RESUMEN
Sophisticated immune evasion strategies enable Helicobacter pylori (H. pylori) to colonize the gastric mucosa of approximately half of the world's population. Persistent infection and the resulting chronic inflammation are a major cause of gastric cancer. To understand the intricate interplay between H. pylori and host immunity, spatial profiling was used to monitor immune cells in H. pylori infected gastric tissue. Dendritic cell (DC) and T cell phenotypes were further investigated in gastric organoid/immune cell co-cultures and mechanistic insights were acquired by proteomics of human DCs. Here, we show that ADP-heptose, a bacterial metabolite originally reported to act as a bona fide PAMP, reduces H. pylori-induced DC maturation and subsequent T cell responses. Mechanistically, we report that H. pylori uptake and subsequent DC activation by an ADP-heptose deficient H. pylori strain depends on TLR2. Moreover, ADP-heptose attenuates full-fledged activation of primary human DCs in the context of H. pylori infection by impairing type I IFN signaling. This study reveals that ADP-heptose mitigates host immunity during H. pylori infection.
Asunto(s)
Células Dendríticas , Infecciones por Helicobacter , Helicobacter pylori , Receptor Toll-Like 2 , Helicobacter pylori/inmunología , Células Dendríticas/inmunología , Células Dendríticas/microbiología , Células Dendríticas/metabolismo , Células Dendríticas/efectos de los fármacos , Humanos , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/inmunología , Receptor Toll-Like 2/metabolismo , Evasión Inmune , Heptosas/metabolismo , Heptosas/farmacología , Mucosa Gástrica/microbiología , Mucosa Gástrica/inmunología , Mucosa Gástrica/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Adenosina Difosfato/metabolismo , LipopolisacáridosRESUMEN
The persistence of Helicobacter pylori in the human gastric mucosa implies that the immune response fails to clear the infection. We found that H. pylori compromises the antigen presentation ability of macrophages, because of the decline of the presenting molecules HLA-II. Here, we reveal that the main bacterial factor responsible for this effect is ADP-heptose, an intermediate metabolite in the biosynthetic pathway of lipopolysaccharide (LPS) that elicits a pro-inflammatory response in gastric epithelial cells. In macrophages, it upregulates the expression of miR146b which, in turn, would downmodulate CIITA, the master regulator for HLA-II genes. Hence, H. pylori, utilizing ADP-heptose, exploits a specific arm of macrophage response to establish its survival niche in the face of the immune defense elicited in the gastric mucosa.
Asunto(s)
Presentación de Antígeno/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Helicobacter pylori/fisiología , Heptosas/farmacología , Antígenos de Histocompatibilidad Clase II/metabolismo , Macrófagos/efectos de los fármacos , Helicobacter pylori/metabolismo , Heptosas/química , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/microbiología , Proteínas Nucleares/metabolismo , Transactivadores/metabolismoRESUMEN
Covering: up to 2020Glycosylated natural products hold great potential as drugs for the treatment of human and animal diseases. Heptoses, known as seven-carbon-chain-containing sugars, are a group of saccharides that are rarely observed in natural products. Based on the structures of the heptoses, the heptose-containing natural products can be divided into four groups, characterized by heptofuranose, highly-reduced heptopyranose, D-heptopyranose, and L-heptopyranose. Many of them possess remarkable biological properties, including antibacterial, antifungal, antitumor, and pain relief activities, thereby attracting great interest in biosynthesis and chemical synthesis studies to understand their construction mechanisms and structure-activity relationships. In this review, we summarize the structural properties, biological activities, and recent progress in the biosynthesis of bacterial natural products featuring seven-carbon-chain-containing sugars. The biosynthetic origins of the heptose moieties are emphasized.
Asunto(s)
Bacterias/metabolismo , Productos Biológicos/metabolismo , Heptosas/biosíntesis , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Productos Biológicos/farmacología , Heptosas/química , Heptosas/aislamiento & purificación , Heptosas/farmacologíaRESUMEN
Beginning at 16 weeks of age and continuing for 44 weeks, male C57BL/6J were fed either a control (CON) diet; a high-fat (HF) diet (60% unsaturated); or the HF diet containing an extract of unripe avocados (AvX) enriched in the 7-carbon sugar mannoheptulose (MH), designed to act as a glycolytic inhibitor (HF + MH). Compared to the CON diet, mice on the HF diet exhibited higher body weights; body fat; blood lipids; and leptin with reduced adiponectin levels, insulin sensitivity, VO2max, and falls from a rotarod. Mice on the HF + MH diet were completely protected against these changes in the absence of significant diet effects on food intake. Compared to the CON diet, oxidative stress was also increased by the HF diet indicated by higher levels of total reactive oxygen species, superoxide, and peroxynitrite measured in liver samples by electron paramagnetic resonance spectroscopy, whereas the HF + MH diet attenuated these changes. Compared to the CON, the HF diet increased signaling in the mechanistic target of the rapamycin (mTOR) pathway, and the addition of the MH-enriched AvX to this diet attenuated these changes. Beyond generating further interest in the health benefits of avocados, these results draw further new attention to the effects of this rare sugar, MH, as a botanical intervention for preventing obesity.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Suplementos Dietéticos , Heptosas/administración & dosificación , Obesidad/etiología , Obesidad/prevención & control , Persea/química , Fitoterapia , Extractos Vegetales/administración & dosificación , Animales , Heptosas/análisis , Heptosas/farmacología , Masculino , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/análisis , Extractos Vegetales/farmacología , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
d-Glycero-d-manno-heptose-1ß,7-bisphosphate (HBP) and d-glycero-d-manno-heptose-1ß-phosphate (H1P) are bacterial metabolites that were recently shown to stimulate inflammatory responses in host cells through the activation of the TIFA-dependent NF-κB pathway. To better understand structure-based activity in relation to this process, a family of nonhydrolyzable phosphonate analogues of HBP and H1P was synthesized. The inflammation modulation by which these molecules induce the TIFA-NF-κB signal axis was evaluated inâ vivo at a low-nanomolar concentration (6â nM) and compared to that of the natural metabolites. Our data showed that three phosphonate analogues had similar stimulatory activity to HBP, whereas two phosphonates antagonized HBP-induced TIFA-NF-κB signaling. These results open new horizons for the design of pro-inflammatory and innate immune modulators that could be used as vaccine adjuvant.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/inmunología , Heptosas/farmacología , Inflamación/inmunología , FN-kappa B/inmunología , Fosfatos/farmacología , Proteínas Adaptadoras Transductoras de Señales/genética , Conformación de Carbohidratos , Diseño de Fármacos , Heptosas/síntesis química , Heptosas/química , Humanos , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/inmunología , FN-kappa B/genética , Fosfatos/síntesis química , Fosfatos/química , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunologíaRESUMEN
Antimetabolites are small molecules that inhibit enzymes by mimicking physiological substrates. We report the discovery and structural elucidation of the antimetabolite 7-deoxy-sedoheptulose (7dSh). This unusual sugar inhibits the growth of various prototrophic organisms, including species of cyanobacteria, Saccharomyces, and Arabidopsis. We isolate bioactive 7dSh from culture supernatants of the cyanobacterium Synechococcus elongatus. A chemoenzymatic synthesis of 7dSh using S. elongatus transketolase as catalyst and 5-deoxy-D-ribose as substrate allows antimicrobial and herbicidal bioprofiling. Organisms treated with 7dSh accumulate 3-deoxy-D-arabino-heptulosonate 7-phosphate, which indicates that the molecular target is 3-dehydroquinate synthase, a key enzyme of the shikimate pathway, which is absent in humans and animals. The herbicidal activity of 7dSh is in the low micromolar range. No cytotoxic effects on mammalian cells have been observed. We propose that the in vivo inhibition of the shikimate pathway makes 7dSh a natural antimicrobial and herbicidal agent.
Asunto(s)
Anabaena/crecimiento & desarrollo , Antimetabolitos/farmacología , Arabidopsis/crecimiento & desarrollo , Cianobacterias/metabolismo , Heptosas/farmacología , Redes y Vías Metabólicas , Ácido Shikímico/metabolismo , Anabaena/efectos de los fármacos , Antifúngicos/farmacología , Arabidopsis/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular , Heptosas/aislamiento & purificación , Herbicidas/toxicidad , Redes y Vías Metabólicas/efectos de los fármacos , Metaboloma , Liasas de Fósforo-Oxígeno/antagonistas & inhibidores , Liasas de Fósforo-Oxígeno/metabolismo , Fotosíntesis/efectos de los fármacos , Plantones/efectos de los fármacos , Plantones/crecimiento & desarrollo , Synechococcus/metabolismoRESUMEN
d-glycero-ß-d-manno-heptose 1,7-biphosphate (HBP) is an enzymatic intermediate in the biosynthesis of the heptose component of lipopolysaccharide (LPS), and was recently revealed to be a pathogen-associated molecular pattern (PAMP) that allows detection of Gram-negative bacteria by the mammalian immune system. Cellular detection of HBP depends upon its stimulation of a cascade that leads to the phosphorylation and assembly of the TRAF-interacting with forkhead-associated domain protein A (TIFA), which activates the transcription factor NF-κB. In this note, an alternate chemical synthesis of HBP is described and its biological activity is established, providing pure material for further assessing and exploiting the biological activity of this compound.
Asunto(s)
Heptosas/química , Heptosas/síntesis química , Fosfatos/química , Fosfatos/síntesis química , Línea Celular Tumoral , Técnicas de Química Sintética , Heptosas/farmacología , Humanos , FN-kappa B/metabolismo , Fosfatos/farmacologíaRESUMEN
We evaluated the major active components isolated from Corni Fructus: loganin, morroniside, and 7-O-galloyl-D-sedoheptulose as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ß-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) for use in Alzheimer's disease treatment. These compounds exhibited predominant cholinesterase (ChEs) inhibitory effects with IC50 values of 0.33, 3.95, and 10.50 ± 1.16 µM, respectively, for AChE, and 33.02, 37.78, and 87.94 ± 4.66 µM, respectively, for BChE. Kinetics studies revealed that loganin and 7-O-galloyl-D-sedoheptulose inhibited AChE with characteristics typical of mixed inhibitors, while morroniside was found to be a noncompetitive inhibitor against AChE and also exerted mixed BChE inhibitory activities. For BACE1, loganin showed noncompetitive type inhibitory effects, while morroniside and 7-O-galloyl-D-sedoheptulose were found to be mixed inhibitors. Furthermore, these compounds exhibited dose-dependent inhibitory activity with ONOO(-)-mediated protein tyrosine nitration. Molecular docking simulation of these compounds demonstrated negative binding energies for ChEs, and BACE1, indicating high affinity and tighter binding capacity for the active site of the enzyme. Loganin was the most potent inhibitor against both ChEs and BACE1. The data suggest that these compounds together can act as a triple inhibitor of AChE, BChE, and BACE1, providing a preventive and therapeutic strategy for Alzheimer's disease treatment.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores de la Colinesterasa/aislamiento & purificación , Cornus/química , Descubrimiento de Drogas/métodos , Glicósidos/aislamiento & purificación , Heptosas/aislamiento & purificación , Iridoides/aislamiento & purificación , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/enzimología , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Glicósidos/química , Glicósidos/farmacología , Heptosas/química , Heptosas/farmacología , Iridoides/química , Iridoides/farmacología , Cinética , Simulación del Acoplamiento Molecular , Unión ProteicaRESUMEN
7-O-Galloyl-D-sedoheptulose (GS) is the bioactive polyphenol isolated from the low-molecular-weight fraction of Corni Fructus (Cornus officinalis Sieb. et Zucc.). The present study was conducted to examine whether GS has an ameliorative effect on the liver of type 2 diabetic db/db mice. GS (20 or 100 mg/kg body weight/day, per os) was administered every day for 6 weeks to db/db mice, and its effect was compared with vehicle-treated db/db and m/m mice. The administration of GS decreased the elevated serum glucose, leptin, insulin, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), resistin, and hepatic functional parameters, and reduced the increased fluorescent advanced glycation endproducts (AGEs) and reactive oxygen species in the liver. The db/db mice exhibited the up-regulation of receptor for AGEs (RAGE) and AGE-related proteins; however, GS treatment significantly reduced those expressions. Moreover, the augmented expressions of oxidative stress- and inflammation-related proteins, phospho-extracellular-signal regulated kinase 1/2, phospho-c-Jun N-terminal kinase, nuclear factor-kappa B, activator protein-1, monocyte chemotactic protein-1, intracellular adhesion molecule-1, TNF-α, and IL-6, were down-regulated by GS administration. Hematoxylin-eosin staining showed that the increased hepatocellular damage in the liver of db/db mice improved with GS administration. The present results support the evidence for GS ameliorating hepatic damage through the RAGE-mediated inflammation pathway.
Asunto(s)
Cornus/química , Diabetes Mellitus Tipo 2/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Heptosas/farmacología , Polifenoles/farmacología , Animales , Biomarcadores/sangre , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/patología , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Productos Finales de Glicación Avanzada/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Tamaño de los Órganos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Polifenoles/aislamiento & purificación , Receptor para Productos Finales de Glicación Avanzada/metabolismoRESUMEN
The aim of the present study was to evaluate the beneficial effects of 7-O-galloyl-D-sedoheptulose (GS), isolated from Corni Fructus, using type 2 diabetic mice. GS was orally administered to db/db mice at doses of 20 and 100 mg/kg body weight per day for 6 weeks, and the effects of GS on biochemical factors in serum and adipose tissue were investigated. To define the underlying mechanism of these effects, protein expressions related to lipid metabolism, inflammation, fibrosis, and apoptosis, were measured. The results showed that levels of glucose, leptin, insulin, C-peptide, resistin, tumor necrosis factor-α, interleukin-6, triglycerides, total cholesterol, non-esterified fatty acids, high-density lipoprotein cholesterol, very low-density lipoprotein cholesterol/low-density lipoprotein cholesterol, reactive oxygen species (ROS), and thiobarbituric acid-reactive substance (TBARS) in serum were down-regulated, while adiponectin was augmented by GS treatment. In addition, the elevated lipid, ROS, and TBARS contents in adipose tissue as well as serum levels in db/db mice were significantly decreased by the oral administration of GS. From protein analysis, the decreased expressions of peroxisome proliferator activated receptor (PPAR)α, PPARγ, and B-cell lymphoma 2 were up-regulated in the adipose tissue of db/db mice. The administration of GS significantly decreased sterol regulatory element binding protein-1, nuclear factor-kappa ?>Bp65, cyclooxygenase-2, inducible nitric oxide synthase, monocyte chemotactic protein-1, intracellular adhesion molecule-1, phosphor c-Jun N-terminal kinase, activator protein-1, transforming growth factor-ß1, Bax, cytochrome c, and caspase-3 expressions. These results suggest that GS acts as a regulator of oxidative stress, inflammation, fibrosis, and apoptosis in the adipose tissue of db/db mice.
Asunto(s)
Tejido Adiposo/efectos de los fármacos , Cornus/química , Diabetes Mellitus Tipo 2/metabolismo , Medicamentos Herbarios Chinos/farmacología , Heptosas/farmacología , Fitoterapia , Tejido Adiposo/metabolismo , Animales , Apoptosis/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/uso terapéutico , Fibrosis , Frutas/química , Heptosas/aislamiento & purificación , Heptosas/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Estrés Oxidativo/efectos de los fármacosRESUMEN
Compelling evidence indicates that polyphenolic antioxidants show protective effects against diabetic complications. We investigated the effects of a polyphenolic compound, 7-O-galloyl-D-sedoheptulose (GS), from Corni Fructus on a type 2 diabetic db/db mouse model. After 6 weeks of GS treatment, the effects of GS on serum and pancreatic biochemical factors were investigated. To define the underlying mechanism of these effects, we examined several key inflammatory markers, and inflammation-related oxidative stress markers. The results showed that levels of glucose, leptin, insulin, C-peptide, resistin, tumor necrosis factor-α, and interleukin-6 in serum were down-regulated, while adiponectin was augmented by GS treatment. In addition, GS suppressed reactive oxygen species and lipid peroxidation in the pancreas, but increased the pancreatic insulin and pancreatic C-peptide contents. Moreover, GS modulated protein expressions of pro-inflammatory nuclear factor-kappa Bp 65, cyclooxygenase-2, inducible nitric oxide synthase, c-Jun N-terminal kinase (JNK), phospho-JNK, activator protein-1, transforming growth factor-ß1, and fibronectin. Based on these results, we conclude that a plausible mechanism of GS's anti-diabetic action may well be its anti-inflammatory property and anti-inflammatory-related anti-oxidative action. Thus, further investigation of GS as an effective anti-diabetic treatment for type 2 diabetes is warranted.
Asunto(s)
Antiinflamatorios/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Heptosas/uso terapéutico , Hipoglucemiantes/uso terapéutico , Animales , Antiinflamatorios/farmacología , Glucemia/análisis , Péptido C/metabolismo , Cornus , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Modelos Animales de Enfermedad , Fibronectinas/metabolismo , Heptosas/farmacología , Hipoglucemiantes/farmacología , Insulina/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Masculino , Ratones , Estrés Oxidativo/efectos de los fármacos , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Páncreas/patología , Especies Reactivas de Oxígeno/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Factor de Transcripción AP-1/metabolismoRESUMEN
OBJECTIVES: This study was carried out to verify the preventive effects of 7-O-galloyl-d-sedoheptulose (GS), a phenolic compound isolated from Corni Fructus, underlying diabetic renal damage in type 2 diabetes. METHODS: GS was orally administered to db/db mice at doses of 20 and 100 mg/kg body weight per day for six weeks, and its effects were compared with those of the vehicle in db/db and m/m mice. KEY FINDINGS: In the serum and kidney, biochemical factors and expression of protein related to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, apoptosis and inflammation were examined. GS treatment attenuated serum and renal oxidative stress through reduction of reactive oxygen species and lipid peroxidation and increase in the ratio of glutathione and its oxidised form. Importantly, GS reduced renal protein expression of Nox-4 and p22(phox) (one of the subunits of NADPH oxidase), pro-apoptotic factors (such as Bax and cytochrome c) and nuclear factor-kappa B-targeting pro-inflammatory inducible nitric oxide synthase and cyclooxygenase-2. CONCLUSIONS: These renoprotective effects of GS were achieved through attenuation of diabetes-induced oxidative stress and its sensitive protein expression associated with inflammation and apoptosis in db/db mice.
Asunto(s)
Apoptosis/efectos de los fármacos , Cornus/química , Nefropatías Diabéticas/prevención & control , Heptosas/uso terapéutico , Inflamación/prevención & control , Riñón/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Animales , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antioxidantes/aislamiento & purificación , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Proteínas Reguladoras de la Apoptosis/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/metabolismo , Glutatión/metabolismo , Heptosas/aislamiento & purificación , Heptosas/farmacología , Inflamación/sangre , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Riñón/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , NADPH Oxidasa 4 , NADPH Oxidasas/sangre , NADPH Oxidasas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fenoles/aislamiento & purificación , Fenoles/farmacología , Fenoles/uso terapéutico , Fitoterapia , Extractos Vegetales/química , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéuticoRESUMEN
The present study was conducted to examine whether 7-O-galloyl-D-sedoheptulose (GS) has an ameliorative effect on diabetic alterations such as oxidative stress, inflammation, and apoptosis in the liver of type 2 diabetic db/db mice. GS was administered at 20 or 100 mg/kg body weight per day for 6 weeks to db/db mice, and its effect was compared with vehicle-treated db/db and m/m mice. In the serum and hepatic tissue, biochemical factors and protein expressions associated with nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, inflammation, and apoptosis were examined. As a result, GS administration to type 2 diabetic mice lowered serum and hepatic oxidative stress through the reduction of reactive oxygen species and lipid peroxidation. These results were derived, at least in part, from attenuating the expression of NADPH oxidase subunit proteins, Nox-4 and p22(phox). In the diabetic condition, augmented nuclear factor (NF)-E2-related factor 2 and heme oxygenase-1 were reduced with a decrease in oxidative stress on GS treatment. Furthermore, in the GS-treated group, NF-kappa B-related pro-inflammatory factors and pro-apoptotic protein expressions were alleviated in the hepatic tissue. Taking these into consideration, our findings support the therapeutic evidence for GS ameliorating the development of diabetic complications via regulating oxidative stress, inflammation, and apoptosis.
Asunto(s)
Antioxidantes/farmacología , Proteínas Reguladoras de la Apoptosis/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Heptosas/farmacología , Hepatopatías/metabolismo , FN-kappa B/metabolismo , Animales , Antioxidantes/uso terapéutico , Apoptosis/efectos de los fármacos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/patología , Modelos Animales de Enfermedad , Heptosas/uso terapéutico , Hepatopatías/tratamiento farmacológico , Hepatopatías/etiología , Hepatopatías/patología , Masculino , Ratones , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
The glucose phosphorylating enzyme glucokinase plays a crucial role in stimulus-secretion coupling in pancreatic beta cells and in glucose metabolism in liver. Glucose mediates a shift of the enzyme's conformational equilibrium towards the closed conformation with high glucokinase activity. Further activation of glucokinase is endogenously mediated by interaction with the bisphosphatase domain (FBPase-2) of the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2) and can be achieved also by a new class of glucokinase activators (GKA), chemical compounds that might be suited for type 2 diabetes therapy. While FBPase-2 increased only the phosphorylating capacity of glucokinase, the GKA LY2121260 augmented in addition the affinity of glucokinase for glucose. PFK-2/FBPase-2 but not LY2121260 antagonized glucokinase inhibition by the competitive glucokinase inhibitor mannoheptulose at increasing glucose concentrations. Interestingly, an additive activation of glucokinase was observed by use of recombinant FBPase-2 together with LY2121260. This new crucial observation could be confirmed with cellular extracts containing the glucokinase and PFK-2/FBPase-2 proteins. Addition of LY2121260 resulted in a further significant increase in glucokinase activity. Because the glucokinase-PFK-2/FBPase-2 complex was conserved under LY2121260 treatment as shown by size exclusion chromatography a concerted action of both activators towards the closed active glucokinase conformation can be anticipated. Thus, as a result of the additive effect of both activators on glucokinase activity, the largest increase of glucose-induced insulin secretion was observed in the combined presence of PFK-2/FBPase-2 and LY2121260.
Asunto(s)
Glucoquinasa/metabolismo , Fosfofructoquinasa-2/metabolismo , Sulfonas/farmacología , Tiazoles/farmacología , Línea Celular , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Glucoquinasa/antagonistas & inhibidores , Glucosa/farmacología , Heptosas/farmacología , Humanos , Insulina/metabolismo , Secreción de Insulina , Manoheptulosa/farmacología , Fosfofructoquinasa-2/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMEN
The protective effect of 7-O-galloyl-D-sedoheptulose (GS), isolated from Corni Fructus as an active component, against acute renal failure (ARF) induced by glycerol was investigated. The administration of GS led to a decline in the levels of blood urea nitrogen and creatinine; on the other hand, it did not have a significant effect on creatinine clearance. Furthermore, GS also significantly decreased the urine volume and fractional excretion of sodium, but it increased the urine osmolarity, suggesting the protective role of GS against renal dysfunction. Oxidative stress under ARF was attenuated by GS through the inhibition of lipid peroxidation, scavenging of reactive oxygen species (ROS), and elevation of the antioxidative status. Renal oxidative stress is related to the overproduction of ROS by nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase; therefore, in the present study, the protein expression of p22(phox) and NAD(P)H oxidase-4 (Nox-4) was investigated. GS down-regulated the protein expression of p22(phox); on the other hand, it did not significantly affect the expression of Nox-4. This indicates that GS inhibits the production of superoxide by regulating a component of NAD(P)H oxidase, p22(phox). Furthermore, GS down-regulated the expressions of nuclear factor-κB (NF-κΒ) and inducible nitric oxide (NO) synthase (iNOS), suggesting that GS protects against NO-induced inflammatory pathological conditions under ARF through the regulation of NF-κB and iNOS expressions. The present study indicates that GS exerts a protective effect against ARF through the recovery of renal dysfunction and attenuation of renal oxidative stress by regulating related protein expression.
Asunto(s)
Lesión Renal Aguda/tratamiento farmacológico , Cornus/química , Medicamentos Herbarios Chinos/uso terapéutico , Heptosas/uso terapéutico , Riñón/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Fitoterapia , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Animales , Antioxidantes/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Regulación hacia Abajo , Medicamentos Herbarios Chinos/farmacología , Frutas , Glicerol , Heptosas/farmacología , Mediadores de Inflamación/metabolismo , Riñón/fisiopatología , Peroxidación de Lípido/efectos de los fármacos , Masculino , NADPH Oxidasa 4 , NADPH Oxidasas/metabolismo , Concentración Osmolar , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Sodio/metabolismo , Superóxidos/metabolismo , Micción/efectos de los fármacosRESUMEN
The aim of the present study was to evaluate the beneficial effects of 7-O-galloyl-D-sedoheptulose (GS), isolated from Corni Fructus, on hepatic and renal lipid metabolisms and advanced glycation endproduct formation followed by oxidative stress and inflammation using type 2 diabetic mice. GS was orally administered to db/db mice at doses of 20 and 100 mg/kg body weight per day for 8 weeks, and its effects were compared with those of the vehicle in db/db and m/m mice. The serum, hepatic, and renal biochemical factors, and protein expressions related to lipid metabolism, inflammation, advanced glycation endproducts, and their receptors, were measured. After 8 weeks of GS treatment, elevation of serum adiponectin as well as an improvement of hepatic and renal functional parameters was shown in db/db mice, and significant reductions of lipids in serum, liver, and kidney were observed according to the down-regulation of sterol regulatory element-binding protein-1. Moreover, GS inhibited oxidative stress and advanced glycation endproduct formation and their receptor expressions in the liver and kidney of db/db mice. These results suggest that GS could effectively inhibit advanced glycation endproduct formation caused by oxidative stress and/or dyslipidemia in the liver and kidney of db/db mice. Furthermore, the augmented expression of nuclear factor-kappa B p65 and its related inflammatory protein expressions were down-regulated in GS-treated groups. In conclusion, GS could have hepato- and reno-protective effects against abnormal lipid metabolism and the reactive oxygen species-related formation of advanced glycation endproducts with inflammation in type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Heptosas/farmacología , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Biomarcadores/metabolismo , Peso Corporal/efectos de los fármacos , Colesterol/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/fisiopatología , Ingestión de Líquidos/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/metabolismo , Pruebas Hematológicas , Riñón/metabolismo , Riñón/patología , Riñón/fisiopatología , Hígado/metabolismo , Hígado/patología , Hígado/fisiopatología , Masculino , Ratones , Tamaño de los Órganos/efectos de los fármacos , Triglicéridos/metabolismoRESUMEN
OBJECTIVES: We investigated the lipid-lowering activity of 7-O-galloyl-D-sedoheptulose, an active component of Corni Fructus, and related mechanisms. METHODS: Rats were fed a high-fructose diet for 6 days, followed by treatment with 7-O-galloyl-D-sedoheptulose, 5, 10 or 20 mg/kg per day, or fenofibrate (positive control). KEY FINDINGS: The high-fructose diet induced an increase in body weight, hypertriglyceridaemia, hyperglycaemia and hypertension. Administration of 7-O-galloyl-D-sedoheptulose significantly reduced the levels of triglyceride in the serum and liver (being more effective than fenofibrate) but did not lead to changes in liver weight or hepatic function, whereas fenofibrate increased the liver weight markedly. The preventive effect of 7-O-galloyl-D-sedoheptulose against the accumulation of triglyceride and cholesterol was related to the up-regulation of peroxisome proliferator-activated receptor alpha expression. CONCLUSIONS: The present study supports the role of 7-O-galloyl-D-sedoheptulose as a promising agent against hypertriglyceridaemia without hepatic side-effects.
Asunto(s)
Cornus/química , Heptosas/aislamiento & purificación , Heptosas/uso terapéutico , Hipertrigliceridemia/tratamiento farmacológico , Hipolipemiantes/aislamiento & purificación , Hipolipemiantes/uso terapéutico , Animales , Glucemia/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Colesterol/sangre , Colesterol/metabolismo , Dieta , Relación Dosis-Respuesta a Droga , Ácidos Grasos no Esterificados/sangre , Fructosa/administración & dosificación , Heptosas/farmacología , Hipolipemiantes/farmacología , Hígado/metabolismo , Masculino , PPAR alfa/metabolismo , Extractos Vegetales/uso terapéutico , Ratas , Ratas Wistar , Triglicéridos/sangre , Triglicéridos/metabolismoRESUMEN
Diabetes is the leading cause of end-stage renal failure, since glucose-dependent metabolic factors are synergistically activated within the diabetic kidney. Accordingly, in Japan, there is much debate over the health benefits of natural therapies to reduce these risk factors. In our previous study, we reported that Cornus officinalis SIEB. et ZUCC. possessed an antidiabetic effect via ameliorating glucose-mediated metabolic disorders as well as aminoguanidine, an inhibitor of advanced glycation endproduct (AGE) formation, with a renoprotective effect. The aim of the present study was to investigate the effect of 7-O-galloyl-D-sedoheptulose (GS) against diabetic oxidative stress and AGE formation. Streptozotocin-induced diabetic rats were orally administered GS for 20 d, and the changes in serum glucose levels, as well as those of body weight every 10 d were evaluated. In addition, glucose, fluorescent AGE, methylglyoxal, glycolaldehyde (GA), and immunoblotting analyses for heme oxygenase-1, receptor for AGE, N(epsilon)-(carboxymethyl)lysine, N(epsilon)-(carboxyethyl)lysine, and GA-pyridine were performed in the kidney at the end of the experiment. The results obtained in this study demonstrated that 20 d of treatment with GS had beneficial effects on hypoglycemic and renal metabolic abnormalities, including renal glucose, oxidative stress, and AGE formation. Together, our data help to elucidate its potential therapeutic value against diabetic kidney disease.
Asunto(s)
Antioxidantes/farmacología , Nefropatías Diabéticas/tratamiento farmacológico , Productos Finales de Glicación Avanzada/metabolismo , Heptosas/farmacología , Estrés Oxidativo/efectos de los fármacos , Aldehídos/metabolismo , Animales , Glucemia/metabolismo , Western Blotting , Peso Corporal/efectos de los fármacos , Cornus/química , Diabetes Mellitus Experimental/complicaciones , Glucosa/metabolismo , Hemo-Oxigenasa 1/biosíntesis , Riñón/efectos de los fármacos , Riñón/metabolismo , Pruebas de Función Renal , Masculino , Piruvaldehído/metabolismo , Ratas , Ratas Wistar , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
We designed and synthesized hydrogen bond based probes 1-8 with the exception of known glycosidase inhibition mechanisms, and aglycon specificity of 11 different sources of alpha-glucosidases were investigated using their probes. Probe 4 (2,6-anhydro-1-deoxy-1-[(1-oxopentyl-5-hydroxy)amino]-D-glycero-D-ido-heptitol) showed a potent inhibition of S. cerevisiae alpha-glucosidase among all alpha-glucosidases. Probe 4 was found to be a competitive inhibitor for S. cerevisiae alpha-glucosidase with Ki 0.13 mM.
Asunto(s)
Glucosamina/análogos & derivados , Inhibidores de Glicósido Hidrolasas , Heptosas/farmacología , 1-Desoxinojirimicina , Animales , Diseño de Fármacos , Geobacillus stearothermophilus/efectos de los fármacos , Geobacillus stearothermophilus/enzimología , Glucosamina/química , Heptosas/síntesis química , Heptosas/química , Enlace de Hidrógeno , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/enzimología , Relación Estructura-Actividad , Especificidad por Sustrato/efectos de los fármacosRESUMEN
The first report dealing with the use of monosaccharide esters as new tools in biomedicine was published in 1997 (1). This topic was first reviewed in 1998 (2). The major aim of the present report is to briefly evoke the background and present knowledge in this field.