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A large number of compounds mimicking the structures of monosaccharides or oligosaccharides have been discovered from natural sources. Such sugar mimics inhibit carbohydrate-degrading enzymes ...because of a structural resemblance to the sugar moiety of the natural substrate. Carbohydrate-degrading enzymes are involved in a wide range of important biological processes, such as intestinal digestion, posttranslational processing of the sugar chain of glycoproteins, their quality control mechanisms, lysosomal catabolism of glycoconjugates, and some viral infections. It has now been realized that inhibitors of the enzymes have enormous therapeutic potential in diabetes and lysosomal storage disorders. In this review, the general bioactivity, current applications, and the prospects for new therapeutic applications are described.
About 40 years have passed since the classical glycosidase inhibitor nojirimycin was discovered from the cultured broth of the Streptomyces species. Since then, over 100 glycosidase inhibitors have ...been isolated from plants and microorganisms. Modifying or blocking biological processes by specific glycosidase inhibitors has revealed the vital functions of glycosidases in living systems. Because enzyme-catalyzed carbohydrate hydrolysis is a biologically widespread process, glycosidase inhibitors have many potential applications as agrochemicals and therapeutic agents. Glycosidases are involved in the biosynthesis of the oligosaccharide chains and quality control mechanisms in the endoplasmic reticulum of the N-linked glycoproteins. Inhibition of these glycosidases can have profound effects on quality control, maturation, transport, and secretion of glycoproteins and can alter cell–cell or cell–virus recognition processes. This principle is the basis for the potential use of glycosidase inhibitors in viral infection, cancer, and genetic disorders. In this review, the past and current applications of glycosidase inhibitors to agricultural and medical fields and the prospect for new therapeutic applications are reconsidered.
It is well established that polymorphisms of the caspase activation and recruitment domain 15 (CARD15) gene, a major risk factor in Crohn's disease (CD), lead to loss of nucleotide-binding ...oligomerization domain 2 (NOD2) function. However, a molecular explanation of how such loss of function leads to increased susceptibility to CD has remained unclear. In a previous study exploring this question, we reported that activation of NOD2 in human dendritic cells by its ligand, muramyl dipeptide (MDP), negatively regulates Toll-like receptor (TLR)-mediated inflammatory responses. Here we show that NOD2 activation results in increased interferon regulatory factor 4 (IRF4) expression and binding to tumor necrosis factor receptor associated factor 6 (TRAF6) and RICK (receptor interacting serine-threonine kinase). We then show that such binding leads to IRF4-mediated inhibition of Lys63-linked polyubiquitination of TRAF6 and RICK and thus to downregulation of nuclear factor (NF)-κB activation. Finally, we demonstrate that protection of mice from the development of experimental colitis by MDP or IRF4 administration is accompanied by similar IRF4-mediated effects on polyubiquitination of TRAF6 and RICK in colonic lamina propria mononuclear cells. These findings thus define a mechanism of NOD2-mediated regulation of innate immune responses to intestinal microflora that could explain the relation of CARD15 polymorphisms and resultant NOD2 dysfunction to CD.
Background
We recently demonstrated in humans that the extent of low-dose aspirin (LDA)-induced gastropathy was directly related to the individual gastric acid secretion level. We also established ...reliable cutoff serum pepsinogen (PG) values to predict gastric acid secretion status. In this study, we investigated the clinical usefulness of measuring the serum pepsinogen values for identifying a high-risk group for gastric mucosal injury among chronic LDA users.
Methods
One hundred long-term LDA users were enrolled in this analysis. Serum from each subject was subjected to determination of
H. pylori
status and measurement of pepsinogen values. According to our recent report, a PG I value ≥ 50 ng/mL was defined as estimated hyperchlorhydria in
H. pylori
-negative subjects, while a PG I/II ≥ 3.3 was defined as estimated hyperchlorhydria in
H. pylori
-positive subjects. The grade of gastric mucosal injury was assessed endoscopically, and multiple logistic regression analyses were used to estimate the risk.
Results
Estimated hyperchlorhydria was a strong independent risk for intensive gastric mucosal injury with an OR (95 % CI): 34.0 (4.5–259) and for gastric ulcer with an OR (95 % CI): 10.2 (1.8–58.3) in
H. pylori
-positive subjects, while it was not a significant risk in
H. pylori
-negative subjects. The association persisted even after excluding those with conventional risks for LDA-gastropathy such as ulcer histories.
Conclusion
Using simple serum measurement of
H. pylori
antibody and pepsinogen concentrations, an extremely high-risk group for LDA-induced gastropathy could be extracted, and these patients should become a therapeutic target for prevention of LDA-induced gastropathy.
High Ki-67 is strongly associated with the risk of CNS relapse in patients with mantle cell lymphoma. Two-year incidence of CNS relapse in patients with Ki-67 ≥ 30 exceeds 25%. The incidence was not ...decreased by rituximab, high-dose cytarabine, high-dose methotrexate or consolidative ASCT. Development of new prophylactic strategies for CNS involvement is mandatory in patients with high Ki-67.
Central nervous system (CNS) relapse is an uncommon but challenging complication in patients with mantle cell lymphoma (MCL). Survival after CNS relapse is extremely poor. Identification of high-risk populations is therefore critical in determining patients who might be candidates for a prophylactic approach.
A total of 608 patients (median age, 67 years; range 22–92) with MCL newly diagnosed between 1994 and 2012 were evaluated. Pretreatment characteristics and treatment regimens were evaluated for their association with CNS relapse by competing risk regression analysis.
None of the patients received intrathecal prophylaxis. Overall, 33 patients (5.4%) experienced CNS relapse during a median follow-up of 42.7 months. Median time from diagnosis to CNS relapse was 20.3 months (range: 2.2–141.3 months). Three-year cumulative incidence of CNS relapse was 5.6% 95% confidence interval (95% CI) 3.7% to 8.0%. Univariate analysis revealed several risk factors including blastoid variant, leukemic presentation, high-risk MCL International Prognostic Index and high Ki-67 (proliferation marker). Multivariate analyses revealed that Ki-67 ≥ 30 was the only significant risk factor for CNS relapse (hazard ratio: 6.0, 95% CI 1.9–19.4, P = 0.003). Two-year cumulative incidence of CNS relapse in patients with Ki-67 ≥ 30 was 25.4% (95% CI 13.5–39.1), while that in the patients with Ki-67 < 30 was 1.6% (95% CI 0.4–4.2). None of the treatment modalities, including rituximab, high-dose cytarabine, high-dose methotrexate or consolidative autologous stem-cell transplant, were associated with a lower incidence of CNS relapse. Survival after CNS relapse was poor, with median survival time of 8.3 months. There was no significant difference in the survival by the site of CNS involvement.
In our previous aircraft observations, the possible influence of high sea surface temperature (SST) along the Kuroshio Current on aerosol‐cloud interactions over the western North Pacific was ...revealed. The cloud droplet number concentration (Nc) was found to increase with decreasing near‐surface static stability (NSS), which was evaluated locally as the difference between the SST and surface air temperature (SAT). To explore the spatial and temporal extent to which this warm SST influence can be operative, the present study analyzed Nc values estimated from Moderate Resolution Imaging Spectroradiometer (MODIS) satellite measurements. The comparison of the local Nc values between the high and low SST − SAT days revealed a marked increase in Nc (up to a factor of 1.8) along the Kuroshio Current in the southern East China Sea, where particularly high SST − SAT values (up to 8 K) were observed in winter under monsoonal cold air outflows from the Asian Continent. This cold airflow destabilizes the atmospheric boundary layer, which leads to enhanced updraft velocities within the well‐developed mixed layer and thus greater Nc. The monsoonal northwesterlies also bring a large amount of anthropogenic aerosols from the Asian continent that increase Nc in the first place. These results suggest that the same modulations of cloud microphysics can occur over other warm western boundary currents, including the Gulf Stream, under polluted cool continental airflows. Possibilities of influencing the cloud liquid water path are also discussed.
Key Points
We found that cloud droplet number concentrations are higher when SST‐surface air temperature is higher over the warm SST region
The observed high cloud droplet number concentrations were due to enhanced updraft velocity upon cold air outbreak and high aerosol amounts
These results suggest that warm SST affects aerosol‐cloud interactions
Nucleotide oligomerization domain (NOD)2 is a member of the NOD-like receptor family of proteins that initiate inflammatory responses when exposed to ligands derived from bacterial components that ...gain access to the intracellular milieu. It is thus somewhat paradoxical that polymorphisms in the gene that encode NOD2 (CARD15) that lead to impaired NOD2 function, are susceptibility factors in Crohn's disease, a condition marked by excessive inflammatory responses to normal bacterial flora. In an initial series of studies conducted in our laboratory to better define NOD2 function and to resolve this paradox we showed that NOD2 activation by its ligand, muramyl dipeptide (MDP) ordinarily downregulates responses to Toll-like receptor (TLR) stimulation, and thus cells lacking NOD2 mount increased responses to such stimulation. This fits with the fact that mice bearing an NOD2 transgene, and thus having cells with increased NOD2 function display decreased responses to TLR stimulation and are resistant to experimental colitis induction. In further studies, we showed that prestimulation of cells with NOD2 ligand renders them unresponsive to TLR stimulation, because such prestimulation results in the elaboration of inhibitory factor (IRF4), an inhibitor of TLR-induced inflammatory pathways. Furthermore, administration of MDP to normal mice induces IRF4 and prevents experimental colitis. These studies strongly suggest that NOD2 polymorphisms are associated with Crohn's disease because they lead to a decrease in the negative regulation of TLR responses occurring in the normal gut, and thus a pathologic increase in responses to the normal flora. The finding that MDP administration prevents experimental colitis opens the door to the possibility that such treatment might quell Crohn's disease relapses in patients without NOD2 abnormalities.
Background:Helicobacter pylori infection is associated with variable clinical outcomes, including gastroduodenal diseases, and genetic factors may be relevant in this process. Aims: We investigated ...the effects of an interleukin 8 (IL-8) gene polymorphism on the risk of gastroduodenal diseases, the degree of H pylori induced gastritis, and IL-8 gene transcription. Subjects: The study was performed in 244 healthy control subjects and 690 H pylori positive patients with non-cardia gastric cancer, gastric ulcer, duodenal ulcer, or gastritis. Methods: We identified the IL-8 −251 A/T polymorphism by direct sequence analysis, and measured the gastritis score and serum pepsinogen (PG). The transcriptional promoter activity of the IL-8 gene was assessed by luciferase assay. Results:IL-8 −251A was associated with a higher risk of gastric cancer and gastric ulcer. Patients carrying IL-8 −251A showed an increased risk of gastric cancer (odds ratios (OR) 2.01 (95% confidence interval (CI) 1.38–2.92)) and gastric ulcer (OR 2.07 (95% CI 1.37–3.12)). Compared with patients younger than 49 years, atrophy and metaplasia scores in the antrum were significantly higher and the PG I/II ratio significantly lower in −251A carriers than in T/T carriers. In the in vitro assay, IL-8 −251A showed enhanced promoter activity in response to IL-1β or tumour necrosis factor α. Conclusions: The IL-8 −251A allele may be associated with progression of gastric atrophy in patients with H pylori infection, and may increase the risk of gastric cancer and gastric ulcer in Japanese people.
Summary
We measured the effect of Patent Blue dye on oxyhaemoglobin saturations after injection into breast tissue: 40 women had anaesthesia for breast surgery maintained with sevoflurane or propofol ...(20 randomly allocated to each). Saturations were recorded with a digital pulse oximeter, in arterial blood samples and with a cerebral tissue oximeter before dye injection and 10, 20, 30, 40, 50, 60, 75, 90, 105 and 120 min afterwards. Patent Blue did not decrease arterial blood oxyhaemoglobin saturation, but it did reduce mean (SD) digital and cerebral oxyhaemoglobin saturations by 1.1 (1.1) % and 6.8 (7.0) %, p < 0.0001 for both. The falsely reduced oximeter readings persisted for at least 2 h. The mean (SD) intra‐operative digital pulse oxyhaemoglobin readings were lower with sevoflurane than propofol, 97.8 (1.2) % and 98.8 (1.0) %, respectively, p < 0.0001.
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