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Xiang Xu,1,2 Fuling Qiu,2 Man Yang,3 Xiaoyong Liu,2 Siming Tao,4,* Bingrong Zheng1,* 1School of Medicine, Yunnan University, Kunming City, Yunnan Province, People’s Republic of China; 2Department of Cardiology, The Second Affiliated Hospital of Kunming Medical University, Kunming City, Yunnan Province, People’s Republic of China; 3School of Medicine, Dali University, Dali City, Yunnan Province, People’s Republic of China; 4Department of Cardiology, The Affiliated Hospital of Yunnan University, Kunming City, Yunnan Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bingrong Zheng; Siming Tao, Email zhengbr@ynu.edu.cn; taosm6450@ynu.edu.cnBackground: Dysregulated macrophages are important causes of Atherosclerosis (AS) formation and increased plaque instability, but the heterogeneity of these plaques and the role of macrophage subtypes in plaque instability have yet to be clarified.Methods: This study integrates single-cell and bulk-seq data to analyze atherosclerotic plaques. Unsupervised clustering was used to reveal distinct plaque subtypes, while survival analysis and gene set variation analysis (GSVA) methods helped in understanding their clinical outcomes. Enrichment of differential expression of macrophage genes (DEMGs) score and pseudo-trajectory analysis were utilized to explore the biological functions and differentiation stages of macrophage subtypes in AS progression. Additionally, CellChat and the BayesPrism deconvolution method were used to elucidate macrophage subtype interaction and their prognostic significance at single-cell resolution. Finally, the expression of biomarkers was validated in mouse experiments.Results: Three distinct AS plaque subtypes were identified, with cluster 3 plaque subtype being particularly associated with higher immune infiltration and poorer prognosis. The DEMGs score exhibited a significant elevation in three macrophage subtypes (SPP1+/VCAN+ macrophages, IL1B+ macrophages, and FLT3LG+ macrophages), associated with cluster 3 plaque subtype and highlighted the prognostic significance of these subtypes. Activation trajectory of the macrophage subtypes is divided into three states (Pre-branch, Cell fate 1, and Cell fate 2), and Cell fate 2 (SPP1+/VCAN+ macrophages, IL1B+ macrophages, and FLT3LG+ macrophages dominant) exhibiting the highest DEMGs score, distinct interactions with other cell components, and relating to poorer prognosis of ischemic events. This study also uncovered a unique SPP1+/VCAN+ macrophage subtype, rare in quantity but significant in influencing AS progression. Machine learning algorithms identified 10 biomarkers crucial for AS diagnosis. The validation of these biomarkers was performed using Mendelian Randomization analysis and in vitro methods, supporting their relevance in AS pathology.Conclusion: Our study provides a comprehensive view of AS plaque heterogeneity and the prognostic significance of macrophage subtypes in plaque instability. Keywords: atherosclerosis, macrophage subtypes, single-cell analysis, plaque heterogeneity, biomarkers, pseudo-trajectory analysis

Mingyang Du,1,* Lili Xu,1,* Xiaohao Zhang,2 Xianjun Huang,3 Hui Cao,1 Feng Qiu,1 Wenya Lan,1 Haibo Jiang1 1Cerebrovascular Disease Center, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu Province, 210029, People’s Republic of China; 2Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210002, People’s Republic of China; 3Department of Neurology, Yijishan Hospital, Wannan Medical College, Wuhu, Anhui Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mingyang Du, Cerebrovascular Disease Center, Nanjing Brain Hospital Affiliated to Nanjing Medical University, No. 264 Guangzhou Road, Nanjing, Jiangsu Province, 210029, People’s Republic of China, Tel/Fax +86 25-82296000, Email dmyang0128@126.comBackground: Inflammatory burden index (IBI) is a systemic inflammation indicator that reflects the inflammatory status. We aimed to investigate the prognostic value of IBI after endovascular thrombectomy (EVT) in patients with acute ischemic stroke.Methods: We enrolled patients treated with EVT from a multicenter cohort between June 2020 and December 2021. The IBI was calculated as C-reaction protein × neutrophil / lymphocyte count. The primary outcome was the unfavorable functional outcome (90-day modified Rankin scale score 3– 6). C-statistics and net reclassification indexes were used to assess the predictive accuracy. Multivariable logistic regression models were used to investigate the association between IBI and unfavorable outcome.Results: A total of 295 patients (mean age, 64.0 ± 12.8 years; male, 63.7%) were enrolled in this study. In multivariable models, higher IBI levels were associated with an increased risk of 90-day unfavorable outcome after EVT (per 1-SD: odds ratio, 1.754; 95% confidence interval, 1.241– 2.587; P = 0.002). Restricted cubic spline curve displayed a linear relationship between the IBI level and 90-day unfavorable outcome (P for nonlinearity = 0.410). Besides, IBI was a more accurate biomarker for predicting unfavorable outcomes with the highest predictive accuracy and reclassification indexes.Conclusion: This study demonstrated that higher IBI was associated with an increased risk of 90-day unfavorable outcome in acute ischemic stroke treated with EVT.Keywords: stroke, thrombectomy, inflammatory burden, systemic, prognosis

Fei Peng,1 Jing Liu,1,2 Yujun Zhang,1,2 Guoyan Zhao,1,2 Deying Gong,1,2 Liu He,1,2 Wensheng Zhang,1,2 Feng Qiu1,2 1Laboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Feng Qiu; Wensheng Zhang, Email fengqiu@scu.edu.cn; zhang_ws@scu.edu.cnIntroduction: Ropivacaine as a conventional local anesthetic has been used more and more frequently in the treatment of postoperative pain, but its analgesic effect can only last for several hours. In order to fulfill the clinic requirement for long-term analgesia, a long-acting ropivacaine nanocrystal formulation was fabricated through the interaction between ropivacaine and a self-assembling peptide.Methods: Transmission electron microscopy, dynamic light scattering, circular dichroism and fluorescence spectrometry were used to examine the structural changes caused by the interaction between ropivacaine and the peptide. Scanning electron microscopy, dynamic light scattering, Fourier transform infrared spectrometry, X-ray diffraction and optical microscopy were used to characterize the ropivacaine-peptide nanocrystal. In vitro drug release and pharmacokinetics study were conducted to evaluate the slow-release profile of the nanocrystal formulation. A rodent cutaneous trunci muscle reflex model was used to evaluate the nociceptive blockade effects, and histological analysis was used to evaluate the local toxicity. A rodent plantar incisional pain model was used to evaluate the analgesic effect.Results: Soluble ropivacaine monomers interacted with the Q11 peptide through π-π stacking and remolded its self-assembling structure, leading to the formation of drug/peptide nanoparticles which could be mineralized to form drug/peptide nanocrystals by adjusting the pH. Under physiological condition, the nanocrystals could release free ropivacaine slowly. As evaluated in rodent models, the anesthetic and analgesic effects of this formulation were significantly extended without causing toxicity.Conclusion: Based on the interaction between ropivacaine and Q11, a controllable biomineralization process could be induced to obtain homogeneous nanocrystals, which could be used as an injectable long-acting analgesic formulation. This crystallization strategy utilizing the peptide-drug interaction also provided a promising pathway to fabricate long-acting formulations for many other small molecular drugs.Keywords: self-assembling peptide, nanocrystal, local anesthetics, π-π stacking, slow release, long-acting analgesia

We demonstrate the guiding principles behind simple two dimensional self-assembly of MOF nanoparticles (NPs) and oleic acid capped iron oxide (Fe3 O4 ) NCs into a uniform two-dimensional bi-layered superstructure. This self-assembly process can be controlled by the energy of ligand-ligand interactions between surface ligands on Fe3 O4 NCs and Zr6 O4 (OH)4 (fumarate)6 MOF NPs. Scanning transmission electron microscopy (TEM)/energy-dispersive X-ray spectroscopy and TEM tomography confirm the hierarchical co-assembly of Fe3 O4 NCs with MOF NPs as ligand energies are manipulated to promote facile diffusion of the smaller NCs. First-principles calculations and event-driven molecular dynamics simulations indicate that the observed patterns are dictated by combination of ligand-surface and ligand-ligand interactions. This study opens a new avenue for design and self-assembly of MOFs and NCs into high surface area assemblies, mimicking the structure of supported catalyst architectures, and provides a thorough fundamental understanding of the self-assembly process, which could be a guide for designing functional materials with desired structure.

Sirui Song,1 Liqin Chen,1 Qianqian Ning,2 Danying Zhu,1 Feng Qiu,2 Guang Li,2 Hong Zhang,3 Tingting Xiao,1 Guohui Ding,4 Min Huang1 1Department of Cardiology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Shanghai Center for Bioinformation Technology, Shanghai, People’s Republic of China; 3Department of Laboratory, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 4International Human Phenome Institutes, Shanghai, 200235, People’s Republic of ChinaCorrespondence: Min HuangDepartment of Cardiology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China, Email huangmin@sjtu.edu.cnGuohui DingInternational Human Phenome Institutes, Shanghai, 200235, People’s Republic of China, Email dingguohui@ihup.org.cnPurpose: Kawasaki disease (KD) is an acute systemic vasculitis mainly found in the medium-sized arteries, especially the coronary arteries. Immune system is involved in the pathogenesis of acute KD in children, but the functional differences in the immune system between healthy children and KD patients remain unclear.Patients and Methods: A total of 190 KD patients and 119 healthy controls were recruited for the next-generation sequencing of 512 targeted genes from 4 immune-related pathways. Subsequently, the peripheral blood mononuclear cells (PBMCs) were isolated. RNA sequencing of the LPS treated PBMCs from additional 20 KD patients and 20 healthy controls was used to examine the differentially expressed genes (DEGs). Then, an expression quantitative trait locus (eQTL) analysis combined with previously analyzed RNA data were used to examine the DEGs. Finally, the serum levels of 13 cytokines were detected before and after LPS treatment in 40 samples to confirm the findings from eQTL analysis.Results: A total of 319 significant eQTL were found, and both eQTL analysis and RNA sequencing showed some DEGs were involved in the connective tissue disorders and inflammatory diseases. DEGs that function to negatively regulate immunity were closely related to the pathogenesis of KD. In addition, the serum levels of IL-10 (an inflammatory and immunosuppressive factor) and SCD25 (an important immunosuppressant) reduced significantly in the KD patients.Conclusion: Our study shows the expression of factors responsible for the negative control of innate immunity is altered, which plays an important role in the etiology of KD.Keywords: Kawasaki disease, innate immunity, inflammation, next generation sequencing, cytokines

The potential emergence of a second-generation ethanol industry in Canada will depend on future production technologies and prices. Financial viability might be improved by producing cellulosic ethanol with co-products such as lignin pellets or electricity. Financial returns to ethanol production will depend on price variability and possible price spillovers among ethanol and its co-products. We use a multivariate BEKK-GARCH approach to investigate past mean price interactions and volatility spillovers between ethanol and electricity prices. Wood pellets are investigated in a univariate framework because of data constraints. Results show substantial price interactions and volatility spillovers among these products. If a second-generation ethanol industry emerges, co-production of products from common feedstocks may strengthen already established relationships between the prices of these energy products. These conditions could create increased risk and the clustering of high-low price fluctuations among co-products. For investors, results suggest that risk reduction strategies should protect against correlated volatility. For policy makers, results suggest that policies that target one commodity may lead to unintended impacts on co-product(s). In sum, understanding links between markets is important for designing future policies and for insights into how a second-generation ethanol industry may emerge. Key words: second-generation ethanol, biofuels, volatility spillovers, biofuel co-products, multivariate price analysis. La possibilite qu'une industrie de l'ethanol de deuxieme generation emerge au Canada dependra des technologies de production et des prix futurs. La viabilite financiere pourrait etre amelioree en produisant de l'ethanol cellulosique avec des coproduits tels que des granules de lignine ou de l'electricite. Les rendements financiers de la production d'ethanol dependront de la variabilite des prix et des retombees possibles des prix entre l'ethanol et ses coproduits. Nous utilisons une approche multivariee BEKK-GARCH pour etudier les interactions passees des prix moyens et la volatilite des retombees entre les prix de l'ethanol et de l'electricite. L'etude des granules de bois s'est faite dans un cadre unidimensionnel en raison des contraintes liees aux donnees. Les resultats presentent des interactions de prix importantes et des retombees de volatilite entre ces produits. Si une industrie de l'ethanol de deuxieme generation se developpe, la coproduction de produits a partir de matieres premieres communes peut renforcer les relations deja etablies entre les prix de ces produits energetiques. Ces conditions pourraient creer un risque accru et un regroupement de la variation des prix eleves ou faibles parmi les coproduits. Pour les investisseurs, les resultats suggerent que les strategies de reduction des risques devraient les proteger de la volatilite correlee. Pour les decideurs, les resultats suggerent que les politiques qui ciblent un produit peuvent conduire a des effets non intentionnels sur le ou les coproduits. En resume, il est important de comprendre les liens entre les marches pour concevoir les politiques futures et avoir un apercu de la facon dont une industrie de l'ethanol de deuxieme generation pourrait voir le jour. Mots-cles : ethanol de deuxieme generation, biocarburants, volatilite des retombees, coproduits du biocarburant, analyse de prix multivariee., 1. Introduction Canada is a relatively small player in global ethanol markets, with approximately 2% of global production (United States Department of Energy 2013). But Canada has been enacting policies, [...]

Fen Qiu,1,2,* Long Xi,2,* Shengshuang Chen,3 Yonghua Zhao,2,4 Zhenping Wang,5 Ying Zheng2 1State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, People’s Republic of China; 2State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, People’s Republic of China; 3Macau Institute for Applied Research in Medicine and Health, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau SAR, People’s Republic of China; 4Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, University of Macau, Macau, People’s Republic of China; 5Department of Dermatology, School of Medicine, University of California, San Diego, La Jolla, CA, USA*These authors contributed equally to this workCorrespondence: Ying ZhengState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau Tel +853 88224687Fax +853 28841358Email yzheng@umac.moPurpose: Psoriasis is an inflammatory skin disease, where keratinocytes play pivotal roles in its pathogenesis. We prepared Celastrol Noisome hydrogel (Cel Nio gel) for the treatment of psoriasis and aimed to study its target site as well as the mechanism.Methods: Cel Nio was fabricated with thin-film hydration and sonication, then topically administered to imiquimod (IMQ)-induced psoriasis mice. The concentrations of Cel in the skin, blood and lymphatic system were determined using LC-MS. The anti-psoriasis effect of Cel Nio gel was studied, and the levels of inflammatory cytokines in blood were evaluated by flow cytometry. For the in vitro study, the uptake of Nio by HaCaT cells was quantified with flow cytometry, and the anti-inflammatory effect of Cel on HaCaT cells was detected with qPCR. The expressions of inflammatory factors and Ki-67 in skin were observed by immunofluorescence.Results: Cel Nio possessed a particle size of 133 nm with encapsulation efficacy (EE%) of 83.2%. After topical administration of Cel Nio gel to mice, Cel was mainly accumulated in the skin instead of exposure in blood or lymphatic system, while the levels of inflammatory factors in blood had a significant decline. In addition, the preparation of Nio enhanced the uptake by HaCaT cells, and Cel obviously reduced the mRNA levels of inflammatory cytokines in HaCaT cells. Moreover, Cel Nio gel significantly decreased the expression of inflammatory cytokines and Ki-67 in the skin.Conclusion: Cel Nio gel achieved the anti-psoriatic effect by inhibiting the inflammation and hyperproliferation of keratinocytes in the skin and further suppressing the systemic inflammation, thus could be a novel topical drug delivery system to treat psoriasis with topical and systemic effects.Keywords: psoriasis, celastrol niosome, topical delivery, keratinocytes, pharmacokinetics

Jing Liu,1,2 Fei Peng,1,2 Yi Kang,1,2 Deying Gong,1,2 Jing Fan,1,2 Wensheng Zhang,1,2 Feng Qiu1,2 1Laboratory of Anesthesia and Critical Care Medicine, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Feng Qiu; Wensheng Zhang Email fengqiu@scu.edu.cn; zhang_ws@scu.edu.cnPurpose: Typical hydrophobic amino acids (HAAs) are important motifs for self-assembling peptides (SAPs), but they lead to low water-solubility or compact packing of peptides, limiting their capacity for encapsulating hydrophobic drugs. As an alternative, we designed a peptide GQY based on atypical HAAs, which could encapsulate hydrophobic drugs more efficiently. Although hydrophobic general anesthetics (GAs) have been formulated as lipid emulsions, their lipid-free formulations have been pursued because of some side effects inherent to lipids. Using GAs as targets, potential application of GQY as a carrier for hydrophobic drugs was evaluated.Methods: Thioflavin-T (ThT) binding test, dynamic light scattering (DLS) and transmission electron microscopy (TEM) were used to examine the self-assembling ability of GQY. Pyrene and 8-Anilino-1-naphthalenesulfonic acid (ANS) were used to confirm formation of hydrophobic domain in GQY nanoparticles. Using pyrene as a model, GQY’s capacity to encapsulate hydrophobic drugs was evaluated. GAs including propofol, etomidate and ET26 were encapsulated by GQY. Loss of righting reflex (LORR) test was conducted to assess the anesthetic efficacy of these lipid-free formulations. Paw-licking test was used to evaluate pain-on-injection of propofol-GQY (PROP-GQY) formulation. Hemolytic and cytotoxicity assay were used to evaluate biocompatibility of GQY.Results: Stable nanoparticles containing plenty of hydrophobic cavities could be formed by GQY, which could encapsulate hydrophobic drugs at very high concentration and form stable suspensions. Propofol, etomidate and ET26 formulated by GQY showed anesthetic efficacy comparable to their currently available formulations. Unlike clinic lipid emulsion, PROP-GQY formulation did not cause pain-on-injection in rats. Neither obvious cytotoxicity nor hemolytic activity of GQY was observed.Conclusion: GQY could encapsulate GAs to obtain stable and effective formulations. As a lipid-free carrier, GQY exhibited considerable biocompatibility and other side benefits such as reducing pain-on-injection. More SAPs based on atypical HAAs could be designed as promising carriers for hydrophobic drugs.Keywords: self-assembling peptides, nanoparticles, hydrophobic drugs, lipid-free formulations, general anesthetics

Si-Sn-C nanocomposites were synthesized via a facile mechanical milling method. Phase composition and morphologies of the asproduced Si-Sn-C nanocomposites were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and Raman spectroscopy. Both XRD and Raman studies revealed the amorphization of Si after mechanical milling process, while Sn remained as the crystalline phase in both Si-Sn and Si-Sn-C nanocomposites. Meanwhile, the particle size was significantly reduced, but Si tended to agglomerate during the milling and it was alleviated through the addition of carbon. The galvanostatic charge/discharge measurements were carried out to evaluate the electrochemical performance. Compared to milled Si, Si-Sn nanocomposites, Si-Sn-C nanocomposites exhibited a higher initial capacity of ∼1000 mAh/g, and its capacity was retained at ∼80% after 50 cycles. The possible buffering effect of Sn and carbon at different operating potentials during the lithiation/delithiation process was discussed.

Ning Yang,1 Feng Qiu,2 Feng Zhu,3 Lei Qi4 1Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, People’s Republic of China; 2Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; 3Department of Thoracic Surgery, Shandong Provincial Chest Hospital, Jinan, Shandong 250013, People’s Republic of China; 4Department of Thoracic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, People’s Republic of ChinaCorrespondence: Lei QiDepartment of Thoracic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 Wenhuaxi Road, Jinan, Shandong Province 250012, People’s Republic of ChinaEmail walker789sdu@sina.comIntroduction: Lung cancer is one of the most aggressive forms of cancer that leads to a high mortality rate amongst several cancer types and it is a widely recurrent cancer globally. The use of zinc oxide nanoparticles (ZnONPs) in the formulation of sun cream, food flavors, and colorings due to its varied biological properties. The extensive significance of nanoparticles encourages their production but the approaches are a common challenge in concluding the direct beneficial effect for the disease treatment. Hence, in the present study, zinc oxide-loaded syringic acid (ZnO-SYR) phytochemical was used to elucidate the therapeutic effect against lung cancer.Methods: The ZnO-SYR nanoparticles were synthesized and characterized by UV-visible spectroscopy, X-ray diffraction, dynamic light scattering, and FT-IR analysis. The characterized ZnO-SYR was tested on in vivo mouse model of lung cancer (benzo(a)pyrene (BAP)) and in vitro A549 cells.Results: The results demonstrated the significant restoration of body weight with attenuated serum marker enzymes compared to BAP-treated animals. In addition, cytokine estimation revealed ameliorated levels of TNF-α, interleukins, IL-6, IL-1β with evidenced histological observations in ZnO-SYR-treated mice compared to BAP-induced lung cancer mice.Discussion: Furthermore, cytotoxicity analysis demonstrated the altered mitochondrial membrane potential (MMP), with a profound increase in reactive oxygen species (ROS) levels, and apoptosis mechanism by ZnO-SYR compared to control cells. The conclusions of the present study put forward an evident confirmation of the protective and beneficial effects of zincoxide-loaded syringic acid against the BAP-induced lung cancer model.Keywords: zinc oxide nanoparticles, syringic acid, lung cancer, apoptosis, A549

Kai Wang,1,* Jinqiu Rao,1,* Tingting Zhang,1 Qing Gao,2 Jichao Zhang,3 Chenxi Guang,3 Liqin Ding,3 Feng Qiu1,3 1School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, People’s Republic of China; 2School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, People’s Republic of China; 3State Key Laboratory of Component-based Chinese Medicine,Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, People’s Republic of China*These authors contributed equally to this workCorrespondence: Feng QiuSchool of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, West Area, Tuanbo New Town, Jinghai District, Tianjin 301617, People’s Republic of ChinaTel/ Fax +86-022-59596223Email fengqiu20070118@163.comIntroduction: Berberrubine (BRB), an isoquinoline alkaloid, is a major constituent of medicinal plants Coptis chinensis Franch or Phellodendron chinense Schneid. BRB exhibits various pharmacological activities, whereas exposure to BRB may cause toxicity in experimental animals.Methods: In this study, we thoroughly investigated the liver injury induced by BRB in mice and rats. To explore the underlying mechanism, a study of the metabolic activation of BRB was conducted. Furthermore, covalent modifications of cysteine residues of proteins were observed in liver homogenate samples of animals after exposure to BRB, by application of an exhaustive proteolytic digestion method.Results: It was demonstrated that BRB-induced hepatotoxicities in a time- and dose-dependent manner, based on the biochemical parameters ALT and AST. H&E stained histopathological examination showed the occurrence of obvious edema in liver of mice after intraperitoneal (i.p.) administration of BRB at a single dose of 100 mg/kg. Slight hepatotoxicity was also observed in rats given the same doses of BRB after six weeks of gavage. As a result, four GSH adducts derived from reactive metabolites of BRB were detected in microsomal incubations with BRB fortified with GSH as a trapping agent. Moreover, four cys-based adducts derived from reaction of electrophilic metabolites of BBR with proteins were found in livers.Conclusion: These results suggested that the formation of protein adducts originating from metabolic activation of BRB could be a crucial factor of the mechanism of BRB-induced toxicities.Keywords: berberrubine, hepatotoxicity, metabolic activation, protein modification

Feng Qiu,1,* Kunyu Wang,1,* Tingting Li,2 Dandan Song,3 Zhiwei Wang,1 Hailing Zhang,4 Jianguo Liu,1 Ming Ren,5 Xiaokun Qi1 1Department of Neurology, Sixth Medical Center of Chinese PLA General Hospital, Beijing, 100048, People’s Republic of China; 2Department of Gastroenterology, Second Medical Center of Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China; 3Department of Medicine, Beijing Northern Hospital of China North Industries Group Corporation, Beijing 100089, People’s Republic of China; 4Department of Neurology, Changhai Hospital, Shanghai 200433, People’s Republic of China; 5Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University, Beijing 100191, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaokun QiDepartment of Neurology, Sixth Medical Center of PLA General Hospital, 6 Fucheng Road, Haidian District, Beijing 100048, People’s Republic of ChinaTel +86 139 1079 7081Email bjqxk@sina.com Ming RenBeijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University, 37 Xueyuan Road, Haidian District, Beijing 100191, People’s Republic of ChinaTel +86 139 1079 7081Email mren201017@hotmail.comBackground: The differential diagnosis of Parkinson’s disease (PD) with multiple-system atrophy (MSA) is difficult because of their similarity in symptoms and signs. The objective of this study was to investigate the value of external anal-sphincter electromyography (EAS-EMG) and urethral-sphincter electromyography (US-EMG) in differentiating MSA from PD.Methods: A total of 201 patients, — 101 MSA and 100 PD — were recruited in this study. Average duration and amplitude of motor unit potentials (MUPs), percentage of polyphasic MUPs, amplitude during strong contractions, and recruitment patterns during maximal voluntary contractions were recorded and analyzed to assess diagnostic efficiency of EAS-EMG and US-EMG for MSA.Results: Significant differences in average MUP duration and recruitment patterns during maximal voluntary contractions were found between patients with MSA and patients with PD using both EAS-EMG (P

Haolong Liu,1,2,* Feng Qiu,1,* Xinwei Yang,1 Haiyu Zhao,3 Baolin Bian,3 Lei Wang11School of Traditional Chinese Medicine, Beijing Key Lab of TCM Collateral Disease Theory Research, Capital Medical University, Beijing 100069, China; 2Beijing Institute For Drug Control, Beijing Key Laboratory of Analysis and Evaluation on Chinese Medicine, Beijing 100035, China; 3Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China*These authors contributed equally to this workPurpose: To determine the pharmacokinetic properties and pharmacological activity of the Yougui pill (YGP), which is a well-known Chinese medicine formula.Methods: An ultra-performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry via electrospray ionization interface (UPLC-ESI-MS/MS) method was developed and validated for the simultaneous determination of several components in rat plasma. The method was then successfully applied to the pharmacokinetics of six bioactive components in experimental autoimmune encephalomyelitis (EAE) model rats after oral administration of YGP. The expression of cAMP response element binding protein (CREB) and growth-associated protein-43 (GAP-43) in SH-SY5Y cells treated with these six components, YGP extract, and YGP-containing serum were investigated to determine the pharmacodyamic material basis of YGP. Six bioactive components were detected in rat plasma, including songorine, benzoylhypaconitine, benzoylmesaconitine, neoline, karacoline and sweroside, which were rapidly absorbed after administration in EAE model rats.Results: The main pharmacokinetic parameters of six bioactive components were determined, and the constituents increased CREB and GAP-43 expressions in serum-deprived SH-SY5Y cells. The YGP-containing serum, six bioactive components, and YGP extract significantly increased the expression of both CREB and GAP-43 (P

Feng Qiu,*,1 Bingsen Su,*,2 Zhao Li,3 Wenke Chen,1 Longbing Cao,1 Fu Chen,4 Dongdong Liu,4 Jingling He,5 Ni Lin31Department of Laboratory Medicine, Nanhai Hospital, Southern Medical University, Foshan, Guangdong 528244, People’s Republic of China; 2Department of Laboratory Medicine, Zhongshan Torch Development Zone Hospital, Zhongshan, Guangdong 528437, People’s Republic of China; 3Department of General Practice Center, Nanhai Hospital, Southern Medical University, Foshan, Guangdong 528244, People’s Republic of China; 4Department of Laboratory Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, People’s Republic of China; 5Department of Gynecology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, People’s Republic of China*These authors contributed equally to this workBackground: According to the statistics of WHO/IARC, cervical cancer (CC) has become the fourth malignant cancer of female worldwide and it is one of the main causes of death of women in developing countries.Purpose: Potential plasma and metabolic biomarkers for CC precancerous lesions and cervicitis were indicated by LC-MS techniques, and their underlying mechanisms and functions were analyzed.Methods: Plasma samples were selected from healthy people (control), low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), CC, and post-treatment patients. All polypeptide types and sequences were detected by LC-MS/MS and the results were normalized by using Pareto-scaling. Potential metabolic biomarkers were screened by applying MetaboAnalyst 4.0 software and XCMS software, and analysis of variance and enrichment analysis were performed. Metabolic pathway analysis and functional enrichment analysis were used to further investigate the significance and pathological mechanisms of potential biomarkers.Results: Compared with healthy people, 9 differentially expressed metabolites were screened, 4 of which were up-regulated and 5 were down-regulated. LSIL group screened 7 differentially expressed metabolites, 5 of which were up-regulated and 2 were down-regulated; CC group screened 12 differentially expressed metabolites were screened, of which 9 were up-regulated and 3 were down-regulated. Eight differentially expressed metabolites were screened in the IF group, of which 5 showed up-regulation and 3 showed down-regulation. In functional enrichment analysis, differential metabolism was found to be associated with addition and coagulation cascades. Among all potential biomarkers, 2-amino-3-methyl-1-butanol, L-carnitine, Asn Asn Gln Arg, Ala Cys Ser Trp, Soladulcidine, Ala Ile Gln Arg, 2-amino-3 -Methyl-1-butanol, L-carnitine, Asn Asn Gln Arg, Ala Cys Ser Trp, Soladulcidine, Ala Ile Gln Arg can be used as predictors of precancerous lesions at different stages of CC. Among all biomarkers, 6α-fluoro-11β1,17-dihydroxypren-4-ene-3,20-dione has higher expression in the CC and HSIL groups and lower expression in the treatment group.Conclusion: By applying molecular markers to assess the progression of the disease, the accuracy and specificity of the diagnosis can be improved, which has certain prospects in clinical applications.Keywords: cervical precancerous lesion, acute cervicitis, LC-MS, metabonomics, serum biomarkers

Guofei Li, Mingming Zhao, Feng Qiu, Yaxin Sun, Limei Zhao Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang 110004, China Purpose: Fenofibrate (Fbt) is a prodrug that has been used to reduce low-density-lipoprotein cholesterol, triglycerides, and increase high-density-lipoprotein cholesterol. Simvastatin (Svt) is a classic lipid-lowering drug that is widely used in the treatment of hypercholesterolemia and hypertriglyceridemia, while berberine chloride (Bbr) is a novel hypolipidemic agent and its blood-lipid-reducing mechanism is distinct from traditional drugs. Currently, drug combination is the trend in treating hyperlipidemia to improve clinical efficacy. The purpose of this study was to evaluate drug interaction from the perspective of pharmacokinetics between Bbr and Fbt/Svt and the tolerability of combined administration in healthy Chinese subjects. Methods: Healthy subjects (n=60) were randomly allocated to five treatment groups: Bbr alone, Fbt alone, Svt alone, Bbr plus Fbt, and Bbr plus Svt. The experiment was divided into two parts: single-dose administration and multiple-dose administration. Bbr, Fbt, and Svt were taken once every 8 hours, 24 hours, and 24 hours, respectively, over 7 days in the multidose group. Plasma samples were collected and liquid chromatography–mass spectrometry/mass spectrometry was used to detect drug concentrations. Results: No serious adverse reactions or intolerance were observed throughout the trial. More importantly, the combined-administration groups did not show an increase in incidence of side effects. Coadministration of Fbt and Svt with Bbr had no significant effect on the pharmacokinetic parameters of Bbr, except time to maximum concentration, apparent volume of distribution, and apparent clearance. Concurrent coadministration of Bbr had no obvious impact on the pharmacokinetic behavior of Fbt or Svt. Additionally, there was no significant correlation between sex and pharmacokinetic results. Conclusion: All treatments were well tolerated. No clinically obvious pharmacokinetic interactions between Bbr and Fbt/Svt were observed with combined administration. The results demonstrated that Bbr can be coadministered safely with Fbt and Svt without dose adjustment. Keywords: Bbr, Fbt, Svt, drug–drug interaction, pharmacokinetics

Background: Prokineticin 2 (PK2) is a secreted protein and causes potent hyperalgesia in vivo, and is therefore considered to be a new pronociceptive mediator. However, the molecular targets responsible for the pronociceptive effects of PK2 are still poorly understood. Here, we have found that PK2 potentiates the activity of acid-sensing ion channels in the primary sensory neurons.Methods: In the present study, experiments were performed on neurons freshly isolated from rat dorsal root ganglion by using whole-cell patch clamp and voltage-clamp recording techniques.Results: PK2 dose-dependently enhanced proton-gated currents with an EC50 of 0.22 ± 0.06 nM. PK2 shifted the proton concentration-response curve upwards, with a 1.81 ± 0.11 fold increase of the maximal current response. PK2 enhancing effect on proton-gated currents was completely blocked by PK2 receptor antagonist. The potentiation was also abolished by intracellular dialysis of GF109203X, a protein kinase C inhibitor, or FSC-231, a protein interacting with C-kinase 1 inhibitor. Moreover, PK2 enhanced the acid-evoked membrane excitability of rat dorsal root ganglion neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acid stimuli. Finally, PK2 exacerbated nociceptive responses to the injection of acetic acid in rats.Conclusion: These results suggest that PK2 increases the activity of acid-sensing ion channels via the PK2 receptor and protein kinase C-dependent signal pathways in rat primary sensory neurons. Our findings support that PK2 is a proalgesic factor and its signaling likely contributes to acidosis-evoked pain by sensitizing acid-sensing ion channels. © 2012 Qiu et al.; licensee BioMed Central Ltd.

Feng Qiu,1,2 Yongzhu Chen,2,3 Chengkang Tang,2,4 Xiaojun Zhao2 1Laboratory of Anaesthesia and Critical Care Medicine, Translational Neuroscience Centre, West China Hospital, Sichuan University, Chengdu 610041, China; 2Institute for Nanobiomedical Technology and Membrane Biology, West China Hospital, Sichuan University, Chengdu 610041, China; 3Periodical Press of West China Hospital, Sichuan University, Chengdu 610041, China; 4Core Facility of West China Hospital, Sichuan University, Chengdu 610041, China Abstract: Designer self-assembling peptides are a category of emerging nanobiomaterials which have been widely investigated in the past decades. In this field, amphiphilic peptides have received special attention for their simplicity in design and versatility in application. This review focuses on recent progress in designer amphiphilic peptides, trying to give a comprehensive overview about this special type of self-assembling peptides. By exploring published studies on several typical types of amphiphilic peptides in recent years, herein we discuss in detail the basic design, self-assembling behaviors and the mechanism of amphiphilic peptides, as well as how their nanostructures are affected by the peptide characteristics or environmental parameters. The applications of these peptides as potential nanomaterials for nanomedicine and nanotechnology are also summarized. Keywords: amphiphilic peptides, self-assembly, nanomaterials

Yongzhu Chen,1 Yusi Hua,2 Wensheng Zhang,3 Chengkang Tang,4 Yan Wang,4 Yujun Zhang,3 Feng Qiu3 1Periodical Press of West China Hospital, Sichuan University, Chengdu, China; 2Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China; 3Laboratory of Anaesthesia and Critical Care Medicine, Translational Neuroscience Centre, West China Hospital, Sichuan University, Chengdu, China; 4Core Facility of West China Hospital, Sichuan University, Chengdu, China Background: Designer self-assembling peptide nanofibers (SAPNFs) as a novel kind of emerging nanomaterial have received more and more attention in the field of nanomedicine in recent years. However, a simple method to monitor and image SAPNFs is still currently absent. Methods: RADA16-I, a well-studied ionic complementary peptide was used as a model to check potential amyloid-like staining properties of SAPNFs. Thioflavin-T (ThT) and Congo red (CR) as specific dyes for amyloid-like fibrils were used to stain RADA16-I nanofibers in solution, combined with drugs or cells, or injected in vivo as hydrogels. Fluorescent spectrometry and fluorescent microscopy were used to check ThT-binding property, and polarized light microscopy was used to check CR-staining property. Results: ThT binding with the nanofibers showed enhanced and blue-shifted fluorescence, and specific apple-green birefringence could be observed after the nanofibers were stained with CR. Based on these properties we further showed that ThT-binding fluorescence intensity could be used to monitor the forming and changing of nanofibers in solution, while fluorescent microscopy and polarized light microscopy could be used to image the nanofibers as material for drug delivery, 3D cell culture, and tissue regeneration. Conclusion: Our results may provide convenient and reliable tools for detecting SAPNFs, which would be helpful for understanding their self-assembling process and exploring their applications. Keywords: self-assembling peptides, nanofibers, amyloid fibrils, thioflavin-T, Congo red

Sha Zhang,1,* Long Meng,1,* Feng Qiu,1 Jia-Dan Yang,1 Shusen Sun2 1Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Pharmacy Practice, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA, USA *These authors contributed equally to this work Background: Previous studies have demonstrated that medication adherence has an impact on health-related quality of life (HRQoL). However, other medication-related factors that may influence HRQoL have not been extensively studied, especially factors based on the Medication-Risk Questionnaire (MRQ), and such studies are mostly done in Western countries. Our objective was to explore risk factors associated with HRQoL among community-dwelling elderly with chronic diseases in mainland China, especially the medication-related risk factors regarding MRQ.Methods: The study was conducted in a community health service center through surveys to eligible patients. The main outcomes of HRQoL were assessed by the EuroQol-5D (EQ-5D) scale and EQ-visual analog scale (EQ-VAS). Medication-related risk factors according to MRQ associated with HRQoL were identified using a multiple linear regression.Results: A total of 311 patients were analyzed, averaging 71.19±5.33 years, and 68.8% were female. The mean EQ-5D index was 0.72±0.09, and the mean EQ-VAS score was 71.37±11.97. The most prevalent problem was pain/discomfort, and 90.0% believed that they could take care of themselves without any problems. Sex, age, educational level, frailty, function status, and certain medication-related factors regarding MRQ were found to be significant factors impacting the HRQoL. A multivariate analysis showed that MRQ factors of polypharmacy, multimorbidity, feeling difficultly with taking medicines as prescribed, and taking medicines with narrow therapeutic index had negative impacts on the quality of life.Conclusion: Patient’s internal characteristics and medication-related risk factors according to MRQ were associated with quality of life. The results of the MRQ is an indicator of quality of life that can identify patients who need interventions. Keywords: quality of life, medication risk factors, elderly, community-dwelling, EQ-5D

Changping Dun,1 Junqian Liu,1 Fucheng Qiu,1 Xueda Wu,2 Yakun Wang,3 Yongyan Zhao,4 Ping Gu1 1Department of Neurology, the First Hospital of Hebei Medical University, 2Department of Cardiac Surgery, the Second Hospital of Hebei Medical University, 3Department of Endocrinology, the Fourth Hospital of Hebei Medical University, Shijiazhuang, 4Department of Nursing, Maternal and Child Health Hospital of Tangshan City, Tangshan, People’s Republic of China Objective: Astragalus polysaccharides (APS) are active constituents of Astragalus membranaceus. In this study, we aimed to investigate the effects of APS on memory impairment in a diabetic rat model and their mechanisms. Methods: A diabetic model was established in 50 male Wistar rats with streptozotocin intraperitoneal injection. A blood glucose level higher than 16.7 mmol/L obtained 72 hours after the injection was regarded as a successful diabetic model. The modeled rats were divided into model group, high, medium, and low doses of APS, and piracetam groups (positive control). A group of ten rats without streptozotocin-induced diabetes were used as a normal control. After respective consecutive 8-week treatments, the levels of blood fasting plasma glucose, insulin, hemoglobin A1c, memory performance, hippocampal malondialdehyde, and superoxide dismutase were determined. Results: After the 8-week APS treatment, serum fasting plasma glucose, hemoglobin A1c, and insulin levels were decreased compared with those of the model group (P

Yongzhu Chen,1 Chengkang Tang,2 Jie Zhang,2 Meng Gong,3 Bo Su,2 Feng Qiu4 1Periodical Press, 2Core Facility of West China Hospital, 3Laboratory of Endocrinology and Metabolism, West China Hospital, 4Laboratory of Anaesthesia and Critical Care Medicine, Translational Neuroscience Centre, West China Hospital, Sichuan University, Chengdu, People’s Republic of China Background: Finding a suitable delivery system to improve the water solubility of hydrophobic drugs is a critical challenge in the development of effective formulations. In this study, we used A6K, a self-assembling surfactant-like peptide, as a carrier to encapsulate and deliver hydrophobic pyrene.Methods: Pyrene was mixed with A6K by magnetic stirring to form a suspension. Confocal laser scanning microscopy, transmission electron microscopy, dynamic light scattering, atomic force microscopy, fluorescence, and cell uptake measurements were carried out to study the features and stability of the nanostructures, the state and content of pyrene, as well as the pyrene release profile.Results: The suspension formed contained pyrene monomers trapped in the hydrophobic cores of the micellar nanofibers formed by A6K, as well as nanosized pyrene crystals wrapped up and stabilized by the nanofibers. The two different encapsulation methods greatly increased the concentration of pyrene in the suspension, and formation of pyrene crystals wrapped up by A6K nanofibers might be the major contributor to this effect. Furthermore, the suspension system could readily release and transfer pyrene into living cells.Conclusion: A6K could be further exploited as a promising delivery system for hydrophobic drugs. Keywords: pyrene, self-assembling peptide, micelles, nanofibers, drug delivery