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1.
Cells ; 10(12)2021 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-34944061

RESUMO

L-Arginine, a semi-essential amino acid, was shown to delay dysfunction of motor neurons and to prolong the lifespan, upon analysis of transgenic mouse models of amyotrophic lateral sclerosis (ALS). We investigated the transport function of arginine and neuronal nitric oxide synthase (nNOS) expression after pretreatment with L-arginine in NSC-34 hSOD1WT (wild-type, WT) and hSOD1G93A (mutant-type, MT) cell lines. [3H]L-Arginine uptake was concentration-dependent, voltage-sensitive, and sodium-independent in both cell lines. Among the cationic amino acid transporters family, including system y+, b0,+, B0,+, and y+L, system y+ is mainly involved in [3H]L-arginine transport in ALS cell lines. System b0,+ accounted for 23% of the transport in both cell lines. System B0,+ was found only in MT, and whereas, system y+L was found only in WT. Lysine competitively inhibited [3H]L-arginine uptake in both cell lines. The nNOS mRNA expression was significantly lower in MT than in WT. Pretreatment with arginine elevated nNOS mRNA levels in MT. Oxidizing stressor, H2O2, significantly decreased their uptake; however, pretreatment with arginine restored the transport activity in both cell lines. In conclusion, arginine transport is associated with system y+, and neuroprotection by L-arginine may provide an edge as a possible therapeutic target in the treatment of ALS.


Assuntos
Esclerose Amiotrófica Lateral/genética , Arginina/metabolismo , Óxido Nítrico Sintase Tipo I/genética , Superóxido Dismutase-1/genética , Sistemas de Transporte de Aminoácidos Básicos , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Animais , Arginina/farmacologia , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/farmacologia , Lisina/genética , Camundongos , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/metabolismo , Estresse Oxidativo/genética , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia
2.
Clin Appl Thromb Hemost ; 27: 10760296211066945, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34905962

RESUMO

INTRODUCTION: Argatroban is licensed for patients with heparin-induced thrombocytopenia and is conventionally monitored by activated partial thromboplastin time (APTT) ratio. The target range is 1.5 to 3.0 times the patients' baseline APTT and not exceeding 100 s, however this baseline is not always known. APTT is known to plateau at higher levels of argatroban, and is influenced by coagulopathies, lupus anticoagulant and raised FVIII levels. It has been used as a treatment for COVID-19 and Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT). Some recent publications have favored the use of anti-IIa methods to determine the plasma drug concentration of argatroban. METHODS: Plasma of 60 samples from 3 COVID-19 patients and 54 samples from 5 VITT patients were tested by APTT ratio and anti-IIa method (dilute thrombin time dTT). Actin FS APTT ratios were derived from the baseline APTT of the patient and the mean normal APTT. RESULTS: Mean APTT ratio derived from baseline was 1.71 (COVID-19), 1.33 (VITT) compared to APTT ratio by mean normal 1.65 (COVID-19), 1.48 (VITT). dTT mean concentration was 0.64 µg/ml (COVID-19) 0.53 µg/ml (VITT) with poor correlations to COVID-19 baseline APTT ratio r2 = 0.1526 p <0.0001, mean normal r2 = 0.2188 p < 0.0001; VITT baseline APTT ratio r2 = 0.04 p < 0.001, VITT mean normal r2 = 0.0064 p < 0.001. CONCLUSIONS: We believe that dTT is a superior method to monitor the concentration of argatroban, we have demonstrated significant differences between APTT ratios and dTT levels, which could have clinical impact. This is especially so in COVID-19 and VITT.


Assuntos
Arginina/análogos & derivados , COVID-19/tratamento farmacológico , Tempo de Tromboplastina Parcial/métodos , Ácidos Pipecólicos/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Sulfonamidas/uso terapêutico , Trombocitopenia/tratamento farmacológico , Trombose/tratamento farmacológico , Idoso , Arginina/farmacologia , Arginina/uso terapêutico , COVID-19/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ácidos Pipecólicos/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , SARS-CoV-2 , Sulfonamidas/farmacologia , Trombocitopenia/induzido quimicamente , Trombose/induzido quimicamente
3.
Adv Skin Wound Care ; 34(12): 630-636, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34807894

RESUMO

GENERAL PURPOSE: To provide information about arginine, its metabolism, and its role in acute and chronic wound healing, to assist providers in understanding the recommendations for arginine supplementation. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant will:1. Describe the characteristics of arginine.2. Choose the metabolic processes that define arginine's role in wound healing.3. Identify the average daily intake of arginine in an American diet.4. Select the evidence that demonstrates the effectiveness of arginine supplementation for wound healing. ABSTRACT: Nutrition has an important and integral role in wound healing. Arginine, a type of indispensable amino acid, has long been thought to have wound healing properties. The 2019 international guideline by the European Pressure Ulcer Advisory Panel, National Pressure Injury Advisory Panel, and Pan Pacific Pressure Injury Alliance recommends use of a high-protein, high-calorie oral nutrition supplement fortified with arginine and other antioxidants to treat adults with stage 2 or greater pressure injury and who are malnourished or at risk of malnutrition to foster healing. This article provides necessary background on this conditionally indispensable amino acid, its metabolism, and its role in acute and chronic wound healing to assist providers in understanding the recommendation for arginine supplementation.


Assuntos
Arginina/farmacologia , Lesão por Pressão/tratamento farmacológico , Arginina/efeitos adversos , Humanos , Cicatrização/efeitos dos fármacos
4.
Molecules ; 26(19)2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34641606

RESUMO

The COVID-19 pandemic outbreak prompts an urgent need for efficient therapeutics, and repurposing of known drugs has been extensively used in an attempt to get to anti-SARS-CoV-2 agents in the shortest possible time. The glycoside rutin shows manifold pharmacological activities and, despite its use being limited by its poor solubility in water, it is the active principle of many pharmaceutical preparations. We herein report our in silico and experimental investigations of rutin as a SARS-CoV-2 Mpro inhibitor and of its water solubility improvement obtained by mixing it with l-arginine. Tests of the rutin/l-arginine mixture in a cellular model of SARS-CoV-2 infection highlighted that the mixture still suffers from unfavorable pharmacokinetic properties, but nonetheless, the results of this study suggest that rutin might be a good starting point for hit optimization.


Assuntos
Antivirais/farmacologia , Arginina/farmacologia , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Rutina/farmacologia , SARS-CoV-2/efeitos dos fármacos , Células A549 , Proteases 3C de Coronavírus/metabolismo , Humanos , Simulação de Acoplamento Molecular , Inibidores de Proteases/farmacologia , SARS-CoV-2/metabolismo , Solubilidade
5.
Int J Mol Sci ; 22(18)2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34576305

RESUMO

Neuropeptide Y (NPY) has anxiolytic-like effects and facilitates the extinction of cued and contextual fear in rodents. We previously showed that intracerebroventricular administration of NPY reduces the expression of social fear in a mouse model of social fear conditioning (SFC) and localized these effects to the dorsolateral septum (DLS) and central amygdala (CeA). In the present study, we aimed to identify the receptor subtypes that mediate these local effects of NPY. We show that NPY (0.1 nmol/0.2 µL/side) reduced the expression of SFC-induced social fear in a brain region- and receptor-specific manner in male mice. In the DLS, NPY reduced the expression of social fear by acting on Y2 receptors but not on Y1 receptors. As such, prior administration of the Y2 receptor antagonist BIIE0246 (0.2 nmol/0.2 µL/side) but not the Y1 receptor antagonist BIBO3304 trifluoroacetate (0.2 nmol/0.2 µL/side) blocked the effects of NPY in the DLS. In the CeA, however, BIBO3304 trifluoroacetate but not BIIE0246 blocked the effects of NPY, suggesting that NPY reduced the expression of social fear by acting on Y1 receptors but not Y2 receptors within the CeA. This study suggests that at least two distinct receptor subtypes are differentially recruited in the DLS and CeA to mediate the effects of NPY on the expression of social fear.


Assuntos
Tonsila do Cerebelo/metabolismo , Neuropeptídeo Y/metabolismo , Fobia Social/metabolismo , Septo do Cérebro/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Benzazepinas/farmacologia , Medo , Masculino , Camundongos , Fobia Social/fisiopatologia , Receptores de Neuropeptídeo Y/metabolismo , Septo do Cérebro/efeitos dos fármacos
6.
Environ Toxicol ; 36(11): 2291-2301, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34363436

RESUMO

Peptidylarginine deiminases 4 (PAD4), a kind of enzyme capable of converting protein arginine or mono-methylarginine into citrulline, has been identified to display a key role in diverse diseases. Radiotherapy is frequently used in nasopharyngeal carcinoma (NPC) treatment and induces DNA double strand breaks. In this study, whether PAD4 inhibitor YW3-56 affects the radiosensitivity of NPC cells was explored. RT-qPCR, immunofluorescence, western blot, clonogenic survival, and flow cytometry assays were used to assess the function of PAD4 and YW3-56 in NPC. We found the upregulation of PAD4 expression in NPC cells. PAD4 overexpression suppressed NPC cell apoptosis and promoted cell cycle, while PAD4 depletion had an opposite result. Moreover, the survival of NPC cells after irradiation was increased by overexpression of PAD4. PAD4 overexpression inhibited DNA damage and sensitivity of NPC cells to irradiation. Functional assays showed that YW3-56 treatment promoted DNA damage, apoptosis, and radiosensitivity of NPC cells. Importantly, YW3-56 treatment inhibited tumor growth in vivo. Overall, this study revealed the efficacy of PAD4 inhibitor YW3-56 in promoting sensitivity of NPC cells to irradiation.


Assuntos
2-Naftilamina/análogos & derivados , Arginina/análogos & derivados , Dano ao DNA , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Proteína-Arginina Desiminase do Tipo 4/antagonistas & inibidores , Tolerância a Radiação , 2-Naftilamina/farmacologia , Apoptose , Arginina/farmacologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Desiminases de Arginina em Proteínas
7.
Cells ; 10(8)2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34440845

RESUMO

Keratoconus (KC) is a common corneal ectatic disease that affects 1:500-1:2000 people worldwide and is associated with a progressive thinning of the corneal stroma that may lead to severe astigmatism and visual deficits. Riboflavin-mediated collagen crosslinking currently remains the only approved treatment to halt progressive corneal thinning associated with KC by improving the biomechanical properties of the stroma. Treatments designed to increase collagen deposition by resident corneal stromal keratocytes remain elusive. In this study, we evaluated the effects of arginine supplementation on steady-state levels of arginine and arginine-related metabolites (e.g., ornithine, proline, hydroxyproline, spermidine, and putrescine) and collagen protein expression by primary human corneal fibroblasts isolated from KC and non-KC (healthy) corneas and cultured in an established 3D in vitro model. We identified lower cytoplasmic arginine and spermidine levels in KC-derived constructs compared to healthy controls, which corresponded with overall higher gene expression of arginase. Arginine supplementation led to a robust increase in cytoplasmic arginine, ornithine, and spermidine levels in controls only and a significant increase in collagen type I secretion in KC-derived constructs. Further studies evaluating safety and efficacy of arginine supplementation are required to elucidate the potential therapeutic applications of modulating collagen deposition in the context of KC.


Assuntos
Arginina/farmacologia , Matriz Extracelular/metabolismo , Ceratocone/patologia , Regulação para Cima/efeitos dos fármacos , Arginase/metabolismo , Arginina/metabolismo , Arginina/uso terapêutico , Estudos de Casos e Controles , Técnicas de Cultura de Células , Células Cultivadas , Colágeno/metabolismo , Colágeno Tipo I/metabolismo , Córnea/citologia , Córnea/metabolismo , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Ceratocone/tratamento farmacológico , Ceratocone/metabolismo , Óxido Nítrico Sintase/metabolismo , Ornitina/metabolismo , Espermidina/metabolismo
8.
Molecules ; 26(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34443485

RESUMO

Epidemiological studies have demonstrated that the intake of green tea is effective in reducing the risk of dementia. The most important component of green tea is epigallocatechin gallate (EGCG). Both EGCG and epigallocatechin (EGC) have been suggested to cross the blood-brain barrier to reach the brain parenchyma, but EGCG has been found to be more effective than EGC in promoting neuronal differentiation. It has also been suggested that the products of EGCG decomposition by the intestinal microbiota promote the differentiation of nerve cells and that both EGCG and its degradation products act on nerve cells with a time lag. On the other hand, the free amino acids theanine and arginine contained in green tea have stress-reducing effects. While long-term stress accelerates the aging of the brain, theanine and arginine suppress the aging of the brain due to their anti-stress effect. Since this effect is counteracted by EGCG and caffeine, the ratios between these green tea components are important for the anti-stress action. In this review, we describe how green tea suppresses brain aging, through the activation of nerve cells by both EGCG and its degradation products, and the reductions in stress achieved by theanine and arginine.


Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , Chá/química , Envelhecimento/efeitos dos fármacos , Animais , Arginina/farmacologia , Encéfalo/efeitos dos fármacos , Catequina/química , Catequina/metabolismo , Catequina/farmacologia , Glutamatos/farmacologia , Humanos
9.
Nutrients ; 13(8)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445028

RESUMO

Growing blueberry (Vaccinium corymbosum L., Highbush blueberry) as a berry crop is developing dynamically, especially in warm temperate, subtropical, and tropical regions of the world. When blueberry is cultivated on plantations, the bushes are pruned annually, and tons of leaves become waste. Thus, the aim of the present study was to create a preparation from blueberry leaves, study their chemical composition and determine their potential as a dietary supplement for the prophylactic and correction of the metabolic syndrome. Several schemes for obtaining extracts from blueberry leaves have been developed, including one with addition of arginine. A total of 18 phenolic substances were identified and quantified in the extracts by TLC and HPLC methods. Chlorogenic acid, hyperoside, and rutin were shown to be dominating constituents. Quantitative determination of hydroxycinnamic acid derivatives, flavonoids and other phenolics in the extracts was performed by spectrophotometric method. The extracts administration led to a significant decrease in the level of glucose, insulin and triacylglycerols in blood serum of adult mature inbred rats with insulin resistance induced by the fructose-enriched diet. The most promising one was the extract modified with arginine. The determined hypoglycemic and hypolipidemic activity of chemically standardized extracts from highbush blueberry leaves indicate the potential of this crop residue in utilization as a dietary supplement recommended in prevention of ailments associated with metabolic syndrome.


Assuntos
Arginina/farmacologia , Mirtilos Azuis (Planta) , Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacologia , Síndrome Metabólica/tratamento farmacológico , Extratos Vegetais/farmacologia , Folhas de Planta , Animais , Arginina/análogos & derivados , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Mirtilos Azuis (Planta)/química , Sacarose na Dieta , Modelos Animais de Doenças , Hipoglicemiantes/isolamento & purificação , Hipolipemiantes/isolamento & purificação , Insulina/sangue , Resistência à Insulina , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/induzido quimicamente , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Ratos Wistar , Triglicerídeos/sangue
10.
BMC Cancer ; 21(1): 800, 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34247580

RESUMO

BACKGROUND: Cancer cachexia causes significant morbidity and mortality in advanced lung cancer patients. Clinical benefit of ß-hydroxy-ß-methylbutyrate, arginine, and glutamine (HMB/Arg/Gln) was assessed in newly diagnosed patients. METHODS: NOURISH, a prospective, two-arm, open-label, multi-centre, randomised controlled phase II trial compared cachexia in patients who received HMB/Arg/Gln with those who did not. All patients received structured nutritional, exercise and symptom control via a Macmillan Durham Cachexia Pack. Conducted in five UK centres, patients aged > 18 years, with newly diagnosed advanced small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC), who were able to take oral nutrition, with a performance status of 0-to-2 and a life expectancy > 4 months were eligible for trial entry. Patients suitable for treatment with curative intent were ineligible. The trial was designed as a signal-seeking pilot study with target recruitment of 96 patients. One-to-one randomisation was stratified by diagnosis (SCLC or NSCLC), stage of disease (locally advanced or metastatic) and performance status. The primary outcome measure was treatment success defined as a patient being alive without significant loss of lean body mass (not > 5%) by 12 weeks. Secondary outcome measures included quality of life. RESULTS: Between February-2012 and February-2013, 38 patients were recruited, 19 to each arm. Baseline characteristics were balanced. The trial was halted due to slow accrual and partial adherence. Trial data demonstrated no evidence of treatment benefit. No serious adverse events were reported during the trial. CONCLUSIONS: Further evaluation of HMB/Arg/Gln in this setting could not be recommended on the basis of this trial. CLINICAL TRIAL REGISTRATION: ISRCTN registry: 39911673; 14-Apr-2011 https://doi.org/10.1186/ISRCTN39911673 .


Assuntos
Arginina/uso terapêutico , Caquexia/tratamento farmacológico , Glutamina/uso terapêutico , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Arginina/farmacologia , Feminino , Glutamina/farmacologia , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento
11.
Am J Physiol Renal Physiol ; 321(3): F369-F377, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34308669

RESUMO

Dahl salt-sensitive (SS) rat kidneys produce less nitric oxide (NO) than those of salt-resistant (SR) rats. Thick ascending limb (TAL) NO synthase 3 (NOS3) is a major source of renal NO, and luminal flow enhances its activity. We hypothesized that flow-induced NO is reduced in TALs from SS rats primarily due to NOS uncoupling and diminished NOS3 expression rather than scavenging. Rats were fed normal-salt (NS) or high-salt (HS) diets. We measured flow-induced NO and superoxide in perfused TALs and performed Western blots of renal outer medullas. For rats on NS, flow-induced NO was 35 ± 6 arbitrary units (AU)/min in TALs from SR rats but only 11 ± 2 AU/min in TALs from SS (P < 0.008). The superoxide scavenger tempol decreased the difference in flow-induced NO between strains by about 36% (P < 0.020). The NOS inhibitor N-nitro-l-arginine methyl ester (l-NAME) decreased flow-induced superoxide by 36 ± 8% in TALs from SS rats (P < 0.02) but had no effect in TALs from SR rats. NOS3 expression was not different between strains on NS. For rats on HS, the difference in flow-induced NO between strains was enhanced (SR rats: 44 ± 10 vs. SS: 9 ± 2 AU/min, P < 0.005). Tempol decreased the difference in flow-induced NO between strains by about 37% (P < 0.012). l-NAME did not significantly reduce flow-induced superoxide in either strain. HS increased NOS3 expression in TALs from SR rats but not in TALs from SS rats (P < 0.003). We conclude that 1) on NS, flow-induced NO is diminished in TALs from SS rats mainly due to NOS3 uncoupling such that it produces superoxide and 2) on HS, the difference is enhanced due to failure of TALs from SS rats to increase NOS3 expression.NEW & NOTEWORTHY The Dahl rat has been used extensively to study the causes and effects of salt-sensitive hypertension. Our study suggests that more complex processes other than simple scavenging of nitric oxide (NO) by superoxide lead to less NO production in thick ascending limbs of the Dahl salt-sensitive rat. The predominant mechanism involved depends on dietary salt. Impaired flow-induced NO production in thick ascending limbs most likely contributes to the Na+ retention associated with salt-sensitive hypertension.


Assuntos
Alça do Néfron/metabolismo , Óxido Nítrico/metabolismo , Cloreto de Sódio na Dieta/metabolismo , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Hipertensão/fisiopatologia , Masculino , Ratos Endogâmicos Dahl , Cloreto de Sódio/metabolismo , Superóxidos/metabolismo
12.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070942

RESUMO

Among mammals, serotonin is predominantly found in the gastrointestinal tract, where it has been shown to participate in pathway-regulating satiation. For the stomach, vascular serotonin release induced by gastric distension is thought to chiefly contribute to satiation after food intake. However, little information is available on the capability of gastric cells to synthesize, release and respond to serotonin by functional changes of mechanisms regulating gastric acid secretion. We investigated whether human gastric cells are capable of serotonin synthesis and release. First, HGT-1 cells, derived from a human adenocarcinoma of the stomach, and human stomach specimens were immunostained positive for serotonin. In HGT-1 cells, incubation with the tryptophan hydroxylase inhibitor p-chlorophenylalanine reduced the mean serotonin-induced fluorescence signal intensity by 27%. Serotonin release of 147 ± 18%, compared to control HGT-1 cells (set to 100%) was demonstrated after treatment with 30 mM of the satiating amino acid L-Arg. Granisetron, a 5-HT3 receptor antagonist, reduced this L-Arg-induced serotonin release, as well as L-Arg-induced proton secretion. Similarly to the in vitro experiment, human antrum samples released serotonin upon incubation with 10 mM L-Arg. Overall, our data suggest that human parietal cells in culture, as well as from the gastric antrum, synthesize serotonin and release it after treatment with L-Arg via an HTR3-related mechanism. Moreover, we suggest not only gastric distension but also gastric acid secretion to result in peripheral serotonin release.


Assuntos
Arginina/farmacologia , Ácido Gástrico/metabolismo , Células Parietais Gástricas/efeitos dos fármacos , Prótons , Serotonina/biossíntese , Linhagem Celular Tumoral , Fenclonina/farmacologia , Expressão Gênica , Granisetron/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Células Parietais Gástricas/citologia , Células Parietais Gástricas/metabolismo , Inibidores de Proteases/farmacologia , Receptores 5-HT3 de Serotonina/genética , Receptores 5-HT3 de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Estômago/citologia , Estômago/efeitos dos fármacos , Técnicas de Cultura de Tecidos , Triptofano Hidroxilase/antagonistas & inibidores , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo
13.
Sci Rep ; 11(1): 10731, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34031449

RESUMO

Cutaneous squamous cell carcinomas (cSCC) are among the most commonly diagnosed malignancies, causing significant morbidity and mortality. Tumor-associated macrophage (TAM) expression of arginase is implicated in tumor progression, and therapeutic use of arginase inhibitors has been studied in various cancers. However, investigating potential cSCC immunotherapies including arginase inhibition in pre-clinical models is hampered by the lack of appropriate tumor models in immunocompetent mice. PDV is a cSCC cell line derived from chemical carcinogenesis of mouse keratinocytes. PDVC57 cells were derived from a PDV tumor in C57BL/6 (B6) mice. Unlike PDV, PDVC57 tumors grow consistently in B6 mice, and have increased TAMs, decreased dendritic and T cell intra-tumor infiltration. Arginase inhibition in cSCC tumors using Nω-hydroxy-nor-arginine (nor-NOHA) reduced tumor growth in B6 mice but not immunodeficient Rag1-deficient mice. nor-NOHA administration increased dendritic and T cell tumor-infiltration and PD-1 expression. The combination of nor-NOHA and anti-PD-1 therapy with nivolumab enhanced anti-PD-1 therapeutic efficacy. This study demonstrates the therapeutic potential of transcutaneous arginase inhibition in cSCC. A competent immune microenvironment is required for tumor growth inhibition using this arginase inhibitor. Synergistic co-inhibition of tumor growth in these results, supports further examination of transcutaneous arginase inhibition as a therapeutic modality for cSCC.


Assuntos
Antineoplásicos/administração & dosagem , Arginase/antagonistas & inibidores , Arginina/análogos & derivados , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Administração Cutânea , Animais , Antineoplásicos/farmacologia , Arginina/administração & dosagem , Arginina/farmacologia , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia
14.
Nat Commun ; 12(1): 2622, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976180

RESUMO

Obesity is caused by an imbalance between food intake and energy expenditure (EE). Here we identify a conserved pathway that links signalling through peripheral Y1 receptors (Y1R) to the control of EE. Selective antagonism of peripheral Y1R, via the non-brain penetrable antagonist BIBO3304, leads to a significant reduction in body weight gain due to enhanced EE thereby reducing fat mass. Specifically thermogenesis in brown adipose tissue (BAT) due to elevated UCP1 is enhanced accompanied by extensive browning of white adipose tissue both in mice and humans. Importantly, selective ablation of Y1R from adipocytes protects against diet-induced obesity. Furthermore, peripheral specific Y1R antagonism also improves glucose homeostasis mainly driven by dynamic changes in Akt activity in BAT. Together, these data suggest that selective peripheral only Y1R antagonism via BIBO3304, or a functional analogue, could be developed as a safer and more effective treatment option to mitigate diet-induced obesity.


Assuntos
Arginina/análogos & derivados , Obesidade/prevenção & controle , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Termogênese/efeitos dos fármacos , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo Marrom/citologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Adulto , Animais , Arginina/farmacologia , Arginina/uso terapêutico , Biópsia , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Obesidade/etiologia , Obesidade/metabolismo , Cultura Primária de Células , Receptores de Neuropeptídeo Y/metabolismo
15.
Breast Dis ; 40(S1): S55-S61, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34057119

RESUMO

BACKGROUND: With essential metals being studied and developed as anticancer agents, this study aims to explore the anticancer activity of Zn(II) arginine dithiocarbamate in the T47D and fibroblast cell lines. METHOD: The Zn(II) arginine dithiocarbamate complex was prepared by the in situ method and characterized using infra-red spectroscopy, melting point, X-ray fluorescence, and X-ray diffraction instruments. The complex compound was tested for its cytotoxicity to the T47D breast cancer and fibroblast cell lines. RESULTS: The cytotoxicity of the Zn(II) arginine dithiocarbamate complex to the T47D breast cancer cell line obtained IC50 = 3.16 µg/mL, while cisplatin obtained IC50 = 28.18 µg/mL. The cytotoxicity of the Zn(II) arginine dithiocarbamate complex to fibroblast cells obtained IC50 = 8709.63 µg/mL. CONCLUSION: The Zn(II) arginine dithiocarbamate complex has increased active cytotoxicity compared to cisplatin in inducing morphological changes in the T47D breast cancer cell line and is relatively non-toxic to fibroblast cells.


Assuntos
Antineoplásicos/farmacologia , Arginina/farmacologia , Fibroblastos/efeitos dos fármacos , Tiocarbamatos/farmacologia , Zinco/farmacologia , Apoptose/efeitos dos fármacos , Arginina/química , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Congressos como Assunto , Feminino , Humanos , Tiocarbamatos/química , Zinco/química
16.
Nutrients ; 13(4)2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33805883

RESUMO

The aim of the study was to determine the effect of simultaneous supplementation of ß-hydroxy-ß-methylbutyrate and L-Arginine α-ketoglutarate on lower limb power and muscle damage in medium distance runners aged 15.3 (±0.9) years old. METHODS: The study group consisted of 40 volunteers aged 14-17 years practicing medium distance running for at least two years. The study lasted 12 days and followed a randomized, double-blind, placebo-controlled, parallel design. All subjects attended a familiarization session on day 0 before the test. The subjects were randomly divided into two groups: supplements and placebo group. The same training cycle protocol was used in both groups during the 12-day training period. Morning warm-up involved 10 min jogging at 60-75% of maximal heart rate and countermovement jump height measurement. Main training units were carried out for both groups with the same volume. Training load assessment (the daily session Rating of Perceived Exertion (s-RPE) method) method takes into consideration the intensity and the duration of the training session to calculate the "training load" (TL). RESULTS: At the end of the training cycle, a significant (p = 0.002) decrease in the countermovement jump (CMJ) height was found in the placebo group when compared to the baseline. In the supplement group, there was no decrease in the countermovement jump height. Creatine kinase and lactate dehydrogenase concentration increased during the training days similarly in both groups and decreased on rest days. There were no differences between groups in enzymes concentration. The research results indicate that the supplement combination used in the supplements group prevented a reduction in the CMJ values. In contrast to the supplements group, in the placebo group, the CMJ changes were statistically significant: a noticeable (p = 0.002) decrease in CMJ was noted between the baseline measurement and the 6th measurement. The well-being of the subjects from both groups changed significantly during the training period, and the intergroup differences in the mood level were similar and not statistically significant. CONCLUSIONS: The results of this study indicate that the daily co-supplementation with calcium salt of ß-hydroxy-ß-methylbutyrate (7.5 g) and L-Arginine α-ketoglutarate (10 g) during training might help to prevent decline in jump performance. No influence on muscle damage markers or mood was shown.


Assuntos
Arginina/análogos & derivados , Atletas/estatística & dados numéricos , Desempenho Atlético/estatística & dados numéricos , Ácidos Cetoglutáricos/farmacologia , Músculo Esquelético/efeitos dos fármacos , Atletismo , Valeratos/farmacologia , Adolescente , Arginina/sangue , Arginina/farmacologia , Creatina Quinase/sangue , Creatina Quinase/efeitos dos fármacos , Método Duplo-Cego , Feminino , Humanos , Ácidos Cetoglutáricos/sangue , L-Lactato Desidrogenase/sangue , L-Lactato Desidrogenase/efeitos dos fármacos , Perna (Membro)/fisiologia , Masculino , Força Muscular/efeitos dos fármacos , Valeratos/sangue
17.
Arch Oral Biol ; 126: 105126, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33872861

RESUMO

OBJECTIVE: To investigate the effects of Dual Zinc plus Arginine formulations (aqueous solution and dentifrice) on tumor necrosis factor-alpha (TNF-α)-induced barrier dysfunction as well as on cell proliferation and migration in an in vitro gingival keratinocyte model. DESIGN: Gingival keratinocytes were seeded onto the membrane of a double-chamber system in the absence and presence of recombinant TNF-α and the formulations under investigation. The barrier function was assessed by determination of transepithelial electrical resistance (TER) and paracellular transport of fluorescein isothiocyanate (FITC)-dextran. The distribution of zonula occludens-1 (ZO-1) and occludin was visualized by immunofluorescence microscopy. The effects of the formulations on keratinocyte cell proliferation were determined using a fluorescent cell tracker dye, while a migration assay kit was used to investigate their effects on cell migration. RESULTS: Under conditions where TNF-α induces loss of keratinocyte barrier integrity, the Dual Zinc plus Arginine formulations (aqueous solution and dentifrice) protected the keratinocyte tight junction against the damages since they prevented the TNF-α-induced drop in TER and increase in FITC-dextran paracellular flux in the in vitro model. The treatment of keratinocytes with the formulations markedly mitigated the altered distribution of ZO-1 and occludin. Both formulations increased the proliferation of keratinocytes and alleviated the negative impact caused by TNF-α. Lastly, the formulations increased the migration capacity of keratinocytes. CONCLUSIONS: The ability of the Dual Zinc plus Arginine formulations to protect the barrier integrity of gingival keratinocytes from TNF-α-induced damage and to promote their proliferation and migration suggests that they may offer benefits for oral health.


Assuntos
Arginina , Fator de Necrose Tumoral alfa , Arginina/farmacologia , Proliferação de Células , Mucosa Intestinal , Queratinócitos , Zinco
18.
Oxid Med Cell Longev ; 2021: 6684568, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815657

RESUMO

Background: Ergogenic nutritional supplementation is sought by professional athletes for improving physical performance; nevertheless, scientific evidence to support the chronic use of L-Arginine among water polo players is missing. Methods: Seventeen male professional water polo players were randomly assigned to assume 5 grams per day of L-Arginine (n = 9) or placebo (n = 8) for 4 weeks. The players' fitness level was assessed in the maximal speed swimming test. Ear lobe blood samples taken before and after the effort for serum lactate content were analyzed. A speed-to-lactate ratio was generated at the baseline and after 4 weeks of treatment. We also tested the effects of L-Arginine in vitro, measuring NO production, mitochondrial respiration, and gene expression in human fibroblasts. Results: L-Arginine did not modify BMI, muscle strength, and maximal speed at 200 meters after 4 weeks. However, L-Arginine ameliorated oxidative metabolism to exercise as suggested by the statistically significant lower lactate-to-speed ratio, which was not observed in placebo-treated controls. In vitro, L-Arginine induced the expression of a key regulator of mitochondrial biogenesis (PGC1α) and genes encoding for complex I and increased the production of nitric oxide and the maximal oxygen consumption rate. Conclusions: Chronic L-Arginine is safe and effective in ameliorating the oxidative metabolism of professional water polo players, through a mechanism of enhanced mitochondrial function.


Assuntos
Arginina/farmacologia , Suplementos Nutricionais , Aptidão Física/fisiologia , Esportes Aquáticos , Adulto , Exercício Físico , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Óxido Nítrico/metabolismo , Biogênese de Organelas
19.
Endocrinology ; 162(8)2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33824978

RESUMO

The neuropeptide Y (NPY) system has been recognized as one of the most critical molecules in the regulation of energy homeostasis and glucose metabolism. Abnormal levels of NPY have been shown to contribute to the development of metabolic disorders including obesity, cardiovascular diseases, and diabetes. NPY centrally promotes feeding and reduces energy expenditure, while the other family members, peptide YY (PYY) and pancreatic polypeptide (PP), mediate satiety. New evidence has uncovered additional functions for these peptides that go beyond energy expenditure and appetite regulation, indicating a more extensive function in controlling other physiological functions. In this review, we will discuss the role of the NPY system in the regulation of pancreatic ß-cell function and its therapeutic implications for diabetes.


Assuntos
Células Secretoras de Insulina/metabolismo , Neuropeptídeo Y/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Arginina/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Humanos , Terapia de Alvo Molecular , Receptores de Neuropeptídeo Y/antagonistas & inibidores
20.
ASAIO J ; 67(5): 573-582, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33902103

RESUMO

Clotting, anticoagulation, platelet consumption, and poor platelet function are major factors in clinical extracorporeal circulation (ECC). We have shown that nitric oxide-releasing (NOReL) coatings prevent thrombosis in a rabbit model of ECC without systemic anticoagulation. Nitric oxide-releasing prevents platelet adhesion and activation, resulting in preserved platelet count and function. Previous work has shown that activated platelets form platelet-derived microparticles (PMPs). These experiments were designed to determine if PMPs can identify platelet function during ECC. The objective of this study is to investigate the effects of NOReL on platelet activation and PMP formation during ECC. Uncoated ECCs, including with and without systemic heparin, and NOReL-coated ECCs, including DBHD/N2O2 and argatroban (AG)/DBHD/N2O2-coated ECCs without systemic heparin, were tested in a 4-hour rabbit thrombogenicity model. Before and after ECC exposure, platelets were stimulated with collagen, and PMPs were measured using flow cytometry. The uncoated ECCs clotted within the first hour, while the NOReL-coated ECCs circulated for 4 hours. During pre-ECC blood exposure, platelets stimulated with collagen produced PMPs. With post-ECC exposure, platelets from uncoated circuits generated less PMPs than baseline (mean ± SDs: 23246 ± 3611 baseline vs. 1300 ± 523 uncoated post circuit, p = 0.018) when stimulated with collagen. However, platelets from the AG/DBHD/N2O2-coated ECCs generated a greater number of PMPs as baseline values (23246 ± 3611 baseline vs. 37040 ± 3263 AG/DBHD/N2O2 post 4 hours circuit, p = 0.023). Blood exposure during ECC results in platelet activation and clotting in uncoated ECCs. The remaining circulating platelets have lost function, as demonstrated by the low PMP formation in response to collagen. AG/DBHD/N2O2-coated ECCs prevented significant platelet activation and clotting, while DBHD/N2O2 trended towards prevention of platelet activation. In addition, function of the circulating platelets was preserved, as demonstrated by PMP formation in response to collagen. These results indicate that PMPs may be an important measure of platelet activation during ECC. Platelet-derived microparticles may provide a simplified way to measure platelet function during clinical ECC.


Assuntos
Antitrombinas/farmacologia , Arginina/análogos & derivados , Plaquetas/fisiologia , Micropartículas Derivadas de Células/fisiologia , Circulação Extracorpórea , Óxido Nítrico/farmacologia , Ácidos Pipecólicos/farmacologia , Sulfonamidas/farmacologia , Trombose/prevenção & controle , Animais , Arginina/farmacologia , Circulação Extracorpórea/métodos , Ativação Plaquetária/fisiologia , Polímeros/farmacologia , Coelhos
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