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1.
J Oleo Sci ; 72(1): 99-104, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36624060

RESUMO

This study aimed to investigate the effects of interleukin-25, which belongs to the interleukin-17 family, on short-term high-fructose diet-induced hepatic triacylglycerol accumulation. Rats were fed a high-starch (control) or high-fructose diet for 7 d, with or without intraperitoneal administration of recombinant interleukin-25 from days 3-7. Treatment with interleukin-25 significantly reduced the mRNA levels and activity of fatty acid synthesis enzymes and caused a nominal reduction in hepatic triacylglycerol levels in rats fed a high-fructose diet but not in those fed a control diet. Interleukin-25 treatment did not affect the mRNA levels of ß-oxidation enzymes in either the control or fructose-fed rats. These results suggest that treatment with interleukin-25 suppresses short-term high-fructose diet-induced fatty acid synthesis and leads to the alleviation of triacylglycerol accumulation in the liver.


Assuntos
Frutose , Interleucina-17 , Fígado , Animais , Ratos , Dieta , Ácidos Graxos/metabolismo , Frutose/farmacologia , Expressão Gênica , Interleucina-17/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Ratos Wistar , RNA Mensageiro/metabolismo , Triglicerídeos/metabolismo
2.
Nat Commun ; 13(1): 7718, 2022 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-36513659

RESUMO

Multidrug-resistant organisms (MDRO) are a major threat to public health. MDRO infections, including those caused by vancomycin-resistant Enterococcus (VRE), frequently begin by colonization of the intestinal tract, a crucial step that is impaired by the intestinal microbiota. However, the specific members of the microbiota that suppress MDRO colonization and the mechanisms of such protection are largely unknown. Here, using metagenomics and mouse models that mimic the patients' exposure to antibiotics, we identified commensal bacteria associated with protection against VRE colonization. We further found a consortium of five strains that was sufficient to restrict VRE gut colonization in antibiotic treated mice. Transcriptomics in combination with targeted metabolomics and in vivo assays indicated that the bacterial consortium inhibits VRE growth through nutrient depletion, specifically by reducing the levels of fructose, a carbohydrate that boosts VRE growth in vivo. Finally, in vivo RNA-seq analysis of each strain of the consortium in combination with ex vivo and in vivo assays demonstrated that a single bacterium (Olsenella sp.) could recapitulate the effect of the consortium. Our results indicate that nutrient depletion by specific commensals can reduce VRE intestinal colonization, which represents a novel non-antibiotic based strategy to prevent infections caused by this multidrug-resistant organism.


Assuntos
Infecções por Bactérias Gram-Positivas , Microbiota , Enterococos Resistentes à Vancomicina , Camundongos , Animais , Vancomicina/farmacologia , Frutose/farmacologia , Enterococos Resistentes à Vancomicina/genética , Antibacterianos/farmacologia , Bactérias , Infecções por Bactérias Gram-Positivas/microbiologia
3.
Nutrients ; 14(24)2022 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-36558393

RESUMO

The Western diet can negatively affect the gut microbiota and is associated with metabolic disorders. Kombucha, a tea fermented by a symbiotic culture of bacteria and yeast (SCOBY), is known for its bioactive properties and has become popular in the last years. In this study, we evaluated the effects of regular kombucha consumption on the gut microbiota and on outcomes related to the intestinal health of Wistar rats fed a high-fat high-fructose diet. After eight weeks receiving a standard diet (AIN-93M) (n = 10) or a high-fat and high-fructose diet (HFHF) (n = 30) to induce metabolic disorders, the animals were subdivided into four groups: AIN-93M (n = 10); HFHF (n = 10); GTK (HFHF + green tea kombucha (n = 10); and BTK (HFHF + black tea kombucha; n = 10) for 10 weeks. Although body composition did not differ among the groups, the HFHF diet was associated with metabolic alterations, and stimulated the growth of gram-negative bacteria such as Proteobacteria and Bacteroides. Kombucha ingestion could somewhat modulate the gut microbiota, attenuating the effects of a Western diet by increasing propionate production and favoring the growth of beneficial bacteria, such as Adlercreutzia in the GTK group. Our results suggest that regular kombucha consumption may be beneficial to intestinal health, which can be mostly attributed to its high content and diversity of phenolic compounds.


Assuntos
Camellia sinensis , Microbioma Gastrointestinal , Ratos , Animais , Chá/microbiologia , Ratos Wistar , Frutose/farmacologia , Polifenóis/farmacologia , Dieta Hiperlipídica/efeitos adversos
4.
Stem Cell Res Ther ; 13(1): 533, 2022 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-36575539

RESUMO

BACKGROUND: Bone marrow mesenchymal stromal cells (BMSCs) are promising for therapeutic use in cartilage repair, because of their capacity to differentiate into chondrocytes. Often, in vitro differentiation protocols employ the use of high amount of glucose, which does not reflect cartilage physiology. For this reason, we investigated how different concentrations of glucose can affect the chondrogenic differentiation of BMSCs in cell culture pellets. Additionally, we investigated how fructose could influence the chondrogenic differentiation in vitro. METHODS: BMSC were isolated from six donors and cultured in DMEM containing glucose at either 25 mM (HG), 5.5 mM (LG) or 1 mM (LLG), and 1% non-essential amino acids, 1% ITS+, in the presence of 100 nM dexamethasone, 50 µg/ml ascorbic acid-2 phosphate and 10 ng/ml TGF-ß1. To investigate the effect of different metabolic substrates, other groups were exposed to additional 25 mM fructose. The media were replaced every second day until day 21 when all the pellets were harvested for further analyses. Biochemical analysis for glycosaminoglycans into pellets and released in medium was performed using the DMMB method. Expression of GLUT3 and GLUT5 was assayed by qPCR and validated using FACS analysis and immunofluorescence in monolayer cultures. Chondrogenic differentiation was further confirmed by qPCR analysis of COL2A1, COL1A1, COL10A1, ACAN, RUNX2, SOX9, SP7, MMP13, and PPARG, normalized on RPLP0. Type 2 collagen expression was subsequently validated by immunofluorescence analysis. RESULTS: We show for the first time the presence of fructose transporter GLUT5 in BMSC and its regulation during chondrogenic commitment. Additionally, decreasing glucose concentration during chondrogenesis dramatically decreased the yield of differentiation. However, the use of fructose alone or together with low glucose concentrations does not limit cell differentiation, but on the contrary it might help in maintaining a stable chondrogenic phenotype comparable with the standard culture conditions (high glucose). CONCLUSION: This study provides evidence that BMSC express GLUT5 and differentially regulate GLUT3 in the presence of glucose variation. This study gives a better comprehension of BMSCs sugar use during chondrogenesis.


Assuntos
Medula Óssea , Células-Tronco Mesenquimais , Humanos , Transportador de Glucose Tipo 3/metabolismo , Condrogênese , Glucose/farmacologia , Glucose/metabolismo , Frutose/farmacologia , Frutose/metabolismo , Condrócitos/metabolismo , Diferenciação Celular , Células-Tronco Mesenquimais/metabolismo , Células Cultivadas , Células da Medula Óssea
5.
Int J Mol Sci ; 23(22)2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36430326

RESUMO

Nonalcoholic fatty liver disease (NAFLD) has become a major public health problem. The effects of sesamolin on obesity-associated NAFLD and its possible mechanism are still poorly understood. The present study investigated the effects of sesamolin on NAFLD and changes in gut microbiota and serum metabolites in high-fat and high-fructose (HF-HF) diet-fed mice. Mice with NAFLD were treated with or without sesamolin. Sesamolin effectively suppressed obesity-associated metabolic disorder, attenuated hepatic steatosis and the infiltration of inflammatory cells, and decreased levels of hepatic proinflammatory cytokines. Sesamolin also altered the composition of gut microbiota at the genus level. Additionally, differential serum metabolite biomarkers identified in an untargeted metabolomics analysis showed that sesamolin changed the levels of metabolites and influenced metabolomics pathways including caffeine metabolism, steroid hormone biosynthesis, and cysteine and methionine metabolism. Changes in metabolite biomarkers and the abundances of Faecalibaculum, Lachnoclostridium, Mucispirillum, Allobaculum, and Bacteroides are highly correlated with those factors involved in the progression of NAFLD. These results are important in deciphering new mechanisms by which changes in bacteria and metabolites in sesamolin treatment might be associated with the alleviation of obesity-associated NAFLD in HF-HF diet-fed mice. Thus, sesamolin may be a potential compound for obesity-associated NAFLD treatment.


Assuntos
Microbioma Gastrointestinal , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Frutose/farmacologia , Dieta Hiperlipídica/efeitos adversos , Bactérias , Obesidade
6.
Cells ; 11(21)2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36359843

RESUMO

Pituitary gonadotropins directly govern ovarian functions, which are in turn regulated by the ovarian steroid hormones. The precise interplay of gonadotropins and steroid hormones is critical for follicle growth and differentiation. Furthermore, autophagy regulates ovarian follicle differentiation. However, how the high-fat-high fructose (HFD-HF) diet regulates gonadotropins and facilitates autophagy-mediated follicular differentiation in the ovary is obscure. We fed prepubertal rats (PND 25) an HFD-HF diet until PND 90. The results showed diminished adenohypophyseal GnRHR, PR, and aromatase expression, whereas AR, ERα, PRLR, and inhibin were augmented, resulting in gonadotropins decline. Interestingly, autophagy biomarkers, Beclin-1, ATG5, ATG12, LC3-II, and LAMP1 were reduced but SQSTM1/p62 was augmented in the ovaries of HFD-HF-fed rats, causing autolysosome to aggregation. The diet altered T, E2, P4, PRL, and their receptors status in the ovary, disturbed estrous cyclicity, and delayed vaginal opening. Ovarian histomorphology exhibited numerous cystic and atretic follicles, along with disturbed follicular maturation and ovulation. Moreover, the reduction of FSHR; steroidogenic proteins; receptor proteins AR, ERß, PR; and signaling proteins Wnt2 and ß-catenin was also noticed in the ovary, whereas PRLR, inhibin, and pGSK3ß were augmented. In conclusion, exposure to a prepubertal HFD-HF diet leads to hypogonadotropism and the autophagy-mediated defective differentiation of ovarian follicles, abating fertility in adult rats.


Assuntos
Dieta Hiperlipídica , Frutose , Folículo Ovariano , Animais , Feminino , Ratos , Autofagia , Dieta Hiperlipídica/efeitos adversos , Frutose/efeitos adversos , Frutose/metabolismo , Frutose/farmacologia , Gonadotropinas/metabolismo , Inibinas/metabolismo , Folículo Ovariano/metabolismo , Folículo Ovariano/patologia , Transtornos do Desenvolvimento Sexual
7.
Nutrients ; 14(19)2022 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-36235682

RESUMO

Studies have shown that genetic variations can influence metabolic response to nutrient intake, and that diets rich in fructose contribute to hyperuricemia. In this pilot study, our aim was to determine the variability of serum urate in response to an acute fructose challenge and to investigate if genetic variants would affect this response in young to middle-aged adults who self-reported as Black or White. Fifty-seven participants consumed a fructose-rich beverage after an overnight fast. Blood was drawn at five time points (baseline, 30, 60, 120, and 180 min after consumption). Thirty urate-related single nucleotide polymorphisms (SNPs) were analyzed for their associations with baseline serum urate and its percent changes, using a two-step modeling approach followed by meta-analysis. At baseline, serum urate (mg/dL, mean ± SD) was higher in Whites (5.60 ± 1.01 vs. 5.37 ± 0.96), men (6.17 ± 1.14 vs. 5.24 ± 0.79), and those with obesity (5.69 ± 1.08 vs. 5.42 ± 1.06 vs. 5.34 ± 0.80). Three SNPs were significantly associated with baseline serum urate or its percent changes, and six SNPs were nominally associated with percent changes in serum urate. In summary, our results showed that genetic variants could play a role in short-term urate metabolism.


Assuntos
Gota , Hiperuricemia , Adulto , Frutose/farmacologia , Humanos , Hiperuricemia/genética , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Fatores de Risco , Ácido Úrico
8.
Int J Mol Sci ; 23(19)2022 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-36232688

RESUMO

Acute myeloid leukemia (AML)-the most frequent form of adult blood cancer-is characterized by heterogeneous mechanisms and disease progression. Developing an effective therapeutic strategy that targets metabolic homeostasis and energy production in immature leukemic cells (blasts) is essential for overcoming relapse and improving the prognosis of AML patients with different subtypes. With respect to metabolic regulation, fructose-1,6-bisphosphatase 1 (FBP1) is a gluconeogenic enzyme that is vital to carbohydrate metabolism, since gluconeogenesis is the central pathway for the production of important metabolites and energy necessary to maintain normal cellular activities. Beyond its catalytic activity, FBP1 inhibits aerobic glycolysis-known as the "Warburg effect"-in cancer cells. Importantly, while downregulation of FBP1 is associated with carcinogenesis in major human organs, restoration of FBP1 in cancer cells promotes apoptosis and prevents disease progression in solid tumors. Recently, our large-scale sequencing analyses revealed FBP1 as a novel inducible therapeutic target among 17,757 vitamin-D-responsive genes in MV4-11 or MOLM-14 blasts in vitro, both of which were derived from AML patients with FLT3 mutations. To investigate FBP1's anti-leukemic function in this study, we generated a new AML cell line through lentiviral overexpression of an FBP1 transgene in vitro (named FBP1-MV4-11). Results showed that FBP1-MV4-11 blasts are more prone to apoptosis than MV4-11 blasts. Mechanistically, FBP1-MV4-11 blasts have significantly increased gene and protein expression of P53, as confirmed by the P53 promoter assay in vitro. However, enhanced cell death and reduced proliferation of FBP1-MV4-11 blasts could be reversed by supplementation with post-glycolytic metabolites in vitro. Additionally, FBP1-MV4-11 blasts were found to have impaired mitochondrial homeostasis through reduced cytochrome c oxidase subunit 2 (COX2 or MT-CO2) and upregulated PTEN-induced kinase (PINK1) expressions. In summary, this is the first in vitro evidence that FBP1-altered carbohydrate metabolism and FBP1-activated P53 can initiate leukemic death by activating mitochondrial reprogramming in AML blasts, supporting the clinical potential of FBP1-based therapies for AML-like cancers.


Assuntos
Metabolismo dos Carboidratos , Células Precursoras de Granulócitos , Leucemia Mieloide Aguda , Mitocôndrias , Proteína Supressora de Tumor p53 , Apoptose , Metabolismo dos Carboidratos/efeitos dos fármacos , Metabolismo dos Carboidratos/genética , Dióxido de Carbono/metabolismo , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Progressão da Doença , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Frutose/farmacologia , Frutose-Bifosfatase/genética , Frutose-Bifosfatase/metabolismo , Glicólise , Células Precursoras de Granulócitos/metabolismo , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas Quinases/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Vitamina D/farmacologia , Vitaminas/farmacologia , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
9.
Steroids ; 188: 109132, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36273542

RESUMO

Several studies have demonstrated that the underlying mechanism of insulin resistance (IR) is linked with developing diseases like diabetes mellitus, hypertension, metabolic syndrome, and polycystic ovary syndrome. In turn, the dysfunction of female gonadal hormones (especially 17ß-estradiol) may be related to the development of IR complications since different studies have shown that 17ß-estradiol has a cardioprotector and vasorelaxant effect. This study aimed was to determine the effect of the 17ß-estradiol administration in insulin-resistant rats and its effects on cardiovascular responses in pithed rats. Thus, the vasopressor responses are induced by sympathetic stimulation or i.v. bolus injections of noradrenaline (α1/2), methoxamine (α1), and UK 14,304 (α2) adrenergic agonist were determined in female pithed rats with fructose-induced insulin resistance or control rats treated with: 1) 17ß-estradiol or 2) its vehicle (oil) for 5 weeks. Thus, 17ß-estradiol decreased heart rate, prevented the increase of blood pressure induced by ovariectomy, but with the opposite effect on sham-operated rats; and decreased vasopressor responses induced by i.v. bolus injections of noradrenaline on sham-operated (control and fructose group) and ovariectomized (control) rats, and those induced by i.v. bolus injections of methoxamine (α1 adrenergic agonist). Overall, these results suggest 17ß-estradiol has a cardioprotective effect, and its effect on vasopressor responses could be mediated mainly by the α1 adrenergic receptor. In contrast, IR with ovariectomy 17ß-estradiol decreases or loses its cardioprotector effect, this could suggest a possible link between the adrenergic receptors and the insulin pathway.


Assuntos
Estradiol , Resistência à Insulina , Sistema Nervoso Simpático , Animais , Feminino , Humanos , Ratos , Agonistas Adrenérgicos/farmacologia , Estradiol/farmacologia , Frutose/farmacologia , Insulina , Resistência à Insulina/fisiologia , Metoxamina/farmacologia , Norepinefrina/farmacologia , Ovariectomia , Ratos Wistar , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologia , Vasoconstritores/farmacologia
10.
Int J Mol Sci ; 23(19)2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-36233028

RESUMO

Changes in the gut ecosystem, including the microbiome and the metabolome, and the host immune system after fructo-oligosaccharide (FOS) supplementation were evaluated. The supplementation of FOS showed large inter-individual variability in the absolute numbers of fecal bacteria and an increase in Bifidobacterium. The fecal metabolome analysis revealed individual variability in fructose utilization in response to FOS supplementation. In addition, immunoglobulin A(IgA) tended to increase upon FOS intake, and peripheral blood monocytes significantly decreased upon FOS intake and kept decreasing in the post-FOS phase. Further analysis using a metagenomic approach showed that the differences could be at least in part due to the differences in gene expressions of enzymes that are involved in the fructose metabolism pathway. While the study showed individual differences in the expected health benefits of FOS supplementation, the accumulation of "personalized" knowledge of the gut ecosystem with its genetic expression may enable effective instructions on prebiotic consumption to optimize health benefits for individuals in the future.


Assuntos
Microbiota , Oligossacarídeos , Frutose/farmacologia , Humanos , Imunoglobulina A/metabolismo , Oligossacarídeos/metabolismo , Oligossacarídeos/farmacologia , Prebióticos
11.
Environ Toxicol ; 37(11): 2728-2742, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36214339

RESUMO

Fructose overconsumption promotes tumor progression. Neuroblastoma is a common extracranial tumor with about 50% 5-year survival rate in high-risk children. The anti-tumor effect of Tribulus terrestris might bring new hope to neuroblastoma therapy. However, whether fructose disturbs the therapeutic effect of T. terrestris is currently unknown. In this study, the mouse neuroblastoma cell line, Neuro 2a (N2a) cells, was used to investigate the therapeutic effects of T. terrestris extract at various dosages (0.01, 1, 100 ng/ml) in regular EMEM medium or extra added fructose (20 mM) for 24 h. 100 ng/ml T. terrestris treatment significantly reduced the cell viability, whereas the cell viabilities were enhanced at the dosages of 0.01 or 1 ng/ml T. terrestris in the fructose milieu instead. The inhibition effect of T. terrestris on N2a migration was blunted in the fructose milieu. Moreover, T. terrestris effectively suppressed mitochondrial functions, including oxygen consumption rates, the activities of electron transport enzymes, the expressions of mitochondrial respiratory enzymes, and mitochondrial membrane potential. These suppressions were reversed in the fructose group. In addition, the T. terrestris-suppressed mitofusin and the T. terrestris-enhance mitochondrial fission 1 protein were maintained at basal levels in the fructose milieu. Together, these results demonstrated that T. terrestris extract effectively suppressed the survival and migration of neuroblastoma via inhibiting mitochondrial oxidative phosphorylation and disturbing mitochondrial dynamics. Whereas, the fructose milieu blunted the therapeutic effect of T. terrestris, particularly, when the dosage is reduced.


Assuntos
Frutose , Neuroblastoma , Animais , Linhagem Celular , Frutose/farmacologia , Camundongos , Mitocôndrias , Neuroblastoma/tratamento farmacológico , Extratos Vegetais/farmacologia , Tribulus
12.
Life Sci ; 309: 120999, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36182846

RESUMO

AIMS: High dietary fructose consumption has been linked to the development of renal fibrosis. Dulaglutide is a long acting glucagon like peptide-1 (GLP-1) analog, showing some renoprotective properties; however its action on renal fibrosis remains uncertain. We investigated the effect of dulaglutide on fructose-induced renal fibrosis in comparison to pirfenidone, as well-established anti-fibrotic drug, and the contribution of epithelial-mesenchymal transition (EMT) process and its upstream signaling. MAIN METHODS: Six week-old male Wistar albino rats received 10%w/v fructose solution in drinking water for 24 weeks and co-treated with either pirfenidone (100 mg/kg/day, orally) or dulaglutide (0.2 mg/kg/week, s.c) for the last four weeks. Lipid profile, glucose homeostasis, kidney functions were assessed. Kidneys were harvested for biochemical and histological analyses. KEY FINDINGS: High dietary fructose consumption for 24 weeks induced insulin resistance, dyslipidemia and renal dysfunction that were ameliorated by dulaglutide and pirfenidone to lesser extent. Histological examination revealed histological lesions and interstitial fibrosis in renal sections of high fructose-fed rats, which were reversed by dulaglutide or pirfenidone treatment. Both drugs modulated the EMT-related proteins by increasing the epithelial marker, E-cadherin, while suppressing the mesenchymal markers, vimentin and alpha-smooth muscle actin (α-SMA) in renal tissue. Moreover, both drugs attenuated fructose-induced upregulation of GSK-3ß/TGF-ß1/Smad3 signaling. SIGNIFICANCE: These findings suggest that dulaglutide can emerge as a promising therapeutic agent for fructose-induced renal fibrosis. These results add mechanistic insights into the anti-fibrotic action of dulaglutide through suppressing EMT and the upstream GSK-3ß/TGF-ß1/Smad3 signaling.


Assuntos
Água Potável , Nefropatias , Animais , Ratos , Masculino , Fator de Crescimento Transformador beta1/metabolismo , Transição Epitelial-Mesenquimal , Glicogênio Sintase Quinase 3 beta/metabolismo , Vimentina/metabolismo , Actinas/metabolismo , Frutose/farmacologia , Ratos Wistar , Fibrose , Nefropatias/tratamento farmacológico , Transdução de Sinais , Caderinas/metabolismo , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Glucose/farmacologia , Lipídeos/farmacologia
13.
Ying Yong Sheng Tai Xue Bao ; 33(7): 1901-1910, 2022 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-36052794

RESUMO

To determine the mitigating effects of exogenous melatonin on salt-alkali stress in cucumber, we mea-sured photosynthetic characteristics and osmoregulatory substance content of cucumber leaves under salt-alkali stress, using 'Xinchun 4' cucumber as the test material and a salt-alkali complex (NaCl:Na2SO4:Na2CO3:NaHCO3 = 1:9:1:9) to simulate stress. The results showed that compared with the normal seedlings, the exogenous application of 10 µmol·L-1 melatonin significantly increased the contents of chlorophyll, soluble sugar, and soluble protein, as well as net photosynthetic rate, stomatal conductance, transpiration rate, photosystem Ⅱ maximum photochemical efficiency, actual photochemical efficiency, apparent photosynthetic electron transfer rate, and photochemical burst coefficient of cucumber seedlings under 40 mmol·L-1 salt-alkali stress, but decreased intercellular CO2 concentration, non-photochemical burst coefficient, and sucrose, fructose, starch, and proline contents by 11.1%, 13.8%, 12.7%, 27.5%, 1.3% and 32.8%, respectively. Moreover, the activities of key enzymes for carbon assimilation (including ribulose-1,5-bisphosphate carboxylase/oxygenase and fructose-1,6-bisphosphate esterase) were significantly increased, whereas the mRNA expression levels of Rubisco subunits (CsrbcS and CsrbcL), CsFBA, CsRCA, CsFBPase and CsTK were downregulated. In conclusion, exogenous melatonin could increase the contents of chlorophyll and osmoregulatory substance, photosynthetic chemical efficiency, and key carbon assimilation enzyme activities of cucumber seedlings under salt-alkali stress, thereby enhance photosynthetic capacity and reduce the stress-induced plant damage. The results would provide theoretical basis for anti-saline plant cultivation.


Assuntos
Cucumis sativus , Melatonina , Álcalis , Carbono/metabolismo , Clorofila/metabolismo , Frutose/metabolismo , Frutose/farmacologia , Melatonina/farmacologia , Fotossíntese , Folhas de Planta/metabolismo , Plântula , Cloreto de Sódio/farmacologia
14.
Chemosphere ; 308(Pt 3): 136543, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36150489

RESUMO

Organophosphorus flame retardants (OPFRs) are frequently detected in food and human samples, and epidemiological studies have found that human exposure to aryl-OPFRs (triphenyl phosphate, TPP) is associated with lipid metabolism. Although toxicity studies suggest a potential obesity risk from TPP exposure, the molecular mechanism remains unclear. This study investigated the subchronic dietary effects on mouse liver significantly changed proteins (SCPs) and elucidated the underlying molecular mechanisms of TPP with or without a high-fructose and high-fat (HFF) diet. Male C57BL/6J mice were exposed to low-dose TPP (corresponding to the oral reference dose, 10 µg/kg body weight (bw)/day) and high-dose TPP (1000 µg/kg bw/day) for 12 weeks. The results showed that exposure to TPP generated changes of liver function and organelle damage as well as increases in total cholesterol and triglyceride levels. TPP exposure at a low dose damaged the liver immune system via major histocompatibility complex-related proteins involved in antigen processing and presentation. TPP exposure at a high dose caused disorders of the biosynthesis of unsaturated fatty acids and steroid hormones, thereby inducing lipid accumulation in the liver. Although 10 µg/kg TPP did not cause serious lipid metabolism disorders in the liver, significant overexpression of fatty acid-binding protein 5, malic enzyme 1, and other related SCPs was observed, which led to disorders of cholesterol metabolism and lipogenesis to activate the proliferator-activated receptor signaling pathway and thus induced potential obesity risks. In addition, lipid metabolism disorders related to TPP were aggravated under the HFF diet, impairing liver mitochondrial and endoplasmic reticulum function in mice by altering the activity of cytochrome P450 enzyme subfamilies. These findings provide an in-depth understanding of the molecular toxicity mechanisms and health risks associated with subchronic exposure to TPP under different dietary regimes.


Assuntos
Retardadores de Chama , Transtornos do Metabolismo dos Lipídeos , Animais , Colesterol/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Dieta Hiperlipídica , Proteínas de Ligação a Ácido Graxo , Retardadores de Chama/metabolismo , Frutose/metabolismo , Frutose/farmacologia , Hormônios/metabolismo , Humanos , Metabolismo dos Lipídeos , Lipídeos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/induzido quimicamente , Obesidade/metabolismo , Organofosfatos , Triglicerídeos/metabolismo
15.
Cell Rep Med ; 3(9): 100742, 2022 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-36130480

RESUMO

Diets rich in added sugars are associated with metabolic diseases, and studies have shown a link between these pathologies and changes in the microbiome. Given the reported associations in animal models between the microbiome and brown adipose tissue (BAT) function, and the alterations in the microbiome induced by high-glucose or high-fructose diets, we investigated the potential causal link between high-glucose or -fructose diets and BAT dysfunction in humans. Primary outcomes are changes in BAT cold-induced thermogenesis and the fecal microbiome (clinicaltrials.gov, NCT03188835). We show that BAT glucose uptake, but not thermogenesis, is impaired by a high-fructose but not high-glucose diet, in the absence of changes in the gastrointestinal microbiome. We conclude that decreased BAT glucose metabolism occurs earlier than other pathophysiological abnormalities during fructose overconsumption in humans. This is a potential confounding factor for studies relying on 18F-FDG to assess BAT thermogenesis.


Assuntos
Tecido Adiposo Marrom , Microbioma Gastrointestinal , Tecido Adiposo Marrom/diagnóstico por imagem , Animais , Fluordesoxiglucose F18/metabolismo , Frutose/farmacologia , Glucose/metabolismo , Humanos
16.
Physiol Behav ; 256: 113954, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36055416

RESUMO

There is debate about the metabolic impact of sugar-sweetened beverages. Here, we tested the hypothesis that ad lib consumption of glucose (Gluc) or high-fructose (HiFruc) syrups improves glucose tolerance in mice. We provided C57BL/6 mice with a control (chow and water) or experimental (chow, water and sugar solution) diet across two consecutive 28-day exposure periods, and monitored changes in body composition, glucose tolerance, cephalic-phase insulin release (CPIR) and insulin sensitivity. The sugar solutions contained 11% concentrations of Gluc or HiFruc syrup; these syrups were derived from either corn starch or cellulose. In Experiment 1, consumption of the Gluc diets reliably enhanced glucose tolerance, while consumption of the HiFruc diets did not. Mice on the Gluc diets exhibited higher CPIR (relative to baseline) by the end of exposure period 1, whereas mice on the control and HiFruc diets did not do so until the end of exposure period 2. Mice on the Gluc diets also exhibited higher insulin sensitivity than control mice at the end of exposure period 2, while mice on the HiFruc diets did not. In Experiment 2, we repeated the previous experiment, but limited testing to the corn-based Gluc and HiFruc syrups. We found, once again, that consumption of the Gluc (but not the HiFruc) diet enhanced glucose tolerance, in part by increasing CPIR and insulin sensitivity. These results show that mice can adapt metabolically to high glucose diets, and that this adaptation process involves upregulating at least two components of the insulin response system.


Assuntos
Glucose , Resistência à Insulina , Animais , Glicemia/metabolismo , Carboidratos , Celulose , Frutose/farmacologia , Glucose/metabolismo , Insulina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Amido , Edulcorantes , Água
17.
Metabolism ; 136: 155310, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36063868

RESUMO

INTRODUCTION: Recurrent hypoglycemia (RH) impairs secretion of counterregulatory hormones. Whether and how RH affects responses within metabolically important peripheral organs to counterregulatory hormones are poorly understood. OBJECTIVE: To study the effects of RH on metabolic pathways associated with glucose counterregulation within liver, white adipose tissue and skeletal muscle. METHODS: Using a widely adopted rodent model of 3-day recurrent hypoglycemia, we first checked expression of counterregulatory hormone G-protein coupled receptors (GPCRs), their inhibitory regulators and downstream enzymes catalyzing glycogen metabolism, gluconeogenesis and lipolysis by qPCR and western blot. Then, we examined epinephrine-induced phosphorylation of PKA substrates to validate adrenergic sensitivity in each organ. Next, we measured hepatic and skeletal glycogen content, degree of breakdown by epinephrine and abundance of phosphorylated glycogen phosphorylase under hypoglycemia and that of phosphorylated glycogen synthase during recovery to evaluate glycogen turnover. Further, we performed pyruvate and lactate tolerance tests to assess gluconeogenesis. Additionally, we measured circulating FFA and glycerol to check lipolysis. The abovementioned studies were repeated in streptozotocin-induced diabetic rat model. Finally, we conducted epinephrine tolerance test to investigate systemic glycemic excursions to counterregulatory hormones. Saline-injected rats served as controls. RESULTS: RH increased counterregulatory hormone GPCR signaling in liver and epidydimal white adipose tissue (eWAT), but not in skeletal muscle. For glycogen metabolism, RH did not affect total content or epinephrine-stimulated breakdown in liver and skeletal muscle. Although RH decreased expression of phosphorylated glycogen synthase 2, it did not affect hepatic glycogen biosynthesis during recovery from hypoglycemia or after fasting-refeeding. For gluconeogenesis, RH upregulated fructose 1,6-bisphosphatase 1 and monocarboxylic acid transporter 1 that imports lactate as precursor, resulting in a lower blood lactate profile during hypoglycemia. In agreement, RH elevated fasting blood glucose and caused higher glycemic excursions during pyruvate tolerance test. For lipolysis, RH did not affect circulating levels of FFA and glycerol after overnight fasting or upon epinephrine stimulation. Interestingly, RH upregulated the trophic fatty acid transporter FATP1 and glucose transporter GLUT4 to increase lipogenesis in eWAT. These aforementioned changes of gluconeogenesis, lipolysis and lipogenesis were validated in streptozotocin-diabetic rats. Finally, RH increased insulin sensitivity to accelerate glucose disposal, which was attributable to upregulated visceral adipose GLUT4. CONCLUSIONS: RH caused metabolic adaptations related to counterregulation within peripheral organs. Specifically, adrenergic signaling was enhanced in liver and visceral fat, but not in skeletal muscle. Glycogen metabolism remained unchanged. Hepatic gluconeogenesis was augmented. Systemic lipolysis was unaffected, but visceral lipogenesis was enhanced. Insulin sensitivity was increased. These findings provided insights into mechanisms underlying clinical problems associated with intensive insulin therapy, such as high gluconeogenic flux and body weight gain.


Assuntos
Diabetes Mellitus Experimental , Hipoglicemia , Resistência à Insulina , Adrenérgicos/efeitos adversos , Adrenérgicos/metabolismo , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Epinefrina , Ácidos Graxos/metabolismo , Frutose/farmacologia , Gluconeogênese , Glucose/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/farmacologia , Glicerol/metabolismo , Glicogênio/metabolismo , Glicogênio Sintase/metabolismo , Hipoglicemia/metabolismo , Insulina/metabolismo , Lactatos/efeitos adversos , Lactatos/metabolismo , Lipólise , Fígado/metabolismo , Glicogênio Hepático/metabolismo , Transportadores de Ácidos Monocarboxílicos/efeitos adversos , Transportadores de Ácidos Monocarboxílicos/metabolismo , Piruvatos/metabolismo , Ratos , Estreptozocina/efeitos adversos , Estreptozocina/metabolismo
18.
BMC Pharmacol Toxicol ; 23(1): 75, 2022 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-36175992

RESUMO

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a chronic disease characterized by inflammation, steatosis, and liver fibrosis. The liver is particularly affected by alterations in lipid metabolism. Our aim was to evaluate the effect of ß-hydroxyphosphocarnitine (ß-HPC) on NASH induced in rats. METHODS: NASH was produced via the ad libitum daily chronic administration of a fructose solution (400 kcal) for 9 weeks, an oral dose of fat solution (16 kcal) for 7 weeks and a subcutaneous injection of CCl4 (30%) two times a week for 2 weeks to Wistar rats. To evaluate the effect of ß-HPC, a dose of 100 mg/kg was administered perorally for 4 weeks and its biochemical and hepatic effects on rats with NASH were analyzed. Serum levels of glucose, triglycerides, cholesterol, and liver enzymes were quantified. Histological changes were evaluated on slices stained with H&E, trichromic and PAS. Glycogen content was measured in liver samples. α-SMA and SREBP-1 immunopositive cells were identified in liver tissue. RESULTS: NASH was characterized by elevated triglycerides, elevated liver damage enzymes, and the presence of necrosis, inflammation, steatosis, and fibrosis. Significant amounts of glycogen were found, along with α-SMA positive cells in fibrosis areas. The over-expression of SREBP-1 in cytoplasm and nuclei was evident. Animals with NASH treated with ß-HPC showed a significant reduction in inflammation, necrosis, and glycogen content in the liver. A reduction in α-SMA and SREBP-1 immunopositive cells correlated with a significant reduction in the degree of fibrosis and steatosis found in liver tissue. ß-HPC reduced the levels of ALP and GGT, and significantly reduced triglyceride levels. Animals treated with ß-HPC did not show any alterations in liver enzyme function. CONCLUSIONS: Our research shows that ß-HPC can improve liver function and morphology in the case of NASH induced in rats, suggesting ß-HPC could be potentially used in the treatment of NASH.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Carnitina/análogos & derivados , Colesterol , Dieta Hiperlipídica , Modelos Animais de Doenças , Frutose/metabolismo , Frutose/farmacologia , Frutose/uso terapêutico , Glucose/metabolismo , Glicogênio/metabolismo , Glicogênio/farmacologia , Glicogênio/uso terapêutico , Inflamação/tratamento farmacológico , Fígado , Cirrose Hepática/metabolismo , Necrose , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Organofosfatos , Ratos , Ratos Wistar , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/farmacologia , Triglicerídeos
19.
Neuroreport ; 33(13): 583-589, 2022 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-36049163

RESUMO

Brain-derived neurotrophic factor (BDNF) is expressed in both hypothalamic neurons and microglia, and plays a critical role in the regulation of metabolism. Although hypothalamic expression of BDNF is regulated by metabolic signals such as nutrients and hormones, it remains unknown whether these signals differentially regulate BDNF expression in different cell types. The present study aimed to determine whether glucose and fructose regulate BDNF expression in microglia via the specific glucose transporter. To determine the effect of glucose and fructose on Bdnf mRNA and protein expression, murine microglial cell line SIM-A9 cells were exposed to the maintenance concentration of glucose (17.5 mmol/l), high glucose (25 mmol/l), or fructose (7.5 mmol/l) for 40 min to 24 h. To determine whether the blockade of glucose transporter 5 (GLUT5) negates the effect of glucose on Bdnf mRNA expression, cells were exposed to 25 mmol/l glucose in the presence or absence of the GLUT5 inhibitor for 4 h. Levels of Bdnf mRNA and protein were measured by real-time PCR and ELISA, respectively. High glucose caused a significant increase in both pan-Bdnf and long-form Bdnf (L-Bdnf) mRNA as well as protein levels when compared with the maintenance of concentration of glucose in a time-dependent manner. Fructose treatment also increased L-Bdnf mRNA expression. Pharmacological blockade of GLUT5 did not affect glucose-induced Bdnf mRNA expression. These findings suggest that glucose and fructose directly stimulate Bdnf mRNA expression in microglia and these responses may mediate the metabolic actions of glucose and fructose.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Frutose , Glucose , Microglia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Frutose/metabolismo , Frutose/farmacologia , Expressão Gênica , Glucose/metabolismo , Glucose/farmacologia , Proteínas Facilitadoras de Transporte de Glucose/farmacologia , Camundongos , Microglia/metabolismo , RNA Mensageiro/metabolismo
20.
Chemosphere ; 308(Pt 1): 136066, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35987273

RESUMO

Ubiquitous plastic pollution is a threat to the organisms' survival and ecosystem functions, especially in aquatic environments. Although there is increasing concern about the toxicity of microplastics, knowledge about the effects of microplastics of diverse sizes and adverse impacts on freshwater organisms is still limited. In the present study, the alteration in life-history traits, antioxidant defense and energy metabolism of the model freshwater zooplankton Daphnia pulex were assessed after chronic exposure to gradient concentrations (0.5, 1, 2 and 4 mg/L) of 500-nm polystyrene microplastics (PS-MPs). Changes in protein abundance were analyzed using proteomics after exposure to 1 mg/L of PS-MPs for 14 days. The results showed that ingested PS-MPs accumulated in the digestive tract of D. pulex. 2 and 4 mg/L of PS-MPs inhibited the survival function and 4 mg/L of PS-MPs reduced the body length of D. pulex after 14 or 21 days of exposure. The exposure did not decrease the fecundity of D. pulex. After 14 days of exposure, PS-MPs changed the antioxidant capacity in a dose-dependent way and all concentrations of PS-MPs induced lipid oxidative damage. Exposure to 500-nm PS-MPs for 14 days decreased glucose and fructose contents and disturbed the lipid transport and utilization in D. pulex. Meanwhile, PS-MPs activated DNA repair and transcription regulation but inhibited lipid metabolism and response to unfolded or misfolded proteins. These results indicated that chronic exposure to 500-nm PS-MPs negatively affected D. pulex and showed similar toxic mechanisms to smaller nano-sized microplastics. Exposure to 500-nm PS-MPs resulted in restricted resources such as inhibited antioxidant capacity or energy metabolisms and D. pulex showed a potential trade-off among life-history traits to maintain fecundity at the cost of self-maintenance. The present study offers perspectives for understanding the differences in ecological effects caused by microplastics of different sizes.


Assuntos
Microplásticos , Poluentes Químicos da Água , Animais , Antioxidantes/farmacologia , Daphnia , Ecossistema , Metabolismo Energético , Frutose/farmacologia , Glucose , Lipídeos , Microplásticos/toxicidade , Plásticos/toxicidade , Poliestirenos/toxicidade , Poluentes Químicos da Água/toxicidade
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