Background:The G26R apolipoprotein A-I (apoA-I Iowa ) mutation causes familial amyloid polyneuropathy. Results: ApoA-I Iowa amyloid cellular interaction and cytotoxicity depended on cell surface heparan sulfate (HS). Enzymatic remodeling of HS by extracellular sulfatase mitigated cytotoxicity. Conclusion: Sulfate moieties of cell surface HS are critical for mediating apoA-I amyloid cytotoxicity. Significance: Enzymatic remodeling of HS may be a novel concept for regulating actions of amyloid on cells.

Highly sulfated domains of heparan sulfate (HS), alias HS S-domains, consist of consecutive clusters of a trisulfated disaccharide unit [iduronic acid (2S)-glucosamine (NS, 6S)]. 1 These HS S-domains are a major determinant of specific interactions between HS and its protein ligands, including growth factors, chemokines, and morphogens, and thus they regulate HS functions in diverse biological processes. 2,3 In addition to being involved in biological processes, HS is associated with various amyloid deposits, including those in transthyretin amyloidosis (ATTR amyloidosis), 4 Alzheimer disease (AD), 5e7 light-chain amyloidosis, 8 and amyloid A (AA) amyloidosis, 9 which suggests that HS may affect amyloid deposition and amyloidosis pathology. Indeed, HS and heparin, whose major components are HS S-domains, reportedly promoted fibrillogenesis of various amyloidogenic proteins, such as transthyretin (TTR) in ATTR amyloidosis, 4,10 amyloid b (Ab) in AD, 11e13 cellular prion, Ig light chain in light-chain amyloidosis, 14 and serum AA in AA amyloidosis. 15e17 Also, HS at the cell surface mediated interactions of cells with and cytotoxicity of amyloid fibrils or protein aggregates, including those of t protein and a-synuclein, 18 Ab, 19 Supported in part by the Japan Society for the Promotion of Science grants-in-aid for young scientists B-15K19488 (K.N.

Our results support the concept that EGCG inhibits amyloid fibril formation of various amyloidogenic proteins. Thus, EGCG may be a candidate for providing a structure to develop de novo inhibitors for amyloidosis treatment.

A high mortality rate is found among septic patients with disseminated intravascular coagulation (DIC). Anticoagulants have been used for treating septic DIC especially in Japanese clinical settings; however, their effectiveness is quite controversial across studies. According to several randomized controlled trials and metaanalyses, antithrombin and recombinant thrombomodulin had no therapeutic benefit in the treatment of sepsis. However, the majority of the previous research did not discuss "septic DIC" but simply "sepsis", and some reviews showed that anticoagulants were benefit only in septic DIC. Although immunothrombosis plays an important role in early host defense, it can lead to DIC and organ failure if dysregulated. Therefore, we advocate anticoagulant therapies might have beneficial effects, but research on optimal patient selection is currently lacking.