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1.
Food Chem ; 401: 134072, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36108381

RESUMO

Plant growth regulator N-(2-chloro-4-pyridyl)-N'-phenylurea (CPPU) is widely used in fruit production. However, the mechanism in which CPPU affects melon fruit quality, especially aroma compound, remains unclear. Here, gas chromatography-mass spectrometry was performed to detect the sugar, citric acid, and aroma content in CPPU-treated and pollinated melon fruit. Results showed that the application of CPPU decreased the sugar and aroma content in melon fruit. The relative content of several important esters, including isobutyl acetate, ethyl acetate, 2-methylbutyl acetate, methyl acetate, benzyl acetate, and phenethyl acetate, in CPPU-treated fruits was significantly lower than that in honeybee-pollinated fruits. The content of many amino acids (isoleucine, leucine, valine, methionine, and l-phenylalanine), which could be metabolized into aroma compounds, in CPPU-treated fruits was significantly higher than that in honeybee-pollinated fruits. In conclusion, CPPU application interferes with amino-acid metabolism and affects the production of aromatic esters in melon fruit.


Assuntos
Cucurbitaceae , Compostos Orgânicos Voláteis , Abelhas , Animais , Frutas/metabolismo , Cucurbitaceae/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Açúcares/metabolismo , Isoleucina , Leucina/metabolismo , Metionina/metabolismo , Ácido Cítrico/metabolismo , Valina/metabolismo , Fenilalanina/metabolismo , Compostos Orgânicos Voláteis/metabolismo , Odorantes
2.
J Hazard Mater ; 441: 129877, 2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-36067563

RESUMO

Soil Cd pollution seriously threatens environment and human health. Due to its ability to absorb and accumulate Cd in mycelia, Stropharia rugosoannulata could be a potential candidate for bioremediation of Cd-contaminated soils; however, the response mechanism of mycelia to Cd stress is still unclear. In this study, the physiologic and proteomic differences of S. rugosoannulata mycelia under 0.2 mg/L (low) and 2 mg/L (high) Cd stress were investigated. The results showed that Cd accumulation and mycelial growth inhibition exhibited a concentration-depended trend. Analysis of antioxidant system indicated that SOD, GR, GSH, GSSG and ASA played key roles in resisting the toxic effects of Cd. Via proteome analysis, 24 and 267 differentially expressed proteins (DEPs) were observed under low and high Cd stress, respectively. GO and KEGG analysis found that the mycelial growth inhibition might due to the down-regulation of some DEPs involved in "valine, leucine and isoleucine biosynthesis" and "tyrosine metabolism"; the certain tolerance to high Cd stress might attribute to the regulation of DEPs referred to energy metabolism and antioxidant system-related pathways, maintaining cellular energy homeostasis and removing ROS. These results provide a theoretical basis for further elucidation of response mechanisms in S. rugosoannulata to Cd stress.


Assuntos
Cádmio , Proteômica , Agaricales , Antioxidantes/metabolismo , Cádmio/toxicidade , Dissulfeto de Glutationa , Humanos , Isoleucina , Leucina , Proteoma , Proteômica/métodos , Espécies Reativas de Oxigênio/metabolismo , Solo , Superóxido Dismutase , Tirosina , Valina
3.
J Hazard Mater ; 441: 129953, 2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-36116313

RESUMO

The neurotoxin ß-N-methylamino-L-alanine (BMAA) has been presumed as an environmental cause of human neurodegenerative disorders, such as Alzheimer's disease. Marine diatoms Thalassiosira minima are demonstrated here to produce BMAA-containing proteins in axenic culture while the isomer diaminobutyric acid was bacterially produced. In the co-culture with Cyanobacterium aponinum, diatom growth was inhibited but the biosynthesis of BMAA-containing proteins was stimulated up to seven times higher than that of the control group by cell-cell interactions. The stimulation effect was not caused by the cyanobacterial filtrate. Nitrogen deprivation also doubled the BMAA content of T. minima cells. Transcriptome analysis of the diatom in mixed culture revealed that pathways involved in T. minima metabolism and cellular functions were mainly influenced, including KEGG pathways valine and leucine/isoleucine degradation, endocytosis, pantothenate and CoA biosynthesis, and SNARE interactions in vesicular transport. Based on the expression changes of genes related to protein biosynthesis, it was hypothesized that ubiquitination and autophagy suppression, and limited COPII vesicles transport accuracy and efficiency were responsible for biosynthesis of BMAA-containing proteins in T. minima. This study represents a first application of transcriptomics to investigate the biological processes associated with BMAA biosynthesis in diatoms.


Assuntos
Diamino Aminoácidos , Diatomáceas , Diamino Aminoácidos/análise , Coenzima A/metabolismo , Toxinas de Cianobactérias , Diatomáceas/genética , Diatomáceas/metabolismo , Humanos , Isoleucina/metabolismo , Leucina/metabolismo , Neurotoxinas/análise , Nitrogênio/metabolismo , Proteínas SNARE/metabolismo , Espectrometria de Massas em Tandem , Transcriptoma , Valina/metabolismo
4.
Medicine (Baltimore) ; 101(43): e31063, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36316880

RESUMO

RATIONALE: Anti-LGI1 antibody encephalitis and anti-mGluR5 are both uncommon encephalitis, and we report the first case of autoimmune encephalitis (AE) with dual seropositive antibodies of leucine-rich glioma-inactivated 1 (LGI1) and mGluR5. PATIENT CONCERNS: We present a case of AE with dual seropositive antibodies of LGI1 and mGluR5 in a 65-year-old woman who presented with sudden onset left faciobrachial dystonic seizures and unresponsive for 5 hours. DIAGNOSIS: The patient was diagnosed with anti-LGI1 AE and anti-mGluR5 AE mainly based on the clinical symptoms and further test of the antibody in serum and cerebral spinal fluid (CSF). INTERVENTIONS AND OUTCOMES: The patient was treated with glucocorticoid intravenous drip. We also gave her the therapy of immunoglobulin (25 g q.d) for 5 days and anti-epileptic therapy. She had no more convulsions on the left side of the face and limbs. She did not complain of any uncomfort until July 18. LESSONS: Early recognition of AE is crucial. Specific autoantibodies are associated with corresponding syndromes. Our patient was initially diagnosed with acute ischemic stroke. Therefore, we should conduct further study on the related symptoms of AE.


Assuntos
Encefalite , Glioma , AVC Isquêmico , Encefalite Límbica , Humanos , Feminino , Idoso , Encefalite Límbica/complicações , Leucina , Peptídeos e Proteínas de Sinalização Intracelular , Encefalite/diagnóstico , Encefalite/tratamento farmacológico , Encefalite/complicações , Autoanticorpos , Glioma/complicações , Convulsões/etiologia , China
5.
Water Res ; 226: 119315, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36369690

RESUMO

Denitrification is one of the major sources of N2O in freshwaters. Diverse forms of organic compounds act as the electron donors for microbial denitrification. However, the influences of carbon sources on N2O production, N2O reduction, isotope fractionation and functional microbes during denitrification were largely unknown. In this study, five forms of carbon sources (i.e. acetate, citrate, glucose, cellobiose and leucine) were used to enrich denitrifiers in freshwater sediments. N2O conversion in the enrichments was investigated by a combination of inhibition technique, natural stable isotope method and metagenomics. Acetylene was effective in inhibiting N2O reduction without influencing the isotopic characteristics during N2O production. Glucose led to the least N2O production and reduction, in accordance with the lowest abundance of both NO and N2O reductases in this enrichment. δ18O and site preference value (SP, =δ15Nα-δ15Nß) of N2O were sensitive to discriminate the five carbon sources, except when comparing acetate and leucine. Isotopic values of N2O were not significantly different in these two enrichments due to the similarity of NO reductases - Pseudomonas-type cNorB. Specifically, the enrichment with cellobiose produced N2O with the lowest δ18O values (39.4‰±1.1‰), due to Alicycliphilus with both cNorB and qNorB. The enrichment with glucose led to the highest SP values (8.9‰±8.6‰), caused by Thiobacillus-type cNorB. Our results demonstrated the link between carbon sources, N2O production and reduction, isotopic signatures, microbial populations and enzymes during denitrification in freshwaters.


Assuntos
Carbono , Desnitrificação , Óxido Nitroso , Isótopos de Nitrogênio/análise , Leucina , Celobiose , Água Doce , Glucose
6.
Nutrients ; 14(21)2022 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-36364703

RESUMO

Type 2 Diabetes (T2D) is a metabolic disease associated with long-term complications, with a multifactorial pathogenesis related to the interplay between genetic and modifiable risk factors, of which nutrition is the most relevant. In particular, the importance of proteins and constitutive amino acids (AAs) in disease susceptibility is emerging. The ability to sense and respond to changes in AA supplies is mediated by complex networks, of which AA transporters (AATs) are crucial components acting also as sensors of AA availability. This study explored the associations between polymorphisms in selected AATs genes and T2D and vascular complications in 433 patients and 506 healthy controls. Analyses revealed significant association of SLC38A3-rs1858828 with disease risk. Stratification of patients based on presence/absence of vascular complications highlighted significant associations of SLC7A8-rs3783436 and SLC38A7-rs9806843 with diabetic retinopathy. Additionally, the SLC38A9-rs4865615 resulted associated with chronic kidney disease. Notably, these genes function as AAs sensors, specifically glutamine, leucine, and arginine, linked to the main nutrient signaling pathway mammalian target of rapamycin complex 1 (mTORC1). Thus, their genetic variability may contribute to T2D by influencing the ability to properly transduce a signal activating mTORC1 in response to AA availability. In this scenario, the contribution of dietary AAs supply to disease risk may be relevant.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Sistemas de Transporte de Aminoácidos/genética , Sistemas de Transporte de Aminoácidos/metabolismo , Aminoácidos/metabolismo , Leucina
7.
Nutrients ; 14(21)2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36364764

RESUMO

Although sarcopenia has been dealt with in several studies, the standardized guidelines for preventing sarcopenia resulting from increased life expectancy are still insufficient. Therefore, this study evaluated the effects of daily resistance exercise and the intake of leucine-rich protein supplements daily for 12 weeks on the body composition and physical function of healthy adults aged >50 years living in Korea. The study analyzed 50 healthy people without medical conditions, who were randomly assigned to two groups (taking either protein powder or placebo powder) twice a day for 12 weeks. All participants performed resistance exercises regularly that could be repeated 8-12 times using a TheraBand for 12 weeks. A total of 41 participants completed the study. When measured via bioimpedance analysis (BIA), body fat mass (kg) and body fat (%) significantly decreased, and lean body mass (LBM) (kg) and skeletal muscle mass (SMM) (kg) significantly increased, in both groups. However, when measured via dual-energy X-ray absorptiometry (DXA), LBM was significantly increased only in the protein powder group. The LBM and SMM change measured via BIA was significantly greater in the protein powder group than in the placebo powder group (LBM: 0.95 ± 0.91 kg in the protein powder group vs. 0.38 ± 1.06 kg in the placebo powder group, p = 0.043; SMM: 0.69 ± 0.58 kg in the protein powder group vs. 0.29 ± 0.65 kg in the placebo powder group, p = 0.039, respectively). In the senior fitness test (SFT), significant functional improvement was found within the two groups, but no significant difference was found between the groups in the degree of improvement. In conclusion, in older people aged >50, to prevent sarcopenia, is more effective to combine resistance exercise and leucine-rich protein supplementation than to simply perform resistance exercise.


Assuntos
Treinamento de Força , Sarcopenia , Adulto , Humanos , Idoso , Leucina/farmacologia , Força Muscular , Pós , Composição Corporal , Músculo Esquelético/metabolismo , Suplementos Nutricionais
8.
Nutrients ; 14(21)2022 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-36364828

RESUMO

Sarcopenia is a complex process characterized by a progressive decrease in muscle mass and strength. Various nutrients have been shown to be effective in supporting muscular performance. This randomized clinical trial aimed to evaluate the effectiveness of a 2-month administration of food for special medical purposes composed of omega-3 fatty acids (500 mg), leucine (2.5 g), and probiotic Lactobacillus paracasei PS23 (LPPS23), on appendicular lean mass (ALM), muscle performance, inflammatory status, and amino acid profile in sarcopenic patients. A total of 60 participants (aged 79.7 ± 4.8 years and a body mass index of 22.2 ± 2.1 kg/m2) were enrolled and randomly assigned to either intervention (n = 22) or placebo group (n = 28). Comparing the differences in effects between groups (intervention minus placebo effects), ALM increased significantly in the intervention group (p < 0.05), with no discernible change in the placebo group. Similarly, significant differences were also observed for the Tinetti scale (+2.39 points, p < 0.05), the SPPB total score (+2.22 points, p < 0.05), and the handgrip strength (4.09 kg, p < 0.05). Visceral adipose tissue significantly decreased in the intervention group compared to the placebo group at 60 days -0.69 g (95% CI: -1.09, 0.29) vs. 0.27 g (95% CI: -0.11, 0.65), groups difference -0.96 (95% CI: -1.52, 0.39, p = 0.001). A statistically significant increase in levels of valine, leucine, isoleucine, and total amino acid profiles was observed in the intervention group compared with the placebo group at 60 days (p = 0.001). When taken together, these beneficial effects may be attributed to the innovative composition of this special medical-purpose food which could be considered for the treatment of sarcopenia in the elderly.


Assuntos
Ácidos Graxos Ômega-3 , Lactobacillus paracasei , Probióticos , Sarcopenia , Idoso , Humanos , Sarcopenia/tratamento farmacológico , Leucina , Lactobacillus paracasei/fisiologia , Força da Mão , Suplementos Nutricionais , Ácidos Graxos Ômega-3/uso terapêutico , Probióticos/uso terapêutico , Método Duplo-Cego
9.
Sci Rep ; 12(1): 19273, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36369511

RESUMO

Higher plasma leucine, isoleucine and valine (BCAA) concentrations are associated with diabetes, obesity and insulin resistance (IR). Here, we evaluated the effects of 6-weeks very-low calorie diet (VLCD) upon fasting BCAA in overweight (OW) non-diabetic men, to explore associations between circulating BCAA and IR, before and after a weight loss intervention. Fasting plasma BCAAs were quantified in an OW (n = 26; BMI 32.4 ± 3 kg/m2; mean age 44 ± 9 y) and a normal-weight (NW) group (n = 26; BMI 24 ± 3.1 kg/m2; mean age 32 ± 12.3 y). Ten of the OW group (BMI 32.2 ± 4 kg/m2; 46 ± 8 y) then underwent 6-weeks of VLCD (600-800 kcal/day). Fasting plasma BCAA (gas chromatography-mass spectrometry), insulin sensitivity (HOMA-IR) and body-composition (DXA) were assessed before and after VLCD. Total BCAA were higher in OW individuals (sum leucine/isoleucine/valine: 457 ± 85 µM) compared to NW control individuals (365 ± 78 µM, p < 0.001). Despite significant weight loss (baseline 103.9 ± 12.3 to 93 ± 9.6 kg and BMI 32.2 ± 4 to 28.9 ± 3.6 kg/m2), no changes were observed in BCAAs after 6-weeks of VLCD. Moreover, although VLCD resulted in a significant reduction in HOMA-IR (baseline 1.19 ± 0.62 to 0.51 ± 0.21 post-VLCD; p < 0.001), Pearson's r revealed no relationships between BCAA and HOMA-IR, either before (leucine R2: 2.49e-005, p = 0.98; isoleucine R2: 1.211-e006, p = 0.9; valine R2: 0.004, p = 0.85) or after VLCD (leucine R2: 0.003, p = 0.86; isoleucine R2: 0.006, p = 0.82; valine R2: 0.002, p = 0.65). Plasma BCAA are higher in OW compared to NW individuals. However, while 6-weeks VLCD reduced body weight and IR in OW individuals, this was not associated with reductions in BCAA. This suggests that studies demonstrating links between BCAA and insulin resistance in OW individuals, are complex and are not normalised by simply losing weight.


Assuntos
Aminoácidos de Cadeia Ramificada , Resistência à Insulina , Masculino , Humanos , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Aminoácidos de Cadeia Ramificada/metabolismo , Restrição Calórica , Controle Glicêmico , Leucina , Isoleucina , Cetoácidos , Glicemia/metabolismo , Obesidade , Redução de Peso , Sobrepeso/terapia , Valina
10.
J Med Case Rep ; 16(1): 409, 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36348436

RESUMO

BACKGROUND: Anti-leucine-rich glioma-inactivated 1 encephalitis is a newly emerged entity characterized by frequent faciobrachial dystonic seizures and a wide spectrum of subacute clinical symptoms such as other seizure types, mood and behavioral changes, and memory loss. We should be aware of differentiating this diagnosis from psychogenic nonepileptic seizures. Mesial temporal, limbic structures, and basal ganglia are the most commonly involved regions. CASE PRESENTATION: Here we review the available data, and report on two young Iranian (White) females, 24 and 18 years old, who represent distinct aspects of the disease. The clinical presentation and degree of tissue involvement varies to some extent in the two reported cases. Case 1 had prominent neuropsychiatric symptoms and suffered from frequent faciobrachial dystonic seizures with more significant basal ganglia involvement, whereas case 2 suffered from severe memory decline and dialeptic seizures along with mesial temporal involvement. Symptoms were refractory to usual treatment and prompt immunotherapy was needed. CONCLUSIONS: This disease has a rather favorable outcome provided that treatment is initiated early. However, resistance to first-line treatment, relapses, and long-term complications highlight the need to establish reliable biomarkers to distinguish different subtypes of this disorder to predict the clinical outcome and prognosis, and to refine management.


Assuntos
Encefalite , Glioma , Encefalite Límbica , Feminino , Humanos , Encefalite Límbica/complicações , Leucina/uso terapêutico , Autoanticorpos , Irã (Geográfico) , Peptídeos e Proteínas de Sinalização Intracelular/uso terapêutico , Recidiva Local de Neoplasia/complicações , Encefalite/diagnóstico , Encefalite/tratamento farmacológico , Convulsões/complicações
11.
PLoS Biol ; 20(11): e3001856, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36318514

RESUMO

Feingold syndrome type 1, caused by loss-of-function of MYCN, is characterized by varied phenotypes including esophageal and duodenal atresia. However, no adequate model exists for studying the syndrome's pathological or molecular mechanisms, nor is there a treatment strategy. Here, we developed a zebrafish Feingold syndrome type 1 model with nonfunctional mycn, which had severe intestinal atresia. Single-cell RNA-seq identified a subcluster of intestinal cells that were highly sensitive to Mycn, and impaired cell proliferation decreased the overall number of intestinal cells in the mycn mutant fish. Bulk RNA-seq and metabolomic analysis showed that expression of ribosomal genes was down-regulated and that amino acid metabolism was abnormal. Northern blot and ribosomal profiling analysis showed abnormal rRNA processing and decreases in free 40S, 60S, and 80S ribosome particles, which led to impaired translation in the mutant. Besides, both Ribo-seq and western blot analysis showed that mTOR pathway was impaired in mycn mutant, and blocking mTOR pathway by rapamycin treatment can mimic the intestinal defect, and both L-leucine and Rheb, which can elevate translation via activating TOR pathway, could rescue the intestinal phenotype of mycn mutant. In summary, by this zebrafish Feingold syndrome type 1 model, we found that disturbance of ribosomal biogenesis and blockage of protein synthesis during development are primary causes of the intestinal defect in Feingold syndrome type 1. Importantly, our work suggests that leucine supplementation may be a feasible and easy treatment option for this disease.


Assuntos
Microcefalia , Peixe-Zebra , Animais , Proteína Proto-Oncogênica N-Myc , Peixe-Zebra/metabolismo , Microcefalia/genética , Serina-Treonina Quinases TOR/metabolismo , Leucina
12.
Int J Mol Sci ; 23(21)2022 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-36361616

RESUMO

Missense mutations of leucine-rich repeat kinase 2 (LRRK2), including the G2019S mutant, are responsible for the pathogenesis of Parkinson's disease. In this work, structure-based virtual screening of a large chemical library was carried out to identify a number of novel inhibitors of the G2019S mutant of LRRK2, the biochemical potencies of which ranged from the low micromolar to the submicromolar level. The discovery of these potent inhibitors was made possible due to the modification of the original protein-ligand binding energy function in order to include an accurate ligand dehydration energy term. The results of extensive molecular docking simulations indicated that the newly identified inhibitors were bound to the ATP-binding site of the G2019S mutant of LRRK2 through the multiple hydrogen bonds with backbone amide groups in the hinge region as well as the hydrophobic interactions with the nonpolar residues in the P-loop, hinge region, and interdomain region. Among 18 inhibitors derived from virtual screening, 4-(2-amino-5-phenylpyrimidin-4-yl)benzene-1,3-diol (Inhibitor 2) is most likely to serve as a new molecular scaffold to optimize the biochemical potency, because it revealed submicromolar inhibitory activity in spite of its low molecular weight (279.3 amu). Indeed, a highly potent inhibitor (Inhibitor 2n) of the G2019S mutant was derived via the structure-based de novo design using the structure of Inhibitor 2 as the molecular core. The biochemical potency of Inhibitor 2n surged to the nanomolar level due to the strengthening of hydrophobic interactions in the ATP-binding site, which were presumably caused by the substitutions of small nonpolar moieties. Due to the high biochemical potency against the G2019S mutant of LRRK2 and the putatively good physicochemical properties, Inhibitor 2n is anticipated to serve as a new lead compound for the discovery of antiparkinsonian medicines.


Assuntos
Trifosfato de Adenosina , Inibidores de Proteínas Quinases , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/química , Simulação de Acoplamento Molecular , Leucina/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Ligantes , Trifosfato de Adenosina/metabolismo , Mutação
13.
Int J Mol Sci ; 23(21)2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36361660

RESUMO

Unlike the α-helical and ß-sheet antimicrobial peptides (AMPs), our knowledge on amino acid-rich AMPs is limited. This article conducts a systematic study of rich AMPs (>25%) from different life kingdoms based on the Antimicrobial Peptide Database (APD) using the program R. Of 3425 peptides, 724 rich AMPs were identified. Rich AMPs are more common in animals and bacteria than in plants. In different animal classes, a unique set of rich AMPs is deployed. While histidine, proline, and arginine-rich AMPs are abundant in mammals, alanine, glycine, and leucine-rich AMPs are common in amphibians. Ten amino acids (Ala, Cys, Gly, His, Ile, Lys, Leu, Pro, Arg, and Val) are frequently observed in rich AMPs, seven (Asp, Glu, Phe, Ser, Thr, Trp, and Tyr) are occasionally observed, and three (Met, Asn, and Gln) were not yet found. Leucine is much more frequent in forming rich AMPs than either valine or isoleucine. To date, no natural AMPs are simultaneously rich in leucine and lysine, while proline, tryptophan, and cysteine-rich peptides can simultaneously be rich in arginine. These findings can be utilized to guide peptide design. Since multiple candidates are potent against antibiotic-resistant bacteria, rich AMPs stand out as promising future antibiotics.


Assuntos
Aminoácidos , Peptídeos Antimicrobianos , Animais , Tripsina , Sequência de Aminoácidos , Leucina , Fragmentos de Peptídeos , Peptídeos , Prolina , Arginina , Mamíferos
14.
Int J Mol Sci ; 23(21)2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36362195

RESUMO

LL-37 is a membrane-active antimicrobial peptide (AMP) that could disrupt the integrity of bacterial membranes due to its inherent cationic and amphipathic nature. Developing a shorter derivative of a long peptide such as LL-37 is of great interest, as it can reduce production costs and cytotoxicity. However, more detailed information about the residual interaction between LL-37 and the membrane is required for further optimization. Previously, molecular dynamics simulation using mixed all-atom and united-atom force fields showed that LL-37 could penetrate the bilayer membrane. This study aimed to perform all-atom molecular dynamics simulations, highlighting the residual interaction of LL-37 with the simplest model of the bacterial membrane, POPE:POPG (2:1), and compare its interaction with the POPC, which represents the eukaryotic membrane. The result showed leucine-leucine as the leading residues of LL-37 that first contact the membrane surface. Then, the cationic peptide of LL-37 started to penetrate the membrane by developing salt bridges between positively charged amino acids, Lys-Arg, and the exposed phosphate group of POPE:POPG, which is shielded in POPC. Residues 18 to 29 are suggested as the core region of LL-37, as they actively interact with the POPE:POPG membrane, not POPC. These results could provide a basis for modifying the amino acid sequence of LL-37 and developing a more efficient design for LL-37 derivatives.


Assuntos
Simulação de Dinâmica Molecular , Fosfatidilgliceróis , Fosfatidilgliceróis/química , Bicamadas Lipídicas/química , Peptídeos Catiônicos Antimicrobianos/química , Leucina , Fosfatidilcolinas/química
15.
Mol Brain ; 15(1): 89, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36333725

RESUMO

Olfactory marker protein (OMP) is a cytosolic protein expressed in mature olfactory receptor neurons (ORNs). OMP modulates cAMP signalling and regulates olfactory sensation and axonal targeting. OMP is a small soluble protein, and passive diffusion between nucleus and cytoplasm is expected. However, OMP is mostly situated in the cytosol and is only sparsely detected in the nuclei of a subset of ORNs, hypothalamic neurons and heterologously OMP-expressing cultured cells. OMP can enter the nucleus in association with transcription factors. However, how OMP is retained in the cytosol at rest is unclear. Because OMP is proposed to affect cell differentiation, it is important to understand how OMP is distributed between cytoplasm and nucleus. To elucidate the structural profile of OMP, we applied several bioinformatics methods to a multiple sequence alignment (MSA) of OMP protein sequences and ranked the evolutionarily conserved residues. In addition to the previously reported cAMP-binding domain, we identified a leucine-rich domain in the Ω-loop of OMP. We introduced mutations into the leucine-rich region and heterologously expressed the mutant OMP in HEK293T cells. Mutations into alanine increased the nuclear distribution of OMP quantified by immunocytochemistry and western blotting. Therefore, we concluded that OMP contains a leucine-rich domain important for nuclear transport.


Assuntos
Neurônios Receptores Olfatórios , Humanos , Proteína de Marcador Olfatório , Transporte Ativo do Núcleo Celular , Leucina , Células HEK293 , Fatores de Transcrição
16.
Microb Cell Fact ; 21(1): 232, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36335365

RESUMO

BACKGROUND: Caprazamycins are liponucleoside antibiotics showing bioactivity against Gram-positive bacteria including clinically relevant Mycobacterium tuberculosis by targeting the bacterial MraY-translocase. Their chemical structure contains a unique 3-methylglutaryl moiety which they only share with the closely related liposidomycins. Although the biosynthesis of caprazamycin is understood to some extent, the origin of 3-methylglutaryl-CoA for caprazamycin biosynthesis remains elusive. RESULTS: In this work, we demonstrate two pathways of the heterologous producer Streptomyces coelicolor M1154 capable of supplying 3-methylglutaryl-CoA: One is encoded by the caprazamycin gene cluster itself including the 3-hydroxy-3-methylglutaryl-CoA synthase Cpz5. The second pathway is part of primary metabolism of the host cell and encodes for the leucine/isovalerate utilization pathway (Liu-pathway). We could identify the liu cluster in S. coelicolor M1154 and gene deletions showed that the intermediate 3-methylglutaconyl-CoA is used for 3-methylglutaryl-CoA biosynthesis. This is the first report of this intermediate being hijacked for secondary metabolite biosynthesis. Furthermore, Cpz20 and Cpz25 from the caprazamycin gene cluster were found to be part of a common route after both individual pathways are merged together. CONCLUSIONS: The unique 3-methylglutaryl moiety in caprazamycin originates both from the caprazamycin gene cluster and the leucine/isovalerate utilization pathway of the heterologous host. Our study enhanced the knowledge on the caprazamycin biosynthesis and points out the importance of primary metabolism of the host cell for biosynthesis of natural products.


Assuntos
Mycobacterium tuberculosis , Streptomyces coelicolor , Leucina/metabolismo , Streptomyces coelicolor/genética , Streptomyces coelicolor/metabolismo , Família Multigênica , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Antibacterianos/química
17.
Nutrients ; 14(20)2022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-36297051

RESUMO

This study aimed to evaluate the potential associations of dietary BCAAs (isoleucine, leucine, and valine) with physical function in the elderly Chinese population. A validated semiquantitative food frequency questionnaire and anthropometric and physical function measurements were used to collect data. We modeled trends in physical function indicators for BCAA quartiles using multivariate linear regression models. Among 4336 (43.97% men) participants aged 72.73 ± 5.48 years, a higher dietary intake of BCAAs was positively associated with increased handgrip strength (all p trends < 0.001), shorter times for 4-m fast walking (all p trends < 0.001) and repeated chair rises (all p trends < 0.001). No linear association was found between subtypes of amino acids and any physical functions (all p trends > 0.05). Individuals in the highest quartiles of BCAA intake had a reduced risk of developing low muscle strength, and the multiadjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for women and men were 0.50 (0.38-0.65) and 0.67 (0.50-0.91), respectively. Similarly, higher BCAA consumption was associated with a lower risk of developing low physical performance (4-m walking speed: OR = 0.68 [0.50-0.93]; repeated chair rises: OR = 0.66 [0.54-0.81]). Higher dietary BCAA intake might be beneficial for physical function in the elderly population.


Assuntos
Aminoácidos de Cadeia Ramificada , Vida Independente , Masculino , Humanos , Idoso , Feminino , Aminoácidos de Cadeia Ramificada/metabolismo , Leucina , Isoleucina , Força da Mão , Fatores de Risco , Valina , China/epidemiologia
18.
Nutrients ; 14(20)2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36297095

RESUMO

INTRODUCTION: Recent studies have concluded that elevated circulating branched chain amino acids (BCAA) are associated with the pathogenesis of type 2 diabetes mellitus (T2DM) and obesity. However, the development of this association over time and the quantification of the strength of this association for individual BCAAs prior to T2DM diagnosis remains unexplored. METHODS: A systematic search was conducted using the Healthcare Databases Advance Search (HDAS) via the National Institute for Health and Care Excellence (NICE) website. The data sources included EMBASE, MEDLINE and PubMed for all papers from inception until November 2021. Nine studies were identified in this systematic review and meta-analysis. Stratification was based on follow-up times (0-6, 6-12 and 12 or more years) and controlling of body mass index (BMI) through the specific assessment of overweight cohorts was also undertaken. RESULTS: The meta-analysis revealed a statistically significant positive association between BCAA concentrations and the development of T2DM, with valine OR = 2.08 (95% CI = 2.04-2.12, p < 0.00001), leucine OR = 2.25 (95% CI = 1.76-2.87, p < 0.00001) and isoleucine OR = 2.12, 95% CI = 2.00-2.25, p < 0.00001. In addition, we demonstrated a positive consistent temporal association between circulating BCAA levels and the risk of developing T2DM with differentials in the respective follow-up times of 0-6 years, 6-12 years and ≥12 years follow-up for valine (OR = 2.08, 1.86 and 2.14, p < 0.05 each), leucine (OR = 2.10, 2.25 and 2.16, p < 0.05 each) and isoleucine (OR = 2.12, 1.90 and 2.16, p < 0.05 each) demonstrated. CONCLUSION: Plasma BCAA concentrations are associated with T2DM incidence across all temporal subgroups. We suggest the potential utility of BCAAs as an early biomarker for T2DM irrespective of follow-up time.


Assuntos
Aminoácidos de Cadeia Ramificada , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Isoleucina , Leucina , Biomarcadores , Valina
19.
Nutrients ; 14(20)2022 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-36297065

RESUMO

The study investigates the effects of wheat biscuits supplemented with plant flours originating from legumes/seeds enriched either in L-arginine (L-arg) or branched-chain amino acids (BCAAs) on postprandial glucose response of healthy subjects. Gastrointestinal hormone and amino acid responses as well as subjective appetite sensations are also evaluated. Subjects consumed wheat-based biscuits, enriched either in L-arg (ArgB) or BCAAs (BCAAsB) or a conventional wheat biscuit (CB) or a glucose solution (GS) in an acute randomized crossover design. Responses of glucose, insulin, ghrelin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY) and glicentin, as well as those of L-arginine, L-leucine, L-isoleucine and L-valine, were evaluated over 180 min. Consumption of ArgB and BCAAsB elicited lower glucose iAUC compared to GS (p < 0.05). A lower iAUC for insulin was observed after consumption of BCAAsB (p < 0.05 compared to CB and ArgB), while ArgB elicited higher iAUC for GLP-1 accompanied by higher glicentin response (p < 0.05 compared to CB). BCAAsB and ArgB increased postprandial amino acid concentrations and caused stronger satiety effects compared to CB. Increasing protein content of wheat biscuits with supplementation of plant flours originating from legumes/seeds decreases postprandial glycemia and provides with healthier snack alternatives which can easily be incorporated into diet.


Assuntos
Hormônios Gastrointestinais , Humanos , Aminoácidos de Cadeia Ramificada , Arginina , Glicemia/metabolismo , Estudos Cross-Over , Grelina , Glicentina , Peptídeo 1 Semelhante ao Glucagon , Glucose , Voluntários Saudáveis , Insulina/metabolismo , Isoleucina , Leucina , Peptídeo YY , Período Pós-Prandial , Triticum/metabolismo , Valina
20.
Metabolomics ; 18(11): 85, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36307737

RESUMO

BACKGROUND & AIMS: There are some problems, such as unclear pathological mechanism, delayed diagnosis, and inaccurate therapeutic target of Contrast-induced acute kidney injury (CI-AKI). It is significantly important to find biomarkers and therapeutic targets that can indicate renal injury in the early stage of CI-AKI. This study aims to establish a multiple-metabolites model to predict preliminary renal injury induced by iodixanol and explore its pathogenesis. METHODS: Both UHPLC/Q-Orbitrap-MS and 1H-NMR methods were applied for urine metabolomics studies on two independent cohorts who suffered from a preliminary renal injury caused by iodixanol, and the multivariate statistical analysis and random forest (RF) algorithm were used to process the related date. RESULTS: In the discovery cohort (n = 169), 6 metabolic markers (leucine, indole, 5-hydroxy-L-tryptophan, N-acetylvaline, hydroxyhexanoycarnine, and kynurenic acid) were obtained by the cross-validation between the RF and liquid chromatography-mass spectrometry (LC-MS). Secondly, the 6 differential metabolites were confirmed by comparison of standard substance and structural identification of 1H-NMR. Subsequently, the multiple-metabolites model composed of the 6 biomarkers was validated in a validation cohort (n = 165). CONCLUSIONS: The concentrations of leucine, indole, N-acetylvaline, 5-hydroxy-L-tryptophan, hydroxyhexanoycarnitine and kynurenic acid in urine were proven to be positively correlated with the degree of renal injury induced by iodixanol. The multiple-metabolites model based on these 6 biomarkers has a good predictive ability to predict early renal injury caused by iodixanol, provides treatment direction for injury intervention and a reference for reducing the incidence of clinical CI-AKI further.


Assuntos
Injúria Renal Aguda , Metabolômica , Humanos , Cromatografia Líquida de Alta Pressão/métodos , Metabolômica/métodos , Ácido Cinurênico/efeitos adversos , Ácido Cinurênico/metabolismo , Leucina/efeitos adversos , Leucina/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Triptofano/metabolismo , Rim/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/metabolismo , Biomarcadores/metabolismo , Indóis/efeitos adversos , Indóis/metabolismo
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