The ongoing studies on oligosaccharide synthesis have resulted in the development of precise synthetic methods by which a large portion of the complex natural oligosaccharides can be duplicated.[1] Although the synthesis of the sequence Neu5Aca(2!8)Neu5Ac (a(2!8)disialic acid; Neu5Ac = Nacetylneuraminic acid) has been a major difficulty, the emergence of several exquisite methods [2] that employ indirect coupling by using a C3-functionalized N-acetyl sialyl donor and direct coupling by using an N-trifluoroacetyl (TFAc)-protected sialic acid donor with the help of the nitrile solvent effect have paved the way for the successful synthesis of a(2!8)disialic acid containing oligosaccharides, such as those with GD3[2c] and GQ1b [3] glycan portions. However, it is obvious that the synthesis of new congeners of disialic acid, such as 8-O-sulfo-Neu5Aca(2!8)Neu5Ac in ganglioside Hps6 [4] and Neu5Gca(2!4)Neu5Ac in ganglioside HLG-2 [5] (Scheme 1), is still difficult because of the diverse modifications possible at the functionality level. On the basis of the predicted biological functions of the disialic acid congener containing oligosaccharides relevant to functions such as neural network formation and fertilization, the establishment of an expedient synthetic method that includes the entire disialic acid family seems essential not only for the progress of glycochemistry but also for studying in detail the molecular basis underlying the biological functions of these compounds.In this study, we report a novel synthetic method for the synthesis of disialic acid congener containing glycans that uses highly reactive lactamized sialyl acceptors and an N-2,2,2-trichloroethoxycarbonyl (Troc)-protected sialyl donor. Recently, we reported an N-Troc-protected sialyl donor (N-Troc donor 1) that shows elevated reactivity and a high degree of accessibility for various sialic acid congeners such as N-glycolylneuraminic acid (Neu5Gc), 8-O-sulfo-Neu5Ac, and 1,5-lactam-Neu.[6] Initially, we anticipated that use of the NTroc donor would enable the design of HLG-2 and Hp-s6 glycan sequences in an expedient manner. However, as depicted in Scheme 2, the results of the condensations with 4-OH and 8-OH sialyl acceptors, 2 and 3, respectively, did not meet expectations with regard to yields and stereoselectivity. Even in the case of 2, which showed the relatively higher reactivity, a-disialyl glycoside was obtained in less than 5 %. We hypothesized that the poor results were mainly due to unfavorable hydrogen bonding with the amide moiety at C5, as proposed previously by Tsvetkov and Schmidt. [7] This hypothesis was the basis of the idea that the conformational transformation from the 2 C 5 chair form to the fixed boat form with the 1,5-lactam bridge would result in increased reactivity of both the C4-and C8-hydroxy groups. [8] To form the 1,5-lactam bridge in the sialoside, the previously reported N-TFAc-sialic acid derivative 6[9] was used as the key precursor (Scheme 3). After the coupling reaction of 6 and tribenzylated glucosyl acceptor 7,...
Recently, much attention has been paid to "nonclassical" bioactive peptides, which are fragmented peptides simultaneously produced during maturation and degradation of various functional proteins. We identified many fragmented peptides derived from various mitochondrial proteins including mitocryptide-1 and mitocryptide-2 that efficiently activate neutrophils. These endogenous, functionally active, fragmented peptides are referred to as "cryptides." Among them, mitocryptide-2 is an N-formylated cryptide cleaved from mitochondrial cytochrome b that is encoded in mitochondrial DNA (mtDNA). It is known that 13 proteins encoded in mtDNA are translated in mitochondria as N-formylated forms, suggesting the existence of endogenous N-formylated peptides other than mitocryptide-2. Here, we investigated the effects of N-formylated peptides presumably cleaved from mtDNA-encoded proteins other than cytochrome b on the functions of neutrophilic cells to elucidate possible regulation by endogenous N-formylated cryptides. Four N-formylated cryptides derived from cytochrome c oxidase subunit I and NADH dehydrogenase subunits 4, 5, and 6 among 12 peptides from mtDNA-encoded proteins efficiently induced not only migration but also β-hexosaminidase release, which is an indicator of neutrophilic phagocytosis, in HL-60 cells differentiated into neutrophilic cells. These activities were comparable to or higher than those induced by mitocryptide-2. Although endogenous N-formylated peptides that are contained in mitochondrial damage-associated molecular patterns (DAMPs) have yet to be molecularly identified, they have been implicated in innate immunity. Thus, N-formylated cryptides including mitocryptide-2 are first-line candidates for the contents of mitochondrial DAMPs to promote innate immune responses. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 580-587, 2016.
Background: Recurrence of IgA nephropathy (IgAN) in the transplanted kidney is associated with graft survival, but no specific treatment is available. Tonsillectomy (TE) reportedly arrests the progression of IgAN in the native kidney. Thus, we conducted a single-center retrospective cohort study to evaluate the effect of TE prior to IgAN recurrence. Methods: Of the 36 patients with biopsy-proven IgAN who underwent kidney transplantation, 27 were included in this study. Nine patients underwent TE at 1 year after kidney transplantation (group 1), and the remaining 18 did not undergo TE (group 2). Results: The rate of histological IgAN recurrence was significantly lower in group 1 than in group 2 (11.1 vs. 55.6%, log-rank p = 0.046). In addition, half of the recurrent patients in group 2 exhibited active lesions, compared to none in group 1. Serum Gd-IgA1 levels decreased after TE in group 1, whereas they remained stable or increased slightly in group 2. In the recurrent cases, IgA and Gd-IgA1 were found in the germinal center in addition to the mantle zone of tonsils. Finally, mesangial IgA and Gd-IgA1 immunoreactivity was reduced after TE in some cases. Conclusion: Our data suggest that TE at 1 year after kidney transplantation might be associated with the reduced rate of histological IgAN recurrence. TE arrested or reduced serum Gd-IgA1 and mesangial Gd-IgA1 immunoreactivity. Therefore, we generated a hypothesis that serum Gd-IgA1 derived from the tonsils may play a pivotal role in the pathogenesis of IgAN. Based on these findings, we need to conduct verification in a prospective randomized controlled trial.
Objectives To examine the correlation among bladder inflammation, angiogenesis, fibrosis and urothelial denudation in biopsied bladder specimens, and O'Leary‐Sant symptom indexes, O'Leary‐Sant problem indexes and visual analog scale pain scores in interstitial cystitis/bladder pain syndrome patients with or without Hunner lesions (Hunner type interstitial cystitis or non‐Hunner type interstitial cystitis). Methods Bladder biopsied tissues were collected from 12 Hunner type interstitial cystitis female patients, 12 non‐Hunner type interstitial cystitis female patients and 12 age‐matched non‐interstitial cystitis female patients (controls). Immunohistochemical stainings of tissue necrotic factor‐α, mast cell tryptase, vascular endothelial growth factor, CD31, transforming growth factor‐β, SLUG associated with epithelial mesenchymal transition and E‐cadherin as well as Masson trichrome staining were evaluated. The significant correlation between the expression of tissue necrotic factor‐α, mast cell tryptase, vascular endothelial growth factor, CD31, transforming growth factor‐β, collagen, SLUG or E‐cadherin, and O'Leary‐Sant symptom indexes, O'Leary‐Sant problem indexes or visual analog scale pain scores was then examined. Results The expression of tissue necrotic factor‐α, vascular endothelial growth factor, CD31, transforming growth factor‐β and SLUG was significantly increased in non‐Hunner type interstitial cystitis and Hunner type interstitial cystitis patients compared with controls whereas the significant increases in the expression of mast cell tryptase and collagen were observed in Hunner type interstitial cystitis patients compared with controls and non‐Hunner type interstitial cystitis patients. On the other hand, the expression of E‐cadherin was significantly decreased in Hunner type interstitial cystitis patients compared with controls and non‐Hunner type interstitial cystitis patients. In addition, the increased expression of CD31 in bladder tissues was strongly correlated with O'Leary‐Sant symptom indexes, O'Leary‐Sant problem indexes and visual analog scale pain scores. Conclusions These results suggest that bladder angiogenesis evident as the increased expression of CD31 is strongly correlated with urinary frequency and bladder pain in patients with non‐Hunner type interstitial cystitis and Hunner type interstitial cystitis.
Urethral closure mechanisms under stress conditions consist of passive urethral closure involving connective tissues, fascia and/or ligaments in the pelvis and active urethral closure mediated by hypogastric, pelvic and pudendal nerves. Furthermore, we have previously reported that the active urethral closure mechanism might be divided into two categories: (i) the central nervous control passing onto Onuf's nucleus under sneezing or coughing; and (ii) the bladder-to-urethral spinal reflex under Valsalvalike stress conditions, such as laughing, exercise or lifting heavy objects. There are over 200 million people worldwide with urinary incontinence, a condition that is associated with a significant social impact and reduced quality of life. Therefore, basic research for urinary continence mechanisms in response to different stress conditions can play an essential role in developing treatments for stress urinary incontinence. It has been clinically shown that the etiology of stress urinary incontinence is divided into urethral hypermobility and intrinsic sphincter deficiency, which could respectively correspond to passive and active urethral closure dysfunction. In this review, we summarize the representative stress urinary incontinence animal models and the methods to measure leak point pressures under stress conditions, and then highlight stress-induced urinary continence mechanisms mediated by active urethral closure mechanisms, as well as future pharmacological treatments of stress urinary incontinence. In addition, we introduce our previous reports including sex differences in urethral closure mechanisms under stress conditions and urethral compensatory mechanisms to maintain urinary continence after pudendal nerve injury in female rats.
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