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Jinlin Li,1 Qi Wang,1 Qingping Zhang,2 Zhengyan Wang,1 Xin Wan,3 Chenfang Miao,4 Xi Zeng5 1Department of Respiratory Medicine, Suizhou Hospital, Hubei University of Medicine, Suizhou, Hubei 441300, People’s Republic of China; 2Department of Otolaryngology Head and Neck Surgery, Suizhou Hospital, Hubei University of Medicine, Suizhou, Hubei 441300, People’s Republic of China; 3Department of Critical Care Medicine, Mindong Hospital of Fujian Medical University, Fuan, Fujian 355000, People’s Republic of China; 4Department of Anesthesiology, Mindong Hospital of Fujian Medical University, Fuan, Fujian 355000, People’s Republic of China; 5Department of Geriatrics, Mindong Hospital of Fujian Medical University, Fuan, Fujian 355000, People’s Republic of ChinaCorrespondence: Xi ZengDepartment of Geriatrics, Mindong Hospital of Fujian Medical University, No. 89 Heshan Road, Fuan City 355000, Fujian Province, People’s Republic of ChinaTel +86 18596658975Email 987295461@qq.comBackground: Vascular cell adhesion molecule-1 (VCAM-1) is associated with vascular-related inflammation and atherosclerosis. This study aimed to evaluate whether VCAM-1 can be used for an indication of increased risk of CV events in patients with COPD.Methods: Serum VCAM-1 levels were measured in 163 COPD patients. All COPD patients were prospectively followed up for a median period of 48 months (range=3– 54). Cox proportional hazard analysis was performed to evaluate the prognostic value of serum VCAM-1 for predicting CV events.Results: Serum VCAM-1 levels were higher in COPD patients with CV events than in those without CV events (1174.4± 365.3 ng/mL vs 947.8± 293.2 ng/mL; P< 0.001). The logistic regression analysis revealed that serum VCAM-1 (OR=1.750; 95% CI, 1.324– 2.428; Ptrend= 0.0012) was independently associated with CVD (cardiovascular disease) history after adjusting for age, sex, BMI, current smoker, current drinker, admission systolic and diastolic BP, LVEF and laboratory measurements in patients with COPD at baseline. The Kaplan–Meier analysis demonstrated that the rate of CV events was higher in COPD patients with serum VCAM-1 levels above the median (517.3 ng/mL) than in those with VCAM-1 levels below the median. The Cox proportional hazard analysis revealed that serum VCAM-1 (HR=2.617; 95% CI, 1.673– 5.328; Ptrend< 0.001) may be an independent prognostic factor for CV events in the COPD patients.Conclusion: Our results suggested that serum VCAM-1 was significantly and independently associated with CV events in COPD patients. The inflammatory marker may help clinicians predict CV complications early.Keywords: vascular cell adhesion molecule-1, chronic obstructive pulmonary disease, cardiovascular events, prognostic value

Xiufeng Zhang,1,2,* Fangping Li,3,* Shiyun Cui,1,2 Lisha Mao,4 Xiaohua Li,3 Furqan Awan,1,2 Weibiao Lv,5 Zhenling Zeng1,2 1College of Veterinary Medicine, Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, National Risk Assessment Laboratory for Antimicrobial Resistance of Microorganisms in Animals, South China Agricultural University, Guangzhou 510642, People’s Republic of China; 2Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, People’s Republic of China; 3Guangdong Provincial Key Laboratory of Plant Molecular Breeding, State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, South China Agricultural University, Guangzhou 510642, People’s Republic of China; 4Department of Clinical Laboratory, Cancer Hospital of Guangxi Medical University, Guangxi Medical University, Nanning 530021, People’s Republic of China; 5Department of Clinical Laboratory, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan 528000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weibiao Lv; Zhenling Zeng Email weibiao2004@163.com; zlzeng@scau.edu.cnBackground: Carbapenem-resistant Klebsiella pneumoniae infections have caused major concern and posed a global threat to public health. As blaKPC-2 and blaNDM-1 genes are the most widely reported carbapenem resistant genes in K. pneumonia, it is crucial to study the prevalence and geographical distribution of these two genes for further understanding of their transmission mode and mechanism.Purpose: Here, we investigated the prevalence and distribution of blaKPC-2 and blaNDM-1 genes in carbapenem-resistant K. pneumoniae strains from a tertiary hospital and from 1579 genomes available in the NCBI database, and further analyzed the possible core structure of blaKPC-2 or blaNDM-1 genes among global genome data.Materials and Methods: K. pneumoniae strains from a tertiary hospital in China during 2013– 2018 were collected and their antimicrobial susceptibility testing for 28 antibiotics was determined. Whole-genome sequencing of carbapenem-resistant K. pneumoniae strains was used to investigate the genetic characterization. The phylogenetic relationships of these strains were investigated through pan-genome analysis. The epidemiology and distribution of blaKPC-2 and blaNDM-1 genes in K. pneumoniae based on 1579 global genomes and carbapenem-resistant K. pneumoniae strains from hospital were analyzed using bioinformatics. The possible core structure carrying blaKPC-2 or blaNDM-1 genes was investigated among global data.Results: A total of 19 carbapenem-resistant K. pneumoniae were isolated in a tertiary hospital. All isolates had a multi-resistant pattern and eight kinds of resistance genes. The phylogenetic analysis showed all isolates in the hospital were dominated by two lineages composed of ST11 and ST25, respectively. ST11 and ST25 were the major ST type carrying blaKPC-2 and blaNDM-1 genes, respectively. Among 1579 global genomes data, 147 known ST types (1195 genomes) have been identified, while ST258 (23.6%) and ST11 (22.1%) were the globally prevalent clones among the known ST types. Genetic environment analysis showed that the ISKpn7-dnaA/ISKpn27 -blaKPC-2-ISkpn6 and blaNDM-1-ble-trpf-nagA may be the core structure in the horizontal transfer of blaKPC-2 and blaNDM-1, respectively. In addition, DNA transferase (hin) may be involved in the horizontal transfer or the expression of blaNDM-1.Conclusion: There was clonal transmission of carbapenem-resistant K. pneumoniae in the tertiary hospital in China. The prevalence and distribution of blaKPC-2 and blaNDM-1 varied by countries and were driven by different transposons carrying the core structure. This study shed light on the genetic environment of blaKPC-2 and blaNDM-1 and offered basic information about the mechanism of carbapenem-resistant K. pneumoniae dissemination.Keywords: Klebsiella pneumoniae, blaKPC-2, *blaNDM-1, bioinformatics

Xiao Ke,1,2,* Yiteng Huang,2,* Liang Li,3 Fuya Xin,3 Luhua Xu,3 Yuangui Zhang,3 Zhicong Zeng,3 Fengxia Lin,3 Yinzhi Song3 1Key Laboratory of Biomaterials of Guangdong Higher Education Institutes, Guangdong Provincial Engineering and Technological Research Center for Drug Carrier Development, Department of Biomedical Engineering, Jinan University, Guangzhou, Guangdong 510632, People’s Republic of China; 2Department of Cardiology, Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen, (Shenzhen Sun Yat-Sen Cardiovascular Hospital), Shenzhen, Guangdong 518057, People’s Republic of China; 3Department of Cardiology, Shenzhen Bao’an Traditional Chinese Medicine Hospital Group, The Affiliated Hospital of Guangzhou University of Chinese Medicine, Shenzhen 518133, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fengxia LinDepartment of Cardiology, Shenzhen Bao’an Traditional Chinese Medicine Hospital Group, The Affiliated Hospital of Guangzhou University of Chinese Medicine, Shenzhen 518133, People’s Republic of ChinaTel +8617301933930Email szlinfx@163.comYinzhi SongDepartment of Cardiology, Shenzhen Bao’an Traditional Chinese Medicine Hospital Group, The Affiliated Hospital of Guangzhou University of Chinese Medicine, Shenzhen 518133, People’s Republic of ChinaTel +8613760298578Email songyinzhi@126.comPurpose: Berberine (BBR) is an effective component of Huanglian and has shown to attenuate atherosclerosis (AS); however, the detailed mechanism of BBR-mediated protective actions against AS remains elusive. This study was undertaken to examine the effects of BBR on aortic atherosclerotic plaque stability and the expression of autophagy-related proteins in AS rats with damp-heat syndrome or yang deficiency.Methods: Thirty SD rats were randomly divided into (1) control (CON); (2) damp-heat syndrome atherosclerosis (AS + DH); (3) yang deficiency syndrome atherosclerosis (AS + YX); (4) damp-heat syndrome atherosclerosis + BBR (AS + DH + BBR); (5) yang deficiency syndrome, atherosclerosis + BBR (AS + YX + BBR); and (6) damp-heat syndrome, atherosclerosis + BBR + 3-methyladenine (AS + DH + BBR + 3-MA) (n = 5/group) groups. Pathological morphology, macrophage plaque infiltration, inflammation, and LC3-II and P62 expression were assessed.Results: Compared with the CON group, the AS + DH and AS + YX groups had an increased plaque area in the aortic tissue with substantial foam cell and macrophage infiltration, and increased levels of IL-1β and TNF-α (P < 0.01). After four weeks of BBR intervention, the plaque area in the AS + DH + BBR group was reduced with decreased foam cells and macrophage infiltration, and decreased levels of TNF-α and IL-1β, whereas LC3-II protein expression was increased and P62 protein expression was decreased in the AS + DH + BBR group when compared to AS + DH group. In addition, the AS + DH + BBR + 3-MA group exhibited a significantly enlarged plaque, substantial foam cell and macrophage infiltration, increased levels of IL-1β and TNF-α, and decreased LC3-II and P62 (P < 0.01) expression when compared to the AS + DH + BBR group.Conclusion: Our results indicated that the BBR could inhibit arterial plaque formation and alleviate the inflammatory response in the aortic tissues in the AS rats with damp-heat syndrome possibly via promoting autophagy. The molecular mechanisms of BBR-mediated protective effects in this animal model still require further investigation.Keywords: berberine, autophagy, LC3-II, P62, arterial plaque, damp-heat syndrome

Jie Li,1– 4 Jiaqian Zhao,2– 5 Tiantian Tan,2– 4 Mengmeng Liu,2– 4 Zhaowu Zeng,2– 4 Yiying Zeng,2– 4 Lele Zhang,6 Chaomei Fu,1 Dajing Chen,2– 4 Tian Xie2– 4 1College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China; 2Holistic Integrative Pharmacy Institutes, Hangzhou Normal University, Hangzhou, Zhejiang, People’s Republic of China; 3Key Laboratory of Elemene Class Anti-Cancer Chinese Medicine of Zhejiang Province, Hangzhou, Zhejiang, People’s Republic of China; 4Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, Hangzhou, Zhejiang, People’s Republic of China; 5College of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 6School of Medicine, Chengdu University, Chengdu, People’s Republic of ChinaCorrespondence: Tian Xie; Zhaowu ZengHolistic Integrative Pharmacy Institutes, Hangzhou Normal University, 1378 Wenyixi Road, Hangzhou, Zhejiang 311121, People’s Republic of ChinaTel +86 5 712 886 8269Email xbs@dljg.sina.net; artgreenking@126.comAbstract: Gliomas are the most common tumor of the central nervous system. However, the presence of the brain barrier blocks the effective delivery of drugs and leads to the treatment failure of various drugs. The development of a nanoparticle drug delivery system (NDDS) can solve this problem. In this review, we summarized the brain barrier (including blood–brain barrier (BBB), blood–brain tumor barriers (BBTB), brain–cerebrospinal fluid barrier (BCB), and nose-to-brain barrier), NDDS of glioma (such as passive targeting systems, active targeting systems, and environmental responsive targeting systems), and NDDS efficacy improvement strategies and deficiencies. The research prospect of drug-targeted delivery systems for glioma is also discussed.Keywords: glioma, brain barrier, nanoparticle drug delivery system, efficacy improvement strategies, deficiencies of NDDS

Peng Wan,1– 3,* Shiyun Cui,1– 3,* Zhenbao Ma,1– 3 Lin Chen,1– 3 Xiaoshen Li,1– 3 Ruonan Zhao,1– 3 Wenguang Xiong,1– 3 Zhenling Zeng1– 3 1Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou 510642, People’s Republic of China; 2National Laboratory of Safety Evaluation (Environmental Assessment) of Veterinary Drugs, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, People’s Republic of China; 3National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou 510642, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenguang Xiong Email xiongwg@scau.edu.cnZhenling Zeng Tel +86 20 85281204Fax +86 20 8528 4896Email zlzeng@scau.edu.cnPurpose: The plasmid-borne mobilized colistin resistance gene (mcr-1) was discovered in 2015. Subsequently, the rapid horizontal transfer of mcr-1 gene to diverse bacterial species poses a serious threat to public health, which urgently needs the introduction of novel antimicrobial strategies. Therefore, the purpose of this study is to sensitize bacteria to colistin and reduce the propagation of mcr-1 gene by curing mcr-1-harboring plasmid in Escherichia coli (E. coli) using the CRISPR-Cas9 system.Methods: Two sgRNAs specific to mcr-1 gene were designed and cloned into plasmid pCas9. The recombinant plasmid pCas9-mcr was transformed into E. coli carrying pUC19-mcr-1 or pHNSHP45, separately. The elimination efficiency in strains was evaluated by PCR and quantitative real-time PCR (qPCR). The antimicrobial susceptibility test was performed using the broth microdilution method.Results: In this study, we constructed the high copy number plasmid pUC19-mcr-1 and recombinant plasmid pCas9-m1 or pCas9-m2, which contain 20 nt or 30 nt sgRNA sequences targeted to mcr-1, respectively. PCR and qPCR results showed that mcr-1-harboring plasmids could be efficiently eliminated, and there was no significant correlation between sgRNA lengths and curing efficiency. However, when comparing restructured high copy number plasmid (pUC19-mcr-1) to natural resistance plasmid (pHNSHP45) in eliminating efficiency, we found that the content of plasmid backbone had an influence on efficiency. Furthermore, the conjugation assays verified that the engineered CRISPR-Cas9 system in bacteria or in bacteria genome can protect the recipient from plasmid-borne mcr-1 transfer via conjugation. Additionally, sequence analysis showed that three different types of defects in CRISPR-Cas9 system lead to escape mutants.Conclusion: We presented a method that only one plasmid-mediated CRISPR-Cas9 system can be used to efficiently resensitize E. coli to colistin. Moreover, this system provided a great potentiality to counteract the propagation of mcr-1 among bacterial pathogens.Keywords: sgRNA lengths, curing efficiency, backbone content, quantitative real-time PCR, conjugation assays, escape mutants

Yu Hei,1 Binhong Teng,2,3 Ziqian Zeng,2,3 Siqi Zhang,3 Qian Li,3 Jijia Pan,3 Zuyuan Luo,3 Chunyang Xiong,1 Shicheng Wei2,3 1Department of Mechanics and Engineering Science, College of Engineering, Peking University, Beijing, People’s Republic of China; 2Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Peking University, Beijing, People’s Republic of China; 3Laboratory of Biomaterials and Regenerative Medicine, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, People’s Republic of ChinaCorrespondence: Chunyang XiongDepartment of Mechanics and Engineering Science, College of Engineering, Peking University, Beijing, People’s Republic of ChinaTel +86 10 62757940Email cyxiong@pku.edu.cnShicheng WeiDepartment of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Peking University, Beijing, People’s Republic of ChinaTel +86 10 82195780Email sc-wei@pku.edu.cnBackground: Immune checkpoint blockades (ICBs) are a promising treatment for cancers such as melanoma by blocking important inhibitory pathways that enable tumor cells to evade immune attack. Programmed death ligand 1 monoclonal antibodies (aPDL1s) can be used as an ICB to significantly enhance the effectiveness of tumor immunotherapy by blocking the PD-1/PD-L1 inhibitory pathway. However, the effectiveness of aPDL1s may be limited by low selectivity in vivo and immunosuppressed tumor microenvironment including hypoxia.Purpose: To overcome the limitations, we develop a multifunctional immunoliposome, called CAT@aPDL1-SSL, with catalase (CAT) encapsulated inside to overcome tumor hypoxia and aPDL1s modified on the surface to enhance immunotherapeutic effects against melanoma.Methods: The multifunctional immunoliposomes (CAT@aPDL1-SSLs) are prepared using the film dispersion/post-insertion method. The efficacy of CAT@aPDL1-SSLs is verified by multiple experiments in vivo and in vitro.Results: The results of this study suggest that the multifunctional immunoliposomes preserve and protect the enzyme activity of CAT and ameliorate tumor hypoxia. Moreover, the enhanced cellular uptake of CAT@aPDL1-SSLs in vitro and their in vivo biodistribution suggest that CAT@aPDL1-SSLs have great targeting ability,resulting in improved delivery and accumulation of immunoliposomes in tumor tissue.Finally, by activating and increasing the infiltration of CD8+ T cells at the tumor site, CAT@aPDL1-SSLs inhibit the growth of tumor and prolong survival time of mice,with low systemic toxicity.Conclusion: In conclusion, the multifunctional immunoliposomes developed and proposed in this study are a promising candidate for melanoma immunotherapy, and could potentially be combined with other cancer therapies like radiotherapy and chemotherapy to produce positive outcomes.Keywords: immunotherapy, programmed death ligand 1 monoclonal antibodies, aPDL1s, tumor hypoxia, melanoma, liposomes

Fengxia Lin,1,* Yiying Yang,2,* Shanyin Wei,1 Xiaojing Huang,1 Zhijian Peng,1 Xiao Ke,3 Zhicong Zeng,1 Yinzhi Song1 1Department of Cardiology, Shenzhen Bao’an Traditional Chinese Medicine Hospital Group, The Affiliated Hospital of Guangzhou University of Chinese Medicine, Shenzhen 518133, People’s Republic of China; 2Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, People’s Republic of China; 3Department of Cardiology, Fuwai Hospital, Chinese Academy of Medical Sciences, (Shenzhen Sun Yat-sen Cardiovascular Hospital), Shenzhen 518057, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhicong Zeng; Yinzhi Song Email 2436225392@qq.com; songyinzhi@126.comPurpose: Dysfunction of endothelial cells plays a key role in the pathogenesis of diabetic atherosclerosis. High glucose (HG) has been found as a key factor in the progression of diabetic complications, including atherosclerosis. PI3K/Akt/eNOS signaling pathway has been shown to involve in HG-induced vascular injuries. Hydrogen sulfide (H2S) has been found to exhibit protective effects on HG-induced vascular injuries. Moreover, H2S activates PI3K/Akt/eNOS pathway in endothelial cells. Thus, the present study aimed to determine if H2S exerts protective effects against HG-induced injuries of human umbilical vein endothelial cells (HUVECs) via activating PI3K/Akt/eNOS signaling.Materials and Methods: The endothelial protective effects of H2S were evaluated and compared to the controlled groups. Cell viability, cell migration and tube formation were determined by in vitro functional assays; protein levels were evaluated by Western blot assay and ELISA; cell apoptosis was determined by Hoechst 33258 nuclear staining; Reactive oxygen species (ROS) production was evaluated by the ROS detection kit.Results: HG treatment significantly inhibited PI3K/Akt/eNOS signaling in HUVECs, which was partially reversed by the H2S treatment. HG treatment inhibited cell viability of HUVECs, which were markedly prevented by H2S or PI3K agonist Y-P 740. HG treatment also induced HUVEC cell apoptosis by increasing the protein levels of cleaved caspase 3, Bax and Bcl-2, which were significantly attenuated by H2S or 740 Y-P. ROS production and gp91phox protein level were increased by HG treatment in HUVECs and this effect can be blocked by the treatment with H2S or Y-P 740. Moreover, HG treatment increased the protein levels of pro-inflammatory cytokines, caspase-1 and phosphorylated JNK, which was significantly attenuated by H2S or Y-P 740. Importantly, the cytoprotective effect of H2S against HG-induced injury was inhibited by LY294002 (an inhibitor of PI3K/Akt/eNOS signaling pathway).Conclusion: The present study demonstrated that exogenous H2S protects endothelial cells against HG-induced injuries by activating PI3K/Akt/eNOS pathway. Based on the above findings, we proposed that reduced endogenous H2S levels and the subsequent PI3K/Akt/eNOS signaling impairment may be the important pathophysiological mechanism underlying hyperglycemia-induced vascular injuries.Keywords: endothelial cells, hydrogen sulfide, high glucose, injury, PI3K/Akt/eNOS

Haiqing Li,1 Zixiong Zeng,1 Juan Cheng,1 Guoping Hu,1 Yuqun Li,1 Liping Wei,1 Yumin Zhou,2 Pixin Ran2 1Department of Respiratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 2Guangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Guoping HuDepartment of Respiratory Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of ChinaTel +86 20-81292146Email hgpgz@126.comPixin RanGuangzhou Institute of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, 151 Yanjiang Road, Guangzhou, Guangdong 510120, People’s Republic of ChinaTel/Fax +86 20-81340482Email pxran@gzhmu.edu.cnBackground and objective: The association between N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations and in-hospital and 1-year mortality in acute exacerbations of chronic obstructive pulmonary disease (AECOPD) patients is largely unknown. Our objective was to explore the usefulness of NT-proBNP concentrations in AECOPD patients as a prognostic marker for in-hospital and 1-year mortality.Methods: NT-proBNP levels were measured in patients upon admission and laboratory and clinical data were also recorded. The cut-point for the NT-proBNP concentration level for in-hospital death was obtained using the receiver operating characteristic (ROC) curve. Univariate and multivariate logistic regression and Cox regression were used in the analyses of factors of in-hospital and 1-year mortality.Results: A total of 429 patients were enrolled. Twenty-nine patients died during hospitalization and 59 patients died during the 1-year follow-up. Patients who died in-hospital compared with those in-hospital survivors were older (80.14±6.56 vs 75.93±9.45 years, p=0.003), had a higher percentage of congestive heart failure (65.52% vs 33.75%, p

Xiufeng Zhang,1–3 Dongdong Han,1–3 Pengfei Pei,1–3 Jie Hao,1–3 Yixing Lu,1–3 Peng Wan,1–3 Xianfeng Peng,4 Weibiao Lv,5 Wenguang Xiong,1–3 Zhenling Zeng1–3 1National Laboratory of Safety Evaluation (Environmental Assessment) of Veterinary Drugs, South China Agricultural University, Guangzhou 510642, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Veterinary Drugs Development and Safety Evaluation, South China Agricultural University, Guangzhou 510642, People’s Republic of China; 3National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou 510642, People’s Republic of China; 4Guangzhou Insighter Biotechnology Co., Ltd, Guangzhou 510642, People’s Republic of China; 5Department of Clinical Laboratory, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan 528000, People’s Republic of ChinaCorrespondence: Wenguang Xiong; Zhenling ZengSouth China Agricultural University, Wushan Road, Tianhe District, Guangzhou 510642, People’s Republic of ChinaTel +86 20-85281204Fax +86 20-85284896Email xiongwg@scau.edu.cn; zlzeng@scau.edu.cnBackground: Bacterial infections cause a serious public health crisis due to the emergence of resistance towards multiple conventional antibacterial drugs. In particular, multidrug-resistant (MDR) Enterococcus faecium which belongs to “ESKAPE” organisms is causing significant problems worldwide. Hence, there is an urgent need to find alternative therapies. Recently, substituted benzene guanidine compounds have been used as lead structures to discover new promising drugs in both synthetic and medicinal chemistry.Purpose: Here we investigated the antimicrobial activity of a new substituted benzene guanidine analog, isopropoxy benzene guanidine, against Enterococci.Material and methods: The isopropoxy benzene guanidine was synthesized by Guangzhou Insighter Biotechnology Co., Ltd and tested on both reference bacterial strain and 32 clinical MDR Enterococci strains. The in vitro antibacterial activity was evaluated by microdilution method and kill kinetic assays. The potential antibacterial mechanism was measured by fluorescence spectrometry using fluorescent membrane potential probe 3, 3-diethyloxacarbocyanine iodide (DiOC2 (3)).Results: Isopropoxy benzene guanidine exhibited potent bactericidal activity against both reference strain and MDR Enterococci isolates. The minimum inhibitory concentration (MIC) range for isopropoxy benzene guanidine was 1–4 μg/mL. Minimum bactericidal concentration (MBC) was about 2-8-fold of its MIC values. Time-kill studies showed that isopropoxy benzene guanidine provided superior bactericidal effect against reference and MDR strains within 12 hrs at 2×MIC. Furthermore, isopropoxy benzene guanidine could cause a large reduction in the magnitude of the generated membrane potential compared to that of the untreated cells.Conclusion: The present study highlights the potent bactericidal activity of isopropoxy benzene guanidine on Enterococci by disrupting the cell membrane potential. These findings demonstrate that isopropoxy benzene guanidine may be a good chemical lead for further medicinal chemistry and pharmaceutical development and could be used as a therapeutic agent for infectious diseases caused by MDR Enterococci.Keywords: isopropoxy benzene guanidine, MDR Enterococci, DiOC2, 3, cell membrane potential, bactericidal activity

Feng-jia Chen,* Geng-peng Lin,* Xin-yan Huang, Yang-li Liu, Zhi-min Zeng, Yu-biao Guo Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yu-biao GuoDepartment of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Institute of Respiratory Diseases of Sun Yat-Sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, Guangdong, People’s Republic of ChinaTel +86 20 8775 5766Email huxineikegyb@163.comBackground: Biotherapy for asthma may be useful in patients suffering from chronic obstructive pulmonary disease (COPD) with asthma characteristics. Therefore, the evaluation and close monitoring of asthma characteristics in severe and extremely severe COPD can guide treatment decisions to improve prognosis.Methods: Stable patients suffering from COPD and having a forced expiratory volume in 1 s (FEV1%) of ≤50% (GOLD 3–4) in the First Affiliated Hospital of Sun Yat-Sen University from December 2014 to June 2018 were retrospectively enrolled in this study and evaluated in terms of their asthma characteristics (blood eosinophil counts, fractional exhaled NO [FeNO] values, and reversibility).Results: A total of 178 patients with an average age of 65.62±9.28 years were enrolled in this study. A total of 85 patients had an improvement of ≥12% in FEV1%, and 61 of these patients had an absolute increase of >200 mL. Of 122 patients, 68 had blood eosinophil counts of ≥150 cells/μl, whereas 27 showed blood eosinophil counts ≥300 cells/μl. The blood eosinophil of ≥2% was found in 66/122 (54.10%) patients, whereas ≥3% was found in 51/122 (41.80%) patients. A total of 46 of 58 patients had an increased serum IgE level of ≥30 IU/mL, and 32 patients had an IgE of ≥100 IU/mL. The FeNO value of ≥25 ACO (ppb) was found in 51/155 (32.90%) patients. Furthermore, 43 patients had asthma–COPD overlap (ACO), and the FeNO values in the ACO group was 26.13±14.91 ppb, which was significantly higher than that in the COPD alone group (20.99±9.16 ppb; P=0.016). A total of 12 patients with ACO had a negative response after bronchodilation. In the COPD alone group, 34 patients had an absolute increase of >200 mL, whereas 55 of the 95 patients had blood eosinophil counts of ≥150 cells/μl. The blood eosinophilia of ≥2% was found in 54/95 (56.84%) patients. A total of 36 of 45 patients had an increased serum IgE level of ≥30 IU/mL. The FeNO value of 34/123 (27.64%) patients was ≥25 ppb.Conclusion: The characteristics of asthma are common findings in patients with severe and extremely severe COPD. Biomarkers should be actively used to evaluate the characteristics of asthma in these patients. If the characteristics of asthma exist, then anti-IgE or anti-IL-5 therapy should be considered to reduce exacerbation.Keywords: chronic obstructive pulmonary disease, asthma–COPD overlap, fractional exhaled nitric oxide, blood eosinophil counts, bronchodilator reversibility

Jiang T, Liu S, Wu X, et al. Cancer Manag Res. 2021;13:4751–4761. Table 2 Distant metastasis events in 28 patients The authors have advised Table 2 on page 4755 is incorrect. The correct table is as follows. Furthermore, page 4755, left column, second paragraph, the text “The median DMFS of these 28 patients was 13.4 months (0.93–62.57 months) (Table 2). The 1-year, 3-year, 5-year DMFS was 95.0%, 89.6%, 88.9%, respectively. Metastatic organs included 1 with bone, 1 with liver, 10 with lung and 16 with multiple metastases to lymph nodes, as we shown in Table 2” should read “The median DMFS of these 28 patients was 13.4 months (0.93–62.57 months). The 1-year, 3-year, 5-year DMFS was 95.0%, 89.6%, 88.9%, respectively. Metastatic organs included 2 with bone, 2 with liver, 12 with lung and 15 with multiple metastases to lymph nodes, as shown in Table 2”. The authors advise these errors do not affect the previously shown results and conclusion of the paper and apologize for any confusion this may have caused.

Keyi Yang, Zhi Zeng, Hu Peng, Yu Jiang Department of Head and Neck Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Yu JiangDepartment of Head and Neck Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37, Guo Xue Lane, Chengdu, Sichuan 610041, People’s Republic of ChinaTel/fax +86 28 85423278Email jiang_yu@scu.edu.cnPurpose: Artificial intelligence (AI) plays a substantial role in many domains, including medical fields. However, we still lack evidence to support whether or not cancer patients will accept the clinical use of AI. This research aims to assess the attitudes of Chinese cancer patients toward the clinical use of artificial intelligence in medicine (AIM), and to analyze the possible influencing factors.Patients and methods: A questionnaire was delivered to 527 participants. Targeted people were Chinese cancer patients who were informed of their cancer diagnosis.Results: The effective response rate was 76.3% (402/527). Most cancer patients trusted AIMs in both stages of diagnosis and treatment, and participants who had heard of AIMs were more likely to trust them in the diagnosis phase. When an AIM’s diagnosis diverged from a human doctor’ s, ethnic minorities, and those who had received traditional Chinese medicine (TCM), had never received chemotherapy, were more likely to choose “AIM”, and when an AIM’s therapeutic advice diverged from a human doctor’s, male participants, and those who had received TCM or surgery, were more likely to choose “AIM”.Conclusion: Most Chinese cancer patients believed in the AIM to some extent. Nevertheless, most still thought that oncology physicians were more trustworthy when their opinions diverged. Participants’ gender, race, treatment received, and AIM related knowledge might influence their attitudes toward the AIM. Most participants thought AIM would assist oncology physicians in the future, while little really believed that oncology physicians would completely be replaced.Keywords: artificial intelligence, attitude, cancer, cancer patient, clinical use, oncology

Jian Peng,1–3 Huiling Long,3 Weiwei Liu,2,3 Zhaoying Wu,1,3 Tao Wang,3 Zhu Zeng,1–3 Guo Guo,2,3 Jianwei Wu31Key Laboratory of Biology and Medical Engineering, Department of Biotechnology, School of Biology & Engineering, Guizhou Medical University, Guiyang 550004, People’s Republic of China; 2Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 550004, People’s Republic of China; 3Key and Characteristic Laboratory of Modern Pathogen Biology, Department of Human Parasitology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang 550004, People’s Republic of China Background: A case of Acinetobacter baumannii (A. baumannii), known as gram-negative bacteria, causes a range of nosocomial infections. Due to the continuous detection of multi-drug resistant A. baumannii in the clinic, there is an urgent need to find alternative therapies, including broad-spectrum antibacterial peptides (AMP). Recently it has been found that the peptide Cec4 has good antibacterial activity against A. baumannii, but the antibacterial mechanism remains elusive.Materials and methods: The basic structure of Cec4 was analyzed by circular dichroism (CD) spectroscopy, and the potential antibacterial mechanism of Cec4 was detected by flow cytometry, transmission electron microscopy, fluorescence and confocal microscopy. The minimum inhibitory concentration (MIC) of antimicrobial peptides against various A. baumannii was determinated with broth microdilution techniques. The biofilm formation and the sensitivity detection of biofilms to antimicrobial peptides were detected by crystal violet staining.Results: In this study, the main secondary structure of the antibacterial peptide Cec4 is α-helix (99.7%) in the hydrophobic environment. Furthermore, after the treatment with Cec4, an amount of leakage of A. baumannii and the destruction of its cell membrane were detected. Moreover, it was observed that FITC-Cec4 can enter the cell, and more cells were held in the G1 phase with peptide Cec4. However, the DNA binding assay of the peptide Cec4 indicates that the peptide does not target DNA. In addition, peptide Cec4 was superior in reducing adherent biofilms of A. baumannii compared to conventional antibiotics and has no cytotoxicity.Conclusion: It is apparent that the antibacterial peptide Cec4 may achieve rapid sterilization by multi-target interaction and presents an attractive therapeutic option for the prevention and control of A. baumannii infections.Keywords: antimicrobial peptides, A. baumannii, antibacterial mechanism, cell membrane

Yuanming Cai,1,* Ruxue Jia,2,3,* Haozhe Xiong,4 Qun Ren,2,3 Weimin Zuo,2,3 Tingting Lin,2,3 Rong Lin,2 Yan Lei,2 Ping Wang,2 Huiyue Dong,2 Hu Zhao,2,3 Ling Zhu,3 Yunfeng Fu,3 Zhiyong Zeng,5 Wei Zhang,6 Shuiliang Wang2,31Undergraduate Grade 2015, The 5th Clinical Medical School of Xinjiang Medical University, Urumchi, People’s Republic of China; 2Department of Urology, The 900th Hospital of the Joint Logistics Team, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 3Fujian Key Laboratory of Transplant Biology, Affiliated Dongfang Hospital, Xiamen University School of Medicine, Fuzhou, Fujian, People’s Republic of China; 4Undergraduate Grade 2017, Department of Bioengineering, College of Life Science, Fujian Normal University, Fuzhou, Fujian, People’s Republic of China; 5Department of Thoracic Surgery, The 900th Hospital of the Joint Logistics Team, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 6Department of Emergency, The 900th Hospital of the Joint Logistics Team, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China*These authors contributed equally to this workBackground: Paclitaxel has shown significant anti-tumor activity against non-small cell lung cancer (NSCLC); however, resistance to paclitaxel frequently occurs and represents a significant clinical problem and its underlying molecular mechanism remains elusive.Methods: Long-term treatment of culture cell with paclitaxel was carried out to mimic the development of acquired drug resistance in NSCLC. Cell proliferation and clonogenic assay and apoptosis evaluation were carried out to determine the efficacy of paclitaxel on NSCLC cells. Western blot analyses were performed to determine the expression and activation of proteins. Apoptosis enzyme-linked immunosorbent assay was used to quantify cytoplasmic histone-associated DNA fragments. Microarray analyses were applied to explore both mRNA and miRNA expression profiles in NSCLC cells followed by integrative analysis. qRT-PCR was carried out to verify the differentially expressed mRNAs and miRNAs.Results: The expression of 652 genes was shown to be changed at least 2-fold in paclitaxel-resistant NSCLC (H460_TaxR) cells with 511 upregulated and 141 downregulated as compared with that in parental H460 cells. The differentially expressed genes were functionally enriched in regulating the cell proliferation, cell death, and response to endogenous stimulus, and clustered in pathways such as cancer and signaling by the G protein-coupled receptor (GPCR). Moreover, 43 miRNAs were shown to be differentially expressed in H460_TaxR cells with 15 upregulated and 28 downregulated as compared with parental H460 cells. A total of 289 pairs of miRNA-potential target gene were revealed in H460_TaxR cells by bioinformatics analysis. Furthermore, integrative analysis of miRNAs and gene expression profiles revealed that dysregulated miR-362-3p, miR-766-3p, and miR-6507-3p might confer paclitaxel resistance in NSCLC via targeting MAPT simultaneously.Conclusion: Our findings suggested that specific manipulation of MAPT-targeting miRNAs may be a novel strategy to overcome paclitaxel resistance in patients with NSCLC especially large-cell lung carcinoma.Keywords: integrative analysis, non-small cell lung cancer, paclitaxel-resistance, gene expression profile, miRNAs

Yu Qian,1,* Ding Ye,1,* David JH Wu,1,2 Chen Feng,3 Zhen Zeng,1 Lihong Ye,1 Rui Zhu,4 Zhenyu Zhang,5 Yingying Mao11School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, People’s Republic of China; 2University of Minnesota Medical School, Minneapolis, MN 55455, USA; 3The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, People’s Republic of China; 4College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, People’s Republic of China; 5Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA*These authors contributed equally to this workPurpose: Numerous studies have indicated that smokers have an increased risk of developing ischemic stroke. However, less is known about the causal relationship between cigarette smoking and ischemic stroke subtypes. In the present study, we aim to determine whether genetically predicted cigarette smoking was associated with subtypes of ischemic stroke using Mendelian randomization (MR).Patients and methods: We used summary-level genetic association data from the MEGASTROKE consortium, including 438,847 individuals of European ancestry (34,217 cases of ischemic stroke and 404,630 controls). We used 176 single nucleotide polymorphisms as instrumental variables, which were previously identified to be associated with smoking in the Study of the Social Science Genetic Association Consortium (n=518,633). MR analyses were performed using inverse-variance-weighted method, weighted-median method, and MR-Egger regression.Results: We found that genetically predicted smoking was associated with a higher risk of ischemic stroke (odds ratio (OR): 1.24, 95% CI: 1.10–1.39) and large artery ischemic stroke (OR: 1.52, 95% CI: 1.14–2.02), but not with risk of cardioembolic ischemic stroke or small vessel ischemic stroke. Sensitivity analyses using alternative MR approaches produced similar results.Conclusion: Genetic predisposition toward smoking is causally associated with a higher incidence of large artery ischemic stroke. Further work is warranted to clarify the underlying mechanism of smoking in the development of large artery ischemic stroke.Keywords: ischemic stroke, Mendelian randomization, polymorphism, single nucleotide, smoking

Qianqian Zhao, Gang Chen, Luxi Ye, Zhaochong Zeng, Shiming Shi, Jian He Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China Purpose: Following surgery for early stage non-small-cell lung cancer (NSCLC), de novo pulmonary tumors are common. This study aimed to assess the efficacy, patterns of failure, and toxicity of stereotactic body radiotherapy (SBRT) in the treatment of de novo pulmonary tumors following curative resection of early stage NSCLC.Patients and methods: We reviewed the medical data of patients who had received definitive intent SBRT for small lung cancer at Zhongshan Hospital, Fudan University, between June 2011 and December 2017. Patients who had experienced complete resection for prior early stage NSCLC before SBRT were identified for further analysis. Incidences of locoregional recurrence (LR) and distant metastasis (DM) were evaluated using the alternative cumulative incidence competing risk method. The probability of survival was estimated using the Kaplan–Meier method.Results: A total of 33 patients with 36 lesions were eligible and included in this study. The median follow-up time was 32 months. Estimated incidences of LR and DM were 37.62% and 15.92%, respectively, at 1 year and 48.02% and 21.23%, respectively, at 2 years. The progression-free survival and overall survival of all patients were 62.40% and 90.30%, respectively, at 1 year and 52.00% and 69.90%, respectively, at 2 years. In all, 26 patients experienced grade 1 SBRT-related toxicity, 11 patients experienced grade 2 SBRT-related toxicity, and three patients experienced grade 3 toxicity. There were no grade 4/5 toxicities or SBRT-related deaths during the follow-up period.Conclusion: SBRT appears to be a safe and potentially effective alternative therapeutic option for de novo pulmonary tumors following early stage NSCLC radical resection, despite impaired pulmonary reserve. Keywords: stereotactic body radiotherapy, de novo pulmonary tumors, surgical resection, clinical outcomes

Bingtao Zhai,1 Yiying Zeng,2–5 Zhaowu Zeng,2–4 Nana Zhang,2–4 Chenxi Li,2–4 Yijun Zeng,2–4 Yu You,1 Shuling Wang,2–4 Xiabin Chen,2–4 Xinbing Sui,2–4 Tian Xie2–4 1College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China; 2Holistic Integrative Pharmacy Institutes, Hangzhou Normal University, Hangzhou, Zhejiang, China; 3Key Laboratory of Elemene Class Anti-cancer Chinese Medicine of Zhejiang Province, Hangzhou, Zhejiang, China; 4Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, Hangzhou, Zhejiang, China; 5College of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China Abstract: β-elemene is a noncytotoxic Class II antitumor drug extracted from the traditional Chinese medicine Curcuma wenyujin Y. H. Chen et C. Ling. β-elemene exerts its effects by inhibiting cell proliferation, arresting the cell cycle, inducing cell apoptosis, exerting antiangiogenesis and antimetastasis effects, reversing multiple-drug resistance (MDR), and enhancing the immune system. Elemene injection and oral emulsion have been used to treat various tumors, including cancer of the lung, liver, brain, breast, ovary, gastric, prostate, and other tissues, for >20 years. The safety of both elemene injection and oral emulsion in the clinic has been discussed. Recently, the secondary development of β-elemene has attracted the attention of researchers and made great progress. On the one hand, studies have been carried out on liposome-based systems (including solid lipid nanoparticles [SLNs], nanostructured lipid carriers [NLCs], long-circulating liposomes, active targeting liposomes, and multidrug-loaded liposomes) and emulsion systems (including microemulsions, self-emulsion drug delivery systems [SEDDSs], and active targeting microemulsion) to solve the issues of poor solubility in water, low bioavailability, and severe phlebitis, as well as to improve antitumor efficacy. The pharmacokinetics of different drug delivery systems of β-elemene are also summarized. On the other hand, a number of highly active anticancer β-elemene derivatives have been obtained through modification of the structure of β-elemene. This review focuses on the two drug delivery systems and derivatives of β-elemene for cancer therapy. Keywords: β-elemene, pharmacokinetics, drug delivery system, derivative, safety

Yan Chen,1,2,* Qinglei Zeng,3,* Xiufang Liu,4 Junliang Fu,1 Zhen Zeng,1 Zhiqin Zhao,1 Ze Liu,1 Wenlin Bai,1 Zheng Dong,1 Hongjin Liu,1 Xiaoxia Lu,1 Yunfeng Zhu,2,5 Yinying Lu1 1Comprehensive Liver Cancer Center, Beijing 302 Hospital, Beijing 100039, P.R. China; 2College of Life Sciences and Bio-Engineering, Beijing Jiaotong University, Beijing 100044, P.R. China; 3Department of Infectious Disease, The First Affiliated Hospital of Zhengzhou University, Zheng Zhou 450052, Henan Province, P.R. China; 4Department of Oncology, Chinese PLA 251 Hospital, Zhangjiakou 075000, P.R. China; 5Cancer Center in Division of Internal Medicine, Chinese PLA General Hospital, Beijing 100853, P.R. China *These authors contributed equally to this work Background: LINE-1 ORF-1p is encoded by the human pro-oncogene LINE-1. Our previous work showed that LINE-1 ORF-1p could enhance the resistance of hepatocellular carcinoma (HCC) cells to antitumor agents. However, the mechanisms involved in LINE-1 ORF-1p-mediated drug resistance remain largely unknown.Materials and methods: The endogenous mRNA level of LINE-1 ORF-1p in clinical HCC specimens was examined using quantitative PCR (qPCR). The prognosis of HCC patients was assessed using time to progression and overall survival. The transcription factor activity of pregnenolone X receptor (PXR) was examined using luciferase gene reporter assays, qPCR, chromatin immunoprecipitation assays and cellular subfraction assays. Protein interaction between LINE-1 ORF-1p and PXR was detected by co-immunoprecipitation. The effect of LINE-1 ORF-1p on sorafenib resistance in HCC cells was studied using in vitro and in vivo models.Results: A high level of LINE-1 ORF-1p in clinical specimens was related to poor prognosis in patients who received sorafenib treatment. LINE-1 ORF-1p increased the transcription factor activity of PXR by interacting with PXR and enhancing its cytoplasmic/nuclear translocation, and recruiting PXR to its downstream gene promoter, in turn enhancing the expression of the sorafenib resistance-related genes, CYP3A4 and mdr-1. LINE-1 ORF-1p enhanced the resistance to and clearance of sorafenib in HCC cells.Conclusion: LINE-1 ORF-1p enhances the transcription factor activation of PXR and promotes the clearance of and resistance to sorafenib in HCC cells. Keywords: LINE-1 ORF-1p, sorafenib resistance, pregnenolone X receptor, hepatocellular carcinoma, transcription factor activation

Cai Y, Jia R, Xiong H, et al. Cancer Manag Res. 2019;11:7391—7404. The authors have advised due to an error at the time of figure assembly, Figure 1D on page 7393 is incorrect. The correct Figure 1 is shown below. The authors apologize for this error and advise it does not affect the results of the paper. Read the original article

Zheng Zeng,1 Dan Yang,2 Xiaoling Huang,3 Zhenliang Xiao4 1Respiratory Medicine, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 2Respiratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Department of Pediatrics, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, 4Respiratory Medicine, Southwest Medical University, Chengdu Military General Hospital, Chengdu, Sichuan, People’s Republic of China Background: COPD is the fourth leading cause of death in the world. It is a common, progressive, treatable and preventable disease. The exacerbation of COPD is associated with the peripheral muscle force, forced expiratory volume in 1 second (FEV1), the quality of life and mortality. Many studies indicated that the mucoactive medicines could reduce the exacerbations of COPD. This study summarized the efficacy of carbocisteine as a treatment for COPD. Methods: We searched the randomized controlled trials (RCTs) following electronic bibliographic databases: MedLine, Embase, Cochrane Library and Web of Science. We additionally searched gray literature database: OpenSIGLE. We also additionally searched the clinical trial registers: ClinicalTrials.gov register and International Clinical Trials Registry Platform Search Portal. We used RCTs to assess the efficacy of the treatments. We included studies of adults (older than 18 years) with COPD. We excluded studies that were published as protocol or written in non-English language (Number 42016047078). Findings: Our findings included data from four studies involving 1,357 patients. There was a decrease in the risk of the rate of total number of exacerbations with carbocisteine compared with placebo (-0.43; 95% confidence interval [CI] -0.57, -0.29, P

Zhi-Fen Zeng, Yan-Ran Liang, Ying Chen, Xiu-Na Jing, Su-Dan Peng, En-Xiang Tao Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China Abstract: Chronic back pain is one of the most common reasons for missed work and visits to the doctor. This report presents 2 interesting cases of chronic back pain that were effectively relieved by low-dose levodopa. These 2 patients showed no sign of anatomical problem of the spine or relative structures, but the discomforts on the back manifested some characteristics resembling those in restless legs syndrome (RLS), and one of them actually developed RLS after many years of back problem. We believe that this type of chronic back pain might be a variant of RLS, which we would like to call “restless back”, and it can be effectively treated by dopaminergic drugs. Keywords: chronic back pain, restless legs syndrome, levodopa

Rongrong Wang,1 Renzhong Xiao,2 Zhaowu Zeng,2 Lili Xu,2 Junjie Wang21Campus Hospital of Zhejiang University, 2Research Center for Biomedicine and Health, Hangzhou Normal University, Hangzhou, ChinaAbstract: Poly(ethylene glycol)–distearoylphosphatidylethanolamine (PEG-DSPE) block copolymers are biocompatible and amphiphilic polymers that can be widely utilized in the preparation of liposomes, polymeric nanoparticles, polymer hybrid nanoparticles, solid lipid nanoparticles, lipid–polymer hybrid nanoparticles, and microemulsions. Particularly, the terminal groups of PEG can be activated and linked to various targeting ligands, which can prolong the circulation time, improve the drug bioavailability, reduce undesirable side effects, and especially target specific cells, tissues, and even the intracellular localization in organelles. This review herein aims to describe recent developments in drug carriers exploiting PEG-DSPE block copolymers and their derivatives, and the incorporation of different ligands to the end groups of PEG-DSPE to target delivery, focusing on their modification approaches, advantages, applications, and the probable associated drawbacks.Keywords: PEG-DSPE, PEG-lipid, Mal-PEG-DSPE, targeting delivery

Xingyan Liu1, Hong Liu1, Zhaowu Zeng2, Weihua Zhou3, Jianqiang Liu2, Zhiwei He11China-America Cancer Research Institute, Guangdong Medical College, 2Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical College, Dongguan, Guangdong, 3Yichun University, Yichun, Jiangxi, People's Republic of ChinaAbstract: The objective of this study was to investigate the pharmacokinetics of the ligustrazine ethosome patch and antimyocardial ischemia and anti-ischemic reperfusion injury effect. Male Sprague Dawley rats were divided randomly into 3 groups: Group A (intragastric ligustrazine), Group B (transdermal ligustrazine ethosome patch), and Group C (conventional transdermal ligustrazine patch). After treatment, samples of blood and of various tissues such as heart, liver, spleen, lung, kidney, brain, and muscle samples were taken at different time points. Drug concentration was measured with HPLC, and the drug concentration–time curve was plotted. Pharmacokinetic software 3p97 was applied to calculate pharmacokinetic parameters and the area under the drug concentration–time curve (AUC) in various tissues. The rat model of acute myocardial ischemia was constructed with intravenous injection of pituitrin and the model of myocardial ischemia-perfusion injury was constructed by tying off the left anterior descending coronary artery of rats to observe the effect of ligustrazine ethosome patches on ischemic myocardium and ischemia-reperfusion injury. Results showed that AUC was highest in the transdermal drug delivery group of ligustrazine ethosome patch. There were significant differences in whole blood viscosity, plasma viscosity, hematocrit, red blood cell aggregation index, and deformation index between ligustrazine the ethosome patch group and ischemic control group (P < 0.01). Moreover, ligustrazine ethosome patches could reduce the scope of myocardial infarction induced by long-term ischemia. Ligustrazine ethosome patches have a sustained-release property. They can maintain stable and sustained blood drug concentration, increase bioavailability, and reduce administration times. The drug patch can decrease hemorheological indices of myocardial ischemia in rats, as well as protect acute ischemic myocardium and ischemia-reperfusion injured myocardium.Keywords: ligustrazine, ethosome, patch, pharmacokinetics, myocardial ischemia, ischemia-reperfusion injury