Design of 11-Residue Peptides with Unusual Biophysical Properties: Induced Secondary Structure in the Absence of Water

AbstractA series of oligopeptides with β-forming and adhesive properties, were synthesized and analyzed for adhesion shear strength, secondary structure, and association properties. The sequences contained related hydrophobic core segments varying in length from 5 to 12 residues and flanked by di- or tri-lysine segments. Three remarkable peptides consisting of just 11 residues with hydrophobic core sequences of FLIVI, IGSII, and IVIGS flanked by three lysine residues gave the highest dry adhesion shear strength and displayed unusual biophysical properties in the presence and absence of water. KKKFLIVIKKK had its highest adhesion strength at 2% (w/v) at pH 12.0 and showed the highest adhesion strength after exposure to water (water resistance). Both KKKIGSIIKKK and KKKIVIGSKKK, at 4% (w/v) at pH 12.0, displayed nearly identical dry shear strength values to that with the FLIVI core sequence. The peptide with IGSII core, however, displayed a lower water resistance and the latter, IVIGS, showed no water resistance, completely delaminating upon soaking in water. These are the smallest peptides with adhesive properties reported to date and show remarkable adhesion strength even at lower concentrations of 0.2% (w/v), which corresponds to 1.6mM. The FLIVI containing peptide adopted a β-sheet secondary structure in water while the IGSII- and IVIGS-containing sequences folded similarly only in the absence of water. Analytical ultracentrifugation studies showed that when the FLIVI sequence adopts β-structure in aqueous solution, it associates into a large molecular weight assembly. The random coils of IGSII and IVIGS showed no tendency to associate at any pH

Design Of 11-Residue Peptides With Unusual Biophysical Properties:Induced Secondary Structure In The Absence Of Water

A series of oligopeptides with β-forming and adhesive properties, were synthesized and analyzed for adhesion shear strength, secondary structure, and association properties. The sequences contained related hydrophobic core segments varying in length from 5 to 12 residues and flanked by di- or tri-lysine segments. Three remarkable peptides consisting of just 11 residues with hydrophobic core sequences of FLIVI, IGSII, and IVIGS flanked by three lysine residues gave the highest dry adhesion shear strength and displayed unusual biophysical properties in the presence and absence of water. KKKFLIVIKKK had its highest adhesion strength at 2% (w/v) at pH 12.0 and showed the highest adhesion strength after exposure to water (water resistance). Both KKKIGSIIKKK and KKKIVIGSKKK, at 4% (w/v) at pH 12.0, displayed nearly identical dry shear strength values to that with the FLIVI core sequence. The peptide with IGSII core, however, displayed a lower water resistance and the latter, IVIGS, showed no water resistance, completely delaminating upon soaking in water. These are the smallest peptides with adhesive properties reported to date and show remarkable adhesion strength even at lower concentrations of 0.2% (w/v), which corresponds to 1.6 mM. The FLIVI containing peptide adopted a β-sheet secondary structure in water while the IGSII- and IVIGS-containing sequences folded similarly only in the absence of water. Analytical ultracentrifugation studies showed that when the FLIVI sequence adopts β-structure in aqueous solution, it associates into a large molecular weight assembly. The random coils of IGSII and IVIGS showed no tendency to associate at any pH. © 2008 by the Biophysical Society

Electroacupuncture Alleviates Osteoarthritis by Suppressing NLRP3 Inflammasome Activation in Guinea Pigs

Osteoarthritis (OA) is an increasingly prevalent disease affecting synovial joints, which includes joint degeneration, inflammation, and joint pain. The activation of nucleotide-binding and oligomerization domain-like receptor containing protein 3 (NLRP3) could promote synovial inflammation. Previous studies have shown that electroacupuncture (EA) has potential anti-inflammatory effect. However, the effect of EA treatment on OA remains unclear. The aim of this study was to investigate the effect of applied EA on OA and joint pain and its relationship with NLRP3 inflammasome. The Hartley guinea pigs with naturally occurring OA at age 18 months were chosen as the OA model and treated with EA for 4 weeks. Mechanical allodynia was quantified by using von Frey filaments. The expression of NLRP3 inflammasome and the downstream proinflammatory factors in the cartilage tissue were quantified. Our results showed that EA treatment significantly reduces mechanical allodynia, improves the articular cartilage structure, and decreases the fibrillation on the cartilage surface in guinea pigs with spontaneous osteoarthritis. Moreover, we also found that EA treatment attenuates the NLRP3 inflammasome activation and suppresses the protein expression levels of caspase-1 and IL-1β in the cartilage tissue. Our findings suggest that EA treatment attenuates OA and joint pain by suppressing NLRP3 inflammasome activation and support further investigation of the potential therapeutic tactics

Famitinib in combination with concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 1, open-label, dose-escalation Study

Abstract Background Famitinib is a tyrosine kinase inhibitor against multiple targets, including vascular endothelial growth factor receptor 2/3, platelet-derived growth factor receptor, and stem cell factor receptor (c-kit). Previous studies have demonstrated anti-tumour activities of famitinib against a wide variety of advanced-stage solid cancers. We aimed to determine the safety and efficacy of famitinib with concurrent chemoradiotherapy (CCRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). We also evaluated the feasibility of contrast-enhanced ultrasound (D-CEUS) as a predictor of early tumour response to famitinib and to correlate functional parameters with clinical efficacy. Methods The trial was conducted in subjects with stage III or IVa-b NPC using a 3 + 3 design of escalating famitinib doses. Briefly, subjects received 2 weeks of famitinib monotherapy followed by 7 weeks of famitinib plus CCRT. D-CEUS of the neck lymph nodes was performed at day 0, 8 and 15 after famitinib was administered before starting concurrent chemoradiotherapy. End points included safety, tolerability and anti-tumour activity. Results Twenty patients were enrolled (six each for 12.5, 16.5 and 20 mg and two for 25 mg). Two patients in the 25 mg cohort developed dose-limiting toxicities, including grade 4 thrombocytopenia and grade 3 hypertension. The most common grade 3/4 adverse events were leukopenia, neutropenia and radiation mucositis. D-CEUS tests showed that more than 60% of patients achieved a perfusion parameter response after 2 weeks taking famitinib alone, and the parameter response was associated with disease improvement. In the famitinib monotherapy stage, three patients (15%) showed partial responses. The complete response rate was 65% at the completion of treatment and 95% 3 months after the treatment ended. After a median follow-up of 44 months, the 3-year progression-free survival (PFS) and distant metastasis-free survival were 70% and 75%, respectively. Subjects with a decrease of perfusion parameter response, such as peak intensity decreased at least 30% after 1 week of famitinib treatment, had higher 3-year PFS (90.9% vs. 44.4%, 95% CI 73.7%–100% vs. 11.9%–76.9%, P < 0.001) than those with an increase or a reduction of less than 30%. Conclusions The recommended famitinib dose for phase II trial is 20 mg with CCRT for patients with local advanced NPC. D-CEUS is a reliable and early measure of efficacy for famitinib therapies. Further investigation is required to confirm the effects of famitinib plus chemoradiotherapy