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1.
Anticancer Res ; 42(1): 609-617, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34969770

RESUMO

BACKGROUND/AIM: We generated a novel disease mouse model in which a fructose-containing western diet (FD) induces development of non-alcoholic steatohepatitis (NASH). MATERIALS AND METHODS: C57BL/6J mice were fed FD for 60 weeks and body weight and blood pressure were monitored. Plasma cholesterol level was measured at the end of the experiments. Histopathology of NASH was examined by hematoxylin and eosin staining, Masson-Trichrome staining, periodic acid-Schiff staining, and immunohistochemistry against a proliferation marker. Circadian gene expression levels were compared by sampling the livers in 4-h intervals, followed by quantitative RT-PCR analysis. RESULTS: FD-fed mice developed obesity, transient hypertension, hypercholesterolemia, and liver adiposity. The mice spontaneously developed hepatic nodules, which were diagnosed as non-neoplastic nodular regenerative hyperplasia. FD-fed mice had increased expression of growth factor genes and cirrhosis markers compared to control mice. Circadian expression of lipid metabolism genes was deregulated by FD intake. CONCLUSION: C57BL/6J mice fed FD developed non-alcoholic steatohepatitis and nodular regenerative hyperplasia over time.


Assuntos
Hiperplasia/genética , Metabolismo dos Lipídeos/genética , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/genética , Animais , Colesterol/sangue , Dieta Ocidental/efeitos adversos , Modelos Animais de Doenças , Frutose/efeitos adversos , Frutose/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hiperplasia/etiologia , Hiperplasia/metabolismo , Hiperplasia/patologia , Fígado/metabolismo , Fígado/patologia , Camundongos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia
2.
Molecules ; 26(20)2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34684891

RESUMO

BACKGROUND: d-Allulose is a rare sugar with antiobesity and antidiabetic activities. However, its direct effect on insulin sensitivity and the underlying mechanism involved are unknown. OBJECTIVE: This study aimed to investigate the effect of d-allulose on high-fat diet (HFD)-induced insulin resistance using the hyperinsulinemic-euglycemic (HE)-clamp method and intramuscular signaling analysis. METHODS: Wistar rats were randomly divided into three dietary groups: chow diet, HFD with 5% cellulose (HFC), and HFD with 5% d-allulose (HFA). After four weeks of feeding, the insulin tolerance test (ITT), intraperitoneal glucose tolerance test (IPGTT), and HE-clamp study were performed. The levels of plasma leptin, adiponectin, and tumor necrosis factor (TNF)-α were measured using the enzyme-linked immunosorbent assay. We analyzed the levels of cell signaling pathway components in the skeletal muscle using Western blotting. RESULTS: d-allulose alleviated the increase in HFD-induced body weight and visceral fat and reduced the area under the curve as per ITT and IPGTT. d-Allulose increased the glucose infusion rate in the two-step HE-clamp test. Consistently, the insulin-induced phosphorylation of serine 307 in the insulin receptor substrate-1 and Akt and expression of glucose transporter 4 (Glut-4) in the muscle were higher in the HFA group than HFC group. Furthermore, d-allulose decreased plasma TNF-α concentration and insulin-induced phosphorylation of stress-activated protein kinase/Jun N-terminal kinase in the muscle and inhibited adiponectin secretion in HFD-fed rats. CONCLUSIONS: d-allulose improved HFD-induced insulin resistance in Wistar rats. The reduction of the proinflammatory cytokine production, amelioration of adiponectin secretion, and increase in insulin signaling and Glut-4 expression in the muscle contributed to this effect.


Assuntos
Frutose/farmacologia , Resistência à Insulina/fisiologia , Músculo Esquelético/efeitos dos fármacos , Animais , Citocinas/metabolismo , Dieta Hiperlipídica , Glucose/metabolismo , Teste de Tolerância a Glucose/métodos , Hipoglicemiantes/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Insulina/metabolismo , Masculino , Músculo Esquelético/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
3.
Physiol Behav ; 241: 113590, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34509472

RESUMO

Inbred mouse strains differ in their postoral appetite stimulating response (appetition) to fructose as demonstrated in intragastric (IG) sugar conditioning and oral sugar vs. nonnutritive conditioning experiments. For example, FVB and SWR strains show experience-induced preferences for 8% fructose over a 0.1% sucralose + 0.1% saccharin (S + S) solution, whereas C57BL/6 (B6) and BALB/c strains do not. All strains, however, learn to prefer 8% glucose to S + S after experience, which is attributed to the potent appetition actions of this sugar. The present study extended this analysis to DBA/2 (DBA) and 129P3 (129) inbred mice. In Experiment 1A, ad libitum fed DBA and 129 mice preferred S + S to fructose before and after separate experience with the two sweeteners, indicating an indifference to the postoral nutrient effects of the sugar. When food restricted (Experiment 1B), 129 mice continued to prefer S + S to fructose while DBA mice showed equal preference for the sweeteners after experience, indicating some sensitivity to fructose appetition. In Experiment 1C, both strains acquired significant preferences for glucose over S + S after experience, confirming their sensitivity to postoral glucose appetition. Experiment 2 revealed that C57BL/6 × 129P3 (B6:129) hybrid mice responded like inbred B6 mice and 129 mice in acquiring a preference for glucose but not fructose over S + S. This is of interest because sweet "taste-blind" P2 × 2 / P2 × 3 double-knockout (DKO) mice on a B6:129 genetic background prefer fructose to water in 24 h tests, which is indicative of fructose appetition. Whether differences in the genetic makeup of DKO and B6:129 hybrid mice or other factors explain the fructose appetition of the DKO mice remains to be determined.


Assuntos
Adoçantes não Calóricos , Edulcorantes , Animais , Preferências Alimentares , Frutose/farmacologia , Glucose , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Açúcares , Paladar
4.
Int J Mol Sci ; 22(18)2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34576111

RESUMO

Mitochondrial functional abnormalities or quantitative decreases are considered to be one of the most plausible pathogenic mechanisms of Parkinson's disease (PD). Thus, mitochondrial complex inhibitors are often used for the development of experimental PD. In this study, we used rotenone to create in vitro cell models of PD, then used these models to investigate the effects of 1,5-anhydro-D-fructose (1,5-AF), a monosaccharide with protective effects against a range of cytotoxic substances. Subsequently, we investigated the possible mechanisms of these protective effects in PC12 cells. The protection of 1,5-AF against rotenone-induced cytotoxicity was confirmed by increased cell viability and longer dendritic lengths in PC12 and primary neuronal cells. Furthermore, in rotenone-treated PC12 cells, 1,5-AF upregulated peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) expression and enhanced its deacetylation, while increasing AMP-activated protein kinase (AMPK) phosphorylation. 1,5-AF treatment also increased mitochondrial activity in these cells. Moreover, PGC-1α silencing inhibited the cytoprotective and mitochondrial biogenic effects of 1,5-AF in PC12 cells. Therefore, 1,5-AF may activate PGC-1α through AMPK activation, thus leading to mitochondrial biogenic and cytoprotective effects. Together, our results suggest that 1,5-AF has therapeutic potential for development as a treatment for PD.


Assuntos
Frutose/análogos & derivados , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Biogênese de Organelas , Rotenona/toxicidade , Adenilato Quinase/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Frutose/química , Frutose/farmacologia , Inativação Gênica/efeitos dos fármacos , Metformina/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios/efeitos dos fármacos , Células PC12 , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fosforilação/efeitos dos fármacos , Ratos
5.
Am J Physiol Endocrinol Metab ; 321(5): E581-E591, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34459218

RESUMO

This study determined if a perturbation in in utero adipogenesis leading to later life adipose tissue (AT) dysfunction underlies programming of cardiometabolic risk in offspring born to dams with metabolic dysfunction. Female mice heterozygous for the leptin receptor deficiency (Hetdb) had 2.4-fold higher prepregnancy fat mass and in late gestation had higher plasma insulin and triglycerides compared with wild-type (Wt) females (P < 0.05). To isolate the role of the intrauterine milieu, wild-type (Wt) offspring from each pregnancy were studied. Differentiation potential in isolated progenitors and cell size distribution analysis revealed accelerated adipogenesis in Wt pups born to Hetdb dams, accompanied by a higher accumulation of neonatal fat mass. In adulthood, whole body fat mass by NMR was higher in male (69%) and female (20%) Wt offspring born to Hetdb versus Wt pregnancies, along with adipocyte hypertrophy and hyperlipidemia (all P < 0.05). Lipidomic analyses by gas chromatography revealed an increased lipogenic index (16:0/18:2n6) after high-fat/fructose diet (HFFD). Postprandial insulin, ADIPO-IR, and ex vivo AT lipolytic responses to isoproterenol were all higher in Wt offspring born to Hetdb dams (P < 0.05). Intrauterine metabolic stimuli may direct a greater proportion of progenitors toward terminal differentiation, thereby predisposing to hypertrophy-induced adipocyte dysfunction.NEW & NOTEWORTHY This study reveals that accelerated adipogenesis during the perinatal window of adipose tissue development predisposes to later life hypertrophic adipocyte dysfunction, thereby compromising the buffering function of the subcutaneous depot.


Assuntos
Adipogenia , Tecido Adiposo/metabolismo , Fatores de Risco Cardiometabólico , Doenças Metabólicas/metabolismo , Adipócitos/ultraestrutura , Tecido Adiposo/embriologia , Tecido Adiposo/crescimento & desenvolvimento , Animais , Tamanho Celular , Dieta Hiperlipídica , Feminino , Frutose/farmacologia , Hiperlipidemias/genética , Insulina/sangue , Lipidômica , Masculino , Doenças Metabólicas/patologia , Camundongos , Gravidez , Receptores para Leptina/genética , Células-Tronco , Triglicerídeos/sangue
6.
Nature ; 597(7875): 263-267, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34408323

RESUMO

Fructose consumption is linked to the rising incidence of obesity and cancer, which are two of the leading causes of morbidity and mortality globally1,2. Dietary fructose metabolism begins at the epithelium of the small intestine, where fructose is transported by glucose transporter type 5 (GLUT5; encoded by SLC2A5) and phosphorylated by ketohexokinase to form fructose 1-phosphate, which accumulates to high levels in the cell3,4. Although this pathway has been implicated in obesity and tumour promotion, the exact mechanism that drives these pathologies in the intestine remains unclear. Here we show that dietary fructose improves the survival of intestinal cells and increases intestinal villus length in several mouse models. The increase in villus length expands the surface area of the gut and increases nutrient absorption and adiposity in mice that are fed a high-fat diet. In hypoxic intestinal cells, fructose 1-phosphate inhibits the M2 isoform of pyruvate kinase to promote cell survival5-7. Genetic ablation of ketohexokinase or stimulation of pyruvate kinase prevents villus elongation and abolishes the nutrient absorption and tumour growth that are induced by feeding mice with high-fructose corn syrup. The ability of fructose to promote cell survival through an allosteric metabolite thus provides additional insights into the excess adiposity generated by a Western diet, and a compelling explanation for the promotion of tumour growth by high-fructose corn syrup.


Assuntos
Frutose/farmacologia , Xarope de Milho Rico em Frutose/farmacologia , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/citologia , Mucosa Intestinal/efeitos dos fármacos , Nutrientes/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Ativação Enzimática , Feminino , Frutoquinases/metabolismo , Frutose/metabolismo , Xarope de Milho Rico em Frutose/metabolismo , Hipóxia/dietoterapia , Hipóxia/patologia , Mucosa Intestinal/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Piruvato Quinase/metabolismo
7.
Int J Food Microbiol ; 354: 109327, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34247022

RESUMO

The species Leuconostoc citreum is often isolated from grain and vegetable fermentations such as sourdough, sauerkraut and kimchi. Lc. citreum has seen an increase in its use as a starter culture for various fermentations and food applications. The strain Lc. citreum TR116 has been applied previously in this laboratory aimed at sugar depletion through metabolism resulting in the reduction of fructose to mannitol, a polyol considered as a sweet carbohydrate. Besides reducing sugar, TR116 showed flavour modulating characteristics and contributes to the extension of microbial shelf life. In order to obtain a better understanding of this strain and to fully use its set of abilities, the genome of Lc. citreum TR116 was sequenced using the Illumina MiSeq, assembly with SPAdes and annotated by the Prokaryotic Genome Annotation Pipeline. Metabolic reconstruction was employed to elucidate carbohydrate, organic acid and amino acid metabolism in the strain. Of particular interest was the gene expression analysis ascertained the influence of fructose on the genes mdh and manX involved in the uptake of fructose and its conversion to mannitol. This investigation, the first in Lc. citreum, illustrates the metabolic processes involved in fermentation used by this strain and demonstrates that in the presence of fructose, expression of the genes mdh and manX is increased. The resulting transparency of the skill set of TR116 contributes highly to future functionalisation of food systems and food ingredients.


Assuntos
Frutose , Regulação Bacteriana da Expressão Gênica , Genoma Bacteriano , Leuconostoc , Manitol , Fermentação , Frutose/farmacologia , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Genoma Bacteriano/genética , Leuconostoc/genética , Manitol/metabolismo
8.
Molecules ; 26(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34210097

RESUMO

Obesity and hyperlipidemia are metabolic dysregulations that arise from poor lifestyle and unhealthy dietary intakes. These co-morbidity conditions are risk factors for vascular diseases. Piper sarmentosum (PS) is a nutritious plant that has been shown to pose various phytochemicals and pharmacological actions. This study aimed to investigate the effect of PS on obesity and hyperlipidemia in an animal model. Forty male Wistar rats were randomly divided into five experimental groups. The groups were as follows: UG-Untreated group; CTRL-control; FDW-olive oil + 20% fructose; FDW-PS-PS (125 mg/kg) + 20% fructose; FDW-NGN-naringin (100 mg/kg) + 20% fructose. Fructose drinking water was administered daily for 12 weeks ad libitum to induce metabolic abnormality. Treatment was administered at week 8 for four weeks via oral gavage. The rats were sacrificed with anesthesia at the end of the experimental period. Blood, liver, and visceral fat were collected for further analysis. The consumption of 20% fructose water by Wistar rats for eight weeks displayed a tremendous increment in body weight, fat mass, percentage fat, LDL, TG, TC, HMG-CoA reductase, leptin, and reduced the levels of HDL and adiponectin as well as adipocyte hypertrophy. Following the treatment period, FDW-PS and FDW-NGN showed a significant reduction in body weight, fat mass, percentage fat, LDL, TG, TC, HMG-CoA reductase, and leptin with an increment in the levels of HDL and adiponectin compared to the FDW group. FDW-PS and FDW-NGN also showed adipocyte hypotrophy compared to the FDW group. In conclusion, oral administration of 125 mg/kg PS methanolic extract to fructose-induced obese rats led to significant amelioration of obesity and hyperlipidemia through suppressing the adipocytes and inhibiting HMG-CoA reductase. PS has the potential to be used as an alternative or adjunct therapy for obesity and hyperlipidemia.


Assuntos
Frutose/efeitos adversos , Hiperlipidemias , Síndrome Metabólica , Metanol/química , Obesidade , Piper/química , Extratos Vegetais , Animais , Frutose/farmacologia , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Masculino , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar
9.
Molecules ; 26(12)2021 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205369

RESUMO

The benefits of natural honeybee products (e.g., honey, royal jelly, beeswax, propolis, beevenom and pollen) to the immune system are remarkable, and many of them are involved in the induction of antibody production, maturation of immune cells and stimulation of the immune system. The type of plants in the geographical area, climatic conditions and production method have a significantly influence on the nutritional quality of honey. However, this variability can influence consumer liking by the sensory attributes of the product. The aim of this work was to compare the most popular honeys from Poland in terms of nutritional value, organoleptic properties and antioxidant activity. In the study, five varieties of honey (honeydew, forest, buckwheat, linden and dandelion) from conventional and organic production methods were tested. The nutritional characteristics of honey samples included acidity, content of water, sugars, vitamin C, HMF and phenolics (total and flavonoids), while honey color, taste, aroma and consistency were investigated in the organoleptic characteristics. The antioxidant activity was determined in water- and ethanol-soluble honey extracts using DPPH and ORAC tests. The results showed that organoleptic and nutritional characteristics of popular Polish honeys differ significantly in relation to plant source and production method. The significant effect of honey variety on the content of HMF, saccharose and phenolics, as well as acidity and antioxidant capacity were noted. The impact of variety and variety × production method interaction was significant in the case of the content of vitamin C, glucose and fructose. A visible difference of buckwheat and forest honeys from other samples was observed. The highest content of total phenolics with antioxidant activity based on the SET mechanism was found in buckwheat honeys, while forest honeys were richer in flavonoids.


Assuntos
Antioxidantes/farmacologia , Abelhas/metabolismo , Mel/análise , Nutrientes/farmacologia , Animais , Ácido Ascórbico/farmacologia , Etanol/química , Fagopyrum , Feminino , Flavonoides/farmacologia , Frutose/farmacologia , Glucose/farmacologia , Sistema Imunitário/efeitos dos fármacos , Masculino , Fenóis/farmacologia , Polônia , Água/química
10.
Mol Med Rep ; 24(1)2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34080650

RESUMO

Diet and exercise are the most effective approaches used to induce weight loss. D­psicose is a low­calorie sweetener that has been shown to reduce weight in obese individuals. However, the effect of D­psicose on muscle cells under oxidative stress, which is produced during exercise, requires further investigation. The present study aimed to determine the effects of D­psicose on C2C12 myogenic cells in vitro. Hydrogen peroxide (H2O2) was used to stimulate the generation of intracellular reactive oxygen species (ROS) in muscle cells to mimic exercise conditions. Cell viability was analyzed using a MTT assay and flow cytometry was used to analyze the levels of apoptosis, mitochondrial membrane potential (MMP), the generation of ROS and the cell cycle distribution following treatment. Furthermore, protein expression levels were analyzed using western blotting and cell proliferation was determined using a colony formation assay. The results of the present study revealed that D­psicose alone exerted no toxicity on C2C12 mouse myogenic cells. However, in the presence of low­dose (100 µM) H2O2­induced ROS, D­psicose induced C2C12 cell injury and significantly decreased C2C12 cell viability in a dose­dependent manner. In addition, the levels of apoptosis and the generation of ROS increased, while the MMP decreased. MAPK family molecules were also activated in a dose­dependent manner following treatment. Notably, the combined treatment induced G2/M phase arrest and reduced the proliferation of C2C12 cells. In conclusion, the findings of the present study suggested that D­psicose may induce toxic effects on muscle cells in a simulated exercise situation by increasing ROS levels, activating the MAPK signaling pathway and disrupting the MMP.


Assuntos
Apoptose/efeitos dos fármacos , Frutose/farmacologia , Peróxido de Hidrogênio/efeitos adversos , Proteínas de Membrana/metabolismo , Desenvolvimento Muscular/efeitos dos fármacos , Músculo Esquelético/metabolismo , Edulcorantes/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Frutose/química , Pontos de Checagem da Fase M do Ciclo Celular , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas de Membrana/genética , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
11.
Am J Physiol Endocrinol Metab ; 320(6): E1173-E1182, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33969706

RESUMO

Retinopathy is a leading cause of blindness, and there is currently no cure. Earlier identification of the progression of retinopathy could provide a better chance for intervention. Diet has profound effects on retinal function. A maternal high-fructose diet (HFD) triggers diseases in multiple organs. However, whether maternal HFD impairs retinal function in adult offspring is currently unknown. By using the rodent model of maternal HFD during pregnancy and lactation, our data indicated a reduced b-wave of electroretinography (ERG) in HFD female offspring at 3 mo of age compared with age-matched offspring of dams fed regular chow (ND). Immunofluorescence and Western blot analyses indicated that the distributions and expressions of synaptophysin, postsynaptic density protein 95 (PSD95), and phospho(p)-Ca2+/calmodulin-stimulated protein kinase IIα (CaMKIIα) were significantly suppressed in the HFD group. Furthermore, the ATP content and the mitochondrial respiratory protein, Mt CPX 4-2, were decreased. Moreover, the expressions of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and mitochondrial transcription factor A (TFAM) in the retina of the HFD group were downregulated. Treatment with coenzyme Q10 (Q10), a key mediator of the electron transport chain, effectively reversed these abovementioned dysfunctions. Together, these results suggested that maternal HFD impaired retinal function in adult female offspring. The mechanism underlying early-onset retinopathy may involve the reduction in the capacity of mitochondrial energy production and the suppression of synaptic plasticity. Most importantly, mitochondria could be a feasible target to reprogram maternal HFD-damaged retinal function.NEW & NOTEWORTHY In this study, we provide novel evidence that maternal high-fructose diet during gestation and lactation could induce early-onset retinopathy in adult female offspring. Of note, the insufficient energy content, downregulated mitochondrial respiratory complex 4-2, and impaired mitochondrial biogenesis might contribute to the decrease of synaptic plasticity resulting in retinal function suppression. Oral application with coenzyme Q10 for 4 wk could at least partially reverse the aforementioned molecular events and retinal function.


Assuntos
Frutose/efeitos adversos , Mitocôndrias/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Doenças Retinianas/induzido quimicamente , Fatores Etários , Animais , Dieta Hiperlipídica/efeitos adversos , Carboidratos da Dieta/efeitos adversos , Carboidratos da Dieta/farmacologia , Regulação para Baixo/efeitos dos fármacos , Feminino , Frutose/farmacologia , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Mitocôndrias/fisiologia , Biogênese de Organelas , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Ratos , Ratos Sprague-Dawley , Doenças Retinianas/fisiopatologia
12.
Sci Rep ; 11(1): 7236, 2021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33790385

RESUMO

The Serine Protease Inhibitor (serpin) protein has been suggested to play a key role in the interaction of bifidobacteria with the host. By inhibiting intestinal serine proteases, it might allow bifidobacteria to reside in specific gut niches. In inflammatory diseases where serine proteases contribute to the innate defense mechanism of the host, serpin may dampen the damaging effects of inflammation. In view of the beneficial roles of this protein, it is important to understand how its production is regulated. Here we demonstrate that Bifidobacterium longum NCC 2705 serpin production is tightly regulated by carbohydrates. Galactose and fructose increase the production of this protein while glucose prevents it, suggesting the involvement of catabolite repression. We identified that di- and oligosaccharides containing galactose (GOS) and fructose (FOS) moieties, including the human milk oligosaccharide Lacto-N-tetraose (LNT), are able to activate serpin production. Moreover, we show that the carbohydrate mediated regulation is conserved within B. longum subsp. longum strains but not in other bifidobacterial taxons harboring the serpin coding gene, highlighting that the serpin regulation circuits are not only species- but also subspecies- specific. Our work demonstrates that environmental conditions can modulate expression of an important effector molecule of B. longum, having potential important implications for probiotic manufacturing and supporting the postulated role of serpin in the ability of bifidobacteria to colonize the intestinal tract.


Assuntos
Proteínas de Bactérias/biossíntese , Bifidobacterium/metabolismo , Frutose/farmacologia , Galactose/farmacologia , Oligossacarídeos/farmacologia , Serpinas/biossíntese , Proteínas de Bactérias/genética , Bifidobacterium/genética , Serpinas/genética
13.
Int J Mol Sci ; 22(4)2021 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-33669913

RESUMO

Candida albicans is a pathogenic fungus that is increasingly developing multidrug resistance (MDR), including resistance to azole drugs such as fluconazole (FLC). This is partially a result of the increased synthesis of membrane efflux transporters Cdr1p, Cdr2p, and Mdr1p. Although all these proteins can export FLC, only Cdr1p is expressed constitutively. In this study, the effect of elevated fructose, as a carbon source, on the MDR was evaluated. It was shown that fructose, elevated in the serum of diabetics, promotes FLC resistance. Using C. albicans strains with green fluorescent protein (GFP) tagged MDR transporters, it was determined that the FLC-resistance phenotype occurs as a result of Mdr1p activation and via the increased induction of higher Cdr1p levels. It was observed that fructose-grown C. albicans cells displayed a high efflux activity of both transporters as opposed to glucose-grown cells, which synthesize Cdr1p but not Mdr1p. Additionally, it was concluded that elevated fructose serum levels induce the de novo production of Mdr1p after 60 min. In combination with glucose, however, fructose induces Mdr1p production as soon as after 30 min. It is proposed that fructose may be one of the biochemical factors responsible for Mdr1p production in C. albicans cells.


Assuntos
Candida albicans/efeitos dos fármacos , Farmacorresistência Fúngica/efeitos dos fármacos , Fluconazol/farmacologia , Frutose/farmacologia , Proteínas Fúngicas/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Candida albicans/citologia , Carbono/farmacologia , Proliferação de Células/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Frutose/sangue , Proteínas de Fluorescência Verde/metabolismo , Frações Subcelulares/metabolismo
14.
Cancer Res ; 81(11): 2824-2832, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33762358

RESUMO

Clinical localization of primary tumors and sites of metastasis by PET is based on the enhanced cellular uptake of 2-deoxy-2-[18F]-fluoro-D-glucose (FDG). In prostate cancer, however, PET-FDG imaging has shown limited clinical applicability, suggesting that prostate cancer cells may utilize hexoses other than glucose, such as fructose, as the preferred energy source. Our previous studies suggested that prostate cancer cells overexpress fructose transporters, but not glucose transporters, compared with benign cells. Here, we focused on validating the functional expression of fructose transporters and determining whether fructose can modulate the biology of prostate cancer cells in vitro and in vivo. Fructose transporters, Glut5 and Glut9, were significantly upregulated in clinical specimens of prostate cancer when compared with their benign counterparts. Fructose levels in the serum of patients with prostate cancer were significantly higher than healthy subjects. Functional expression of fructose transporters was confirmed in prostate cancer cell lines. A detailed kinetic characterization indicated that Glut5 represents the main functional contributor in mediating fructose transport in prostate cancer cells. Fructose stimulated proliferation and invasion of prostate cancer cells in vitro. In addition, dietary fructose increased the growth of prostate cancer cell line-derived xenograft tumors and promoted prostate cancer cell proliferation in patient-derived xenografts. Gene set enrichment analysis confirmed that fructose stimulation enriched for proliferation-related pathways in prostate cancer cells. These results demonstrate that fructose promotes prostate cancer cell growth and aggressiveness in vitro and in vivo and may represent an alternative energy source for prostate cancer cells. SIGNIFICANCE: This study identifies increased expression of fructose transporters in prostate cancer and demonstrates a role for fructose as a key metabolic substrate supporting prostate cancer cells, revealing potential therapeutic targets and biomarkers.


Assuntos
Biomarcadores Tumorais/metabolismo , Dieta/efeitos adversos , Frutose/farmacologia , Regulação Neoplásica da Expressão Gênica , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Transportador de Glucose Tipo 5/metabolismo , Neoplasias da Próstata/patologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Ciclo Celular , Movimento Celular , Proliferação de Células , Proteínas Facilitadoras de Transporte de Glucose/genética , Transportador de Glucose Tipo 5/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias da Próstata/induzido quimicamente , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Nat Commun ; 12(1): 1209, 2021 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-33619282

RESUMO

Fructose intake has increased substantially throughout the developed world and is associated with obesity, type 2 diabetes and non-alcoholic fatty liver disease. Currently, our understanding of the metabolic and mechanistic implications for immune cells, such as monocytes and macrophages, exposed to elevated levels of dietary fructose is limited. Here, we show that fructose reprograms cellular metabolic pathways to favour glutaminolysis and oxidative metabolism, which are required to support increased inflammatory cytokine production in both LPS-treated human monocytes and mouse macrophages. A fructose-dependent increase in mTORC1 activity drives translation of pro-inflammatory cytokines in response to LPS. LPS-stimulated monocytes treated with fructose rely heavily on oxidative metabolism and have reduced flexibility in response to both glycolytic and mitochondrial inhibition, suggesting glycolysis and oxidative metabolism are inextricably coupled in these cells. The physiological implications of fructose exposure are demonstrated in a model of LPS-induced systemic inflammation, with mice exposed to fructose having increased levels of circulating IL-1ß after LPS challenge. Taken together, our work underpins a pro-inflammatory role for dietary fructose in LPS-stimulated mononuclear phagocytes which occurs at the expense of metabolic flexibility.


Assuntos
Frutose/farmacologia , Glutamina/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Ácidos/metabolismo , Animais , Ciclo do Ácido Cítrico/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Glucose/farmacologia , Glicólise/efeitos dos fármacos , Marcação por Isótopo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Análise do Fluxo Metabólico , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Oxirredução , Fosforilação Oxidativa/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Fenótipo , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
16.
J Nutr Biochem ; 90: 108572, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33388348

RESUMO

We investigated whether combined long-term fructose and prednisolone intake would be more detrimental to the glucose homeostasis than if ingested separately. We also evaluated whether fish oil administration or interruption of treatments has any positive impact. For this, male adult Wistar rats ingested fructose (20%) (F) or prednisolone (12.5 µg/mL) (P) or both (FP) through drinking water for 12 weeks. A separate group of fructose and prednisolone-treated rats received fish oil treatment (1 g/kg) in the last 6 weeks. In another group, the treatment with fructose and prednisolone was interrupted after 12 weeks, and the animals were followed for more 12 weeks. Control groups ran in parallel (C). The F group had higher plasma TG (+42%) and visceral adiposity (+63%), whereas the P group had lower insulin sensitivity (-33%) and higher insulinemia (+200%). Only the the FP group developed these alterations combined with higher circulating uric acid (+126%), hepatic triacylglycerol content (+16.2-fold), lipid peroxidation (+173%) and lower catalase activity (-32%) that were associated with lower protein kinase B content and AMP-activated protein kinase (AMPK) phosphorylation in the liver, lower AMPK phosphorylation in the adipose tissue and higher beta-cell mass. Fish oil ingestion attenuated the elevation in circulating triacylglycerol and uric acid values, while the interruption of sugar and glucocorticoid intake reverted almost all modified parameters. In conclusion, long-term intake of fructose and prednisolone by male rats are more detrimental to glucose and lipid homeostasis than if ingested separately and the benefits of treatment interruption are broader than fish oil treatment.


Assuntos
Óleos de Peixe/farmacologia , Frutose/farmacologia , Glucocorticoides/farmacologia , Glucose/metabolismo , Metabolismo dos Lipídeos , Prednisolona/farmacologia , Tecido Adiposo/metabolismo , Adiposidade/efeitos dos fármacos , Animais , Óleos de Peixe/administração & dosagem , Frutose/administração & dosagem , Glucocorticoides/administração & dosagem , Homeostase , Humanos , Insulina/metabolismo , Resistência à Insulina , Peroxidação de Lipídeos , Fígado/metabolismo , Masculino , Prednisolona/administração & dosagem , Ratos , Ratos Wistar , Bebidas Adoçadas com Açúcar , Triglicerídeos/sangue , Ácido Úrico/metabolismo
17.
J Nutr Biochem ; 88: 108527, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33068743

RESUMO

Polyphenolic biologically active substances (BAS) including resveratrol (R) can exert beneficial effects on fat accumulation, blood pressure, glycemia, insulin sensitivity, and plasma lipid profile in patients with obesity, and associated diseases. The study aimed to determine the effect of R at a dose of 25 mg/kg body weight on the DBA/2J and DBCB mice with diet-induced obesity followed by the consumption high-fat high-carbohydrate diet (HFCD). Behavioral reactions (elevated plus maze [EPM]) and muscle tone (the strength of the forepaw grip) were tested, and plasma biochemical and immunological parameters were assessed. In the repeated EPM test, anxiety increased only in DBCB mice during the second trial. In DBCB mice treated with HFCD, the muscle tone decreased with the second trial; however, this effect was not observed in the background of R consumption. R decreased the level of triglycerides, diminished the activities of alanine and asparagine aminotransferases, which were elevated upon HFCD consumption. Ghrelin level increased after R consumption in mice of both genotypes. The leptin to ghrelin ratio was reduced in DBCB mice receiving R. Consumption of R increased IL-3 and IL-10 levels in both DBA/2J and DBCB mice. IL-12p70 level increased in DBCB mice in response to R. R addition to HFCD reduced several symptoms of dyslipidemia in highly sensitive tetrahybrid mice. The results obtained indicate the importance of a personalized (depending on the genotype) approach when any R prescription, among other BAS and dietary factors, are used in diet therapy for patients with low, moderate and high-risk obesity.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Frutose/efeitos adversos , Obesidade/tratamento farmacológico , Resveratrol/farmacologia , Animais , Antioxidantes/farmacologia , Comportamento Animal , Carboidratos da Dieta/efeitos adversos , Gorduras na Dieta/farmacologia , Teste de Labirinto em Cruz Elevado , Frutose/farmacologia , Grelina/metabolismo , Inflamação/metabolismo , Resistência à Insulina , Interleucina-10/metabolismo , Interleucina-3/metabolismo , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos DBA , Obesidade/metabolismo , Triglicerídeos/metabolismo
18.
Oxid Med Cell Longev ; 2020: 8850266, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33354281

RESUMO

Currently, there is the paradox of low water intake but increased intake of sugar-sweetened beverages (SB) in several populations; those habits are associated with an increased prevalence of metabolic derangements and greater chronic disease mortality. Persistent heat dehydration and increased SB intake stimulate the continued release of vasopressin and overactivation of the polyol-fructokinase pathway, synergizing each other, an effect partially mediated by oxidative stress. The objective of the present study was to evaluate whether water restriction concurrent with SB hydration can cause renal damage by stimulating similar pathways as heat dehydration. Three groups of male Wistar rats (n = 6) were fluid restricted; from 10 am to 12 pm animals could rehydrate with tap water (W), or sweetened beverages, one prepared with 11% of a fructose-glucose combination (SB), or with the noncaloric edulcorant stevia (ST). A normal control group of healthy rats was also studied. The animals were followed for 4 weeks. Markers of dehydration and renal damage were evaluated at the end of the study. Fluid restriction and water hydration mildly increased urine osmolality and induced a 15% fall in CrCl while increased the markers of tubular damage by NAG and KIM-1. Such changes were in association with a mild overexpression of V1a and V2 renal receptors, polyol fructokinase pathway overactivation, and increased renal oxidative stress with reduced expression of antioxidant enzymes. Hydration with SB significantly amplified those alterations, while in stevia hydrated rats, the changes were similar to the ones observed in water hydrated rats. These data suggest that current habits of hydration could be a risk factor in developing kidney damage.


Assuntos
Nefropatias , Rim/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Bebidas Adoçadas com Açúcar/efeitos adversos , Animais , Desidratação/metabolismo , Desidratação/patologia , Frutoquinases/metabolismo , Frutose/efeitos adversos , Frutose/farmacologia , Glucose/efeitos adversos , Glucose/farmacologia , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Ratos , Ratos Wistar , Receptores de Vasopressinas/metabolismo
19.
Int J Mol Sci ; 21(21)2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33167400

RESUMO

There is strong evidence that exposure to fine particulate matter (PM2.5) and a high-fat diet (HFD) increase the risk of mortality from atherosclerotic cardiovascular diseases. Recent studies indicate that PM2.5 generated by combustion activates the Aryl Hydrocarbon Receptor (AHR) and inflammatory cytokines contributing to PM2.5-mediated atherogenesis. Here we investigate the effects of components of a HFD on PM-mediated activation of AHR in macrophages. Cells were treated with components of a HFD and AHR-activating PM and the expression of biomarkers of vascular inflammation was analyzed. The results show that glucose and triglyceride increase AHR-activity and PM2.5-mediated induction of cytochrome P450 (CYP)1A1 mRNA in macrophages. Cholesterol, fructose, and palmitic acid increased the PM- and AHR-mediated induction of proinflammatory cytokines in macrophages. Treatment with palmitic acid significantly increased the expression of inflammatory cytokines and markers of vascular injury in human aortic endothelial cells (HAEC) after treatment with PM2.5. The PM2.5-mediated activation of the atherogenic markers C-reactive protein (CRP) and S100A9, a damage-associated molecular pattern molecule, was found to be AHR-dependent and involved protein kinase A (PKA) and a CCAAT/enhancer-binding protein (C/EBP) binding element. This study identified nutritional factors interacting with AHR signaling and contributing to PM2.5-induced markers of atherogenesis and future cardiovascular risk.


Assuntos
Aterosclerose/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Biomarcadores/metabolismo , Inflamação/genética , Nutrientes/farmacologia , Receptores de Hidrocarboneto Arílico/fisiologia , Aorta , Aterosclerose/etiologia , Aterosclerose/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Calgranulina B/efeitos dos fármacos , Calgranulina B/genética , Calgranulina B/metabolismo , Células Cultivadas , Colesterol/farmacologia , Dieta Hiperlipídica , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Frutose/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/farmacologia , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/genética , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Ácido Palmítico/farmacologia , Material Particulado/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Triglicerídeos/farmacologia , Células U937
20.
Nutrients ; 12(11)2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33233570

RESUMO

Aim: The objective of this study was to characterize the early effects of high fructose diets (with and without high fat) on both the composition of the gut microbiota and lipid metabolism in Syrian hamsters, a reproducible preclinical model of diet-induced dyslipidemia. Methods: Eight-week-old male hamsters were fed diets consisting of high-fat/high-fructose, low-fat/high-fructose or a standard chow diet for 14 days. Stool was collected at baseline (day 0), day 7 and day 14. Fasting levels of plasma triglycerides and cholesterol were monitored on day 0, day 7 and day 14, and nonfasting levels were also assayed on day 15. Then, 16S rRNA sequencing of stool samples was used to determine gut microbial composition, and predictive metagenomics was performed to evaluate dietary-induced shifts in deduced microbial functions. Results: Both high-fructose diets resulted in divergent gut microbiota composition. A high-fat/high-fructose diet induced the largest shift in overall gut microbial composition, with dramatic shifts in the Firmicute/Bacteroidetes ratio, and changes in beta diversity after just seven days of dietary intervention. Significant associations between genus level taxa and dietary intervention were identified, including an association with Ruminococceace NK4A214 group in high-fat/high-fructose fed animals and an association with Butryimonas with the low-fat/high-fructose diet. High-fat/high-fructose feeding induced dyslipidemia with increases in plasma triglycerides and cholesterol, and hepatomegaly. Dietary-induced changes in several genus level taxa significantly correlated with lipid levels over the two-week period. Differences in microbial metabolic pathways between high-fat/high-fructose and low-fat/high-fructose diet fed hamsters were identified, and several of these pathways also correlated with lipid profiles in hamsters. Conclusions: The high-fat/high-fructose diet caused shifts in the host gut microbiota. These dietary-induced alterations in gut microbial composition were linked to changes in the production of secondary metabolites, which contributed to the development of metabolic syndrome in the host.


Assuntos
Dieta da Carga de Carboidratos/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Dislipidemias , Frutose/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Bactérias/classificação , Bactérias/genética , Colesterol/sangue , Fezes/microbiologia , Metabolismo dos Lipídeos , Masculino , Mesocricetus , Metagenômica , RNA Ribossômico 16S/genética , Triglicerídeos/sangue
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