Removal of Aβ Oligomers from the Blood: A Potential Therapeutic System for Alzheimer's Disease.

Purpose: Amyloid-β protein (Aβ) is one of the causative proteins of Alzheimer's disease. We have been developing extracorporeal blood Aβ-removal systems as a method for enhancing Aβ clearance from the brain. We reported previously that medical adsorbents and hemodialyzers removed Aβ monomers from peripheral blood, which was associated with influx of Aβ monomers from the brain into the bloodstream.

Influx of Tau and Amyloid-β Proteins into the Blood During Hemodialysis as a Therapeutic Extracorporeal Blood Amyloid-β Removal System for Alzheimer's Disease.

The accumulation of amyloid-β protein (Aβ) and tau in the brain is a major pathological change related to Alzheimer's disease. We have continued to develop Extracorporeal Blood Aβ Removal Systems (E-BARS) as a method for enhancing Aβ clearance from the brain. Our previous report revealed that dialyzers effectively remove blood Aβ and evoke large Aβ influxes into the blood, resulting in a decrease in brain Aβ accumulation after initiating hemodialysis, and that patients who underwent hemodialysis had lower brain Aβ accumulation than those who did not.

Adsorptive filtration systems for effective removal of blood amyloid β: a potential therapy for Alzheimer's disease.

Accumulation of amyloid-β protein (Aβ) in the brain causes cognitive impairment in Alzheimer's disease. We hypothesized that an extracorporeal system that rapidly removed Aβ from the blood may accelerate Aβ drainage from the brain. We previously reported that dialyzers remove blood Aβs effectively, mainly by adsorption on the inner surfaces of the hollow fibers, resulting in lower Aβ accumulation in the brains of patients undergoing hemodialysis than the controls without hemodialysis.

The Level of IgA Antibodies to Endothelial Cells Correlates with Histological Evidence of Disease Activity in Patients with Lupus Nephritis.

Anti-endothelial cell antibodies (AECA) are frequently detected in patients with systemic lupus erythematosus (SLE), but their pathological role remains unclear. We recently developed a solubilized cell surface protein capture enzyme-linked immunosorbent assay (CSP-ELISA) to detect antibodies against membrane proteins involved in autoimmune reactions. In this study, sera from 51 patients with biopsy-proven lupus nephritis (LN), 25 with SLE without renal involvement (non-LN SLE), 42 disease control (DC) subjects, and 80 healthy control (HC) subjects were tested for IgG- and IgA-AECA for human umbilical vein endothelial cells (HUVEC) and human glomerular EC (HGEC) by using CSP-ELISA.

Patients that have Undergone Hemodialysis Exhibit Lower Amyloid Deposition in the Brain: Evidence Supporting a Therapeutic Strategy for Alzheimer's Disease by Removal of Blood Amyloid.

As a proof of concept that removal of blood amyloid-β (Aβ) can reduce Aβ deposition in the brains of patients with Alzheimer's disease, cortices of patients who had undergone hemodialysis (HD), which removes Aβ from the blood, were histochemically analyzed; postmortem brain sections were stained with anti-Aβ antibodies. Brains from patients who had undergone HD had significantly fewer senile plaques than those of patient who had not undergone HD. This significant difference was also confirmed by silver staining.

Toward the treatment for Alzheimer's disease: adsorption is primary mechanism of removing amyloid β protein with hollow-fiber dialyzers of the suitable materials, polysulfone and polymethyl methacrylate.

The accumulation of amyloid β protein (Aβ) in the brain reflects cognitive impairment in Alzheimer's disease. We hypothesized that the rapid removal of Aβ from the blood by an extracorporeal system may act as a peripheral Aβ sink from the brain. The present study aimed to determine the optimal materials and modality for Aβ removal by hemodialyzers.

A prospective study on blood Aβ levels and the cognitive function of patients with hemodialysis: a potential therapeutic strategy for Alzheimer's disease.

To obtain the proof of concept of a novel therapy for Alzheimer's disease (AD), we conducted two prospective studies with hemodialysis patients who had amyloid β protein (Aβ) removed from their blood three times a week. One major pathological change in the brain associated with AD is Aβ deposition, mainly 40 amino acids Aβ1-40 and 42 amino acids Aβ1-42. Impaired Aβ clearance is proposed to be one cause of increased Aβ in the AD brain.

Appropriate nonwoven filters effectively capture human peripheral blood cells and mesenchymal stem cells, which show enhanced production of growth factors.

Scaffolds, growth factors, and cells are three essential components in regenerative medicine. Nonwoven filters, which capture cells, provide a scaffold that localizes and concentrates cells near injured tissues. Further, the cells captured on the filters are expected to serve as a local supply of growth factors.

Specificity of two monoclonal antibodies against a synthetic glycopeptide, an analogue to the hypo-galactosylated IgA1 hinge region.

Increased levels of hypo-galactosylated immunoglobulin (Ig)A1 (HG-IgA1) in IgA nephropathy (IgAN) have been detected using a Helix aspersa agglutinin lectin enzyme-linked immunosorbent assay (ELISA). In this study, we developed monoclonal antibodies to evaluate the HG-IgA1 in IgA nephropathy, aiming to gain a more consistent and reproducible assay. As an analogue to the HG-IgA1 hinge region, a 19 mer synthetic peptide with five GalNAc (sHGP) residues at positions 4, 7, 9, 11 and 15 [VPST(GalNAc)PPT(GalNAc)PS(GalNAc)PS(GalNAc)TPPT (GalNAc)PSPS-NH2] was synthesized.

Enzymatic sialylation of IgA1 O-glycans: implications for studies of IgA nephropathy.

Patients with IgA nephropathy (IgAN) have elevated circulating levels of IgA1 with some O-glycans consisting of galactose (Gal)-deficient N-acetylgalactosamine (GalNAc) with or without N-acetylneuraminic acid (NeuAc). We have analyzed O-glycosylation heterogeneity of naturally asialo-IgA1 (Ale) myeloma protein that mimics Gal-deficient IgA1 (Gd-IgA1) of patients with IgAN, except that IgA1 O-glycans of IgAN patients are frequently sialylated. Specifically, serum IgA1 of healthy controls has more α2,3-sialylated O-glycans (NeuAc attached to Gal) than α2,6-sialylated O-glycans (NeuAc attached to GalNAc).

A potential therapeutic system for Alzheimer's disease using adsorbents with alkyl ligands for removal of blood amyloid β.

Amyloid beta proteins (Aβ) in the brain are the main cause of Alzheimer's disease. Peripheral administration of Aβ-binding substances, which may act as a sink for Aβ from the brain, has been reported to reduce brain Aβ. We previously found C16-cellulose beads had high Aβ-removal activity in vitro.

Comparison of effective impact among tonsillectomy alone, tonsillectomy combined with oral steroid and with steroid pulse therapy on long-term outcome of immunoglobulin A nephropathy.

Background: To clarify the therapeutic impact of tonsillectomy and combined therapies of tonsillectomy plus steroid on the long-term prognosis of immunoglobulin A nephropathy (IgAN).

Methods: A retrospective study was conducted on 208 patients with IgAN between 1986 and 2009. According to the strategies for treatments, patients were divided into four groups: tonsillectomy and steroid pulse (TSP, n = 47), tonsillectomy and oral steroid (TOS, n = 33), tonsillectomy alone (T, n = 56), and N group (no particular therapy, n = 72).

Potential therapeutic system for Alzheimer's disease: removal of blood Aβs by hemodialzyers and its effect on the cognitive functions of renal-failure patients.

The pathological changes of Alzheimer's disease include the deposition of amyloid β protein (Aβ) as senile plaques in the brain. We hypothesized that the rapid removal of Aβs from the blood may act as a peripheral Aβ drainage sink from the brain. In this study, the plasma Aβ concentrations and the cognitive functions were investigated for in 57 patients on hemodailysis (69.

Global Gene Expression Profiling in PPAR-γ Agonist-Treated Kidneys in an Orthologous Rat Model of Human Autosomal Recessive Polycystic Kidney Disease.

Kidneys are enlarged by aberrant proliferation of tubule epithelial cells leading to the formation of numerous cysts, nephron loss, and interstitial fibrosis in polycystic kidney disease (PKD). Pioglitazone (PIO), a PPAR-γ agonist, decreased cell proliferation, interstitial fibrosis, and inflammation, and ameliorated PKD progression in PCK rats (Am. J.

Abnormalities of glycogenes in tonsillar lymphocytes in IgA nephropathy.

Glycosylation, which represents the most complex post-translational modification, plays a pivotal role during protein maturation, and is orchestrated by numerous glycosyltransferases. Aberrant O-glycosylation of serum and tonsillar IgA1 is presumed to be one of the pathogeneses of IgA nephropathy (IgAN). However, the synthesis of underglycosylated IgA1 in tonsils has not yet been characterized.

IgA nephropathy and aberrant glycosylation of tonsillar, serum and glomerular IgA1.

Human IgA1, which is the predominant subtype deposited in the glomeruli in IgA nephropathy (IgAN), has a unique mucin-like structure in its hinge region. Several studies suggested that the IgA1 molecules in IgAN patients had an aberrant structure of O-glycans. The paper summarizes the analyses of O-glycan structure in the IgA1 molecules taken from tonsils, sera and glomeruli of patients with IgAN.

Evaluation of blood purification and bortezomib plus dexamethasone therapy for the treatment of acute renal failure due to myeloma cast nephropathy.

Aggressive removal of circulating free light chains (FLC) by blood purification accompanied by chemotherapy is a promising approach for the treatment of acute renal failure due to myeloma cast nephropathy. Plasma exchange has been performed to remove serum FLC; in order to examine an alternative strategy we performed hemodiafiltration using protein-leaking dialyzers for the treatment of dialysis-dependent acute renal failure due to myeloma cast nephropathy. In the first case with κ-light chain cast nephropathy, the pre-treatment serum creatinine was 9.

PPAR-gamma agonist ameliorates kidney and liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease.

In autosomal recessive polycystic kidney disease (ARPKD), progressive enlargement of fluid-filled cysts is due to aberrant proliferation of tubule epithelial cells and transepithelial fluid secretion leading to extensive nephron loss and interstitial fibrosis. Congenital hepatic fibrosis associated with biliary cysts/dilatations is the most common extrarenal manifestation in ARPKD and can lead to massive liver enlargement. Peroxisome proliferator-activated receptor γ (PPAR-γ), a member of the ligand-dependent nuclear receptor superfamily, is expressed in a variety of tissues, including the kidneys and liver, and plays important roles in cell proliferation, fibrosis, and inflammation.

Differential expression of glycogenes in tonsillar B lymphocytes in association with proteinuria and renal dysfunction in IgA nephropathy.

Aberrant O-glycosylation of serum and tonsillar IgA1 is one of the main pathogeneses of IgA nephropathy (IgAN). However, the synthesis of underglycosylated IgA1 in tonsils has not yet been characterized. This study examined tonsillar B lymphocytes of IgAN (n=34) using tonsils derived from patients with chronic tonsillitis (n=24) and sleep apnea syndrome (n=14) as a control.

Evaluation of the specific structures of IgA1 hinge glycopeptide in 30 IgA nephropathy patients by mass spectrometry.

Background: Although many reports have described the abnormal structures of O-glycan in the IgA1 hinge region in IgA nephropathy (IgAN), the specific glycopeptide that can be used as a diagnostic biomarker for IgAN has not yet been identified. To pursue this diagnostic approach, we used mass spectrometric analysis to search for specific structures in IgA1 hinge glycopeptides in 30 IgAN patients contrasted with 30 healthy controls.

Method: IgA1 hinge glycopeptides were individually purified from the sera of 30 biopsy-proven IgAN patients and 30 healthy controls.

Comparison of methods for profiling O-glycosylation: Human Proteome Organisation Human Disease Glycomics/Proteome Initiative multi-institutional study of IgA1.

The Human Proteome Organisation Human Disease Glycomics/Proteome Initiative recently coordinated a multi-institutional study that evaluated methodologies that are widely used for defining the N-glycan content in glycoproteins. The study convincingly endorsed mass spectrometry as the technique of choice for glycomic profiling in the discovery phase of diagnostic research. The present study reports the extension of the Human Disease Glycomics/Proteome Initiative's activities to an assessment of the methodologies currently used for O-glycan analysis.

Expression of tumor necrosis factor receptors on granulocytes in patients with myeloperoxidase anti-neutrophil cytoplasmic autoantibody-associated vasculitis.

Background/aims: To clarify the clinical significance of tumor necrosis factor (TNF) receptors in patients with myeloperoxidase (MPO)-anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, we evaluated the cell surface expression of TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2).

Patients And Methods: 43 patients with MPO-ANCA-associated vasculitis, 16 patients with chronic renal failure, 10 patients with sepsis, 15 patients with systemic lupus erythematosus, and 18 healthy controls were enrolled in this study, and the surface expression levels of TNFR1, TNFR2, CD63, and CD64 on granulocytes were assessed. In 21 patients with MPO-ANCA-associated vasculitis, soluble TNFR1 (sTNFR1), soluble TNFR2(sTNFR2), and TNF-alpha in the serum were also measured.

Serum levels of 5-s-cysteinyldopa are correlated with skin colors in hemodialysis patients but not in peritoneal dialysis patients.

Background: Diffuse hyperpigmentation is common in patients with chronic renal failure undergoing hemodialysis (HD) or peritoneal dialysis (PD). We previously reported that serum levels of 5-S-cysteinyldopa (5SCD, a pheomelanin precursor) and pheomelanin were significantly elevated in HD patients.

Methods: Skin color was assessed using a Mexameter that measures the melanin index (MI) and the erythema index (EI).

A library of mutated Maackia amurensis hemagglutinin distinguishes putative glycoforms of immunoglobulin A1 from IgA nephropathy patients.

Ten genetically modified Maackia amurensis hemagglutinin (MAH) clones at the carbohydrate-recognition loop were found to bind glycophorin A and a mucin mimetic with NeuAcalpha2-3Galbeta1-3GalNAcalpha (monosialyl-T antigen) in different relative intensity. Binding profiles of these lectins to human serum IgA1 from healthy individuals and from IgA nephropathy patients were subjected to the cluster analysis. Two large groups, one with only healthy individuals and another with all IgA nephropathy patients, were generated.

O-linked oligosaccharides of the IgA1 hinge region: roles of its aberrant structure in the occurrence and/or progression of IgA nephropathy.

Primary IgA nephropathy (IgAN) has been regarded as an immune complex-mediated glomerulonephritis characterized immunohistologically by the predominant deposition of IgA in the glomerular mesangial area with a variety of histopathologic injuries (Clarkson et al. in Ann Rev Med 38:157-168, 1987). In 1992, the characteristic structure of O-linked oligosaccharides (O-glycans) in the IgA1 hinge and its possible aberrancy were simultaneously and independently proposed by Mesteckey et al.