Structure and Activity of a Selective Antibiofilm Peptide SK-24 Derived from the NMR Structure of Human Cathelicidin LL-37

The deployment of the innate immune system in humans is essential to protect us from infection. Human cathelicidin LL-37 is a linear host defense peptide with both antimicrobial and immune modulatory properties. Despite years of studies of numerous peptides, SK-24, corresponding to the long hydrophobic domain (residues 9–32) in the anionic lipid-bound NMR structure of LL-37, has not been investigated. This study reports the structure and activity of SK-24. Interestingly, SK-24 is entirely helical (~100%) in phosphate buffer (PBS), more than LL-37 (84%), GI-20 (75%), and GF-17 (33%), while RI-10 and 17BIPHE2 are essentially randomly coiled (helix%: 7–10%). These results imply an important role for the additional N-terminal amino acids (likely E16) of SK-24 in stabilizing the helical conformation in PBS. It is proposed herein that SK-24 contains the minimal sequence for effective oligomerization of LL-37. Superior to LL-37 and RI-10, SK-24 shows an antimicrobial activity spectrum comparable to the major antimicrobial peptides GF-17 and GI-20 by targeting bacterial membranes and forming a helical conformation. Like the engineered peptide 17BIPHE2, SK-24 has a stronger antibiofilm activity than LL-37, GI-20, and GF-17. Nevertheless, SK-24 is least hemolytic at 200 µM compared with LL-37 and its other peptides investigated herein. Combined, these results enabled us to appreciate the elegance of the long amphipathic helix SK-24 nature deploys within LL-37 for human antimicrobial defense. SK-24 may be a useful template of therapeutic potentia

Significant Upregulation of Alzheimer's β-Amyloid Levels in a Living System Induced by Extracellular Elastin Polypeptides

Alzheimer's disease (AD) is a neurodegenerative disorder and the primary cause of age-related dementia. The etiology of AD is complex and has not been completely elucidated. Herein, we report that treatment with elastin-like polypeptides (ELPs), a component of the brain extracellular matrix (ECM), significantly increased the levels of AD-related amyloid-β peptides (Aβ) both in vitro and in vivo. Regarding the molecular mechanism(s), the upregulation of Aβ levels was related to increased proteolytic processing of the amyloid precursor protein. Furthermore, nesting tests demonstrated that the ELP-treated animals showed significant neurobehavioral deficits with cognitive impairment. These results suggest that the elastin is associated with AD-related pathological and behavioral changes. This finding presents a new aspect for Alzheimer's amyloidosis event and provides a great promise in developing ELP-based model systems to better understand the pathogenesis of AD. © 201

Evaluation and Analysis Model of Wine Quality Based on Mathematical Model

This paper takes wine quality evaluation as the research object, establishes the analysis and evaluation model of wine quality, and explores the influence of physical with chemical indicators of wine grapes and wine on the wine quality. Firstly, the Mann-Whitney U test is used to analyze the wine evaluation results of the two wine tasters, and it is found that the significant difference between the two is small. Then this paper uses the Cronbach Alpha coefficient method to analyze the credibility of the two groups of data. It is found that the credibility of the first group of wine scores is significantly greater than that of the second group and the white wine scores are more reliable than the red wine. Therefore, the first set of data and white wine can be applied for follow-up studies. Next, the principal component analysis is used to extract the main indicators and calculate the factor coefficients as the Ward method in cluster analysis is used to classify the wine into four grades according to the quality score of the wine. Then, based on the extracted principal components that is physical with chemical indicators, this paper does the multiple linear regression analysis of wine quality, and takes the influence of aromatic substances on the aroma of wine in physical with chemical indicators as an example. Regression analysis shows that there is a positive correlation linear relationship between the scores of the aroma of wine and C2H6O, C6H12O2, C3H8O, C11H24, C7H12O2, C5H10O2 and C10H16. It can be judged that the aromatic substances in the wine such as C2H6O have a regular influence on the odor of the wine, and it is inferred that other physical and chemical properties have a similar regular relationship with the wine quality. This provides an effective reference for the analysis and evaluation of wine quality by using physical with chemical indicators such as aromatic substances in wine in the future

Oral vinorelbine and continuous low doses of cyclophosphamide in pediatric rhabdomyosarcoma: a real-world study

Introduction: Metronomic maintenance therapy (MMT) has significantly improved the survival of patients with high-risk rhabdomyosarcoma in clinical trials. However, there remains a lack of relevant data on its effectiveness in real-world situations.Methods: We retrospectively retrieved data of 459 patients < 18 years of age diagnosed with rhabdomyosarcoma at Sun Yat-sen University Cancer Center from January 2011 to July 2020 from our database. The MMT regimen was oral vinorelbine 25–40 mg/m2 for twelve 4-week cycles on days 1, 8, and 15, and oral cyclophosphamide 25–50 mg/m2 daily for 48 consecutive weeks.Results: A total of 57 patients who underwent MMT were included in the analysis. The median follow-up time was 27.8 (range: 2.9–117.5) months. From MMT to the end of follow-up, the 3-year PFS and OS rates were 40.6% ± 6.8% and 58.3% ± 7.2%, respectively. The 3-year PFS was 43.6% ± 11.3% in patients who were initially diagnosed as low- and intermediate-risk but relapsed after comprehensive treatment (20/57), compared with 27.8% ± 10.4% in high-risk patients (20/57) and 52.8% ± 13.3% in intermediate-risk patients who did not relapse (17/57). The corresponding 3-year OS for these three groups was 65.8% ± 11.4%, 50.1% ± 12.9%, and 55.6% ± 13.6%, respectively.Conclusion: We present a novel study of MMT with oral vinorelbine and continuous low doses of cyclophosphamide in real-world pediatric patients with RMS. Our findings showed that the MMT strategy significantly improved patient outcomes and may be an effective treatment for high-risk and relapsed patients

Host Langerin (CD207) is a receptor for Yersinia pestis phagocytosis and promotes dissemination

Yersinia pestis is a Gram-negative bacterium that causes plague. After Y. pestis overcomes the skin barrier, it encounters antigen-presenting cells (APCs), such as Langerhans and dendritic cells. They transport the bacteria from the skin to the lymph nodes. However, the molecular mechanisms involved in bacterial transmission are unclear. Langerhans cells (LCs) express Langerin (CD207), a calcium-dependent (C-type) lectin. Furthermore, Y. pestis possesses exposed core oligosaccharides. In this study, we show that Y. pestis invades LCs and Langerin-expressing transfectants. However, when the bacterial core oligosaccharides are shielded or truncated, Y. pestis propensity to invade Langerhans and Langerin-expressing cells decreases. Moreover, the interaction of Y. pestis with Langerin-expressing transfectants is inhibited by purified Langerin, a DC-SIGN (DC-specific intercellular adhesion molecule 3 grabbing nonintegrin)-like molecule, an anti-CD207 antibody, purified core oligosaccharides and several oligosaccharides. Furthermore, covering core oligosaccharides reduces the mortality associated with murine infection by adversely affecting the transmission of Y. pestis to lymph nodes. These results demonstrate that direct interaction of core oligosaccharides with Langerin facilitates the invasion of LCs by Y. pestis. Therefore, Langerin-mediated binding of Y. pestis to APCs may promote its dissemination and infection.Peer reviewe

Dynamics of Oxygen-Independent Photocleavage of Blebbistatin as a One-Photon Blue or Two-Photon Near-Infrared Light-Gated Hydroxyl Radical Photocage

Development of versatile, chemically tunable photocages for photoactivated chemotherapy (PACT) represents an excellent opportunity to address the technical drawbacks of conventional photodynamic therapy (PDT) whose oxygen-dependent nature renders it inadequate in certain therapy contexts such as hypoxic tumors. As an alternative to PDT, oxygen free mechanisms to generate cytotoxic reactive oxygen species (ROS) by visible light cleavable photocages are in demand. Here, we report the detailed mechanisms by which the small molecule blebbistatin acts as a one-photon blue light-gated or two-photon near-infrared light-gated photocage to directly release a hydroxyl radical (•OH) in the absence of oxygen. By using femtosecond transient absorption spectroscopy and chemoselective ROS fluorescent probes, we analyze the dynamics and fate of blebbistatin during photolysis under blue light. Water-dependent photochemistry reveals a critical process of water-assisted protonation and excited state intramolecular proton transfer (ESIPT) that drives the formation of short-lived intermediates, which surprisingly culminates in the release of •OH but not superoxide or singlet oxygen from blebbistatin. CASPT2//CASSCF calculations confirm that hydrogen bonding between water and blebbistatin underpins this process. We further determine that blue light enables blebbistatin to induce mitochondria-dependent apoptosis, an attribute conducive to PACT development. Our work demonstrates blebbistatin as a controllable photocage for •OH generation and provides insight into the potential development of novel PACT agents

Optimization of Porphyran Extraction from <i>Pyropia yezoensis</i> by Response Surface Methodology and Its Lipid-Lowering Effects

Macroalgae polysaccharides are phytochemicals that are beneficial to human health. In this study, response surface methodology was applied to optimize the extraction procedure of Pyropia yezoensis porphyran (PYP). The optimum extraction parameters were: 100 °C (temperature), 120 min (time), and 29.32 mL/g (liquid–solid ratio), and the maximum yield of PYP was 22.15 ± 0.55%. The physicochemical characteristics of PPYP, purified from PYP, were analyzed, along with its lipid-lowering effect, using HepG2 cells and Drosophila melanogaster larvae. PPYP was a β-type sulfated hetero-rhamno-galactan-pyranose with a molecular weight of 151.6 kDa and a rhamnose-to-galactose molar ratio of 1:5.3. The results demonstrated that PPYP significantly reduced the triglyceride content in palmitic acid (PA)-induced HepG2 cells and high-sucrose-fed D. melanogaster larvae by regulating the expression of lipid metabolism-related genes, reducing lipogenesis and increasing fatty acid β-oxidation. To summarize, PPYP can lower lipid levels in HepG2 cells and larval fat body (the functional homolog tissue of the human liver), suggesting that PPYP may be administered as a potential marine lipid-lowering drug