Accelerated involution of germinal center in palatine tonsils in IgA nephropathy.

BACKGROUND: Altered immunological responses in the palatine tonsils may be involved in the pathogenesis of IgA nephropathy (IgAN). The germinal center serves as the site for antigen-specific humoral immune responses in the palatine tonsils. Germinal center involution is frequently observed in the palatine tonsils of IgAN (IgAN tonsils). However, the pathogenic significance of these characteristic changes remains unclear. This study aimed to investigate the morphological changes in secondary lymphoid follicles in IgAN tonsils and to evaluate the correlation between the morphometric results and the clinicopathological severity of IgAN. METHODS: The tonsils of age-matched patients with recurrent tonsillitis (RT tonsils) were used as controls. The correlation between the degree of lymphoid follicular involution and histopathological severities in clinical or kidney biopsy was evaluated. RESULTS: In total, 87 patients with IgAN were included (48% male, median age 35 years, median estimated glomerular filtration rate: 74 mL/min/1.73 m2). Compared to RT tonsils, IgAN tonsils showed smaller median sizes of lymphoid follicles and germinal centers (P < 0.001). The relative areas of lymphoid follicles (%LFA) and germinal centers (%GCA) in the total tonsillar tissue were smaller in the IgAN tonsils than in the RT tonsils (P < 0.001). In contrast, the median proportion of mantle zones in the total tonsillar tissue was comparable between the groups. A lower %LFA was associated with a longer period from the onset of urinary abnormalities to biopsy diagnosis and higher urinary protein excretion (P = 0.01). %LFA showed significant negative correlations with frequencies of glomeruli with both global and segmental sclerosis. CONCLUSIONS: The present study confirmed accelerated germinal center involution in the tonsils of patients with IgAN. This characteristic change in the IgAN tonsil correlates with heavy proteinuria and advanced chronic histopathological changes in the kidneys, thereby suggesting the involvement of repeated tonsillar immunoreactions during IgAN progression.

Possible prevention of uremic nausea by vitamin D receptor activators in non-dialysis patients with stage 5 chronic kidney disease.

BACKGROUND: Nausea is a major uremic symptom and a frequent indication for starting dialysis. However, preventive medication for uremic nausea has not yet been identified. Vitamin D receptor activators (VDRAs) may prevent uremic nausea via their pleiotropic actions. The objective of this study was to explore whether VDRA administration during the predialysis period is associated with a reduced prevalence of uremic nausea just prior to beginning dialysis. METHODS: A multicenter, retrospective, cross-sectional study was performed to identify a medication to prevent uremic nausea. Patients with stage 5 CKD who were followed-up over 3 months were included. The primary outcomes examined were the prevalence of uremic nausea, congestive heart failure (CHF), and intractable edema at dialysis commencement. The predictor variable was VDRA use during the predialysis period. RESULTS: One thousand five hundred and thirty six patients who had just begun dialysis in nine Japanese facilities between January 2006 and October 2013 were included. Two hundred and thirty (15.0%) patients had commenced dialysis because of uremic nausea, and three hundred and ninety two (25.5%) patients had been using VDRAs before initiating dialysis. Logistic regression analysis showed that, among the medications examined in this study, only VDRA use was independently associated with a lower frequency of uremic nausea (OR 0.512, 95% CI 0.347-0.738, P = 0.0003). On the other hand, CHF and intractable edema were not associated with VDRA administration. CONCLUSION: Use of VDRAs during the predialysis period was the only factor associated with a lower prevalence of uremic nausea, suggesting that VDRAs may prevent uremic nausea in patients with advanced CKD.

New Insights into the Pathogenesis of IgA Nephropathy.

BACKGROUND: IgA nephropathy, a frequent cause of end-stage renal disease, is an autoimmune disease wherein immune complexes consisting of IgA1 with galactose-deficient O-glycans (autoantigen) and anti-glycan autoantibodies deposit in glomeruli and induce renal injury. Multiple genetic loci associated with disease risk have been identified. The prevalence of risk alleles varies geographically, highest in eastern Asia and northern Europe, fewer in other parts of Europe and North America, and the least in Africa. IgA nephropathy is diagnosed from pathological assessment of a renal biopsy specimen. Currently, therapy is not disease-targeted but rather is focused on maintaining control of blood pressure and proteinuria, ideally with suppression of angiotensin II. Possible additional approaches differ between countries. Disease-specific therapy as well as new tools for diagnosis, prognosis, and assessment of responses to therapy are needed. SUMMARY: Glycosylation pathways associated with aberrant O-glycosylation of IgA1 and, thus, production of autoantigen, have been identified. Furthermore, unique characteristics of the autoantibodies in IgA nephropathy have been uncovered. Many of these biochemical features are shared by patients with IgA nephropathy and Henoch-Schönlein purpura nephritis, suggesting that the two diseases may represent opposite ends of a spectrum of a disease process. Understanding the molecular mechanisms involved in formation of pathogenic IgA1-containing immune complexes will enable development of disease-specific therapies as well as diagnostic and prognostic biomarkers. KEY MESSAGES: IgA nephropathy is an autoimmune disease caused by glomerular deposition of nephritogenic circulating immune complexes consisting of galactose-deficient IgA1 (autoantigen) bound by anti-glycan autoantibodies. A better understanding of the multi-step process of pathogenesis of IgA nephropathy and the genetic and environmental contributing factors will lead to development of biomarkers to identify patients with progressive disease who would benefit from a future disease-specific therapy.

A combination of unnatural phosphatidyl acceptor and tandem electrospray ionization mass spectrometry for tracing phospholipase D activity.

Phospholipase D (PLD) is a biocatalyst in the synthesis of bioactive compounds and a key enzyme in a variety of biological signal transductions. A combination of unnatural phosphatidyl acceptor, N,N,N-triethyl-N-2-hydroxyethylammonium bromide 6, as a substrate for PLD, and tandem electrospray ionization mass spectrometry (ESI MS) was found to provide information as to whether a given phospholipid serves as a substrate for the PLD-catalyzed reaction. Thus 2-(13'-hydroperoxy-octadecadienoyl)-1-palmitoylglycerophosphocholine 1, and its degradation products 2-(13'-oxo-octadecadienoyl)-1-palmitoylglycerophosphocholine 9 and 2-(13'-hydroxy-octadecadienoyl)-1-palmitoylglycerophosphocholine 11, in a mixture were found to be a substrate of the PLD-catalyzed transphosphatidylation. The sensitivity of this method was exemplified by the observation that PLD activity in cabbage leaves was detected using a small amount of crude crushed leaves with little pretreatment. This simple method can be used in screening for PLD activity and searching for inhibitors of the enzyme from various natural sources.

Cyclomaltodextrin glucanotransferase-catalyzed transglycosylation from dextrin to alkanol maltosides.

Maltosides of butanol, octanol, and lauryl alcohol were found for the first time to serve as substrates for cyclomaltodextrin glucanotransferase (CGTase), and glycosyl residue was transfered from dextrin to the substrate affording novel maltosides with 3-4 glucose units.

Antianaphylactic and antipruritic effects of the flowers of Impatiens textori MIQ.

The anti-anaphylactic and anti-pruritic activities of a 35% EtOH extract (IT) of the flowers of Impatiens textori MIQ. were investigated by in vivo assay. IT and apigenin (1), apigenin 7-glucoside (2) and luteolin (3), principal compounds from IT, inhibited compound 48/80 (COM)-induced by blood pressure (BP) decrease, which was an immunoglobulin (Ig)E-independent anaphylaxis-like response. Compounds 1-3 all inhibited BP decrease induced by IgE-dependent anaphylaxis. Furthermore, IT also inhibited the blood flow (BF) decrease induced by antigen-induced anaphylaxis in actively sensitized mice. IT showed a significant inhibitory effect on scratching behavior induced by COM without a central depressant. IT also significantly inhibited platelet activating factor (PAF)- and serotonin (5-HT)-induced scratching behavior and mitigated protease (PA)-induced scratching behavior. These findings showed that the flowers of I. textori can be utilized as an anti-anaphylactic and anti-pruritic agent in addition to the traditional applications of this plant.

Development of an in vivo bioassay method for allergy-preventive substances using hen-egg white lysozyme (HEL)-induced blood flow decrease.

We discovered a phenomenon in which the blood flow in vein microcirculation markedly decreases in response to hen-egg white lysozyme (HEL)-sensitization without any change in blood pressure. Using this blood flow decrease as a guide, we developed an in vivo assay method to search for substances, which can prevent allergies. Antagonists of histamine, serotonin and platelet activating factor (PAF) did not affect the blood flow decrease in response to HEL-sensitization. On the other hand, cyclooxygenase (COX)-1, COX-2, thromboxane (TX) A(2), endothelin-1 (ET-1), prostacyclin (PGI(2)) and granulocytic elastase (GE) as well as nitric oxide (NO) from inducible NO synthase (iNOS) were involved in the blood flow decrease. Thus, these substances might injure vascular endothelial cells, and cause a decrease in blood flow in vein microcirculation. Our method can be used to search for preventive agents against allergies involving NO, COX-1, 2 and PGI(2). This is the first report to applying to an assay method the specific blood flow decrease to occur in the promotion stage of allergy.

Inhibitory effects of xanthones from guttiferae plants on PAF-induced hypotension in mice.

The inhibitory effects of 22 xanthones from three Guttiferae plants (Hypericum patulum, Calophyllum inophyllum and C. austroindium) on exogenous platelet activating factor (PAF)-induced hypotension were examined using a blood pressure monitoring in vivo assay method. Guanandin (2), caloxanthone E (3), 1,3,5,6-tetrahydroxy-2-isoprenylxanthone (8), 6-deoxyjacareubin (11) and patulone (18) showed strong inhibition of PAF-induced hypotension, with inhibitory effects of more than 60 %. Their ID50 values were greater than that of ginkgolide B (BN-52 021), a natural PAF-antagonist from the Ginkgo biloba.

Effects on blood pressure decrease in response to PAF of Impatiens textori MIQ.

A 35% EtOH extract of flowers of Impatiens textori MIQ. showed an inhibitory effect on blood pressure decrease in response to platelet activating factor (PAF) measured with a blood pressure monitoring system. Bioassay-guided fractionation of the 35% EtOH extract (IT) led to isolation of the flavones apigenin (1) and luteolin (3), which significantly inhibited blood pressure decrease in response to PAF. Their compounds and apigenin 7-glucoside (2), chrysoeriol (4), quercetin (5), quercetin 3-glucoside (6), kaempferol (7), kaempferol 3-glucoside (8) and kaempferol 3-rhamnosyldiglucoside (9) were also isolated from the flowers of I. textori for the first time. This study revealed that the flowers of I. textori might be a possible anti-allergy agent.

Antipruritic effects of the fruits of Chaenomeles sinensis.

A 35% EtOH extract of the fruits of Chaenomeles sinensis, long utilized as a folk medicine for cough, significantly inhibited the pruritogenic agent compound 48/80 (COM)-induced scratching behavior in mice. Antipruritic activity-guided fractionation and purification yielded active quercetin, apigenin, and catechin derivatives, which exhibited significant inhibitory effects on COM-induced scratching behavior. To the best of our knowledge, apigenin (5), apigenin 7-glucronide (6), and apigenin 4'-methoxy-7-glucronide (acacetin 7-glucronide) (7) were isolated from the fruits of C. sinensis for the first time. The active fraction and these compounds also inhibited serotonin-, platelet activating factor-, and prostaglandin E(2)-induced scratching behavior, but did not inhibit histamine-induced scratching behavior or locomotive behavior. This study also showed that the fruits of C. sinensis could be used to treat allergic itching sensation.