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1.
J Hazard Mater ; 470: 134129, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38565019

RESUMO

Butylparaben, a common endocrine disruptor in the environment, is known to be toxic to the reproductive system, heart, and intestines, but its nephrotoxicity has rarely been reported. In order to study the nephrotoxicity and mechanism of butylparaben, we examined the acute and chronic effects on human embryonic kidney cells (HEK293T) and zebrafish. Additionally, we assessed the potential remedial effects of salidroside against butylparaben-induced nephrotoxicity. Our in vitro findings demonstrated oxidative stress and cytotoxicity to HEK293T cells caused by butylparaben. In the zebrafish model, the concentration of butylparaben exposure ranged from 0.5 to 15 µM. An assortment of experimental techniques was employed, including the assessment of kidney tissue morphology using Hematoxylin-Eosin staining, kidney function analysis via fluorescent dextran injection, and gene expression studies related to kidney injury, development, and function. Additionally, butylparaben caused lipid peroxidation in the kidney, thereby damaging glomeruli and renal tubules, which resulted from the downregulation of the PI3K-AKT signaling pathway. Furthermore, salidroside ameliorated butylparaben-induced nephrotoxicity through the PI3K-AKT signaling pathway. This study reveals the seldom-reported kidney toxicity of butylparaben and the protective effect of salidroside against toxicological reactions related to nephrotoxicity. It offers valuable insights into the risks to kidney health posed by environmental toxins.


Assuntos
Rim , Parabenos , Fenóis , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Peixe-Zebra , Animais , Parabenos/toxicidade , Fosfatidilinositol 3-Quinases/metabolismo , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Células HEK293 , Transdução de Sinais/efeitos dos fármacos , Fenóis/toxicidade , Glucosídeos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Peroxidação de Lipídeos/efeitos dos fármacos , Nefropatias/induzido quimicamente , Nefropatias/patologia , Nefropatias/metabolismo
2.
Food Chem ; 448: 139182, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38569413

RESUMO

Amylosucrase (ASase) efficiently biosynthesizes α-glucoside using flavonoids as acceptor molecules and sucrose as a donor molecule. Here, ASase from Deinococcus wulumuqiensis (DwAS) biosynthesized more naringenin α-glucoside (NαG) with sucrose and naringenin as donor and acceptor molecules, respectively, than other ASases from Deinococcus sp. The biotransformation rate of DwAS to NαG was 21.3% compared to 7.1-16.2% for other ASases. Docking simulations showed that the active site of DwAS was more accessible to naringenin than those of others. The 217th valine in DwAS corresponded to the 221st isoleucine in Deinococcus geothermalis AS (DgAS), and the isoleucine possibly prevented naringenin from accessing the active site. The DwAS-V217I mutant had a significantly lower biosynthetic rate of NαG than DwAS. The kcat/Km value of DwAS with naringenin as the donor was significantly higher than that of DgAS and DwAS-V217I. In addition, NαG inhibited human intestinal α-glucosidase more efficiently than naringenin.


Assuntos
Proteínas de Bactérias , Biotransformação , Deinococcus , Flavanonas , Glucosídeos , Glucosiltransferases , Inibidores de Glicosídeo Hidrolases , Flavanonas/metabolismo , Flavanonas/química , Deinococcus/enzimologia , Deinococcus/metabolismo , Deinococcus/química , Deinococcus/genética , Glucosiltransferases/metabolismo , Glucosiltransferases/química , Glucosiltransferases/genética , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Glucosídeos/metabolismo , Glucosídeos/química , Simulação de Acoplamento Molecular , Cinética , alfa-Glucosidases/metabolismo , alfa-Glucosidases/química
3.
J Am Coll Cardiol ; 83(15): 1386-1398, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38599715

RESUMO

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors are believed to improve cardiac outcomes due to their osmotic diuretic potential. OBJECTIVES: The goal of this study was to test the hypothesis that vasopressin-driven urine concentration overrides the osmotic diuretic effect of glucosuria induced by dapagliflozin treatment. METHODS: DAPA-Shuttle1 (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment) was a single-center, double-blind, randomized, placebo-controlled trial, in which patients with chronic heart failure NYHA functional classes I/II and reduced ejection fraction were randomly assigned to receive dapagliflozin 10 mg daily or placebo (1:1) for 4 weeks. The primary endpoint was change from baseline in urine osmolyte concentration. Secondary endpoints included changes in copeptin levels and solute free water clearance. RESULTS: Thirty-three randomized, sodium-glucose cotransporter 2 inhibitor-naïve participants completed the study, 29 of whom (placebo: n = 14; dapagliflozin: n = 15) provided accurate 24-hour urine collections (mean age 59 ± 14 years; left ventricular ejection fraction 31% ± 9%). Dapagliflozin treatment led to an isolated increase in urine glucose excretion by 3.3 mmol/kg/d (95% CI: 2.51-4.04; P < 0.0001) within 48 hours (early) which persisted after 4 weeks (late; 2.7 mmol/kg/d [95% CI: 1.98-3.51]; P < 0.0001). Dapagliflozin treatment increased serum copeptin early (5.5 pmol/L [95% CI: 0.45-10.5]; P < 0.05) and late (7.8 pmol/L [95% CI: 2.77-12.81]; P < 0.01), leading to proportional reductions in free water clearance (early: -9.1 mL/kg/d [95% CI: -14 to -4.12; P < 0.001]; late: -11.0 mL/kg/d [95% CI: -15.94 to -6.07; P < 0.0001]) and elevated urine concentrations (late: 134 mmol/L [95% CI: 39.28-229.12]; P < 0.01). Therefore, urine volume did not significantly increase with dapagliflozin (mean difference early: 2.8 mL/kg/d [95% CI: -1.97 to 7.48; P = 0.25]; mean difference late: 0.9 mL/kg/d [95% CI: -3.83 to 5.62]; P = 0.70). CONCLUSIONS: Physiological-adaptive water conservation eliminated the expected osmotic diuretic potential of dapagliflozin and thereby prevented a glucose-driven increase in urine volume of approximately 10 mL/kg/d · 75 kg = 750 mL/kg/d. (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment [DAPA-Shuttle1]; NCT04080518).


Assuntos
Compostos Benzidrílicos , Conservação dos Recursos Hídricos , Diurese , Glucosídeos , Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Idoso , Humanos , Pessoa de Meia-Idade , Diuréticos Osmóticos/farmacologia , Diuréticos Osmóticos/uso terapêutico , Transportador 2 de Glucose-Sódio , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Volume Sistólico , Função Ventricular Esquerda , Água
4.
Toxins (Basel) ; 16(4)2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38668591

RESUMO

Trichothecenes produced by Fusarium species are commonly detected in oats. However, the ratios of the concentrations of free trichothecenes and their conjugates and how they are impacted by different interacting environmental conditions are not well documented. This study aims to examine the effect of water activity (0.95 and 0.98 aw) and temperature (20 and 25 °C) stress on the production of T-2 and HT-2 toxins, deoxynivalenol and their conjugates, as well as diacetoxyscirpenol (DAS). Multiple mycotoxins were detected using liquid chromatography-tandem mass spectrometry from 64 contaminated oat samples. The highest concentrations of HT-2-glucoside (HT-2-Glc) were observed at 0.98 aw and 20 °C, and were higher than other type A trichothecenes in the natural oats' treatments. However, no statistical differences were found between the mean concentrations of HT-2-Glc and HT-2 toxins in all storage conditions analysed. DAS concentrations were generally low and highest at 0.95 aw and 20 °C, while deoxynivalenol-3-glucoside levels were highest at 0.98 aw and 20 °C in the naturally contaminated oats. Emerging mycotoxins such as beauvericin, moniliformin, and enniatins mostly increased with a rise in water activity and temperature in the naturally contaminated oats treatment. This study reinforces the importance of storage aw and temperature conditions in the high risk of free and modified toxin contamination of small cereal grains.


Assuntos
Avena , Contaminação de Alimentos , Fusarium , Glucosídeos , Toxina T-2/análogos & derivados , Tricotecenos , Fusarium/metabolismo , Avena/microbiologia , Avena/química , Tricotecenos/análise , Glucosídeos/análise , Contaminação de Alimentos/análise , Temperatura , Micotoxinas/análise , Toxina T-2/análise
5.
Planta ; 259(5): 114, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38587670

RESUMO

MAIN CONCLUSION: Two glycosyltransferase genes belonging to UGT88 family were identified to have 6'-deoxychalcone 4'-glucosyltransferase activity in dahlia. 6'-Deoxychalcones (isoliquiritigenin and butein) are important pigments for yellow and orange to red flower color. 6'-Deoxychalcones are glucosylated at the 4'-position in vivo, but the genes encoding 6'-deoxychalcone 4'-glucosyltransferase have not yet been identified. In our previous study, it was indicated that snapdragon (Antirrhinum majus) chalcone 4'-O-glucosyltransferase (Am4'CGT) has isoliquiritigenin 4'-glucosylation activity. Therefore, to identify genes encoding 6'-deoxychalcone 4'-glucosyltransferase in dahlia (Dahlia variabilis), genes expressed in ray florets that shared high homology with Am4'CGT were explored. As a result, c34671_g1_i1 and c35662_g1_i1 were selected as candidate genes for 6'-deoxychalcone 4'-glucosyltransferases in dahlia. We conducted transient co-overexpression of three genes (c34671_g1_i1 or c35662_g1_i1, dahlia aldo-keto reductase1 (DvAKR1) or soybean (Glycine max) chalcone reductase5 (GmCHR5), and chili pepper (Capsicum annuum) MYB transcription factor (CaMYBA)) in Nicotiana benthamiana by agroinfiltration. Transient overexpression of c34671_g1_i1, DvAKR1, and CaMYBA resulted in increase in the accumulation of isoliquiritigenin 4'-glucosides, isoliquiritigenin 4'-O-glucoside, and isoliquiritigenin 4'-O-[6-O-(malonyl)-glucoside]. However, transient overexpression of c35662_g1_i1, DvAKR1, and CaMYBA did not increase accumulation of isoliquiritigenin 4'-glucosides. Using GmCHR5 instead of DvAKR1 showed similar results suggesting that c34671_g1_i1 has isoliquiritigenin 4'-glucosyltransferase activity. In addition, we conducted co-overexpression of four genes (c34671_g1_i1, c35662_g1_i1 or Am4'CGT, DvAKR1 or GmCHR5, CaMYBA, and chalcone 3-hydroxylase from dahlia). Accumulation of butein 4'-O-glucoside and butein 4'-O-[6-O-(malonyl)-glucoside] was detected for c35662_g1_i1, suggesting that c35662_g1_i1 has butein 4'-glucosyltransferase activity. Recombinant enzyme analysis also supported butein 4'-glucosyltransferases activity of c35662_g1_i1. Therefore, our results suggested that both c34671_g1_i1 and c35662_g1_i1 are 6'-deoxychalcone 4'-glucosyltransferases but with different substrate preference.


Assuntos
Capsicum , Chalcona , Chalconas , Dahlia , Glucosiltransferases/genética , Glucosídeos , Glycine max
6.
Zhongguo Zhong Yao Za Zhi ; 49(4): 961-967, 2024 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-38621903

RESUMO

The chemical composition of the aqueous part of the extract from Lindera aggregata was studied, which was separated and purified by the macroporous resin column chromatography, MCI medium pressure column chromatography, semi-preparative high-performance liquid phase and other methods. The structures of the compounds were identified according to physical and chemical properties and spectroscopic data. Thirteen compounds were isolated and identified from the aqueous extracts, which were identified as(1S,3R,5R,6R,8S,10S)-epi-lindenanolide H(1), tachioside(2), lindenanolide H(3), leonuriside A(4), 3,4-dihydroxyphenyl ethyl ß-D-glucopyranoside(5), 3,4,5-trimethoxyphenol-1-O-6-α-L-rhamnose-(1→6)-O-ß-D-glucoside(6), 5-hydroxymethylfurfural(7),(+)-lyoniresin-4-yl-ß-D-glucopyranoside(8), lyoniside(9), norboldine(10), norisopordine(11), boldine(12), reticuline(13). Among them, compound 1 was a new one, and compounds 2, 5, 6, 8, 9 were obtained from L. aggregata for the first time. The inflammatory model was induced by lipopolysaccharide(LPS) in the RAW264.7 cells. The results showed that compounds 1, 8, 10 and 12 had significant anti-inflammatory activity.


Assuntos
Lindera , Sesquiterpenos , Lindera/química , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Glucosídeos
7.
Zhongguo Zhong Yao Za Zhi ; 49(5): 1255-1259, 2024 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-38621972

RESUMO

The components with hypoglycemic activity in Plumeria rubra were isolated and purified by various column chromatography techniques and activity tracing methods. The physical and chemical properties of all the purified monomer compounds were characterized and analyzed, and a total of six compounds were isolated and identified, including 6″-acetyl-6-hydroxy-benzyl-benzoate-2-O-ß-D-glucoside(1), 6-acetyl-6-hydroxy-benzyl-benzoate-2-O-ß-D-glucoside-(1→6″)-ß-D-glucoside(2), 2-hydroxy-6-methoxy-benzyl-benzoate-2-O-ß-D-glucoside(3), 6-hydroxy-benzyl-benzoate-2-O-ß-D-glucoside(4), 6-hydroxy-benzyl-benzoate-2-O-ß-D-glucoside-(1→6″)-ß-D-glucoside(5), and 6-hydroxy-benzyl-benzoate-2-O-ß-D-glucoside-(1→6″)-ß-D-xyloside(6). Compounds 1 and 2 were new compounds, and compounds 3-6 were isolated from Plumeria for the first time. The α-glucosidase inhibitory activity of six identified compounds was tested. The results show that compounds 1-6 show certain inhibitory activity with an IC_(50) value ranging from 8.2 to 33.5 µmol·L~(-1).


Assuntos
Apocynaceae , Glucosídeos , Glucosídeos/química , Benzoatos
8.
Medwave ; 24(3): e2758, 2024 Apr 17.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-38631041

RESUMO

Background: Type 2 diabetes mellitus is a highly prevalent disease and is associated with increased morbidity and mortality. Due to the low percentage of adequate glycemic control, new strategies for the treatment of type 2 diabetes mellitus have been sought, including sodium-glucose cotransporter type 2 inhibitorss. Objective: To describe the evolution of patients with type 2 diabetes mellitus with insulin requirements treated with empagliflozin at the Peñaflor Hospital. The primary objective was to evaluate the efficacy of the medication regarding glycosylated hemoglobin A1c (HbA1c). The secondary objectives were: 1) achievement of HbA1c equal to or less than 7.5% according to survival analysis. 2) Change in glomerular filtration rate and urinary albumin excretion post treatment. Methods: Review of clinical records of all patients treated with empagliflozin from November 2019 to June 2023. Average follow-up of 19 (16.3 to 40) months. To compare HbA1c values according to follow-up ranges, the paired T test or Wilcoxon test was used. Results: We included 58 patients, 15 men and 43 women (74.1%), with an average age of 58.5 ± 9.2 years, ranging from 35 to 75 years. Baseline HbA1c of 10.3 ± 1.6% and 8.98% ± 2.2 in a follow-up of 18 to 24 months post-treatment, resulted in a decrease of 1.27% (p = 0.002; confidence interval 95%: 0.5 to 2.03). The most common adverse effect was urinary tract infection. Conclusions: Patients with type 2 diabetes mellitus with insulin requirements treated with empagliflozin at the Peñaflor Hospital achieved better glycemic control with few adverse effects.


Introducción: La diabetes mellitus tipo 2 es una enfermedad de alta prevalencia y está asociada a mayor morbimortalidad. Debido al bajo porcentaje de compensación, se han buscado nuevas estrategias de tratamiento farmacológico, como los inhibidores del cotransportador sodio-glucosa tipo 2. Objetivo: Describir la evolución de pacientes diabéticos tipo 2 insulino-requirentes tratados con empagliflozina en el Hospital Peñaflor, ubicado en el sector poniente de la Región Metropolitana, Chile. El objetivo primario fue evaluar la eficacia del medicamento respecto a hemoglobina glicosilada A1c. Los objetivos secundarios fueron registrar el logro de hemoglobina glicosilada A1c igual o menor a 7,5% según análisis de supervivencia. Luego, consignar el cambio en la velocidad de filtración glomerular y en la excreción urinaria de albúmina post tratamiento. Métodos: Revisión de ficha clínica de todos los pacientes tratados con empagliflozina desde noviembre de 2019 a junio de 2023. Media de seguimiento de 19 (de 16,3 a 40) meses. Para comparación entre valores de hemoglobina glicosilada A1c según rangos de seguimiento, se utilizó prueba T de Student de términos pareados o prueba de Wilcoxon. Resultados: Se estudió a 58 pacientes, 15 hombres y 43 mujeres (74,1%). Edad 58,5 ± 9,2 años, rango de 35 a 75 años. Hemoglobina glicosilada A1c basal de 10,3 ± 1,6% y 8,98% ± 2,2 en un rango de seguimiento de 18 a 24 meses post tratamiento, resultando en un descenso de 1,27% (p = 0,002; intervalo de confianza 95%: 0,5 a 2,03). El efecto adverso más frecuente fue infección del tracto urinario. Conclusiones: Los pacientes diabéticos tipo 2 insulino-requirentes tratados con empagliflozina en el Hospital Peñaflor lograron un mejor control glicémico con pocos efectos adversos.


Assuntos
Diabetes Mellitus Tipo 2 , Glucosídeos , Insulinas , Inibidores do Transportador 2 de Sódio-Glicose , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Hipoglicemiantes/efeitos adversos , Hemoglobinas Glicadas , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Compostos Benzidrílicos/efeitos adversos , Resultado do Tratamento , Insulinas/uso terapêutico , Glicemia/metabolismo
9.
ACS Synth Biol ; 13(4): 1332-1342, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38563122

RESUMO

Gastrodin, 4-hydroxybenzyl alcohol-4-O-ß-D-glucopyranoside, has been widely used in the treatment of neurogenic and cardiovascular diseases. Currently, gastrodin biosynthesis is being achieved in model microorganisms. However, the production levels are insufficient for industrial applications. In this study, we successfully engineered a Yarrowia lipolytica strain to overproduce gastrodin through metabolic engineering. Initially, the engineered strain expressing the heterologous gastrodin biosynthetic pathway, which comprises chorismate lyase, carboxylic acid reductase, phosphopantetheinyl transferase, endogenous alcohol dehydrogenases, and a UDP-glucosyltransferase, produced 1.05 g/L gastrodin from glucose in a shaking flask. Then, the production was further enhanced to 6.68 g/L with a productivity of 2.23 g/L/day by overexpressing the key node DAHP synthases of the shikimate pathway and alleviating the native tryptophan and phenylalanine biosynthetic pathways. Finally, the best strain, Gd07, produced 13.22 g/L gastrodin in a 5 L fermenter. This represents the highest reported production of gastrodin in an engineered microorganism to date, marking the first successful de novo production of gastrodin using Y. lipolytica.


Assuntos
Yarrowia , Yarrowia/genética , Yarrowia/metabolismo , Engenharia Metabólica , Glucosídeos/metabolismo , Álcoois Benzílicos/metabolismo
10.
Endocrinol Diabetes Metab ; 7(3): e00482, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38556697

RESUMO

BACKGROUND: Stevioside (SV) with minimal calories is widely used as a natural sweetener in beverages due to its high sweetness and safety. However, the effects of SV on glucose uptake and the pyruvate dehydrogenase kinase isoenzyme (PDK4) as an important protein in the regulation of glucose metabolism, remain largely unexplored. In this study, we used C2C12 skeletal muscle cells that was induced by palmitic acid (PA) to assess the effects and mechanisms of SV on glucose uptake and PDK4. METHODS: The glucose uptake of C2C12 cells was determined by 2-NBDG; expression of the Pdk4 gene was measured by quantitative real-time PCR; and expression of the proteins PDK4, p-AMPK, TBC1D1 and GLUT4 was assessed by Western blotting. RESULTS: In PA-induced C2C12 myotubes, SV could significantly promote cellular glucose uptake by decreasing PDK4 levels and increasing p-AMPK and TBC1D1 levels. SV could promote the translocation of GLUT4 from the cytoplasm to the cell membrane in cells. Moreover, in Pdk4-overexpressing C2C12 myotubes, SV decreased the level of PDK4 and increased the levels of p-AMPK and TBC1D1. CONCLUSION: SV was found to ameliorate PA-induced abnormal glucose uptake via the PDK4/AMPK/TBC1D1 pathway in C2C12 myotubes. Although these results warranted further investigation for validation, they may provide some evidence of SV as a safe natural sweetener for its use in sugar-free beverages to prevent and control T2DM.


Assuntos
Proteínas Quinases Ativadas por AMP , Diterpenos do Tipo Caurano , Glucosídeos , Ácido Palmítico , Ácido Palmítico/metabolismo , Ácido Palmítico/farmacologia , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Quinases Ativadas por AMP/farmacologia , Músculo Esquelético/metabolismo , Glucose/metabolismo , Glucose/farmacologia , Fibras Musculares Esqueléticas/metabolismo , Edulcorantes/farmacologia , Edulcorantes/metabolismo
11.
J Am Coll Cardiol ; 83(14): 1295-1306, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38569758

RESUMO

BACKGROUND: The primary goals during acute heart failure (AHF) hospitalization are decongestion and guideline-directed medical therapy (GDMT) optimization. Unlike diuretics or other GDMT, early dapagliflozin initiation could achieve both AHF goals. OBJECTIVES: The authors aimed to assess the diuretic efficacy and safety of early dapagliflozin initiation in AHF. METHODS: In a multicenter, open-label study, 240 patients were randomized within 24 hours of hospital presentation for hypervolemic AHF to dapagliflozin 10 mg once daily or structured usual care with protocolized diuretic titration until day 5 or hospital discharge. The primary outcome, diuretic efficiency expressed as cumulative weight change per cumulative loop diuretic dose, was compared across treatment assignment using a proportional odds model adjusted for baseline weight. Secondary and safety outcomes were adjudicated by a blinded committee. RESULTS: For diuretic efficiency, there was no difference between dapagliflozin and usual care (OR: 0.65; 95% CI: 0.41-1.02; P = 0.06). Dapagliflozin was associated with reduced loop diuretic doses (560 mg [Q1-Q3: 260-1,150 mg] vs 800 mg [Q1-Q3: 380-1,715 mg]; P = 0.006) and fewer intravenous diuretic up-titrations (P ≤ 0.05) to achieve equivalent weight loss as usual care. Early dapagliflozin initiation did not increase diabetic, renal, or cardiovascular safety events. Dapagliflozin was associated with improved median 24-hour natriuresis (P = 0.03) and urine output (P = 0.005), expediting hospital discharge over the study period. CONCLUSIONS: Early dapagliflozin during AHF hospitalization is safe and fulfills a component of GDMT optimization. Dapagliflozin was not associated with a statistically significant reduction in weight-based diuretic efficiency but was associated with evidence for enhanced diuresis among patients with AHF. (Efficacy and Safety of Dapagliflozin in Acute Heart Failure [DICTATE-AHF]; NCT04298229).


Assuntos
Compostos Benzidrílicos , Glucosídeos , Insuficiência Cardíaca , Inibidores de Simportadores de Cloreto de Sódio e Potássio , Humanos , Inibidores de Simportadores de Cloreto de Sódio e Potássio/uso terapêutico , Doença Aguda , Insuficiência Cardíaca/tratamento farmacológico , Diuréticos
12.
Physiol Rep ; 12(7): e15990, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38575554

RESUMO

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are rapidly gaining ground in the treatment of heart failure (HF) with reduced ejection fraction (HFrEF) and acute myocardial infarction (AMI) by an unknown mechanism. Upregulation of Na+/H+ exchanger 1 (NHE1), SGLT1, and Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the diseased hearts was found to be attenuated by prolonged SGLT2i treatment. Unfortunately, dapagliflozin is not well understood as to how Na+/Ca2+ homeostasis is affected in cardiomyocytes. In this study, we aimed to investigate whether mechanical stretch in cardiomyocytes upregulate SGLT2, resulted to loss of Na+/Ca2+ homeostasis via ERK and eNOS signaling. AMI (+) and AMI (-) serum levels were estimated using ELISA assays of TGFß-1 or endoglin (CD105). Human cardiomyocyte cell line AC16 was subjected to different stresses: 5% mild and 25% aggressive, at 1 Hz for 24 h. Immunofluorescence assays were used to estimate troponin I, CD105, SGLT1/2, eNOSS633, and ERK1/2T202/Y204 levels was performed for 5% (mild), and 25% elongation for 24 h. AMI (+) serum showed increased TGFß1 and CD105 compared to AMI (-) patients. In consistent, troponin I, CD105, SGLT1/2, eNOSS633 and ERK1/2T202/Y204 were upregulated after 25% of 24 h cyclic stretch. Dapagliflozin addition caused SGLT2 inhibition, which significantly decreased troponin I, CD105, SGLT1/2, eNOSS633, and ERK1/2T202/Y204 under 25% cyclic stretching. In summary, SGLT2 may have sensed mechanical stretch in a way similar to cardiac overloading as in vivo. By blocking SGLT2 in stretched cardiomyocytes, the AMI biomarkers (CD105, troponin I and P-ERK) were decreased, potentially to rescue eNOS production to maintain normal cellular function. This discovery of CD105 and SGLT2 increase in mechanically stretched cardiomyocytes suggests that SGLT2 may conceive a novel role in direct or indirect sensing of mechanical stretch, prompting the possibility of an in vitro cardiac overloaded cell model, an alternative to animal heart model.


Assuntos
Compostos Benzidrílicos , Glucosídeos , Insuficiência Cardíaca , Infarto do Miocárdio , Humanos , Animais , Endoglina/metabolismo , Insuficiência Cardíaca/metabolismo , Regulação para Cima , Transportador 2 de Glucose-Sódio/metabolismo , Troponina I/metabolismo , Volume Sistólico , Miócitos Cardíacos/metabolismo
13.
Sci Rep ; 14(1): 8630, 2024 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-38622211

RESUMO

Glycogen storage disease type Ib (GSD-Ib) is a rare inborn error of glycogen metabolism caused by mutations in SLC37A4. Patients with GSD-Ib are at high risk of developing inflammatory bowel disease (IBD). We evaluated the efficacy of empagliflozin, a renal sodium‒glucose cotransporter protein 2 (SGLT2) inhibitor, on colonic mucosal healing in patients with GSD-associated IBD. A prospective, single-arm, open-label clinical trial enrolled eight patients with GSD-associated IBD from Guangdong Provincial People's Hospital in China from July 1, 2022 through December 31, 2023. Eight patients were enrolled with a mean age of 10.34 ± 2.61 years. Four male and four female. The endoscopic features included deep and large circular ulcers, inflammatory hyperplasia, obstruction and stenosis. The SES-CD score significantly decreased at week 48 compared with before empagliflozin. Six patients completed 48 weeks of empagliflozin therapy and endoscopy showed significant improvement or healing of mucosal ulcers, inflammatory hyperplasia, stenosis, and obstruction. One patient had severe sweating that required rehydration and developed a urinary tract infection. No serious or life-threatening adverse events. This study suggested that empagliflozin may promote colonic mucosal healing and reduce hyperplasia, stenosis, and obstruction in children with GSD-associated IBD.


Assuntos
Compostos Benzidrílicos , Glucosídeos , Doença de Depósito de Glicogênio Tipo I , Doenças Inflamatórias Intestinais , Criança , Humanos , Masculino , Feminino , Adolescente , Constrição Patológica/complicações , Úlcera , Hiperplasia , Estudos Prospectivos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Doença de Depósito de Glicogênio Tipo I/complicações , Doença de Depósito de Glicogênio Tipo I/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo I/genética , Proteínas de Transporte de Monossacarídeos/genética , Antiporters/genética
14.
Int J Mol Sci ; 25(7)2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38612578

RESUMO

Ultraviolet radiation (UVR) has various effects on human cells and tissues, which can lead to a variety of skin diseases and cause inconvenience to people's lives. Among them, solar dermatitis is one of the important risk factors for malignant melanoma, so prevention and treatment of solar dermatitis is very necessary. Additionally, liquiritin (LQ) has anti-inflammatory effects. In this study, we aimed to evaluate the anti-inflammatory and pro-wound healing effects of liquiritin carbomer gel cold paste (LQ-CG-CP) in vitro and in vivo. The results of MTT experiments showed no cytotoxicity of LQ at concentrations of 40 µg/mL and below and cell damage at UVB irradiation doses above 60 mJ/cm2. Moreover, LQ can promote cell migration. ELISA results also showed that LQ inhibited the elevation of the inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) after UVB irradiation. In the mouse model of solar dermatitis, 2% LQ-CG-CP showed the best therapeutic efficacy for wound healing and relief of itching compared to MEIBAO moist burn moisturizer (MEBO). What is more, the results of skin histopathological examination show that LQ-CG-CP promotes re-epithelialization, shrinks wounds, and promotes collagen production, thus promoting wound healing. Simultaneously, LQ-CG-CP reduced TNF-α, IL-1ß, and IL-6 expression. In addition, LQ-CG-CP was not observed to cause histopathological changes and blood biochemical abnormalities in mice. Overall, LQ-CG-CP has great potential for the treatment of solar dermatitis.


Assuntos
Resinas Acrílicas , Dermatite , Flavanonas , Glucosídeos , Queimadura Solar , Animais , Camundongos , Humanos , Raios Ultravioleta , Interleucina-6 , Fator de Necrose Tumoral alfa , Cicatrização , Interleucina-1beta , Anti-Inflamatórios
15.
Int J Mol Sci ; 25(7)2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38612774

RESUMO

D-arginine (D-Arg) can promote embryogenic callus (EC) proliferation and increase the rate of somatic embryo induction of litchi (Litchi chinensis Sonn.), yet the mechanism underlying the processes is incompletely understood. To investigate the mechanism, physiological responses of polyamines (PAs) [putrescine (Put), spermidine (Spd), and spermine (Spm)] were investigated for D-Arg-treated litchi EC and enzyme activity related to polyamine metabolism, plant endogenous hormones, and polyamine- and embryogenic-related genes were explored. Results showed that the exogenous addition of D-Arg reduces the activity of diamine oxidase (DAO) and polyamine oxidase (PAO) in EC, reduces the production of H2O2, promotes EC proliferation, and increases the (Spd + Spm)/Put ratio to promote somatic embryo induction. Exogenous D-Arg application promoted somatic embryogenesis (SE) by increasing indole-3-acetyl glycine (IAA-Gly), kinetin-9-glucoside (K9G), and dihydrozeatin-7-glucoside (DHZ7G) levels and decreasing trans-zeatin riboside (tZR), N-[(-)-jasmonoyl]-(L)-valine (JA-Val), jasmonic acid (JA), and jasmonoyl-L-isoleucine (Ja-ILE) levels on 18 d, as well as promoting cell division and differentiation. The application of exogenous D-Arg regulated EC proliferation and somatic embryo induction by altering gene expression levels of the WRKY family, AP2/ERF family, C3H family, and C2H2 family. These results indicate that exogenous D-Arg could regulate the proliferation of EC and the SE induction of litchi by changing the biosynthesis of PAs through the alteration of gene expression pattern and endogenous hormone metabolism.


Assuntos
Ciclopentanos , Isoleucina/análogos & derivados , Litchi , Oxilipinas , Litchi/genética , Peróxido de Hidrogênio , Desenvolvimento Embrionário , Poliaminas , Espermidina , Putrescina , Espermina , Arginina , Divisão Celular , Glucosídeos
16.
Orphanet J Rare Dis ; 19(1): 155, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38605407

RESUMO

BACKGROUND: Glycogen storage disease type Ib (GSD Ib) is a rare disorder characterized by impaired glucose homeostasis caused by mutations in the SLC37A4 gene. It is a severe inherited metabolic disease associated with hypoglycemia, hyperlipidemia, lactic acidosis, hepatomegaly, and neutropenia. Traditional treatment consists of feeding raw cornstarch which can help to adjust energy metabolism but has no positive effect on neutropenia, which is fatal for these patients. Recently, the pathophysiologic mechanism of the neutrophil dysfunction and neutropenia in GSD Ib has been found, and the treatment with the SGLT2 inhibitor empaglifozin is now well established. In 2020, SGLT2 inhibitor empagliflozin started to be used as a promising efficient remover of 1,5AG6P in neutrophil of GSD Ib patients worldwide. However, it is necessary to consider long-term utility and safety of a novel treatment. RESULTS: In this study, we retrospectively examined the clinical manifestations, biochemical examination results, genotypes, long-term outcomes and follow-up of thirty-five GSD Ib children who visited our department since 2009. Fourteen patients among them underwent empagliflozin treatment since 2020. This study is the largest cohort of pediatric GSD Ib patients in China as well as the largest cohort of pediatric GSD Ib patients treated with empagliflozin in a single center to date. The study also discussed the experience of long-term management on pediatric GSD Ib patients. CONCLUSION: Empagliflozin treatment for pediatric GSD Ib patients is efficient and safe. Increase of urine glucose is a signal for pharmaceutical effect, however attention to urinary infection and hypoglycemia is suggested.


Assuntos
Compostos Benzidrílicos , Glucosídeos , Doença de Depósito de Glicogênio Tipo I , Hipoglicemia , Neutropenia , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Criança , Estudos Retrospectivos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Seguimentos , Doença de Depósito de Glicogênio Tipo I/tratamento farmacológico , Glucose , Proteínas de Transporte de Monossacarídeos/genética , Antiporters
17.
Front Immunol ; 15: 1374900, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38605968

RESUMO

Introduction: Cells expressing taste signaling elements in non-gustatory tissues have been described as solitary chemosensory cells (SCCs) or tuft cells. These "taste-like" cells play a critical role in the maintenance of tissue homeostasis. Although the expression of SCC markers and taste signaling constituents has been identified in mouse gingivae, their role in periodontal homeostasis is still unclear. Methods: Public RNA sequencing datasets were re-analyzed and further validated with RT-PCR/qRT-PCR and immunofluorescent staining to explore the expression of TAS2Rs and downstream signaling constituents in mouse gingival fibroblasts (MGFs). The specific action of salicin on MGFs via Tas2r143 was validated with RNA silence, heterologous expression of taste receptor/Gα-gustducin and calcium imaging. The anti-inflammatory effects of salicin against LPS-induced MGFs were investigated in cell cultures, and were further validated with a ligature-induced periodontitis mouse model using Ga-gustducin-null (Gnat3-/-) mice. Results: The expression of Tas2r143, Gnat3, Plcb2, and TrpM5 was detected in MGFs. Moreover, salicin could activate Tas2r143, elicited taste signaling and thus inhibited LPS-induced chemokines expression (CXCL1, CXCL2, and CXCL5) in MGFs. Consistently, salicin-treatment inhibited periodontal bone loss, inflammatory/chemotactic factors expression, and neutrophil infiltration in periodontitis mice, while these effects were abolished in Gnat3-/- mice. Discussion: Gingival fibroblasts play a critical role in the maintenance of periodontal homeostasis via "SCC-like" activity. Salicin can activate Tas2r143-mediated bitter taste signaling and thus alleviate periodontitis in mouse, indicating a promising approach to the resolution of periodontal inflammation via stimulating the "SCC-like" function of gingival fibroblasts.


Assuntos
Álcoois Benzílicos , Glucosídeos , Lipopolissacarídeos , Periodontite , Transducina , Camundongos , Animais , Periodontite/tratamento farmacológico , Periodontite/metabolismo , Fibroblastos/metabolismo
18.
BMC Biotechnol ; 24(1): 19, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38609923

RESUMO

BACKGROUND: Flavonoids are one of the bioactive ingredients of Lonicera macranthoides (L. macranthoides), however, their biosynthesis in the flower is still unclear. In this study, combined transcriptomic and targeted metabolomic analyses were performed to clarify the flavonoids biosynthesis during flowering of L. macranthoides. RESULTS: In the three sample groups, GB_vs_WB, GB_vs_WF and GB_vs_GF, there were 25, 22 and 18 differentially expressed genes (DEGs) in flavonoids biosynthetic pathway respectively. A total of 339 flavonoids were detected and quantified at four developmental stages of flower in L. macranthoides. In the three sample groups, 113, 155 and 163 differentially accumulated flavonoids (DAFs) were detected respectively. Among the DAFs, most apigenin derivatives in flavones and most kaempferol derivatives in flavonols were up-regulated. Correlation analysis between DEGs and DAFs showed that the down-regulated expressions of the CHS, DFR, C4H, F3'H, CCoAOMT_32 and the up-regulated expressions of the two HCTs resulted in down-regulated levels of dihydroquercetin, epigallocatechin and up-regulated level of kaempferol-3-O-(6''-O-acetyl)-glucoside, cosmosiin and apigenin-4'-O-glucoside. The down-regulated expressions of F3H and FLS decreased the contents of 7 metabolites, including naringenin chalcone, proanthocyanidin B2, B3, B4, C1, limocitrin-3,7-di-O-glucoside and limocitrin-3-O-sophoroside. CONCLUSION: The findings are helpful for genetic improvement of varieties in L.macranthoides.


Assuntos
Lonicera , Lonicera/genética , Apigenina , Quempferóis , Perfilação da Expressão Gênica , Flavonoides , Flores/genética , Glucosídeos
19.
Mol Biol Rep ; 51(1): 562, 2024 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-38644407

RESUMO

BACKGROUND: Obesity is associated with a wide variety of metabolic disorders that impose significant burdens on patients and society. The "browning" phenomenon in white adipose tissue (WAT) has emerged as a promising therapeutic strategy to combat metabolic disturbances. However, though the anti-diabetic drug dapagliflozin (DAPA) is thought to promote "browning," the specific mechanism of this was previously unclear. METHODS: In this study, C57BL/6 J male mice were used to establish an obesity model by high-fat diet feeding, and 3T3-L1 cells were used to induce mature adipocytes and to explore the role and mechanism of DAPA in "browning" through a combination of in vitro and in vivo experiments. RESULTS: The results show that DAPA promotes WAT "browning" and improves metabolic disorders. Furthermore, we discovered that DAPA activated "browning" through the fibroblast growth factor receptors 1-liver kinase B1-adenosine monophosphate-activated protein kinase signaling pathway. CONCLUSION: These findings provide a rational basis for the use of DAPA in treating obesity by promoting the browning of white adipose tissue.


Assuntos
Células 3T3-L1 , Tecido Adiposo Branco , Compostos Benzidrílicos , Dieta Hiperlipídica , Glucosídeos , Camundongos Endogâmicos C57BL , Obesidade , Proteínas Serina-Treonina Quinases , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Transdução de Sinais , Animais , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Glucosídeos/farmacologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , Masculino , Compostos Benzidrílicos/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Obesidade/metabolismo , Obesidade/tratamento farmacológico , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Adipócitos/metabolismo , Adipócitos/efeitos dos fármacos
20.
Toxicol Ind Health ; 40(6): 306-311, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38575135

RESUMO

Rinse-off cosmetic products, primarily shampoos, are frequently implicated in the onset of allergic contact dermatitis (ACD) caused by alkyl glucosides (AGs). AGs are increasingly popular surfactants and known contact allergens. Glucoside-induced ACD was most frequently observed with shampoos and skin-cleansing products in both consumer and occupational settings. Thereby, studies have shown that atopic individuals are the most susceptible to ACD. Also, several investigations have indicated that individuals with sensitive skin might be more prone to skin allergies. This is why the presence of AGs was investigated in shampoos and body cleansers marketed as hypoallergenic or for sensitive skin. For this purpose, the website of Amazon.com was surveyed. Four groups of cosmetics were obtained by using the following keywords: "hypoallergenic shampoo for adults," "sensitive skin shampoo for adults," "hypoallergenic body cleanser for adults," and "sensitive skin body cleanser for adults." The first 30 best-selling cosmetics in each group were investigated for the presence of AGs, by analyzing the product information pages. The results showed that as much as 56.7% of hypoallergenic shampoos contained AGs, as ingredients, whereas the percentage was somewhat lower for other product categories. Even though decyl and lauryl glucoside were nearly ubiquitously used AGs in cosmetics over the past decade, the most commonly present AG in our analysis was coco-glucoside. The results of this study indicated a necessity to include coco-glucoside in the baseline series of patch testing allergens. Industry, regulators, and healthcare providers should be made aware of the frequent presence of AGs in rinse-off cosmetic products marketed as hypoallergenic or for sensitive skin to ensure the safety and well-being of consumers and patients.


Assuntos
Cosméticos , Dermatite Alérgica de Contato , Glucosídeos , Glucosídeos/análise , Humanos , Dermatite Alérgica de Contato/etiologia , Cosméticos/efeitos adversos , Cosméticos/química , Alérgenos/análise , Preparações para Cabelo/efeitos adversos , Preparações para Cabelo/química , Pele/efeitos dos fármacos
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