (P < 0.01). CET-S showed lower oxidative stress and inflammation markers and higher heat shock protein 72 kDa content and mRNA expression for calcium transporters in the skeletal muscle compared to SED. CONCLUSION: CET together with ß-alanine and L-histidine supplementation in rats with HF can elicit adaptations in both maximum oxygen uptake, running distance, time to exhaustion, maximum strength, oxidative stress, inflammation and mRNA expression. Carnosine may influence beneficial adjustments in the cell stress response in the skeletal muscle and upregulate the mRNA expression of calcium transporters.


Assuntos
Carnosina/farmacologia , Insuficiência Cardíaca , Oxigênio/sangue , Condicionamento Físico Animal , Animais , Modelos Animais de Doenças , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Histidina/farmacologia , Masculino , Ratos , Ratos Wistar , beta-Alanina/farmacologia
3.
Acta Biochim Biophys Sin (Shanghai) ; 53(8): 1055-1064, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34125142

RESUMO

Histidine treatment has anti-inflammatory effects on several diseases such as colitis and obesity. We revealed that histidine levels were decreased in the serum of patients with chronic obstructive pulmonary disease (COPD) in our previous study. However, whether histidine confers protection against COPD is unclear. In the present study, we evaluated the protective effects of histidine in a porcine pancreatic elastase- and lipopolysaccharide-induced COPD mouse model. We found that the serum histidine concentration was decreased in COPD mice. Histidine supplementation improved the COPD mouse lung function and reduced the inflammatory cell counts and production of cytokines in bronchoalveolar lavage fluid. In addition, histidine treatment ameliorated lung inflammation by inhibiting the nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 inflammasome activation both in vivo and in vitro. Furthermore, we found that the potential anti-inflammatory mechanism involved the upregulation of silent information regulator factor 2-related enzyme 1. These results suggest that histidine may be a valuable therapeutic target for COPD.


Assuntos
Histidina/farmacologia , Lipopolissacarídeos/toxicidade , Pulmão/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Elastase Pancreática/toxicidade , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Feminino , Inflamassomos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Pulmão/patologia , Camundongos , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Suínos
4.
Insect Biochem Mol Biol ; 134: 103586, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33992752

RESUMO

Many foods and drinks contain histamine; however, the mechanisms that drive histamine taste perception have not yet been investigated. Here, we use a simple model organism, Drosophila melanogaster, to dissect the molecular sensors required to taste histamine. We first investigated histidine and histamine taste perception by performing a binary food choice assay and electrophysiology to identify essential sensilla for histamine sensing in the labellum. Histamine was found to activate S-type sensilla, which harbor bitter-sensing gustatory receptor neurons. Moreover, unbiased genetic screening for chemoreceptors revealed that a gustatory receptor, GR22e and an ionotropic receptor, IR76b are required for histamine sensing. Ectopic expression of GR22e was sufficient to induce a response in I-type sensilla, which normally do not respond to histamine. Taken together, our findings provide new insights into the mechanisms by which insects discriminate between the toxic histamine and beneficial histidine via their taste receptors.


Assuntos
Proteínas de Drosophila , Histamina , Histidina , Receptores de Superfície Celular , Receptores Ionotrópicos de Glutamato , Animais , Células Quimiorreceptoras/efeitos dos fármacos , Proteínas de Drosophila/efeitos dos fármacos , Proteínas de Drosophila/genética , Proteínas de Drosophila/fisiologia , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Eletrofisiologia , Histamina/farmacologia , Histidina/farmacologia , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/fisiologia , Receptores Ionotrópicos de Glutamato/efeitos dos fármacos , Receptores Ionotrópicos de Glutamato/genética , Receptores Ionotrópicos de Glutamato/fisiologia , Sensilas/efeitos dos fármacos , Sensilas/metabolismo , Canais de Sódio/efeitos dos fármacos , Canais de Sódio/genética , Canais de Sódio/fisiologia , Paladar/genética , Paladar/fisiologia
5.
Int J Mol Sci ; 22(4)2021 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-33561977

RESUMO

Zinc compounds have a number of beneficial properties for the skin, including antimicrobial, sebostatic and demulcent activities. The aim of the study was to develop new anti-acne preparations containing zinc-amino acid complexes as active ingredients. Firstly, the cytotoxicity of the zinc complexes was evaluated against human skin fibroblasts (1BR.3.N cell line) and human epidermal keratinocyte cell lines, and their antimicrobial activity was determined against Cutibacterium acnes. Then, zinc complexes of glycine and histidine were selected to create original gel formulations. The stability (by measuring pH, density and viscosity), microbiological purity (referring to PN-EN ISO standards) and efficacy of the preservative system (according to Ph. Eur. 10 methodology) for the preparations were evaluated. Skin tolerance was determined in a group of 25 healthy volunteers by the patch test. The preparations containing zinc(II) complexes with glycine and histidine as active substances can be topically used in the treatment of acne skin due to their high antibacterial activity against C. acnes and low cytotoxicity for the skin cells. Dermatological recipes have been appropriately composed; no irritation or allergy was observed, and the preparations showed high microbiological purity and physicochemical stability.


Assuntos
Acne Vulgar/tratamento farmacológico , Antibacterianos/farmacologia , Glicina/farmacologia , Histidina/farmacologia , Propionibacteriaceae/efeitos dos fármacos , Compostos de Zinco/farmacologia , Acne Vulgar/microbiologia , Linhagem Celular , Glicina/química , Histidina/química , Humanos , Queratinócitos/efeitos dos fármacos , Propionibacteriaceae/crescimento & desenvolvimento , Pele/efeitos dos fármacos , Pele/microbiologia , Pele/patologia , Creme para a Pele , Zinco/química , Compostos de Zinco/química
6.
Interact Cardiovasc Thorac Surg ; 32(2): 319-324, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33398332

RESUMO

OBJECTIVES: Energy demand and supply need to be balanced to preserve myocardial function during paediatric cardiac surgery. After a latent aerobic period, cardiac cells try to maintain energy production by anaerobic metabolism and by extracting oxygen from the given cardioplegic solution. Myocardial oxygen consumption (MVO2) changes gradually during the administration of cardioplegia. METHODS: MVO2 was measured during cardioplegic perfusion in patients younger than 6 months of age (group N: neonates; group I: infants), with a body weight less than 10 kg. Histidine-tryptophan-ketoglutarate crystalloid solution was used for myocardial protection and was administered during a 5-min interval. To measure pO2 values during cardioplegic arrest, a sample of the cardioplegic fluid was taken from the inflow line before infusion. Three fluid samples were taken from the coronary venous effluent 1, 3 and 5 min after the onset of cardioplegia administration. MVO2 was calculated using the Fick principle. RESULTS: The mean age of group N was 0.2 ± 0.09 versus 4.5 ± 1.1 months in group I. The mean weight was 3.1 ± 0.2 versus 5.7 ± 1.6 kg, respectively. MVO2 decreased similarly in both groups (min 1: 0.16 ± 0.07 vs 0.36 ± 0.1 ml/min; min 3: 0.08 ± 0.04 vs 0.17 ± 0.09 ml/min; min 5: 0.05 ± 0.04 vs 0.07 ± 0.05 ml/min). CONCLUSIONS: We studied MVO2 alterations after aortic cross-clamping and during delivery of cardioplegia in neonates and infants undergoing cardiac surgery. Extended cardioplegic perfusion significantly reduces energy turnover in hearts because the balance procedures are both volume- and above all time-dependent. A reduction in MVO2 indicates the necessity of a prolonged cardioplegic perfusion time to achieve optimized myocardial protection.


Assuntos
Soluções Cardioplégicas/farmacologia , Coração/efeitos dos fármacos , Histidina/farmacologia , Ácidos Cetoglutáricos/farmacologia , Consumo de Oxigênio/fisiologia , Triptofano/farmacologia , Animais , Aorta , Vasos Coronários/metabolismo , Soluções Cristaloides/metabolismo , Parada Cardíaca Induzida , Humanos , Recém-Nascido , Ácidos Cetoglutáricos/administração & dosagem , Masculino , Miocárdio/metabolismo , Perfusão , Triptofano/administração & dosagem
7.
Life Sci ; 270: 119134, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33513395

RESUMO

AIMS: Salt-sensitive hypertension is a risk factor for cardiovascular disease. Previous studies have shown that insufficient arginine in the kidney caused by metabolic imbalance is an important factor in salt-sensitive hypertension. Whether the high nitrogen content of histidine can affect the balance of nitrogen metabolism in Dahl salt-sensitive (SS) rats. This article aimed to study the effects of oral histidine on salt-sensitive hypertension, kidney damage and metabolic patterns of high-salt diet in SS rats. MAIN METHODS: Adult rats were divided into four groups, and blood pressure was measured using a non-invasive tail-cuff system. Gas chromatography-mass spectrometry analyzed metabolites in serum and kidney tissues. KEY FINDINGS: High-salt diet significantly increased the blood pressure of rats and aggravated kidney damage. Of note, histidine can attenuate salt-sensitive hypertension and kidney damage by improving metabolic pattern, reducing Reactive Oxygen Species (ROS) and increasing nitric oxide levels in SS rats. SIGNIFICANCE: These results suggest that histidine could be a potential adjuvant to prevent and control salt-sensitive hypertension.


Assuntos
Histidina/farmacologia , Hipertensão/tratamento farmacológico , Administração Oral , Animais , Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/metabolismo , Dieta , Histidina/metabolismo , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Rim/metabolismo , Nefropatias/metabolismo , Masculino , Óxido Nítrico/metabolismo , Ratos , Ratos Endogâmicos Dahl , Espécies Reativas de Oxigênio/metabolismo , Cloreto de Sódio na Dieta/efeitos adversos
8.
J Trace Elem Med Biol ; 65: 126723, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33508549

RESUMO

BACKGROUND: The objective of this study was to investigate the effects of different chromium histidinate (CrHis) complexes added to the diet of rats fed a high-fat diet (HFD) on body weight changes, glucose and lipid metabolism parameters, and changes in biomarkers such as PPAR-γ, IRS-1, GLUTs, and NF-κB proteins. METHODS: Forty-two Sprague-Dawley rats were divided equally into six groups and fed either a control, an HFD, or an HFD supplemented with either CrHis1, CrHis2, CrHis3, or a combination of the CrHis complexes as CrHisM. RESULTS: Feeding an HFD to rats increased body weights, HOMA-IR values, fasting serum glucose, insulin, leptin, free fatty acid, total cholesterol, low-density lipoprotein cholesterol, and MDA concentrations as well as AST activities, and decreased serum and brain serotonin concentrations compared with rats fed a control diet (P < 0.0001). The levels of the PPAR-γ, IRS-1, and GLUTs in the liver and brain decreased, while NF-κB level increased, with feeding an HFD (P < 0.05). Although all the CrHis supplements reversed the negative effects of feeding an HFD (P < 0.05), the CrHis1 complex was most effective in changing the protein levels, while CrHisM was most effective in influencing certain parameters such as body weight and serum metabolites. CONCLUSION: The results of the present work suggest that the CrHis1 complex is most potent for alleviating the negative effects of feeding an HFD. The efficacy of CrHisM is likely due to the presence of the CrHis1 complex.


Assuntos
Glicemia/efeitos dos fármacos , Transportador de Glucose Tipo 1/antagonistas & inibidores , Histidina/análogos & derivados , Proteínas Substratos do Receptor de Insulina/antagonistas & inibidores , NF-kappa B/metabolismo , Compostos Organometálicos/farmacologia , PPAR gama/antagonistas & inibidores , Animais , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Transportador de Glucose Tipo 1/metabolismo , Histidina/administração & dosagem , Histidina/farmacologia , Proteínas Substratos do Receptor de Insulina/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Compostos Organometálicos/administração & dosagem , PPAR gama/metabolismo , Ratos , Ratos Sprague-Dawley
9.
Behav Brain Res ; 399: 112997, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33166570

RESUMO

The present study investigated the plausible modulatory role of central histaminergic transmission on the expression of nicotine withdrawal induced anxiety and somatic behavior in mice. Abrupt cessation of chronic nicotine (2 mg/kg, i.p. × 3/day) treatment for 12 days to mice, expressed increased anxiety in light & dark test and total abstinence (somatic) score at 24 h post nicotine withdrawal time. The somatic signs includes a composite score of all behaviors such as grooming, rearing, jumping, body shakes, forelimb tremors, head shakes, abdominal constrictions, scratching, empty mouth chewing or teeth chattering, genital licking, tail licking. Mice exhibited higher expression to nicotine withdrawal induced anxiety in light & dark test at 24 h post-nicotine withdrawal time on pre-treatment centrally (i.c.v) with histaminergic agents like histamine (0.1, 50 µg/mouse), histamine H3 receptor inverse agonist, thioperamide (2, 10 µg/mouse), histamine H1 receptor agonist, FMPH (2, 6.5 µg/mouse) or H2 receptor agonist amthamine (0.1, 0.5 µg/mouse) or intraperitoneally (i.p.) with histamine precursor, l-histidine (250, 500 mg/kg) as compared to control nicotine withdrawn animals. Furthermore, mice pre-treated with all these histaminergic agents except histamine H1 receptor agonist, FMPH shows exacerbated expression to post-nicotine withdrawal induced total abstinence (somatic) score in mice. On the other hand, central injection of selective histamine H1 receptor antagonist, cetirizine (0.1 µg/mouse, i.c.v.) or H2 receptor antagonist, ranitidine (50 µg/mouse, i.c.v) to mice 10 min before 24 h post-nicotine withdrawal time completely alleviated the expression of nicotine withdrawal induced anxiety and somatic behavior. Thus, it can be contemplated that the blockade of central histamine H1 or H2 receptor during the nicotine withdrawal phase could be a novel approach to mitigate the nicotine withdrawal associated anxiety-like manifestations. Contribution of endogenous histamine via H1 or H2 receptor stimulation in the nicotine withdrawal induced anxiety and somatic behavior is proposed.


Assuntos
Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Comportamento Animal/efeitos dos fármacos , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Síndrome de Abstinência a Substâncias/etiologia , Animais , Ansiedade/fisiopatologia , Cetirizina/farmacologia , Histamina/farmacologia , Agonistas dos Receptores Histamínicos/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Antagonistas dos Receptores Histamínicos H3/administração & dosagem , Histidina/farmacologia , Masculino , Camundongos , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Fenil-Hidrazinas/farmacologia , Piperidinas/farmacologia , Ranitidina/farmacologia , Síndrome de Abstinência a Substâncias/fisiopatologia , Tiazóis/farmacologia
10.
J Nutr ; 150(Suppl 1): 2580S-2587S, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33000153

RESUMO

Dietary supplementation of the amino acid histidine has demonstrable benefits in various clinical conditions. Recent work in a pediatric leukemia mouse model exposed a surprising potential application of histidine supplementation for cancer therapy enhancement. These findings demand a deeper reassessment of the physiological effects and potential drawbacks of histidine supplementation. As pertinent to this question, we discuss the safety of high doses of histidine and its relevant metabolic fates in the human body. We refrain from recommendations or final conclusions because comprehensive preclinical evidence for safety and efficacy of histidine supplementation is still lacking. However, we emphasize the incentive to study the safety of histidine supplementation and its potential to improve the clinical outcome of pediatric blood cancers through a simple dietary supplementation. The need for comprehensive preclinical testing of histidine supplementation in healthy and tumor-bearing mice is fundamental, and we hope that this review will facilitate such studies.


Assuntos
Suplementos Nutricionais , Histidina/metabolismo , Histidina/farmacologia , Neoplasias/metabolismo , Animais , Ácido Fólico/metabolismo , Ácido Formiminoglutâmico/metabolismo , Histidina/efeitos adversos , Histidina/uso terapêutico , Humanos , Leucemia/tratamento farmacológico , Metotrexato/uso terapêutico , Neoplasias/tratamento farmacológico
11.
J Nutr ; 150(Suppl 1): 2576S-2579S, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33000160

RESUMO

Atopic dermatitis (AD) is an incurable, inflammatory skin condition that is prevalent (∼20%) in young children. There is an unmet clinical need, particularly in children, for safe interventions that target the etiology of the disease. Deficiencies in the skin barrier protein, filaggrin (FLG) have been identified as major predisposing factors in AD. In mammals, l-histidine is rapidly incorporated into epidermal FLG and subsequent FLG proteolysis releases l-histidine as an important natural moisturizing factor (NMF). It has therefore been hypothesized that l-histidine supplementation would be a safe approach to augment both FLG and the NMF, enhance skin barrier function, and reduce AD severity. In a clinical pilot study, adult subjects (n = 24) with AD took either a placebo or 4 g oral l-histidine daily for 8 wk. Unlike the placebo, l-histidine reduced AD (34% reduction in SCORing Atopic Dermatitis scores; P < 0.003) after 4 wk. Nine and 8 adverse events (AEs), and 1 and 0 severe AEs were recorded in the l-histidine or placebo groups, respectively, with no AE being causally related to l-histidine ingestion. A survey of adults (n = 98) taking 4 g l-histidine daily reiterated a lack of causal AEs and also reported a 33% reduction in topical corticosteroid use. A placebo-controlled, clinical pilot study conducted in young children with AD (n = 49; mean age 3.5 y) taking 0.8 g l-histidine daily, showed that eczema area and severity index scores were reduced by 49% (P < 0.02) at 12 wk, whereas a placebo had no effect. The children taking l-histidine had 50 minor AEs (compared with 39 on placebo), with 78% considered as "not," 18% "unlikely," and 4% "possibly" related to l-histidine ingestion. These studies indicate that at the levels reported, oral l-histidine supplementation is well tolerated and has potential as a safe intervention for long-term use in the management of AD in all age groups.


Assuntos
Dermatite Atópica/tratamento farmacológico , Suplementos Nutricionais , Eczema/tratamento farmacológico , Histidina/uso terapêutico , Pele/efeitos dos fármacos , Adulto , Pré-Escolar , Feminino , Histidina/metabolismo , Histidina/farmacologia , Humanos , Masculino , Pele/metabolismo
12.
J Nutr ; 150(Suppl 1): 2588S-2592S, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33000165

RESUMO

Histidine is a nutritionally essential amino acid with many recognized benefits to human health, while circulating concentrations of histidine decline in pathologic conditions [e.g., chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD)]. The purpose of this review is to examine the existing literature regarding the benefits of histidine intake, the adverse effects of excess histidine, and the upper tolerance level for histidine. Supplementation with doses of 4.0-4.5 g histidine/d and increased dietary histidine intake are associated with decreased BMI, adiposity, markers of glucose homeostasis (e.g., HOMA-IR, fasting blood glucose, 2-h postprandial blood glucose), proinflammatory cytokines, and oxidative stress. It is unclear from the limited number of studies in humans whether the improvements in glucoregulatory markers, inflammation, and oxidative stress are due to reduced BMI and adiposity, increased carnosine (a metabolic product of histidine with antioxidant effects), or both. Histidine intake also improves cognitive function (e.g., reduces appetite, anxiety, and stress responses and improves sleep) potentially through the metabolism of histidine to histamine; however, this relation is ambiguous in humans. At high intakes of histidine (>24 g/d), studies report adverse effects of histidine such as decreased serum zinc and cognitive impairment. There is limited research on the effects of histidine intake at doses between 4.5 and 24 g/d, and thus, a tolerable upper level has not been established. Determining tolerance to histidine supplementation has been limited by small sample sizes and, more important, a lack of a clear biomarker for histidine supplementation. The U-shaped curve of circulating zinc concentrations with histidine supplementation could be exploited as a relevant biomarker for supplemental histidine tolerance. Histidine is an important amino acid and may be necessary as a supplement in some populations; however, gaps in knowledge, which this review highlights, need to be addressed scientifically.


Assuntos
Glicemia/metabolismo , Índice de Massa Corporal , Suplementos Nutricionais , Histidina/farmacologia , Inflamação/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/efeitos adversos , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Carnosina/metabolismo , Deficiências Nutricionais/tratamento farmacológico , Deficiências Nutricionais/etiologia , Deficiências Nutricionais/metabolismo , Histamina/metabolismo , Histidina/efeitos adversos , Histidina/metabolismo , Histidina/uso terapêutico , Humanos , Inflamação/prevenção & controle , Processos Mentais/efeitos dos fármacos , Obesidade/metabolismo , Obesidade/prevenção & controle , Zinco/deficiência
13.
J Zhejiang Univ Sci B ; 21(9): 703-715, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32893527

RESUMO

Oxidative stress and apoptosis are the key factors that limit the hypothermic preservation time of donor hearts to within 4-6 h. The aim of this study was to investigate whether the histone deacetylase 3 (HDAC3) inhibitor RGFP966 could protect against cardiac injury induced by prolonged hypothermic preservation. Rat hearts were hypothermically preserved in Celsior solution with or without RGFP966 for 12 h followed by 60 min of reperfusion. Hemodynamic parameters during reperfusion were evaluated. The expression and phosphorylation levels of mammalian STE20-like kinase-1 (Mst1) and Yes-associated protein (YAP) were determined by western blotting. Cell apoptosis was measured by the terminal deoxynucleotidyl-transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) method. Addition of RGFP966 in Celsior solution significantly inhibited cardiac dysfunction induced by hypothermic preservation. RGFP966 inhibited the hypothermic preservation-induced increase of the phosphorylated (p)-Mst1/Mst1 and p-YAP/YAP ratios, prevented a reduction in total YAP protein expression, and increased the nuclear YAP protein level. Verteporfin (VP), a small molecular inhibitor of YAP-transcriptional enhanced associate domain (TEAD) interaction, partially abolished the protective effect of RGFP966 on cardiac function, and reduced lactate dehydrogenase activity and malondialdehyde content. RGFP966 increased superoxide dismutase, catalase, and glutathione peroxidase gene and protein expression, which was abolished by VP. RGFP966 inhibited hypothermic preservation-induced overexpression of B-cell lymphoma protein 2 (Bcl-2)-associated X (Bax) and cleaved caspase-3, increased Bcl-2 mRNA and protein expression, and reduced cardiomyocyte apoptosis. The antioxidant and anti-apoptotic effects of RGFP966 were cancelled by VP. The results suggest that supplementation of Celsior solution with RGFP966 attenuated prolonged hypothermic preservation-induced cardiac dysfunction. The mechanism may involve inhibition of oxidative stress and apoptosis via inactivation of the YAP pathway.


Assuntos
Acrilamidas/farmacologia , Criopreservação , Transplante de Coração/métodos , Inibidores de Histona Desacetilases/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Fenilenodiaminas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Dissacarídeos/farmacologia , Eletrólitos/farmacologia , Glutamatos/farmacologia , Glutationa/farmacologia , Coração/efeitos dos fármacos , Coração/fisiologia , Fator de Crescimento de Hepatócito/antagonistas & inibidores , Histidina/farmacologia , Masculino , Manitol/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
14.
ChemMedChem ; 15(23): 2273-2279, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-32827245

RESUMO

Anaerobic choline metabolism by human gut microbiota to produce trimethylamine (TMA) has recently evolved as a potential therapeutic target because of its association with chronic kidney disease and increased cardiovascular risks. Limited examples of choline analogues have been reported as inhibitors of bacterial enzyme choline TMA-lyase (CutC), a key enzyme regulating choline anaerobic metabolism. We used a new workflow to discover CutC inhibitors based on focused screening of a diversified library of small molecules for intestinal metabolic stability followed by in vitro CutC inhibitory assay. This workflow identified a histidine-based scaffold as a CutC inhibitor with an IC50 value of 1.9±0.2 µM. Remarkably, the identified CutC inhibitor was able to reduce the production of TMA in whole-cell assays using various bacterial strains as well as in complex gut microbiota environment. The improved efficiency of the new scaffold identified in this study in comparison to previously reported CutC inhibitors would enable optimization of potential leads for in vivo screening and clinical translation. Finally, docking studies and molecular-dynamic simulations were used to predict putative interactions created between inhibitor and CutC.


Assuntos
Colina/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Histidina/farmacologia , Liases/antagonistas & inibidores , Metilaminas/antagonistas & inibidores , Colina/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Histidina/química , Humanos , Liases/metabolismo , Metilaminas/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular
15.
Am J Clin Nutr ; 112(5): 1358-1367, 2020 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-32766885

RESUMO

BACKGROUND: Histidine is an essential amino acid with health benefits that may warrant histidine supplementation; however, the clinical safety of histidine intake above the average dietary intake (1.52-5.20 g/d) needs to be vetted. OBJECTIVES: We aimed to determine the tolerance to graded dosages of histidine in a healthy adult population. METHODS: Healthy adults aged 21-50 y completed graded dosages of histidine supplement (4, 8, and 12 g/d, Study 1) (n = 20 men and n = 20 women) and/or a 16-g/d dosage of histidine (Study 2, n = 21 men and n = 19 women); 27 participants (n = 12 men and n = 15 women) completed both studies. After study enrollment and baseline measures, participants consumed encapsulated histidine for 4 wk followed by a 3-wk recovery period. Primary outcomes included vitals, select biochemical analytes, anthropometry, serum zinc, and body composition (via DXA). RESULTS: No changes in vitals or body composition occurred with histidine supplementation in either study. Plasma histidine (measured in subjects who completed all dosages for Studies 1 and 2) was elevated at the 12- and 16-g/d dosages (compared with 0-8 g/d, P < 0.05) and blood urea nitrogen increased with dosage (P = 0.013) and time (P < 0.001) in Study 1 and with time in Study 2 (P < 0.001). In Study 1, mean ferritin concentrations were lower in 12 g/d (46.0 ng/mL; 95% CI: 34.8, 60.9 ng/mL) than in 4 g/d (51.6 ng/mL; 95% CI: 39.0, 68.4 ng/mL; P = 0.038). In Study 2, 16 g/d increased mean aspartate aminotransferase from baseline (19 U/L; 95% CI: 17, 22 U/L) to week 4 (24 U/L; 95% CI: 21, 27 U/L; P < 0.001) and mean serum zinc decreased from baseline (0.75 µg/dL; 95% CI: 0.71, 0.80 µg/dL) to week 4 (0.70 µg/dL; 95% CI: 0.66, 0.74 µg/dL; P = 0.011). CONCLUSIONS: Although values remained within the normal reference ranges for all analytes measured, in all dosages tested, the human no-observed adverse effect level was determined to be 8 g/d owing to changes in blood parameters at the 12-g/d dosage.This trial was registered at clinicaltrials.gov as NCT04142294.


Assuntos
Histidina/farmacologia , Adulto , Glicemia/efeitos dos fármacos , Proteína C-Reativa , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Histidina/administração & dosagem , Histidina/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
Chem Asian J ; 15(17): 2754-2762, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32592289

RESUMO

A series of histidine derived Au(I) bis-NHC complexes bearing different ester, amide and carboxylic acid functionalities as well as wingtip substituents is synthesized and characterized. The stability in aqueous media, in vitro cytotoxicity in a set of cancer cell lines (MCF7, PC3 and A2780/A2780cisR) along with the cellular uptake are evaluated. Stability tests suggest hydrolysis of the ester within 8 h, which might lead to deactivation. Furthermore, the bis-NHC system shows a sufficient stability against cysteine and the thiol containing peptide GSH. The benzyl ester and amide show the highest activity comparable to the benchmark compound cisplatin, with the ester only displaying a slightly lower cytotoxicity than the amide. A cellular uptake study revealed that the benzyl ester and the amide could have different intracellular distribution profiles but both complexes induce perturbations of the cellular physiological processes. The simple modifiability and high stability of the complexes provides a promising system for upcoming post modifications to enable targeted cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Ouro/farmacologia , Compostos Heterocíclicos/farmacologia , Histidina/farmacologia , Metano/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ouro/química , Compostos Heterocíclicos/química , Histidina/química , Humanos , Metano/química , Metano/farmacologia , Estrutura Molecular , Imagem Óptica , Relação Estrutura-Atividade
17.
Physiol Res ; 69(4): 555-564, 2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32584129

RESUMO

Histidine (HIS) is an essential amino acid investigated for therapy of various diseases, used for tissue protection in transplantation and cardiac surgery, and as a supplement to increase muscle performance. The data presented in the review show that HIS administration may increase ammonia and affect the level of several amino acids. The most common are increased levels of alanine, glutamine, and glutamate and decreased levels of glycine and branched-chain amino acids (BCAA, valine, leucine, and isoleucine). The suggested pathogenic mechanisms include increased flux of HIS through HIS degradation pathway (increases in ammonia and glutamate), increased ammonia detoxification to glutamine and exchange of the BCAA with glutamine via L-transporter system in muscles (increase in glutamine and decrease in BCAA), and tetrahydrofolate depletion (decrease in glycine). Increased alanine concentration is explained by enhanced synthesis in extrahepatic tissues and impaired transamination in the liver. Increased ammonia and glutamine and decreased BCAA levels in HIS-treated subjects indicate that HIS supplementation is inappropriate in patients with liver injury. The studies investigating the possibilities to elevate carnosine (beta-alanyl-L-histidine) content in muscles show positive effects of beta-alanine and inconsistent effects of HIS supplementation. Several studies demonstrate HIS depletion due to enhanced availability of methionine, glutamine, or beta-alanine.


Assuntos
Aminoácidos/metabolismo , Amônia/metabolismo , Histidina/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Animais , Suplementos Nutricionais , Humanos
18.
Nutrients ; 12(5)2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32423010

RESUMO

Histidine is an essential amino acid (EAA) in mammals, fish, and poultry. We aim to give an overview of the metabolism and physiological effects of histidine in humans and different animal species through a systematic review following the guidelines of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). In humans, dietary histidine may be associated with factors that improve metabolic syndrome and has an effect on ion absorption. In rats, histidine supplementation increases food intake. It also provides neuroprotection at an early stage and could protect against epileptic seizures. In chickens, histidine is particularly important as a limiting factor for carnosine synthesis, which has strong anti-oxidant effects. In fish, dietary histidine may be one of the most important factors in preventing cataracts. In ruminants, histidine is a limiting factor for milk protein synthesis and could be the first limiting AA for growth. In excess, histidine supplementation can be responsible for eating and memory disorders in humans and can induce growth retardation and metabolic dysfunction in most species. To conclude, the requirements for histidine, like for other EAA, have been derived from growth and AA composition in tissues and also have specific metabolic roles depending on species and dietary levels.


Assuntos
Suplementos Nutricionais , Ingestão de Alimentos/efeitos dos fármacos , Absorção Gastrointestinal/efeitos dos fármacos , Histidina/farmacologia , Animais , Galinhas , Peixes , Humanos , Ratos , Ruminantes
19.
Enzyme Microb Technol ; 137: 109534, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32423671

RESUMO

We have reported previously that the water extract of the earthworm Eisenia fetida has inhibitory effect on human dipeptidyl-peptidase IV (DPP IV) in vitro. Here we studied to identify DPP IV inhibitors in a low-molecular mass extract (designated U3EE) under 3 kDa prepared from the water extract. U3EE showed 50 % inhibition (IC50) at the concentration of 5.3 ± 0.3 mg/mL. An inhibitory active fraction obtained by solid-phase extraction of U3EE was separated into three parts by reversed-phase HPLC. These parts were shown by GC/MS to be composed of ten (Ala, Gly, Thr, Ser, Asn, Asp, Lys, His, Orn, and cystine), two (Leu and Ile), and one (Met) amino acids, respectively. Among them, Met, Leu, and His showed strong inhibition with IC50 values of 3.4 ± 0.3, 6.1 ± 0.3 and 14.7 ± 1.2 mM, respectively; Ala, Lys, Orn, and Ile showed rather weaker inhibition than those, while the others showed no inhibition. Met, Leu, and Ile were competitive inhibitors and His was a mixed-type one. DPP IV inhibition by U3EE might be due to additive and/or synergistic effects of the inhibitory amino acids, suggesting that it could be useful as pharmaceutical and supplement for diabetes prevention.


Assuntos
Aminoácidos/farmacologia , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Oligoquetos/química , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/isolamento & purificação , Histidina/farmacologia , Humanos , Concentração Inibidora 50 , Isoleucina/farmacologia , Leucina/farmacologia , Metionina/farmacologia , Peso Molecular
20.
Exp Physiol ; 105(5): 831-841, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32125738

RESUMO

NEW FINDINGS: What is the central question of the study? Does ß-alanine with l-histidine supplementation associated with endurance and strength training improve echocardiographic parameters, functional capacity, and maximum strength in rats with chronic heart failure? What is the main finding and its importance? ß-Alanine with l-histidine supplementation associated with endurance and strength training increased functional capacity and maximum strength through increasing exercise capacity peripherally but did not affect echocardiographic parameters in rats with chronic heart failure. Combined training (CT) has been associated with positive responses in the clinical status of patients with chronic heart failure (CHF). Other non-pharmacological tools, such as amino acid supplementation, may further enhance its adaptation. However, the effects of ß-alanine and l-histidine supplementation in CHF remain unclear. In the present study, the aim was to test whether supplementing carnosine precursors with CT could give improved responses in the functional capacity and echocardiographic variables of rats with CHF. Twenty-four Wistar rats, were submitted to myocardial infarction and allocated to three groups: animals with CHF kept in sedentary conditions (SED, n = 8), animals with CHF submitted to CT in strength and aerobic exercise supplemented with placebo (CT-P, n = 8) and animals with CHF submitted to CT in strength and aerobic exercise supplemented with ß-alanine and l-histidine (CT-S, n = 8). The trained animals were submitted to a strength protocol three times per week with intensity of 65-75% of one repetition maximum test. Aerobic training was conducted two times per week (50 min, 15 m min-1 ). The supplemented group received ß-alanine and l-histidine orally (each 250 mg kg-1  day-1 ). No changes in echocardiographic and morphological parameters were found among the groups (P > 0.05). Functional capacity, Δ V ̇ O 2 max and maximum strength were higher in CT-P than in SED and even higher in CT-S than in CT-P (P < 0.01). The CT was able to improve functional capacity, but the supplementation was shown to enhance these parameters even further in the CHF rats. We conclude that the increase in functional capacity and strength gained through CT and supplementation were associated with the improvement in peripheral parameters with no changes in cardiac variables.


Assuntos
Suplementos Nutricionais , Insuficiência Cardíaca/terapia , Histidina/farmacologia , Músculo Esquelético/fisiologia , Condicionamento Físico Animal , beta-Alanina/farmacologia , Animais , Carnosina/análise , Ecocardiografia , Insuficiência Cardíaca/fisiopatologia , Masculino , Força Muscular , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/terapia , Distribuição Aleatória , Ratos , Ratos Wistar
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