ADP-heptose enables Helicobacter pylori to exploit macrophages as a survival niche by suppressing antigen-presenting HLA-II expression.

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.

Heptose-containing bacterial natural products: structures, bioactivities, and biosyntheses.

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.

Alternate synthesis to d-glycero-ß-d-manno-heptose 1,7-biphosphate.

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.

Polyphenol isolated from Corni Fructus, 7-O-galloyl-D-sedoheptulose, modulates advanced glycation endproduct-related pathway in type 2 diabetic db/db mice.

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.

Evaluation of 7-O-galloyl-D-sedoheptulose, isolated from Corni Fructus, in the adipose tissue of type 2 diabetic db/db mice.

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.

Anti-diabetic action of 7-O-galloyl-D-sedoheptulose, a polyphenol from Corni Fructus, through ameliorating inflammation and inflammation-related oxidative stress in the pancreas of type 2 diabetics.

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.

7-O-galloyl-D-sedoheptulose ameliorates renal damage triggered by reactive oxygen species-sensitive pathway of inflammation and apoptosis.

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.

Monosaccharide esters: new tools in biomedicine.

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.

Indonesian medicinal plants. XXIV. Stereochemical structure of perseitol x K+ complex isolated from the leaves of Scurrula fusca (Loranthaceae).

A complex of perseitol (D-glycero-D-galacto-heptitol) and K+ ions in a molar ratio of 20:1 was isolated from the leaves of Scurrula fusca (Loranthaceae), which has been traditionally used for the treatment of cancer in Sulawesi Island, Indonesia. The stereochemical structure of the complex in H2O solution has been elucidated by use of several kinds of NMR techniques. Furthermore, it has been found that the complex exhibits a potent inhibitory effect on [3H]-leucine incorporation for protein synthesis in Ehrlich ascites tumor cells in mice.

Separation of 6-deoxy-heptan [correction of 6-deoxy-heptane] from a smooth-type lipopolysaccharide preparation of Burkholderia pseudomallei.

Smooth-type lipopolysaccharide (LPS) of Burkholderia pseudomallei has been reported to contain two kinds of O-antigenic polysaccharides, a 1,3-linked homopolymer of 6-deoxy-heptose and a polymer with a repeating unit of -->3)-glucose-(1-->3)-6-deoxy-talose-(1--> with O-acetyl or O-methyl modifications. A LPS preparation containing these two polysaccharides was separated by gel-permeation chromatography in this study. Chemical analysis of the separated fractions revealed the 6-deoxy-heptan [corrected] to be a polysaccharide without a lipid portion and the polymer of glucose and 6-deoxy-talose to be an O-antigenic polysaccharide of the LPS. This result was further supported by the assay of these polysaccharide molecules for macrophage activation activity. The 6-deoxy-heptan [corrected] showed no macrophage activation, indicating that this polysaccharide was not the LPS, but one of the capsular polysaccharides of B. pseudomallei.

Increased adenine nucleotides in liver mitochondria after mannoheptulose injection in vivo.

In adult rats, mannoheptulose injection causes a transient decrease in the serum insulin-to-glucagon ratio and a concomitant increase in serum glucose concentration. These effects attain a maximum 1 h after the injection and then decline toward normal. Correlated with the hormone changes is a dramatic increase in the adenine nucleotide content (ATP + ADP + AMP) of liver mitochondria, which peaks to over 50% of control values at 1 h. The increase in mitochondrial adenine nucleotides must occur by uptake from the cytosol, because the adenine nucleotide content of the whole tissue remains constant. The accumulation of adenine nucleotides by the mitochondria probably occurs over the recently characterized carboxyatractyloside-insensitive transport pathway that allows exchange of ATP-Mg for Pi. The actual mechanism by which net uptake is regulated after mannoheptulose injection has not yet been elucidated; however, changes in the Km or Vmax of the carrier and an increase in the tissue ATP/ADP ratio were eliminated as possibilities. The increase in matrix adenine nucleotide content in response to hormone changes brought about by mannoheptulose was much greater and more reproducible than what is achieved with glucagon injection. Mannoheptulose treatment may therefore be preferable as a model for further study of hormone effects on mitochondrial function.

The effects of calcitonin on pancreatic exocrine secretion in dogs.

The effect of calcitonin on pancreatic secretion was studied in unanesthetized dogs with a Thomas cannula implanted opposite the main pancreatic duct. Pancreatic juice was collected for a 60 minute control period, during which time secretion was stimulated by the intravenous infusion of secretin and pancreozymin. After the 60 minute control period, calcitonin was infused along with the secretin and pancreozymin. The infusion of calcitonin caused the volume, bicarbonate and enzyme output in the pancreatic juice to decrease to about one-half of that during the control period. During the one hour period, after calcitonin infusion was stopped, the volume, bicarbonate and enzyme content of the pancreatic juice increased but remained slightly lower than that of the control period. The infusion of calcium gluceptate, along with secretin and pancreozymin, overcame the inhibitory effect of calcitonin on pancreatic secretion.

Effects of mannoheptulose and DL-glyceraldehyde on glucose induced insulin release and adenosine 3',5'-monophosphate levels in isoalted islets of rat pancreas.

The effects of mannoheptulose and DL-glyceraldehyde on glucose-induced insulin release and cycli AMP levels in islets isolated from rat pancreas were investigated. Mannoheptulose inhibition on glucose-induced insulin release was observed after only 5-min incubation period, indicating an inhibitory effect on the early phase of insulin release. This inhibition on insulin release was accompanied with the simultaneous depression of cyclic AMP levels in islets. By the addition of DL-glyceraldehyde to the medium in which glucose and mannoheptulose were present, the depressed cyclic AMP levels in islets were recovered to the control level completely but the restoration of insulin release in the early phase was not complete. In the absence of glucose, DL-glyceraldehyde did not demonstrate a significant increase of insulin release during 5 min incubation, though a marked stimulation was observed after 30-min incubation. Cyclic AMP levels in islets were not affected by DL-glyceraldehyde. When DL-glyceraldehyde was added to the medium with glucose, significant inhibition of glucos-induced insulin release in its early phase was observed without the reduction of cyclic AMP levels in islets. From these findings, the following possibilities are suggested and discussed. 1. Maintenance of the cyclic AMP levels in islets is a necessary but insufficient condition for glucose-induced insulin release particularly for its early phase. 2. Glucose-induced insulin release seems to depend on both the binding of glucose with glucoreceptor and the supply of some metabolites. Mannoheptulose inhibits both mechanisms. DL-glyceraldehyde may supply metabolites but competitively inhibit the binding of glucose to the glucoreceptor.

Effect of hexoses and mannoheptulose on cyclic AMP accumulation and insulin secretion in rat pancreatic islets.

The effects of various sugars on the simultaneous release of insulin and accumulation of cyclic AMP were studied in collagenase isolated rat pancreatic islets. D-Glucose stimulated the formation of cyclic AMP at 3 and 60 min of incubation, whether measured by a label incorporation technique, or by the protein kinase binding assay of Gilman. Only D-glucose and D-mannose were able to stimulate insulin release and cyclic [3H]AMP accumulation in the absence of other substrate. D-fructose had a stimulatory effect in the presence of 3.3 mM D-glucose only at a high concentration (33.8 mM), and enhanced the effects of 8.3 mM glucose when added at the concentration of 8.3 mM. D-Galactose was effective only together with 8.3 mM D-glucose. The order of potency of these hexoses, both regarding insulin secretion and cyclic [3H]AMP accumulation, was glucose-mannose-fructose-galactose. L-Glucose and 3-O-methylglucose had no effects at 60 min when incubated together with 8.3 mM D-glucose, whereas at 3 min, 3-O-methylglucose induced a small stimulation of the cyclic [3H]AMP response. D-mannoheptulose and D-glucosamine inhibited the insulin and cyclic [3H]AMP responses to 27.7 mM glucose. Mannoheptulose suppressed completely the glucose effect on cyclic nucleotide accumulation within 90 s. Although under all incubation conditions, the threshold stimulatory or inhibitory concentration of a given agent was identical for insulin release and cyclic [3H]AMP accumulation, these two variables showed quantitative differences in incubations of 60 min, the magnitude of the changes in insulin secretion being larger than that for the cyclic nucleotide. It is suggested that modulation of islet cyclic AMP level is an important step in the transmission of the effect of various sugars on insulin release; however, glucose and possibly other sugars may also enhance insulin release by additional mechanisms not involving the adenylate cyclase-cyclic AMP system of the beta-cell.

Gluconeogenic response to mannoheptulose in the rat.

Since administration of mannoheptulose induces temporary hyperglycemia, the present study was conducted to elucidate this phenomenon. The results indicate that mannoheptulose stimulates the activity of hepatic fructose-1,6-diphosphatase and phosphoenolpyruvate carboxykinase, and enhances incorporation of alanine into blood glucose and hepatic glycogen. In addition, mannoheptulose increases plasma levels of glucagon and hepatic cyclic AMP concentration. Gluconeogenic effects of mannoheptulose appear to be mediated by glucagon.

Development of pathways of insulin secretion in the rabbit.

Insulin release was studied in vitro using pieces of pancreas from rabbits of between 24 days gestational age and 6 weeks postnatal age. When allowance was made for the fraction of pancreas which was endocrine, 16-5mM-glucose caused increasing stimulation of insulin release as development advanced and 3-3 mM-glucose caused a similar rate of secretion at all ages. Secretion was not significantly influenced by insulin destruction in the incubation medium. Glucagon (5 mug/ml) did not stimulate insulin secretion from 24-day foetal pancreas but did so postnatally. Theophylline (1 mmol/1) stimulated insulin release at all ages and was equipotent on 24-day foetal pancreas in 3-3 or 16-5 mM-glucose. The stimulation of insulin release from 24-day foetal pancreas by 1 mM-theophylline occurred in the absence of extracellular glucose, pyruvate, fumarate and glutamate and in the presence of mannoheptulose and 2-deoxyglucose (each 3 mg/ml). Adrenaline (1 mumol/1) and diazoxide (250 mug/ml) abolished or attenuated the stimulation of insulin release by glucose, leucine plus arginine or theophylline from 24-day foetal, 1 day and 6 weeks postnatal pancreas. The stimulation of insulin release from 6-week-old pancreas by 1mM-barium was blocked by adrenaline and diazoxide but the effect became less with increasing immaturity. The experimental results illustrate some of the ways in which insulin secretion by the rabbit beta cell changes as a function of development and draw attention to the importance of glucose and cyclic adenosine monophosphate in this process.

Interrelationship of islet metabolism, adenosine triphosphate content and insulin release.

The oxidation of some exogenous substrates and their effects on ATP content and insulin release in mouse pancreatic islets were measured. The ATP concentration of islets incubated without exogenous substrate shows a gradual decrease, which can be prevented by glucose or mannose (20mm) or leucine (2.5mm); d-glyceraldehyde (5mm) is as effective as glucose (5mm); fructose or N-acetylglucosamine (20mm), pyruvate (10mm) and dl-3-hydroxybutyrate (2mm) are less effective; galactose (20mm), acetate (10mm), octanoate (2mm) and succinate (10mm) have no ATP-maintaining ability. Islets oxidize glucose, mannose, glyceraldehyde, leucine and, less readily, N-acetylglucosamine and glucosamine; galactose, however, is poorly metabolized. Mannoheptulose inhibits the oxidation of glucose but not of glyceraldehyde. Insulin release, measured over a 2h incubation, is stimulated by glucose, mannose, leucine, glyceraldehyde or glucosamine but not by fructose or N-acetylglucosamine. The latter, however, potentiates the effects of glucose or glyceraldehyde (5mm) or leucine (2.5mm) on release; the potentiating effects are inhibited by mannoheptulose, which also blocks glucose-, but not glyceraldehyde- or leucine-stimulated release. In the presence of glucose (20mm), metabolic inhibitors depress insulin release and islet ATP content in parallel. However, rates of insulin release and ATP content measured after incubation with various combinations of exogenous substrates do not appear to be correlated. Sulphonylureas stimulate insulin release but decrease islet ATP concentrations. These results provide further evidence of a close association between the metabolic activity of exogenous substrates and their ability to initiate insulin release. Glucoreceptor models are formulated in the light of these observations and discussed.