RESUMO
Hyperuricemia (HUA) is a metabolic disease characterized by the increase of serum uric acid (UA) level. Sargentodoxae Caulis (SC) is a commonly used herbal medicine for the treatment of gouty arthritis, traumatic swelling, and rheumatic arthritis in clinic. In this study, a total of fifteen compounds were identified in SC water extract using UHPLC-Q-TOF-MS/MS, including three phenolic acids, seven phenolic glycosides, four organic acids, and one lignan. Then, to study the hypouricemia effect of SC, a HUA mouse model was induced using a combination of PO, HX, and 20% yeast feed. After 14 days of treatment with the SC water extract, the levels of serum UA, creatinine (CRE), blood urea nitrogen (BUN) were reduced significantly, and the organ indexes were restored, the xanthine oxidase (XOD) activity were inhibited as well. Meanwhile, SC water extract could ameliorate the pathological status of kidneys and intestine of HUA mice. Additionally, quantitative real-time PCR (qRT-PCR) and western blotting results showed that SC water extract could increase the expression of ATP binding cassette subfamily G member 2 (ABCG2), organic cation transporter 1 (OCT1), organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3), whereas decrease the expression of glucose transporter 9 (GLUT9). This study provided a data support for the clinical application of SC in the treatment of HUA.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Hiperuricemia , Ácido Úrico , Xantina Oxidase , Animais , Camundongos , Hiperuricemia/tratamento farmacológico , Masculino , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Ácido Úrico/sangue , Xantina Oxidase/metabolismo , Modelos Animais de Doenças , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Rim/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Transportadores de Ânions Orgânicos/metabolismo , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Hidroxibenzoatos/isolamento & purificação , Hidroxibenzoatos/farmacologiaRESUMO
The glucose transporter 1 (GLUT1) protein is involved in the basal-level absorption of glucose in tumor cells. Inhibiting GLUT1 decreases tumor cell proliferation and induces tumor cell damage. Natural GLUT1 inhibitors have been studied only to a small extent, and the structures of known natural GLUT1 inhibitors are limited to a few classes of natural products. Therefore, discovering and researching other natural GLUT1 inhibitors with novel scaffolds are essential. Physalis angulata L. var. villosa is a plant known as Mao-Ku-Zhi (MKZ). Withanolides are the main phytochemical components of MKZ. MKZ extracts and the components of MKZ exhibited antitumor activity in recent pharmacological studies. However, the antitumor-active components of MKZ and their molecular mechanisms remain unknown. A cell membrane-biomimetic nanoplatform (CM@Fe3O4/MIL-101) was used for target separation of potential GLUT1 inhibitors from MKZ. A new withanolide, physagulide Y (2), together with six known withanolides (1, 3-7), was identified as a potential GLUT1 inhibitor. Physagulide Y was the most potent GLUT1 inhibitor, and its antitumor activity and possible mechanism of action were explored in MCF-7 human cancer cells. These findings advance the development of technologies for the targeted separation of natural products and identify a new molecular framework for the investigation of natural GLUT1 inhibitors.
Assuntos
Antineoplásicos Fitogênicos , Physalis , Vitanolídeos , Humanos , Physalis/química , Transportador de Glucose Tipo 1 , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Proteínas Facilitadoras de Transporte de Glucose , Extratos Vegetais/química , Vitanolídeos/farmacologia , Vitanolídeos/química , Proteínas de Membrana Transportadoras , Estrutura MolecularRESUMO
BACKGROUND: Lipopolysaccharide (LPS)-induced dysfunction of pancreatic ß-cells leads to impaired insulin (INS) secretion. Astragalus polysaccharide (APS) is a bioactive heteropolysaccharide extracted from Astragalus membranaceus and is a popular Chinese herbal medicine. This study aimed to elucidate the mechanisms by which APS affects INS secretion from ß-cells under LPS stress. METHODS: Rat insulinoma (INS-1) cells were treated with LPS at a low, medium, or high concentration of APS. Glucose-stimulated insulin secretion (GSIS) was evaluated using an enzyme-linked immunosorbent assay (ELISA). Transcriptome sequencing was used to assess genome-wide gene expression. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to determine the signaling pathways affected by APS. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed to evaluate the gene expression of glucose transporter 2 (GLUT2), glucokinase (GCK), pancreatic duodenal homeobox-1 (PDX-1), and INS. Western blot analysis was used to detect the protein expression of phosphorylated protein kinase B (p-Akt), total Akt (t-Akt), phosphorylated mammalian target of rapamycin (p-mTOR), total mTOR (t-mTOR), and GLUT2. RESULTS: LPS decreased GLUT2, GCK, PDX-1, and INS expression and reduced GSIS. These LPS-induced decreases in gene expression and GSIS were restored by APS treatment. In addition, transcriptome sequencing in combination with KEGG enrichment analysis revealed changes in the INS signaling pathway following APS treatment. LPS decreased p-Akt and p-mTOR expression, which was restored by APS treatment. The restorative effects of APS on GSIS as well as on the expression of GLUT2, GCK, PDX-1, and INS were abolished by treatment with the Akt inhibitor MK2206 or the mTOR inhibitor rapamycin (RPM). CONCLUSIONS: APS restored GSIS in LPS-stimulated pancreatic ß-cells by activating the Akt/mTOR/GLUT2 signaling pathway.
Assuntos
Lipopolissacarídeos , Proteínas Proto-Oncogênicas c-akt , Ratos , Animais , Secreção de Insulina , Lipopolissacarídeos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sirolimo , Glucose/metabolismo , Polissacarídeos/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Mamíferos/metabolismoRESUMO
Diabetes mellitus is the leading disorder and affects more than millions of people worldwide. Nowadays, the usage of herbal drugs is said to control adiposity and hyperglycemia. The current research investigated the anti-adiposity and antidiabetic activity of S. saman leaf extract and bioactive compounds. Therefore, the results lower the sugar absorption into the blood and reveal the extract's antidiabetic properties. STZ-induced diabetic rats, Samanea saman methanolic extract show improvement in the parameters like fasting blood glucose levels, body weight, other biochemical parameters supported by the histopathological analysis, and an increase in serum levels in the experimental groups. The antioxidant plays a vital role by increasing SOD and catalase activity levels and decreasing lipid peroxidation levels. The methanolic extract protects the tissue from oxidation stress, which is responsible for the glycemic properties. According to the findings, diabetic-treated rats had overnight blood glucose levels lower and near standard biochemical markers. Histopathology of the liver, pancreas, kidneys, and adipose tissues supported the pharmacological observations. Further, we screened and documented S. saman extract used for in vitro and in vivo methods. In terms of effectiveness, the crude extracts exhibit 0.8-fold GLUT4 down-regulation. Consequently, this result contributes to clinical trials and develops antidiabetic therapy as a substitute for synthetic pharmaceuticals.
Assuntos
Glicemia , Diabetes Mellitus Experimental , Animais , Ratos , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Antioxidantes/metabolismo , Glicemia/análise , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Fígado/metabolismo , Estresse Oxidativo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Estreptozocina , Transportador de Glucose Tipo 4RESUMO
Individuals with glucose transporter type I deficiency (G1D) habitually experience nutrient-responsive epilepsy associated with decreased brain glucose. However, the mechanistic association between blood glucose concentration and brain excitability in the context of G1D remains to be elucidated. Electroencephalography (EEG) in G1D individuals revealed nutrition time-dependent seizure oscillations often associated with preserved volition despite electrographic generalization and uniform average oscillation duration and periodicity, suggesting increased facilitation of an underlying neural loop circuit. Nonlinear EEG ictal source localization analysis and simultaneous EEG/functional magnetic resonance imaging converged on the thalamus-sensorimotor cortex as one potential circuit, and 18F-deoxyglucose positron emission tomography (18F-DG-PET) illustrated decreased glucose accumulation in this circuit. This pattern, reflected in a decreased thalamic to striatal 18F signal ratio, can aid with the PET imaging diagnosis of the disorder, whereas the absence of noticeable ictal behavioral changes challenges the postulated requirement for normal thalamocortical activity during consciousness. In G1D mice, 18F-DG-PET and mass spectrometry also revealed decreased brain glucose and glycogen, but preserved tricarboxylic acid cycle intermediates, indicating no overall energy metabolism failure. In brain slices from these animals, synaptic inhibition of cortical pyramidal neurons and thalamic relay neurons was decreased, and neuronal disinhibition was mitigated by metabolic sources of carbon; tonic-clonic seizures were also suppressed by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition. These results pose G1D as a thalamocortical synaptic disinhibition disease associated with increased glucose-dependent neuronal excitability, possibly in relation to reduced glycogen. Together with findings in other metabolic defects, inhibitory neuron dysfunction is emerging as a modulable mechanism of hyperexcitability.
Assuntos
Glicemia , Estado de Consciência , Animais , Erros Inatos do Metabolismo dos Carboidratos , Carbono/metabolismo , Desoxiglucose , Eletroencefalografia , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Glicogênio/metabolismo , Camundongos , Proteínas de Transporte de Monossacarídeos/deficiência , Convulsões , Tálamo/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol PropiônicoRESUMO
Hyperhimatins A-P (1-16), sixteen new bicyclic polyprenylated acylphloroglucinols (BPAPs), were isolated and identified from Hypericum himalaicum. The planner structures of hyperhimatins A-P were confirmed via extensive NMR and careful HRESIMS data analysis. The absolute configurations of the new compounds were mainly determined by electronic circular dichroism (ECD) calculation, NMR calculation, and the circular dichroism data of the in situ formed [Rh2(OCOCF3)4] complexes. All compounds were assessed for the glucose transporter 4 (GLUT-4) translocation and expression enhancing effects in L6 myotubes. Compounds 1-16 could promote the GLUT-4 expression by the range of 1.95-6.04 folds, and accelerate the GLUT-4 fusion with the plasma membrane ranged from 53.56% to 76.97% at a consistence of 30 µg/mL, among compound 10 displayed the strongest GLUT-4 translocation effect.
Assuntos
Hypericum , Hypericum/química , Floroglucinol/farmacologia , Floroglucinol/química , Espectroscopia de Ressonância Magnética , Dicroísmo Circular , Proteínas Facilitadoras de Transporte de Glucose , Estrutura MolecularRESUMO
Wendlandia tinctoria var. grandis (Roxb.) DC. (Family: Rubiaceae) is a semi-evergreen shrub distributed over tropical and subtropical Asia. The present research intended to explore the pharmacological potential of the stem extract of W. tinctoria, focusing on the antioxidant, hypoglycemic, and antidiarrheal properties, and to isolate various secondary metabolites as mediators of such activities. A total of eight phenolic compounds were isolated from the dichloromethane soluble fraction of the stem extract of this plant, which were characterized by electrospray ionization (ESI) mass spectrometric and 1H NMR spectroscopic data as liquiritigenin (1), naringenin (2), apigenin (3), kaempferol (4), glabridin (5), ferulic acid (6), 4-hydroxybenzoic acid (7), and 4-hydroxybenzaldehyde (8). The dichloromethane soluble fraction exhibited the highest phenolic content (289.87 ± 0.47 mg of GAE/g of dried extract) and the highest scavenging activity (IC50 = 18.83 ± 0.07 µg/mL) against the DPPH free radical. All of the isolated compounds, except 4-hydroxybenzaldehyde, exerted a higher antioxidant effect (IC50 = 6.20 ± 0.10 to 16.11 ± 0.02 µg/mL) than the standard butylated hydroxytoluene (BHT) (IC50 = 17.09 ± 0.01 µg/mL). Significant hypoglycemic and antidiarrheal activities of the methanolic crude extract at both doses (200 mg/kg bw and 400 mg/kg bw) were observed in a time-dependent manner. Furthermore, the computational modeling study supported the current in vitro and in vivo findings, and the isolated constituents had a higher or comparable binding affinity for glutathione reductase and urase oxidase enzymes, glucose transporter 3 (GLUT 3), and kappa-opioid receptor, inferring potential antioxidant, hypoglycemic, and antidiarrheal properties, respectively. This is the first report of all of these phenolic compounds being isolated from this plant species and even the first demonstration of the plant stem extract's antioxidant, hypoglycemic, and antidiarrheal potentials. According to the current findings, the W. tinctoria stem could be a potential natural remedy for treating oxidative stress, hyperglycemia, and diarrhea. Nevertheless, further extensive investigation is crucial for thorough phytochemical screening and determining the precise mechanisms of action of the plant-derived bioactive metabolites against broad-spectrum molecular targets.
Assuntos
Hiperglicemia , Rubiaceae , Antidiarreicos , Antioxidantes/química , Apigenina , Benzaldeídos , Hidroxitolueno Butilado , Diarreia , Radicais Livres , Proteínas Facilitadoras de Transporte de Glucose , Glutationa Redutase , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Quempferóis , Cloreto de Metileno , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Receptores OpioidesRESUMO
Obesity is a leading global health problem contributing to various chronic diseases, including type II diabetes mellitus (T2DM). The aim of this study was to investigate whether blueberries, yoghurt, and their respective bioactive components, Cyanidin-3-O-ß-glucoside (C3G) and peptides alone or in combinations, alter the expression of genes related to glucose metabolism in skeletal muscles from diet-induced obese mice. In extensor digitorum longus (EDL), yoghurt up-regulated the expression of activation of 5'adenosine monophosphate-activated protein kinase (AMPK), insulin receptor substrate-1 (IRS-1), phosphatidylinositol-3 kinase (PI3K) and glucose transporter 4 (GLUT4), and down-regulated the expression of angiotensin II receptor type 1 (AGTR-1). The combination of blueberries and yoghurt down-regulated the mRNA expression of AGTR-1 and Forkhead box protein O1 (FoxO1) in the EDL. Whereas the combination of C3G and peptides down-regulated AGTR-1 and up-regulated GLUT4 mRNA expression in the EDL. In the soleus, blueberries and yoghurt alone, and their combination down-regulated AGTR-1 and up-regulated GLUT4 mRNA expression. In summary blueberries and yoghurt, regulated multiple genes associated with glucose metabolism in skeletal muscles, and therefore may play a role in the management and prevention of T2DM.
Assuntos
Antocianinas , Mirtilos Azuis (Planta) , Diabetes Mellitus Tipo 2 , Glucose , Obesidade , Iogurte , Proteínas Quinases Ativadas por AMP/metabolismo , Monofosfato de Adenosina/metabolismo , Animais , Antocianinas/metabolismo , Antocianinas/farmacologia , Mirtilos Azuis (Planta)/química , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Proteína Forkhead Box O1/metabolismo , Expressão Gênica , Glucose/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Camundongos , Camundongos Obesos , Músculo Esquelético/metabolismo , Obesidade/genética , Obesidade/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositóis/metabolismo , RNA Mensageiro/metabolismo , Receptores de Angiotensina/metabolismoRESUMO
Purpose: We have previously shown that maintenance of ATP levels is a promising strategy for preventing neuronal cell death, and that branched chain amino acids (BCAAs) enhanced cellular ATP levels in cultured cells and antagonized cell death. BCAAs attenuated photoreceptor degeneration and retinal ganglion cell death in rodent models of retinal degeneration or glaucoma. This study aimed to elucidate the mechanisms through which BCAAs enhance ATP production. Methods: Intracellular ATP concentration was measured in HeLa cells under glycolysis and citric acid cycle inhibited conditions. Next, glucose uptake was quantified in HeLa cells and in 661W retinal photoreceptor-derived cells under glycolysis inhibition, endoplasmic reticulum stress, and glucose transporters (GLUTs) inhibited conditions, by measuring the fluorescence of fluorescently labeled deoxy-glucose analog using flow cytometry. Then, the intracellular behavior of GLUT1 and GLUT3 were observed in HeLa or 661W cells transfected with enhanced green fluorescent protein-GLUTs. Results: BCAAs recovered intracellular ATP levels during glycolysis inhibition and during citric acid cycle inhibition. BCAAs significantly increased glucose uptake and recovered decreased glucose uptake induced by endoplasmic reticulum stress or glycolysis inhibition. However, BCAAs were unable to increase intracellular ATP levels or glucose uptake when GLUTs were inhibited. Fluorescence microscopy revealed that supplementation of BCAAs enhanced the translocation of GLUTs proteins to the plasma membrane over time. Conclusions: BCAAs increase ATP production by promoting glucose uptake through promotion of glucose transporters translocation to the plasma membrane. These results may help expand the clinical application of BCAAs in retinal neurodegenerative diseases, such as glaucoma and retinal degeneration.
Assuntos
Glaucoma , Degeneração Retiniana , Trifosfato de Adenosina/metabolismo , Aminoácidos de Cadeia Ramificada/metabolismo , Glucose/metabolismo , Proteínas Facilitadoras de Transporte de Glucose , Células HeLa , HumanosRESUMO
Mitochondrial dysfunction, oxidative stress, inflammation and glucose dysmetabolism are pathological signs of Alzheimer's disease (AD). Dietary aluminum (Al) overload is often used to induce AD in rodents and trigger the onset of oxidative-stress hallmarks resembling those of the human disease. The Nuclear factor erythroid 2-related factor 2 (Nrf2), owing to its key role in redox homeostasis, mitochondrial function and inflammation, is a promising drug target for neurological disorders, but only a few data are available on its modulatory effects on glucose transporter expression levels. While it has been found that the protective effect of Conjugated linoleic acid (CLA) occurs through the activation of an Nrf2-mediated adaptive response, its beneficial effect on the considered pathological signs in the Al-induced model has not been established yet. Thirty-five male BalbC mice were divided into 5 groups: two Al-intoxicated groups were treated for 5 weeks with low or high Al doses (8 or 100 mg/kg/day in drinking water, respectively; L or H). Two groups of animals, orally supplemented with CLA (600 mg/kg bw/day) for 7 weeks (2 preliminary weeks plus the 5-week treatment with Al; CLA + L, CLA + H) were used to investigate its protective effect, while untreated mice were used as control (Cntr). We provide evidence that mitochondrial dysfunction, Nrf2 alteration, inflammation and Acetylcholinesterase (AChE) hyperactivation can occur even from L exposure. Interestingly, animal pre-treatment with an allometric CLA dose led to significant downregulation of the toxic effects elicited by L or H, likely through the activation of an adaptive response. In conclusion, CLA ability to increase the level of glucose transporters - along with its antioxidant and anti-inflammatory effect - expands the therapeutic targets of these molecules and comes out as an intriguing suitable candidate for the treatment of multifactorial disease.
Assuntos
Doença de Alzheimer , Encéfalo , Ácidos Linoleicos Conjugados , Acetilcolinesterase/metabolismo , Alumínio/toxicidade , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Encéfalo/metabolismo , Modelos Animais de Doenças , Glucose/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Humanos , Inflamação/tratamento farmacológico , Ácidos Linoleicos Conjugados/farmacologia , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse OxidativoRESUMO
Maintenance of intestinal metabolic function is important for optimal growth performance in post-weaning pigs. This study aimed to evaluate the effect of pyrroloquinoline quinone (PQQ) on maintaining intestinal glycolipid metabolism in weaned pigs. Seventy-two Duroc × Landrace × Yorkshire crossbred pigs were divided into two groups: pigs fed a basal diet (CTRL group) and pigs fed a basal diet supplemented with 3.0 mg kg-1 PQQ (PQQ group). On d 14, serum was harvested from six pigs per group and the pigs were slaughtered to sample jejunal tissue. Compared with the CTRL group, pigs in the PQQ group had increased average daily gain (P < 0.05), decreased feed : gain (P < 0.05) and tended to have a reduced diarrhea ratio (P = 0.057). Jejunal villus height and villus height/crypt depth ratio were increased, and the crypt depth was decreased in the PQQ group (P < 0.01). The proteomics results showed that PQQ supplementation acted on three metabolic pathways, type I diabetes mellitus, the pancreatic secretion pathway and immune-related signalling. Compared with the CTRL group, PQQ supplementation increased (P < 0.05) serum insulin and jejunal mucosal pyruvate, triglyceride, total cholesterol and low-density lipoprotein cholesterol in the pigs. Jejunal mucosal lactic dehydrogenase and high-density lipoprotein cholesterol levels in the pigs were decreased by PQQ supplementation (P < 0.05). In addition, PQQ supplementation reduced glucose transporter 5 and phosphorylated-AMP-activated protein kinase expression in the jejunal mucosa of the pigs (P < 0.05). In conclusion, dietary supplementation with PQQ improved the growth performance and jejunal morphology and regulated glycolipid metabolism via inhibiting AMPK phosphorylation in weaned pigs.
Assuntos
Insulinas , Jejuno , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Ração Animal/análise , Animais , Colesterol/metabolismo , Dieta/veterinária , Suplementos Nutricionais , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Glicolipídeos/metabolismo , Insulinas/metabolismo , Jejuno/metabolismo , Lipoproteínas HDL , Lipoproteínas LDL/metabolismo , Oxirredutases/metabolismo , Cofator PQQ , Fosforilação , Piruvatos/metabolismo , Suínos , Triglicerídeos/metabolismo , DesmameRESUMO
Diabetes is a metabolic disease that is mainly characterized by hyperglycemia. The present work investigated the efficacy of the flavanones hesperetin (HES) and quercetin (Q) extracted from Trifolium alexandrinum (TA) to treat type 2 diabetic rats. Wistar albino rats were supplemented with a high fat diet (HFD) for 2 weeks and then administered streptozotocin to induce diabetes. Diabetic rats were orally treated with Q, HES, and TA extract at concentrations of 40, 50, and 200 mg/kg BW, respectively, for 4 weeks. Various biochemical, molecular, and histological analysis were performed to evaluate the antidiabetic effects of these treatments. Q, HES, and TA extract treatments all significantly improved diabetic rats' levels of serum glucose, insulin, glucagon, liver function enzymes, hepatic glycogen, α-amylase, lipase enzymes, lipid profiles, oxidative stress indicators, and antioxidant enzymes as compared with control diabetic untreated rats. In addition, supplementation with Q, HES, and TA extract attenuated the activities of glucose-6-phosphate; fructose-1,6-bisphospahate; 6-phosphogluconate dehydrogenase; glucose-6-phosphate dehydrogenase; glucokinase; and hexokinase in pancreatic tissue, and they improved the levels of glucose transporter 2 and glucose transporter 4. Furthermore, these treatments modulated the expressions levels of insulin receptor (IR), phosphoinositide 3-kinase (PI3K), AMP-activated protein kinase (AMPK), caspase-3, and interleukin-1ß (IL-1ß). Enhancement of the histological alterations in pancreatic tissues provided further evidence of the ability of Q, HES, and TA extract to exert antidiabetic effects. Q, HES, and TA extract remedied insulin resistance by altering the IR/PI3K and AMPK signaling pathways, and they attenuated type 2 diabetes by improving the antioxidant defense system.
Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Trifolium , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Metabolismo dos Carboidratos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Hesperidina , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina , Fígado , Fosfatidilinositol 3-Quinases/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Quercetina/farmacologia , Ratos , Ratos Wistar , Receptor de Insulina/metabolismo , Estreptozocina/farmacologia , Trifolium/química , Trifolium/metabolismoRESUMO
Insulin receptor substrate (IRS) 2 is a key mediator of insulin signaling and IRS-2 knockout (IRS2-/-) mice are a preclinical model to study the development of diabetes, as they develop peripheral insulin resistance and beta-cell failure. The differential inflammatory profile and insulin signaling in the hypothalamus of non-diabetic (ND) and diabetic (D) IRS2-/- mice might be implicated in the onset of diabetes. Because the lipid profile is related to changes in inflammation and insulin sensitivity, we analyzed whether ND IRS2-/- mice presented a different hypothalamic fatty acid metabolism and lipid pattern than D IRS2-/- mice and the relationship with inflammation and markers of insulin sensitivity. ND IRS2-/- mice showed elevated hypothalamic anti-inflammatory cytokines, while D IRS2-/- mice displayed a proinflammatory profile. The increased activity of enzymes related to the pentose-phosphate route and lipid anabolism and elevated polyunsaturated fatty acid levels were found in the hypothalamus of ND IRS2-/- mice. Conversely, D IRS2-/- mice have no changes in fatty acid composition, but hypothalamic energy balance and markers related to anti-inflammatory and insulin-sensitizing properties were reduced. The data suggest that the concurrence of an anti-inflammatory profile, increased insulin sensitivity and polyunsaturated fatty acids content in the hypothalamus may slow down or delay the onset of diabetes.
Assuntos
Citocinas/metabolismo , Hipotálamo/metabolismo , Proteínas Substratos do Receptor de Insulina/genética , Animais , Glicemia/metabolismo , Quimiocina CX3CL1/sangue , Citocinas/sangue , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Metabolismo Energético/genética , Ácidos Graxos Insaturados/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Proteínas Substratos do Receptor de Insulina/deficiência , Interleucina-1beta/sangue , Interleucina-1beta/metabolismo , Leptina/metabolismo , Metabolismo dos Lipídeos/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Camellia japonica bee pollen is one of the major types of bee pollen in China and exhibits antioxidant and anti-inflammatory activities. The aims of our study were to evaluate the effects and the possible mechanism of Camellia japonica bee pollen polyphenols on the treatment of hyperuricemia induced by potassium oxonate (PO). The results showed that Camellia japonica bee pollen ethyl acetate extract (CPE-E) owned abundant phenolic compounds and strong antioxidant capabilities. Administration with CPE-E for two weeks greatly reduced serum uric acid and improved renal function. It inhibited liver xanthine oxidase (XOD) activity and regulated the expression of urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), organic anion transporter 1 (OAT1), organic cation transporter 1 (OCT1) and ATP-binding cassette superfamily gmember 2 (ABCG2) in kidneys. Moreover, CPE-E suppressed the activation of the toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-κB (TLR4/MyD88/NF-κB) signaling pathway and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in PO-treated mice, and related inflammatory cytokines were reduced. CPE-E also modulated gut microbiota structure, showing that the abundance of Lactobacillus and Clostridiaceae increased in hyperuicemic mice. This study was conducted to explore the protective effect of CPE-E on hyperuricemia and provide new thoughts for the exploitation of Camellia japonica bee pollen.
Assuntos
Abelhas , Camellia/química , Hiperuricemia/tratamento farmacológico , Ácido Oxônico/efeitos adversos , Pólen/química , Polifenóis/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Anti-Inflamatórios , Antioxidantes , China , Modelos Animais de Doenças , Proteínas Facilitadoras de Transporte de Glucose , Humanos , Hiperuricemia/induzido quimicamente , Inflamassomos/metabolismo , Rim/metabolismo , Fígado/metabolismo , Camundongos , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Fator 1 de Transcrição de Octâmero , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like , Ácido ÚricoRESUMO
BACKGROUND: Hyperuricemia (HUA) is characterized by abnormal serum uric acid (UA) levels and demonstrated to be involved in renal injury leading to hyperuricemic nephropathy (HN). Apigenin (API), a flavonoid naturally present in tea, berries, fruits, and vegetables, exhibits various biological functions, such as antioxidant and anti-inflammatory activity. PURPOSE: To investigate the effect of API treatment in HN and to reveal its underlying mechanisms. METHODS: The mice with HN were induced by potassium oxonate intraperitoneally and orally administered for two weeks. The effects of API on renal function, inflammation, fibrosis, and uric acid (UA) metabolism in mice with HN were evaluated. The effects of API on urate transporters were further examined in vitro. RESULTS: The mice with HN exhibited abnormal renal urate excretion and renal dysfunction accompanied by increased renal inflammation and fibrosis. In contrast, API reduced the levels of serum UA, serum creatinine (CRE), blood urea nitrogen (BUN) and renal inflammatory factors in mice with HN. Besides, API ameliorated the renal fibrosis via Wnt/ß-catenin pathway suppression. Furthermore, API potently promoted urinary UA excretion and inhibited renal urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in mice with HN. In vitro, API competitively inhibited URAT1 and GLUT9 in a dose-dependent manner, with IC50 values of 0.64 ± 0.14 µM and 2.63 ± 0.69 µM, respectively. CONCLUSIONS: API could effectively attenuate HN through co-inhibiting UA reabsorption and Wnt/ß-catenin pathway, and thus it might be a potential therapy to HN.
Assuntos
Apigenina/farmacologia , Proteínas Facilitadoras de Transporte de Glucose/antagonistas & inibidores , Hiperuricemia/tratamento farmacológico , Nefropatias/tratamento farmacológico , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Animais , Apigenina/administração & dosagem , Creatinina/sangue , Relação Dose-Resposta a Droga , Fibrose , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Células HEK293 , Humanos , Hiperuricemia/induzido quimicamente , Hiperuricemia/fisiopatologia , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Camundongos , Nefrite/tratamento farmacológico , Nefrite/patologia , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Ácido Oxônico/toxicidade , Ácido Úrico/sangue , Ácido Úrico/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismoRESUMO
Although benzbromarone (BBR) is a conventional, highly potent uricosuric drug, it is not a standard medicine because it causes rare but fatal fulminant hepatitis. We transformed the bis-aryl ketone structure of BBR to generate novel monocyclic amide-linked phenol derivatives that should possess uric acid excretion activity without adverse properties associated with BBR. The derivatives were synthesized and tested for uric acid uptake inhibition (UUI) in two assays using either urate transporter 1-expressing cells or primary human renal proximal tubule epithelial cells. We also evaluated their inhibitory activity against mitochondrial respiration as a critical mitochondrial toxicity parameter. Some derivatives with UUI activity had no mitochondrial toxicity, including compound 3f, which effectively lowered the plasma uric acid level in Cebus apella. Thus, 3f is a promising candidate for further development as a uricosuric agent.
Assuntos
Amidas/química , Fenol/síntese química , Ácido Úrico/metabolismo , Uricosúricos/síntese química , Animais , Benzobromarona/química , Benzobromarona/farmacologia , Avaliação Pré-Clínica de Medicamentos , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Humanos , Mitocôndrias/efeitos dos fármacos , Fenol/efeitos adversos , Fenol/farmacologia , Pirróis/química , Sapajus apella , Transdução de Sinais , Relação Estrutura-Atividade , Ácido Úrico/sangue , Uricosúricos/efeitos adversos , Uricosúricos/farmacocinéticaRESUMO
BACKGROUND: This study aim at assessing C. abbreviata aqueous extracts for its potential to exhibit anti-diabetic activity in skeletal muscle cells. In addition to the toxicological and glucose absorption studies, the action of C. abbreviata extracts on some major genes involved in the insulin signaling pathway was established. METHODS: The in vitro cytotoxic effects C. abbreviata was evaluated on muscle cells using the MTT assay and the in vitro glucose uptake assay conducted using a modified glucose oxidase method described by Van de Venter et al. (2008). The amount of GLUT-4 on cell surfaces was estimated quantitatively using the flow cytometry technique. Real time quantitative PCR (RT-qPCR) was used to determine the expression of GLUT-4, IRS-1, PI3 K, Akt1, Akt2, PPAR-γ. RESULTS: Cytotoxicity tests revealed that all extracts tested at various concentrations were non-toxic (LC50 > 5000). Aqueous extracts of leaves, bark and seeds resulted in a dose-dependent increase in glucose absorption by cells, after 1 h, 3 h and 6 h incubation period. Extracts of all three plant parts had the best effect after 3 h incubation, with the leaf extract showing the best activity across time (Glucose uptake of 29%, 56% and 42% higher than untreated control cells after treatment with 1 mg/ml extract at 1 h, 3 h and 6 h, respectively). All extracts, with the exception 500 µg/ml seed extract, induced a two-fold increase in GLUT-4 translocation while marginally inducing GLUT-10 translocation in the muscle cells. The indirect immunofluorescence confirmed that GLUT-4 translocation indeed occurred. There was an increased expression of GLUT-4, IRS1 and PI3 K in cells treated with insulin and bark extract as determined by the RT-qPCR. CONCLUSION: The study reveals that glucose uptake involves GLUT-4 translocation through a mechanism that is likely to involve the upstream effectors of the PI3-K/Akt pathway.
Assuntos
Cassia , Animais , Glucose , Proteínas Facilitadoras de Transporte de Glucose , Camundongos , Fibras Musculares Esqueléticas , Músculo Esquelético , Extratos VegetaisRESUMO
Bee pollen possesses potential hypoglycemic effects but its inhibitory mechanisms on glucose absorption and transportation in intestinal cells still need to be clarified. Here, we determined the inhibitory effects of bee pollen extract originating from Camellia sinensis L. (BP-Cs) as well as its representative phenolic compounds on glucose uptake and transport through a human intestinal Caco-2 cell monolayer model. It showed that three representative phenolic compounds, including gallic acid (GA), 3-O-[6'-O-(trans-p-coumaroyl)-ß-d-glucopyranosyl]kaempferol (K1), and 3-O-[2',6'-di-O-(trans-p-coumaroyl)-ß-d-glucopyranosyl]kaempferol (K2), with contents of 27.7 ± 0.86, 9.88 ± 0.54, and 7.83 ± 0.46 µg/mg in BP-Cs extract, respectively, exerted mutual antagonistic actions interacting with glucose transporters to inhibit glucose uptake and transport based on their combination index (CI) and molecular docking analysis. K1, K2, and GA might compete with d-glucose to form hydrogen bonds with the same active residues including GLU-412, GLY-416, GLN-314, and TRP-420 in GLUT2. These findings provide us a deep understanding of the mechanisms underlying the anti-hyperglycemia by bee pollen, which provide a new sight on dietary intervention strategies against diabetes.
Assuntos
Camellia sinensis , Animais , Abelhas , Células CACO-2 , Glucose , Proteínas Facilitadoras de Transporte de Glucose , Humanos , Simulação de Acoplamento Molecular , Extratos Vegetais/farmacologia , PólenRESUMO
Reduction of intestinal glucose absorption might result from either delayed carbohydrate digestion or blockage of glucose transporters. Previously, oxyresveratrol was shown to inhibit α-glucosidase, but its effect on glucose transporters has not been explored. The present study aimed to assess oxyresveratrol-induced inhibition of the facilitative glucose transporter 2 and the active sodium-dependent glucose transporter 1. An aqueous extract of Artocarpus lacucha, Puag Haad, which is oxyresveratrol-enriched, was also investigated. Glucose transport was measured by uptake into Caco-2 cells through either glucose transporter 2 or sodium-dependent glucose transporter 1 according to the culture conditions. Oxyresveratrol (40 to 800 µM) dose-dependently reduced glucose transport, which appeared to inhibit both glucose transporter 2 and sodium-dependent glucose transporter 1. Puag Haad at similar concentrations also inhibited these transporters but with greater efficacy. Oxyresveratrol and Puag Haad could help reduce postprandial hyperglycemic peaks, which are considered to be most damaging in diabetics.
Assuntos
Artocarpus , Proteínas Facilitadoras de Transporte de Glucose/antagonistas & inibidores , Extratos Vegetais/farmacologia , Estilbenos/farmacologia , Artocarpus/química , Células CACO-2 , Glucose , HumanosRESUMO
Inhibition of fructose absorption may suppress adiposity and adiposity-related diseases caused by fructose ingestion. Eucalyptus leaf extract (ELE) inhibits intestinal fructose absorption (but not glucose absorption); however, its active compound has not yet been identified. Therefore, we evaluated the inhibitory activity of ELE obtained from Eucalyptus globulus using an intestinal fructose permeation assay with the human intestinal epithelial cell line Caco-2. The luminal sides of a cell monolayer model cultured on membrane filters were exposed to fructose with or without the ELE. Cellular fructose permeation was evaluated by measuring the fructose concentration in the medium on the basolateral side. ELE inhibited 65% of fructose absorption at a final concentration of 1 mg/mL. Oenothein B isolated from the ELE strongly inhibited fructose absorption; the inhibition rate was 63% at a final concentration of 5 µg/mL. Oenothein B did not affect glucose absorption. In contrast, the other major constituents (i.e., gallic acid and ellagic acid) showed little fructose-inhibitory activity. To our knowledge, this is the first report that oenothein B in ELE strongly inhibits fructose absorption in vitro. ELE containing oenothein B can prevent and ameliorate obesity and other diseases caused by dietary fructose consumption.