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Puhua Wu,1,2 Zhicheng Zhang,1 Yan Zhou,2 Quan Liu,2 Kin-Yip Tam,2 Zhenhong Su1 1Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, School of Medicine, Hubei Polytechnic University, Huangshi, People’s Republic of China; 2Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, People’s Republic of ChinaCorrespondence: Puhua Wu, Email wph75000@hotmail.comBackground: Pyruvate dehydrogenase kinases (PDHKs), important metabolic and abnormally expressed enzymes in cancer cells, are promising targets for cancer therapy, especially for non-small-cell lung cancer (NSCLC).Methods: In this study, a new hit, dichloroacetophenone (DAP) analog 9, was postulated to bind to the PDHK1 allosteric pocket, guided by molecular modeling and kinase biochemical experiments. Based on this binding mode, novel DAP analogs were designed and synthesized to confirm the importance of Phe180, Tyr411, and the hydrophobic core at the bottom of the pocket.Results: This structure–activity relationship (SAR) study led to the discovery of a novel potent hybrid scaffold, dichloroacetophenone biphenylsulfone ether. Dichloroacetophenone biphenylsulfone ether 31 and 32 inhibited PDHK1 with IC50 values of 86 and 140 nM, respectively.Conclusion: Compound 32 with acceptable in vitro metabolic stability, predicted drug-likeness properties and ADME/T profiles, showed promising therapeutic efficacy in a lung cancer xenograft mouse model. Keywords: PDHK1, dichloroacetophenone, allosteric pocket, anti-NSCLC activity, tumor xenograft mouse model

Ziwei Huang,1 Shanli Zhang,1 Zehui Qin,1 Gaoxiang Ai,1 Minhua Li,1 Shiting Gong,1 Yuhong Liu,1 Huifang Zeng,2 Jiannan Chen,1 Ziren Su,1 Zhengquan Lai3 1School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 2The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 3Department of Pharmacy, Shenzhen University General Hospital/Shenzhen University Clinical Medical Academy, Shenzhen University, Shenzhen, Guangdong, People’s Republic of ChinaCorrespondence: Zhengquan Lai, Department of Pharmacy, Shenzhen University General Hospital/Shenzhen University Clinical Medical Academy, Shenzhen University, Shenzhen, Guangdong, People’s Republic of China, Email cruise0303@163.com Ziren Su, School of pharmaceutical sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China, Email suziren@gzucm.edu.cnPropose: Oxyberberine (OBB), one of the main metabolites of berberine derived from intestinal and erythrocyte metabolism, exhibits appreciable anti-hyperuricemic activity. However, the low water solubility and poor plasma concentration–effect relationship of OBB hamper its development and utilization. Therefore, an OBB-hydroxypropyl-β-cyclodextrin (HP-β-CD) supersaturated drug delivery system (SDDS) was prepared and characterized in this work.Methods: OBB-HP-β-CD SDDS was prepared using the ultrasonic-solvent evaporation method and characterized. Additionally, the in vitro and in vivo release experiments were conducted to assess the release kinetics of OBB-HP-β-CD SDDS. Subsequently, the therapeutic efficacy of OBB-HP-β-CD SDDS on hyperuricemia (HUA) was investigated by means of histopathological examination and evaluation of relevant biomarkers.Results: The results of FT-IR, DSC, PXRD, NMR and molecular modeling showed that the crystallized form of OBB was transformed into an amorphous OBB-HP-β-CD complex. Dynamic light scattering indicated that this system was relatively stable and maintained by formation of nanoaggregates with an average diameter of 23 nm. The dissolution rate of OBB-HP-β-CD SDDS was about 5 times higher than that of OBB raw material. Furthermore, the AUC0-t of OBB-HP-β-CD SDDS (10.882 μg/mL*h) was significantly higher than that of the raw OBB counterpart (0.701 μg/mL*h). The oral relative bioavailability of OBB-HP-β-CD SDDS was also enhanced by 16 times compared to that of the raw material. Finally, in vivo pharmacodynamic assay showed the anti-hyperuricemic potency of OBB-HP-β-CD SDDS was approximately 5– 10 times higher than that of OBB raw material.Conclusion: Based on our findings above, OBB-HP-β-CD SDDS proved to be an excellent drug delivery system for increasing the solubility, dissolution, bioavailability, and anti-hyperuricemic potency of OBB. Keywords: oxyberberine, cyclodextrin, supersaturated drug delivery systems, pharmacokinetics, hyperuricemia

Ting Su, Wentong Wang, Xixi Xiong, Meihua Zhang, Yan Lu,* Zhonglan Su* Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan Lu; Zhonglan Su, Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, People’s Republic of China, Email luyan6289@163.com; alice_su2595@126.comBackground: Cytophagic histiocytic panniculitis (CHP) is a rare panniculitis associated with systemic features characterized by the infiltration of subcutaneous adipose tissue by benign-appearing T lymphocytes and phagocytic histiocytes, mimicking hemophagocytic lymphohistiocytosis (HLH) and subcutaneous panniculitis-like T-cell lymphoma (SPTCL).Purpose: To establish the clinicopathological features and response to treatment of CHP and evaluate the prognosis of patients and guide therapy based on the current state of knowledge.Material and Methods: Clinical, laboratory, histopathological, and outcome data of 12 patients with CHP were retrospectively collected between 2009 and 2022.Results: All the patients presented with plaques or nodules, mostly located in the lower extremities (11/12). Fewer cases involved systemic symptoms (9/12) and laboratory abnormalities (6/12), and none were positive for serum Epstein-Barr virus (EBV)-DNA. Histopathological examination revealed mixed septal and lobular inflammatory infiltration of histiocytes and lymphocytes. Large or atypical lymphocytes were rarely present (2/12). In some patients, varying proportions of plasma cells, neutrophils, and eosinophils were observed. The extent of histocytophagy was mild (9/12), moderate (2/12), and severe (1/12). HLH was not observed in any of our cases, none of which were fatal.Conclusion: The uniqueness of our study lies in the presence of neutrophil-rich dermal and subcutaneous infiltrates, associated with connective tissue disorders (CTD) and streptococcal infections. Our study reveals that EBV-negative CHP tends to a better prognosis than previously research, filling the gap in the much-needed details of CHP in the Chinese population. Moreover, CHP may present as a reactive process in combined primary diseases; further studies are required to validate these findings.Plain Language Summary: Cytophagic histiocytic panniculitis (CHP) is a rare panniculitis associated with systemic features characterized by the infiltration of subcutaneous adipose tissue by benign-appearing T lymphocytes and phagocytic histiocytes, also may be present in hemophagocytic lymphohistiocytosis and subcutaneous panniculitis-like T-cell lymphoma.The presence of neutrophil-rich dermal and subcutaneous infiltrates, associated with connective tissue disorders and streptococcal infections. In addition, EBV-negative CHP has a better prognosis than previously thought and provides knowledge of its prognosis in the Chinese population.With changes in the disease pedigree supported by the development of medical technology, CHP may present as a reactive process of a combined primary disease.Keywords: Cytophagic histiocytic panniculitis, Epstein-Barr virus, hemophagocytic lymphohistiocytosis, retrospective study

Mei Ieng Lam,1,2 Hong Cai,2,3 Pan Chen,2,3 Ka-In Lok,4 Ines Hang Iao Chow,2 Tong Leong Si,2 Zhaohui Su,5 Chee H Ng,6 Feng-Rong An,7 Yu-Tao Xiang2,3 1Education Department, Kiang Wu Nursing College of Macau, Macau SAR, People’s Republic of China; 2Unit of Psychiatry, Department of Public Health and Medicinal Administration, & Institute of Translational Medicine, University of Macau, Macao SAR, People’s Republic of China; 3Centre for Cognitive and Brain Sciences, University of Macau, Macao SAR, People’s Republic of China; 4Faculty of Health Sciences and Sports, Macao Polytechnic University, Macao, People’s Republic of China; 5School of Public Health, Southeast University, Nanjing, People’s Republic of China; 6Department of Psychiatry, The Melbourne Clinic and St Vincent’s Hospital, University of Melbourne, Richmond, Victoria, Australia; 7Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Anding Hospital; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Chee H Ng, Department of Psychiatry, The Melbourne Clinic and St Vincent’s Hospital, University of Melbourne, Richmond, Victoria, Australia, Email cng@unimelb.edu.au Yu-Tao Xiang, Faculty of Health Sciences, University of Macau, 1/F, Building E12, Macau, People’s Republic of China, Email xyutly@gmail.comBackground: Suicidality is a global public health problem which has increased considerably during the coronavirus disease 2019 (COVID-19) pandemic. This study examined the inter-relationships between depressive symptoms and suicidality using network analysis among Macau residents after the “relatively static management” COVID-19 strategy.Methods: An assessment of suicidal ideation (SI), suicide plan (SP), suicide attempt (SA) and depressive symptoms was conducted with the use of individual binary response items (yes/no) and Patient Health Questionnaire (PHQ-9). In the network analysis, central and bridge symptoms were identified in the network through “Expected Influence” and “Bridge Expected Influence”, and specific symptoms that were directly associated with suicidality were identified via the flow function. Network Comparison Tests (NCT) were conducted to examine the gender differences in network characteristics.Results: The study sample included a total of 1008 Macau residents. The prevalence of depressive symptoms and suicidality were 62.50% (95% CI = 59.4– 65.5%) and 8.9% (95% CI = 7.2– 10.9%), respectively. A network analysis of the sample identified SI (“Suicidal ideation”) as the most central symptom, followed by SP (“Suicide plan”) and PHQ4 (“Fatigue”). SI (“Suicidal ideation”) and PHQ6 (“Guilt”) were bridge nodes connecting depressive symptoms and suicidality. A flow network revealed that the strongest connection was between S (“Suicidality”) and PHQ6 (“Guilt”), followed by S (“Suicidality”) and PHQ 7 (“Concentration”), and S (“Suicidality”) and PHQ3 (“Sleep”).Conclusion: The findings indicated that reduction of specific depressive symptoms and suicidal thoughts may be relevant in decreasing suicidality among adults. Further, suicide assessment and prevention measures should address the central and bridge symptoms identified in this study.Keywords: COVID-19, depression, suicidality, adults, network analysis

Lin Sheng,1– 4,* Yumeng Wei,1,3,* Chao Pi,1,3,* Ju Cheng,3,4 Zhilian Su,1– 4 Yuanyuan Wang,1,5 Tao Chen,1– 4 Jie Wen,1– 4 Yuxun Wei,1– 4 Jingwen Ma,1– 4 Jia Tang,1– 4 Huiyang Liu,1– 4 Zerong Liu,6,7 Hongping Shen,8 Ying Zuo,9 Wenwu Zheng,10 Ling Zhao2– 4 1Key Laboratory of Medical Electrophysiology, Ministry of Education, School of Pharmacy of Southwest Medical University, Luzhou, People’s Republic of China; 2Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 3Key Laboratory of Medical Electrophysiology, Ministry of Education, Development Planning Department of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 4Central Nervous System Drug Key Laboratory of Sichuan Province, School of Pharmacy of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 5Department of Clinical Pharmacy, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 6Central Nervous System Drug Key Laboratory of Sichuan Province, Sichuan Credit Pharmaceutical CO., Ltd. Luxian County, Luzhou City, People’s Republic of China; 7Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400030, People’s Republic of China; 8Clinical Trial Center, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 9Department of Comprehensive Medicine, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 10Department of cardiology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenwu Zheng, Department of Cardiology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China, Tel/Fax +86 830 3165311, Email zhengwenwu888@163.com Ling Zhao, Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, No. 182, Chunhui Road, Longmatan District, Luzhou, Sichuan, 646000, People’s Republic of China, Tel/Fax +86 830 3160093, Email zhaoling@swmu.edu.cnPurpose: The early stage of this study verified that a turmeric extract (TUR) including 59% curcumin (CU), 22% demethoxycurcumin (DMC), and 18% bisdemethoxycurcumin (BDMC), could enhance the stability of CU and had greater antidepressant potential in vitro. The objective of the study was to develop a nano-delivery system containing TUR (TUR-NE) to improve the pharmacokinetic behavior of TUR and enhance its antidepressant effect.Methods: The antidepressant potential of TUR was explored using ABTS, oxidative stress-induced cell injury, and a high-throughput screening model. TUR-NE was fabricated, optimized and characterized. The pharmacokinetic behaviors of TUR-NE were evaluated following oral administration to normal rats. The antidepressant effect of TUR-NE was assessed within chronic unpredictable mild stress model (CUMS) mice. The behavioral and biochemical indexes of mice were conducted.Results: The results depicted that TUR had 3.18 and 1.62 times higher antioxidant capacity than ascorbic acid and CU, respectively. The inhibition effect of TUR on ASP+ transport was significantly enhanced compared with fluoxetine and CU. TUR-NE displayed a particle size of 116.0 ± 0.31 nm, polydispersity index value of 0.121 ± 0.007, an encapsulation rate of 98.45%, and good release and stability in cold storage. The results of pharmacokinetics indicated the AUC(0-t) of TUR-NE was 8.436 and 4.495 times higher than that of CU and TUR, while the Cmax was 9.012 and 5.452 times higher than that of CU and TUR, respectively. The pharmacodynamic study confirmed that the superior antidepressant effect of TUR-NE by significantly improving the depressant-like behaviors and elevating the content of 5-hydroxytryptamine in plasma and brain in CUMS mice. TUR-NE showed good safety with repeated administration.Conclusion: TUR-NE, which had small and uniform particle size, enhanced the bioavailability and antidepressant effect of TUR. It could be a promising novel oral preparation against depression.Keywords: turmeric extract, curcuminoids, nanoemulsion, stability, antidepressant effect, 5-hydroxytryptamine

Feihong Huang,1,2,* Zhiping Su,3,* Chaojie Yu1 1Department of Bone and Soft Tissue Surgery, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 2Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 3Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chaojie Yu, Guangxi Medical University Cancer Hospital, Department of Bone and Soft Tissue Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China, Email h2021020@sr.gxmu.edu.cnObjective: The mechanism of ankylosing spondylitis (AS) remains unclear, and clinical diagnosis still pose challenges. This study aims to explore potential regulatory mechanisms underlying AS and develop a novel diagnostic model.Methods: Interspinous ligament (ISL) tissues were collected from control samples and ankylosing spondylitis with kyphotic deformity (AS-KD) samples during surgery, followed by high-throughput sequencing. By integrating gene expression profiles from publicly available AS peripheral blood (PB) samples, differentially expressed immune genes (DEIRGs) were identified. Through gene set enrichment analysis(GSEA), gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, the regulatory mechanisms of the immune gene family in AS were explored. A diagnostic model for AS were constructed and validated it externally. Additionally, a competing endogenous RNA(ceRNA)-protein regulatory network was built for key immune genes.Results: Adrenergic receptor beta 2 (ADRB2) was downregulated in both ISL and PB samples. It was enriched in common pathways, including natural killer cell-mediated cytotoxicity, B cell receptor signaling pathway, Th1 and Th2 cell differentiation. Using the LASSO algorithm, 12 DEIRGs were identified, including the downregulated ADRB2. Based on the DEIRGs family, a novel diagnostic model was constructed with an AUC of 0.87 for the validation set and 0.7 for the test set. The AUC for ADRB2 alone was 0.75. Subgrouping AS based on these immune genes revealed a close association with neutrophils. GSEA and KEGG analysis of ISL, PB, and subgrouping of AS showed that ADRB2 may be involved in regulating the T cell receptor signaling pathway. Immune infiltration analysis indicated a decrease in CD8+ T cell infiltration, which was positively correlated with ADRB2. ADRB2 in AS-KD was regulated by multiple ceRNA-protein (lncRNA-[hsa-miR-513a-5p]-mRNA-protein).Conclusion: The immune gene family, especially ADRB2, participates in the mechanism and contributes to the diagnosis of AS.Keywords: ankylosing spondylitis, immune genes, adrenergic receptor beta-2, ADRB2, diagnostic model, competing endogenous RNA network, ceRNA network

Zitian Liang,1,* Ding Chen,2,* Ye Jiang,1 Zhikang Su,2 Yixing Pi,2 Tao Luo,2 Qianzhou Jiang,1 Li Yang,1 Lvhua Guo2 1Department of Endodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, 510182, People’s Republic of China; 2Department of Prosthodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, 510182, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li Yang; Lvhua Guo, Affiliated Stomatology Hospital of Guangzhou Medical University, No. 195 West Dongfeng Road, Guangzhou, 510182, People’s Republic of China, Tel +86-020-81299942, Email 2019686001@gzhmu.edu.cn; 2010686002@gzhmu.edu.cnIntroduction: Effective infection control without irritating the pulp tissue is the key to successful vital pulp therapy. Developing a novel antibacterial biomaterial that promotes dentin regeneration for pulp capping is thus a promising strategy for enhancing vital pulp therapy.Methods: Lithium-doped mesoporous nanoparticles (Li-MNPs) were synthesized using an alkali-catalyzed sol-gel method. The particle size, elemental distribution, surface morphology, pore structure, and ion release from Li-MNPs were measured. Human dental pulp stem cells (hDPSCs) and Streptococcus mutans (S. mutans) were used to evaluate the biological effects of Li-MNPs. In addition, a dental pulp exposure mouse model was used to evaluate the regenerative effects of Li-MNPs.Results: Li-MNPs had a larger surface area (221.18 m2/g), a larger pore volume (0.25 cm3/g), and a smaller particle size (520.92 ± 35.21 nm) than MNPs. The in vitro investigation demonstrated that Li-MNPs greatly enhanced the biomineralization and odontogenic differentiation of hDPSCs through the Wnt/β-catenin signaling pathway. Li-MNPs showed a strong antibacterial effect on S. mutans. As expected, Li-MNPs significantly promoted dentin regeneration in situ and in vivo.Conclusion: Li-MNPs promoted dentin regeneration and inhibited S. mutans growth, implying a possible application as a pulp capping agent in vital pulp therapy.Graphical Abstract: Keywords: lithium, mesoporous nanoparticles, dental pulp stem cells, dentin regeneration, Wnt/β-catenin signaling pathway, antibacterial properties

Zehui Qin,1 Minhua Li,1,2 Juanjuan Cheng,1,2 Ziwei Huang,1,2 Gaoxiang Ai,1,2 Chang Qu,3 Youliang Xie,1 Yucui Li,1 Huijun Liao,4 Jianhui Xie,5– 7 Ziren Su1,2 1School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of China; 2Dongguan Institute of Guangzhou University of Chinese Medicine, Dongguan, 523808, People’s Republic of China; 3College of Forestry and Landscape Architecture, South China Agricultural University, Guangzhou, 510006, People’s Republic of China; 4Department of Clinical Pharmacy and Pharmaceutical Services, Huazhong University of Science and Technology Union Shenzhen Hospital (the 6th affiliated Hospital of Shenzhen University), Shenzhen, People’s Republic of China; 5The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 6State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 7Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, People’s Republic of ChinaCorrespondence: Ziren Su, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China, Dongguan Institute of Guangzhou University of Chinese Medicine, Dongguan, 523808, People’s Republic of China, Email suziren@gzucm.edu.cn Huijun Liao, Department of Clinical Pharmacy and Pharmaceutical Services, Huazhong University of Science and Technology Union Shenzhen Hospital (the 6th affiliated hospital of Shenzhen University), Shenzhen, People’s Republic of China, Email liaohuijun1016@163.comPropose: Berberine (BBR) is extensively studied as an outstanding anti-hyperuricemia drug. However, the clinical application of BBR was limited due to its poor absorption and low bioavailability. Therefore, there is an urgent necessity to find a novel drug formulation to address the issues of BBR in clinical application.Methods: Herein, we conducted the solubility, characterization experiments to verify whether BBR and sodium taurocholate (STC) self-assembled nanoparticles (STC@BBR-SANPs) could form. Furthermore, we proceeded the release experiment in vitro and in vivo to investigate the drug release effect. Finally, we explored the therapeutic effect of STC@BBR-SANPs on hyperuricemia (HUA) through morphological observation of organs and measurement of related indicators.Results: The solubility, particle size, scanning electron microscopy (SEM), and stability studies showed that the stable STC@BBR-SANPs could be formed in the BBR-STC system at ratio of 1:4. Meanwhile, the tissue distribution experiments revealed that the STC@BBR-SANPs could accelerate the absorption and distribution of BBR. In addition, the pharmacology study demonstrated that both BBR and STC@BBR-SANPs exhibited favorable anti-HUA effects and nephroprotective effects, while STC@BBR-SANPs showed better therapeutic action than that of BBR.Conclusion: This work indicated that STC@BBR-SANPs can be self-assembly formed, and exerts excellent uric acid-lowering effect. STC@BBR-SANPs can help to solve the problems of poor solubility and low absorption rate of BBR in clinical use, and provide a new perspective for the future development of BBR.Graphical Abstract: Keywords: berberine, sodium taurocholate, intermolecular interactions, self-assembled, nanoparticles, hyperuricemia

Xinghua Guo,1,2,* Pan Song,1,2,* Feng Li,1,2,* Qihao Yan,1,2,* Yan Bai,3 Jincan He,3 Qishi Che,4 Hua Cao,5 Jiao Guo,2 Zhengquan Su1 1Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou, 510006, People’s Republic of China; 2Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, 510006, People’s Republic of China; 3School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, People’s Republic of China; 4Guangzhou Rainhome Pharm & Tech Co., Ltd, Science City, Guangzhou, 510663, People’s Republic of China; 5School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan, 528458, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhengquan Su, Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Pharmaceutical University, Guangzhou, 510006, People’s Republic of China, Tel +86-20-3935-2067, Fax +86-20-3935-2067, Email suzhq@scnu.edu.cnAbstract: Bone, like most organs, has the ability to heal naturally and can be repaired slowly when it is slightly injured. However, in the case of bone defects caused by diseases or large shocks, surgical intervention and treatment of bone substitutes are needed, and drugs are actively matched to promote osteogenesis or prevent infection. Oral administration or injection for systemic therapy is a common way of administration in clinic, although it is not suitable for the long treatment cycle of bone tissue, and the drugs cannot exert the greatest effect or even produce toxic and side effects. In order to solve this problem, the structure or carrier simulating natural bone tissue is constructed to control the loading or release of the preparation with osteogenic potential, thus accelerating the repair of bone defect. Bioactive materials provide potential advantages for bone tissue regeneration, such as physical support, cell coverage and growth factors. In this review, we discuss the application of bone scaffolds with different structural characteristics made of polymers, ceramics and other composite materials in bone regeneration engineering and drug release, and look forward to its prospect.Graphical Abstract: Keywords: bone scaffold, drug loading, slow release, osteogenesis, biomaterial

Zhaohua Yang,1,* Jinying Wei,1,* Yashu Wang,1 Yunxia Du,1 Shan Song,1 Jiawei Li,2 Ziyuan Su,2 Yonghong Shi,1 Haijiang Wu1 1Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, People’s Republic of China; 2Basic Medical College, Hebei Medical University, Shijiazhuang, 050017, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haijiang Wu, Email haijianglaoqi@163.comBackground: The primary pathophysiology of diabetic kidney disease (DKD) is tubulointerstitial fibrosis (TIF), and an essential contributing element is excessive extracellular matrix deposition. Irisin is a polypeptide formed by splitting fibronectin type III domain containing 5 (FNDC5), which participates in a number of physiological and pathological processes.Methods: The purpose of this article is to examine irisin’s function in DKD and analyze both its in vitro and in vivo effects. The Gene Expression Omnibus (GEO) database was used to download GSE30122, GSE104954, and GSE99325. Analysis of renal tubule samples from nondiabetic and diabetic mice identified 94 differentially expressed genes (DEGs). The transforming growth factor beta receptor 2 (TGFBR2), irisin, and TGF-β 1 were utilized as DEGs to examine the impact of irisin on TIF in diabetic kidney tissue, according to the datasets retrieved from the GEO database and Nephroseq database. Additionally, the therapeutic impact of irisin was also examined using Western blot, RT-qPCR, immunofluorescence, immunohistochemistry, and kits for detecting mouse biochemical indices.Results: In vitro, the findings demonstrated that irisin not only down-regulated the expression of Smad4 and β-catenin but also reduced the expression of proteins linked to fibrosis, the epithelial-mesenchymal transition (EMT), and mitochondrial dysfunction in HK-2 cells maintained in high glucose (HG) environment. In vivo, overexpressed FNDC5 plasmid was injected into diabetic mice to enhance its expression. Our studies found that overexpressed FNDC5 plasmid not only reversed the biochemical parameters and renal morphological characteristics of diabetic mice but also alleviated EMT and TIF by inhibiting Smad4/β-catenin signaling pathway.Conclusion: The above experimental results revealed that irisin could reduce TIF in diabetic mice via regulating the Smad4/β-catenin pathway.Keywords: irisin, diabetic kidney disease, tubulointerstitial fibrosis, Smad4, β-catenin

Yuxun Wei,1– 4,* Yumeng Wei,1– 4,* Lin Sheng,1– 4 Jingwen Ma,1– 4 Zhilian Su,1– 4 Jie Wen,1– 4 Lanmei Li,5 Qiang Jia,2,6 Huiyang Liu,1– 4 Hui Si,2,4 Linjin Xiong,1– 4 Jinglin Chen,1– 4 Ju Cheng,3,4 Ying Zuo,2,7 Hongru Yang,8 Ling Zhao2– 4 1Key Laboratory of Medical Electrophysiology, Ministry of Education, School of Pharmacy of Southwest Medical University, Luzhou, People’s Republic of China; 2Key Laboratory of Medical Electrophysiology, Ministry of Education, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University; Luzhou, Sichuan, People’s Republic of China; 3Central Nervous System Drug Key Laboratory of Sichuan Province, School of Pharmacy of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 4Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 5Nanchong Key Laboratory of Individualized Drug Therapy, Department of Pharmacy, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan, People’s Republic of China; 6Ethics Committee Office, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 7Department of Comprehensive Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 8Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ling Zhao, Key Laboratory of Medical Electrophysiology, Ministry of Education, Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China, Tel/Fax +86 830 3160093, Email zhaoling-998@163.com Hongru Yang, Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China, Tel/Fax +86 830 8585668, Email yanghongru801@126.comPurpose: The present study aimed to construct a co-loading platform encapsulating curcumin and paclitaxel at ratios of 2:1– 80:1 (w/w) designated “CU-PTX-LNP” and explored the synergistic effects of CU-PTX at different composite proportions on liver cancer cells using the combination index (CI) method.Methods: The CU lipid nanoplatform (CU-LNP) formulation was optimized via single-factor and orthogonal experiments. Various concentrations of PTX were added to the optimal formulation of CU-LNP to generate CU-PTX-LNP and the nanoplatform characterized via differential scanning calorimetry (DSC), transmission electron microscope (TEM), X-ray diffraction (XRD), zeta potential, polydispersity index (PDI), and size analyses. The cumulative release, stability, and cytotoxicity of CU-PTX-LNP in LO2, HepG2, and SMMC-7221 cells were assessed in vitro, followed by safety investigation and pharmacokinetic studies in vivo. The anti-tumor activity of CU-PTX-LNP was also evaluated using nude mice.Results: CU-PTX-LNP formulations containing CU:PTX at a range of proportions (2:1– 80:1; w/w) appeared as uniformly dispersed nanosized spherical particles with high entrapment efficiency (EE> 90%), sustained release and long-lasting stability. Data from in vitro cytotoxicity assays showed a decrease in the IC50 value of PTX of CU-PTX-LNP (by 5.47– 332.7 times in HepG2 and 4.29– 143.21 times in SMMC-7221 cells) compared to free PTX. In vivo, CU-PTX-LNP displayed excellent biosafety, significant anti-tumor benefits and enhanced pharmacokinetic behavior with longer mean residence time (MRT(0-t); CU: 4.31-fold, PTX: 4.61-fold) and half-life (t1/2z; CU: 1.83-fold, PTX: 2.28-fold) relative to free drugs.Conclusion: The newly designed CU-PTX-LNP platform may serve as a viable technological support system for the successful production of CU-PTX composite preparations.Keywords: curcumin, paclitaxel, lipid nano platform, synergistic effect

Qiang Xiao,1,&ast; Shukun Tan,1,2,&ast; Changzhi Liu,3,&ast; Bin Liu,1 Yingxiong Li,1 Yehui Guo,1 Peiyan Hu,1 Zhuoying Su,1 Siqin Chen,1 Wei Lei,1 Xi Li,1 Minhong Su,4 Fu Rong1 1Pulmonary and Critical Care Medicine, Shunde Hospital, Southern Medical University (the First People’s Hospital of Shunde Foshan), Foshan, 528300, People’s Republic of China; 2Respiratory Medicine of the Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, 528222, People’s Republic of China; 3Critical Care Medicine, Shunde Hospital, Southern Medical University (the First People’s Hospital of Shunde Foshan), Foshan, 528300, People’s Republic of China; 4Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fu Rong, Pulmonary and Critical Care Medicine, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde Foshan), No. 1, Jiazi Road, Lunjiao Street, Shunde District, Foshan, 528300, People’s Republic of China, Tel +86-757-22318689, Email rongfu828@sina.com Minhong Su, Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, 253 Gongye Middle Avenue, Haizhu District, Guangzhou, 510280, People’s Republic of China, Tel +86-20-62782290, Email 878697159@qq.comPurpose: Community-acquired pneumonia (CAP) is one of the most frequently encountered infectious diseases worldwide. Few studies have explored the microbial composition of the lower respiratory tract (LRT) and host metabolites of CAP. We analyzed the microbial composition of the LRT and levels of host metabolites to explore new biomarkers for CAP.Patients and Methods: Bronchoalveolar lavage fluid (BALF) was collected from 28 CAP patients and 20 healthy individuals. Following centrifugation, BALF pellets were used for amplicon sequencing of a variable region of the bacterial 16S rDNA gene to characterize the microbial composition. Non-targeted metabolomics was used to detect host’s metabolites in the supernatant.Results: Compared with healthy individuals, the bacterial alpha diversity in the LRT of CAP patients was significantly lower in CAP patients (p< 0.05). On the bacterial genus level, over 20 genera were detected with lower relative abundance (p< 0.05), while the relative abundance of Ruminiclostridium-6 was significantly higher in CAP patients. The levels of the host metabolites dimethyldisulfide, choline, pyrimidine, oleic acid and N-acetyl-neuraminic acid were all increased in BALF of CAP patients (p< 0.05), while concentrations of lysophosphatidylcholines (LPC (12:0/0:0)) and phosphatidic acid (PA (20:4/2:0)) were decreased (p< 0.05). Furthermore, the relative abundance of Parvimonas, Treponema-2, Moraxella, Aggregatibacter, Filifactor, Fusobacterium, Lautropia and Neisseria negatively correlated with concentrations of oleic acid (p< 0.05). A negative correlation between the relative abundance of Treponema-2, Moraxella, Filifactor, Fusobacterium and dimethyldisulfide concentrations was also observed (p< 0.05). In contrast, the relative abundance of Treponema-2, Moraxella, Filifactor, and Fusobacterium was found to be positively associated with concentrations of LPC (12:0/0:0) and PA (20:4/2:0) (p< 0.05).Conclusion: The composition of the LRT microbiome differed between healthy individuals and CAP patients. We propose that some respiratory microbial components and host metabolites are potentially novel diagnostic markers of CAP.Keywords: community-acquired pneumonia, microbiome, metabolites, biomarker, diagnosis

Minhua Li,1,&ast; Zehui Qin,1,&ast; Qiuxia Yu,2 Ziwei Huang,3 Juanjuan Cheng,1 Linjiang Zhong,1 Yuhong Liu,1 Jianhui Xie,4– 6 Yucui Li,1 Jiannan Chen,1 Ruoting Zhan,1 Ziren Su1 1School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of China; 2The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, 510120, People’s Republic of China; 3The First Affiliated Hospital of Chinese Medicine Guangzhou University of Chinese Medicine, Guangzhou, 510120, People’s Republic of China; 4The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, People’s Republic of China; 5State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, People’s Republic of China; 6Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, 510120, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ruoting Zhan; Ziren Su, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, no. 232, Waihuandong Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, People’s Republic of China, Email zhanrt@gzucm.edu.cn; suziren@gzucm.edu.cnBackground: Berberine (BBR) is the primary active component of Phellodendri Chinensis Cortex (PCC), which has been traditionally used to treat inflammatory diseases. However, the discrepancy between its low bioavailability and significant therapeutic effect remains obscure. The purpose of this study was to explore the previously unsolved enigma of the low bioavailability of BBR and its appreciable anti-inflammatory effect to reveal the action mechanism of BBR and PCC.Methods: The quantitative analysis of BBR and its metabolite oxyberberine (OBB) in blood and tissues was performed using high-performance liquid chromatography to investigate the conversion and distribution of BBR/OBB mediated by erythrocytes. Routine blood tests and immunohistochemical staining were used to explore the potential relationship between the amounts of monocyte/macrophage and the drug concentration in erythrocytes and tissues (liver, heart, spleen, lung, kidney, intestine, muscle, brain and pancreas). To comparatively explore the anti-inflammatory effects of BBR and OBB, the acetic acid-induced vascular permeability mice model and lipopolysaccharide-induced RAW 264.7 macrophages were employed.Results: Nearly 92% of BBR existed in the erythrocytes in rats. The partition coefficient of BBR between plasma and erythrocytes (Kp/b) decreased with time. OBB was found to be the oxidative metabolite of BBR in erythrocytes. Proportion of BBR/OBB in erythrocytes changed from 9.38% to 16.30% and from 13.50% to 46.24%, respectively. There was a significant relationship between the BBR/OBB concentration in blood and monocyte depletion after a single administration of BBR. BBR/OBB was transported via erythrocytes to various tissues (liver, kidney, spleen, lung, and heart, etc), with the liver achieving the highest concentration. OBB exhibited similar anti-inflammatory effect in vitro and in vivo as BBR with much smaller dosage.Conclusion: BBR was prodominantly found in erythrocytes, which was critically participated in the biodistribution, pharmacokinetics, metabolism and target delivery of BBR and its metabolite. The anti-inflammatory activity of BBR and PCC was intimately associated with the metabolism into the active congener OBB and the targeted delivery to monocytes/macrophages mediated by the erythrocytes.Graphical Abstract: Keywords: erythrocytes, Phellodendri Chinensis Cortex, transformation, berberine, anti-inflammation

Zhan Su,&ast; Jie Zhang,&ast; Peijie Tan, Songsong Zhu,&ast; Nan Jiang&ast; State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral & Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Songsong Zhu; Nan Jiang, Email zss_1977@163.com; dent_jn@163.comIntroduction: Polyetheretherketone (PEEK) has good biosafety and chemical stability for bone repair. However, PEEK is biologically inert and cannot promote bone apposition. This study investigated whether graphene-modified PEEK (G-PEEK) could improve cell adhesion and osteogenic differentiation.Methods: G-PEEK was prepared by melted blending and was characterized. In vitro, the biocompatibility of G-PPEK and the ability to promote cell adhesion and osteogenic differentiation in rabbit bone marrow mesenchymal stem cells (rBMSCs) were examined using live and dead cell double staining, the cell counting kit-8 (CCK-8) assay, immunofluorescence and quantitative real-time PCR (qRT‒PCR). An in vivo rabbit extra-articular graft-to-bone healing model was established. At 4 and 12 weeks after surgery, CT analysis and histological evaluation were performed.Results: In vitro, G-PEEK significantly improved the adhesion and proliferation of rBMSCs, with good biocompatibility. In vivo, G-PEEK promoted new bone formation at the site of the bone defect.Conclusion: G-PEEK showed excellent osteogenesis performance, which promises new applications in implant materials.Keywords: polyetheretherketone, graphene, nanocomposites, cell adhesion, osteogenic differentiation

Yumeng Wei,1– 3,&ast; Mingtang Zeng,1– 4,&ast; Chao Pi,1– 3 Hongping Shen,2,5 Jiyuan Yuan,2,5 Ying Zuo,2,6 Jie Wen,1– 3 Pu Guo,7 Wenmei Zhao,1– 3 Ke Li,1– 3 Zhilian Su,1– 3 Xinjie Song,8,9 Shaozhi Fu,10 Robert J Lee,11 Ling Zhao2,3 1Key Laboratory of Medical Electrophysiology, Ministry of Education, School of Pharmacy of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 2Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 3Central Nervous System Drug Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, 646000, People’s Republic of China; 4Department of Clinical Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 5Clinical Trial Center, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 6General Department, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 7Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 8School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, 310023, People’s Republic of China; 9Department of Food Science and Technology, Yeungnam University, Gyeongsan-si, Gyeongsangbuk-do, 38541, Republic of Korea; 10Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 11Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA&ast;These authors contributed equally to this workCorrespondence: Shaozhi Fu, Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China, Tel +86 830-3165698, Fax +86 830-3165690, Email shaozhifu513@swmu.edu.cn Ling Zhao, Luzhou Key Laboratory of Traditional Chinese Medicine for Chronic Diseases Jointly Built by Sichuan and Chongqing, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China, Tel/Fax +86 830 3160093, Email zhaoling-998@163.comPurpose: Paclitaxel (PTX) has been widely utilized for the treatment of breast cancer. However, drawbacks, such as poor aqueous solubility, rapid blood clearance and severe toxicity, greatly reduce its efficacy and safety. Herein, a novel self-developed curcumin derivative (CUD) was chosen as the carrier to develop a long-acting PTX nano-delivery system (PTX-Sln@CUD) in order to improve its pharmacokinetic behavior, anti-breast cancer efficacy and safety.Methods: PTX-Sln@CUD was prepared using solid dispersion and ultrasonic technology. Relevant physical and chemical properties, including stability and release behavior, were characterized. The clearance of PTX-Sln@CUD in vivo was studied by pharmacokinetic experiments. The anti-tumor activity of PTX-Sln@CUD was investigated in vitro and in vivo. Hemolysis experiments, acute toxicity and cumulative toxicity studies were performed in mice to determine the safety of PTX-Sln@CUD.Results: The average particle size, PDI, Zeta potential, encapsulation efficiency and loading efficiency of the PTX-Sln@CUD were 238.5 ± 4.79 nm, 0.225 ± 0.011, − 33.8 ± 1.26 mV, 94.20 ± 0.49% and 10.98 ± 0.31%, respectively. PTX-Sln@CUD was found to be stable at room temperature for half a year. The cumulative release rates of PTX-Sln@CUD at 24, 96 and 168 h were 17.98 ± 2.60, 57.09 ± 2.32 and 72.66 ± 4.16%, respectively, which were adherent to zero-order kinetics. T1/2, MRT (0-t) and AUC (0-t) of the PTX-Sln@CUD group were 4.03-fold (44.293 h), 7.78-fold (38.444 h) and 6.18-fold (14.716 mg/L&ast;h) of the PTX group, respectively. PTX-Sln@CUD group demonstrated stronger anti-breast cancer activity than the PTX group. Importantly, the PTX-Sln@CUD group was safer compared to the PTX group both in vitro and in vivo.Conclusion: PTX-Sln@CUD was verified as promising therapeutic nanoparticles for breast cancer and provided a novel strategy to solve the problem of low efficacy and poor safety of clinical chemotherapy drugs.Graphical Abstract: Keywords: breast cancer, long-acting, paclitaxel nanoparticles, curcumin derivative

Youxin Wang,1,&ast; Xinglei Huang,1,&ast; Zhaohui Su,1,&ast; Junquan He,1 Na Zhao,1 Liyun Nie,1 Yanmei Tang,1 Huiliu Zhao,2 Qingqing Nong1,3 1Department of Environmental Health, School of Public Health, Guangxi Medical University, Nanning, 530021, People’s Republic of China; 2Department of Clinical Laboratory, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, People’s Republic of China; 3Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, 530021, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qingqing Nong, Department of Environmental Health, School of Public Health, Guangxi Medical University, Nanning, 530021, People’s Republic of China, Tel +86 771-5358146, Fax +86 771-5350823, Email nnqq@gxmu.edu.cnBackground: The dysfunction of Essential meiotic endonuclease 1 homolog 1 (EME1) can lead to genomic instability and tumorigenesis. Single nucleotide polymorphisms (SNPs) in the EME1 gene have been reported to be associated with the risk of several cancers, but its association with hepatocellular carcinoma (HCC) has not been investigated. This study aimed to determine the association between EME1 SNPs and the risk of HCC.Methods: This study included 645 HCC patients and 649 healthy controls from a Guangxi population of Southern China, and genotyped three functional SNPs (Glu69Asp: rs3760413A>C, Ile350Thr: rs12450550T>C, and rs11868055A>G) of the EME1 gene utilizing the Agena MassARRAY platform.Results: The rs3760413C variant genotypes (AC+CC: Glu/Asp+Asp/Asp) conferred a 1.419-fold risk of HCC compared to the AA (Glu/Glu) genotype (adjusted OR = 1.419, 95% CI = 1.017– 1.980), and the allele C increased the risk of HCC in a dose-dependent manner (Ptrend = 0.017). Moreover, the effects of the rs3760413C variant genotypes were more pronounced in individuals who drank pond/ditch water (adjusted OR = 3.956, 95% CI = 1.413– 11.076) than in those who never drank (P = 0.033). We further observed that a potential carcinogen microcystin-LR induced more DNA oxidative damages in peripheral blood mononuclear cells from the carriers of rs3760413C variant genotypes than those from the subjects with AA genotype (P = 0.006). A nomogram was also constructed combining the rs3760413A>C polymorphism and environmental risk factors for predicting HCC risk with a good discriminatory ability (concordance index = 0.892, 95% CI: 0.874– 0.911) and good calibration (mean absolute error = 0.005).Conclusion: Our data suggest that the Glu69Asp missense polymorphism (rs3760413) of EME1 gene is associated with the risk of HCC, which may be a susceptible biomarker of HCC in the Guangxi population.Keywords: EME1, hepatocellular carcinoma, missense polymorphism, pond/ditch water, nomogram

Hai-Ying Chen,1,&ast; Ming-Chao Li,2,&ast; Dan Liao,1 Chi Li,1 Qiu-Ming Ji,1 Ping Guo,1 Zou Su,1 Yu-Hong Yang,1 Wen-Hao Xiao,1 Wen-Hui Zhai1 1Department of Psychiatry, Wuhan Wudong Hospital, Wuhan, People’s Republic of China; 2Department of Psychiatry, Wuhan Mental Health Center, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dan Liao; Chi Li, Department of Psychiatry, Wuhan Wudong Hospital, No. 46 of Wudong Street, Qingshan District, Wuhan, 430084, People’s Republic of China, Tel +86 27 5052 8367, Fax +86 27 8643 8247, Email danliaodr@21cn.comObjective: Our study aimed to investigate the effects of computer-assisted cognitive remediation therapy (CCRT) on cognitive function, social function and quality of life in patients with vascular dementia (VD).Methods: Ninety-eight patients with VD were treated with CCRT in four 45-minute sessions per week over a course of 40 sessions to exercise four cognitive functions, including flexibility, working memory, plan execution and social cognition. The Mini-Mental State Examination (MMSE), Social Disability Screening Schedule (SDSS), Personal and Social Performance Scale (PSP), and Generic Quality of Life Inventory-74 (GQOL-74) were used to assess before and after treatment.Results: (1) The scores of orientation (5.60 ± 1.35), calculation (2.20 ± 0.79), verbal ability (7.10 ± 0.36), spatial ability (0.78 ± 0.42), immediate memory (2.42 ± 0.53), short-term memory (1.17 ± 0.78) and MMSE (23.36 ± 2.98) were all improved after treatment (P < 0.05) compared with those before treatment; (2) The scores of SDSS, PSP and Activities of Daily Living (ADL) after treatment were 8.23 ± 0.94, 81.36 ± 14.23, and 32.7 ± 12.1, and all of which improved (P < 0.05); (3) The scores of physical health were 68.24 ± 7.44, mental health were 69.75 ± 7.15, social function were 69.08 ± 7.43, material life were 37.46 ± 4.85 and the total score were 230.79 ± 9.56, all of which improved (P < 0.05).Conclusion: For patients with VD, CCRT can improve their cognitive function, social function, daily life ability and quality of life.Keywords: computer-assisted cognitive remediation, vascular dementia, cognitive function, social function, daily life ability

Zhenxing Su,1 Yaqin Kang2 1Dermatology, First Hospital of Shanxi Medical University, Taiyuan City, People’s Republic of China; 2Pediatrics, First Hospital of Shanxi Medical University, Taiyuan City, People’s Republic of ChinaCorrespondence: Zhenxing Su, Dermatology, First Hospital of Shanxi Medical University, No. 85, Jiefang South Road, Yingze District, Taiyuan City, People’s Republic of China, Email zhenxingsu@outlook.comObjective: Infantile eczema (IE), a common pediatric allergic skin disease caused by multiple inherent and external factors, is common in infants and young children, with skin lesions and itching as the main clinical manifestations. At present, its pathological mechanism has not been thoroughly clarified, but scholars believe that it is related to the joint action of various internal and external factors. This research aims to investigate the influences of bifid triple viable capsules plus cetirizine (CTZ) on gut microbiota (GMB) and immunity in children with eczema.Methods: The complete clinical data of 162 cases of IE presented between July 2019 and July 2020 to the First Hospital of Shanxi Medical University were retrospectively analyzed. Children treated by CTZ alone were assigned to the control group (n = 81) and those by CTZ plus bifid triple viable capsules were included in the observation group (n = 81). Therapeutic efficacy, adverse reactions (ARs), disease recurrence, as well as changes in GMB, inflammatory factors (IFs) and immunoglobulins (Igs) were observed.Results: The observation group was observed with a higher overall response rate and increased fecal Lactobacillus, Escherichia coli (E. coli) and Bifidobacterium counts after treatment versus the control group. After treatment, reduced IgG and IgM, as well as IFs, were found in both groups, with lower levels in the observation group. A lower incidence of ARs was determined in the observation group.Conclusion: With high efficacy for the treatment of IE, bifid triple viable capsules plus CTZ can validly regulate the GMB of children, improve their immune function and clinical symptoms, and reduce the disease recurrence rate, which is worthy of clinical promotion.Keywords: bifid triple viable capsules, cetirizine, eczema, gut microbiota, immune function

Hong Cai,1– 3,&ast; Yan-jie Zhao,1– 3,&ast; Xiaomeng Xing,4,&ast; Tengfei Tian,4,&ast; Wang Qian,4 Sixiang Liang,4 Zhe Wang,4 Teris Cheung,5 Zhaohui Su,6 Yi-Lang Tang,7,8 Chee H Ng,9 Sha Sha,4 Yu-Tao Xiang1– 3 1Unit of Psychiatry, Department of Public Health and Medicinal Administration, & Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macao Special Administrative Region, People’s Republic of China; 2Centre for Cognitive and Brain Sciences, University of Macau, Macao Special Administrative Region, People’s Republic of China; 3Institute of Advanced Studies in Humanities and Social Sciences, University of Macau, Macao Special Administrative Region, People’s Republic of China; 4The National Clinical Research Center for Mental Disorder & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital & the Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, People’s Republic of China; 5School of Nursing, Hong Kong Polytechnic University, Hong Kong Special Administrative Region, People’s Republic of China; 6School of Public Health, Southeast University, Nanjing, China, Nanjing, People’s Republic of China; 7Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA; 8Atlanta VA Medical Center, Decatur, GA, USA; 9Department of Psychiatry, The Melbourne Clinic and St Vincent’s Hospital, University of Melbourne, Richmond, Victoria, Australia&ast;These authors contributed equally to this workCorrespondence: Sha Sha, The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders Beijing Anding Hospital & the Advanced Innovation Center for Human Brain Protection, Capital Medical University, School of Mental Health, Beijing, People’s Republic of China, Email sarahbon@163.com Chee H Ng, Department of Psychiatry, The Melbourne Clinic and St Vincent’s Hospital, University of Melbourne, Richmond, Victoria, Australia, Email cng@unimelb.edu.auBackground: A high proportion of clinicians experienced common anxiety, insomnia and depression during the COVID-19 pandemic. This study examined the item-level association of comorbid anxiety and insomnia symptoms among clinicians who suffered from depressive symptoms during the late stage of the COVID-19 pandemic using network analysis (NA).Methods: Clinicians with depressive symptoms (with a Patients Health Questionnaire (PHQ-9) total score of 5 and above) were included in this study. Anxiety and insomnia symptoms were measured using the Generalized Anxiety Disorder Scale - 7-item (GAD-7) and Insomnia Severity Index (ISI), respectively. Network analysis was conducted to investigate the network structure, central symptoms, bridge symptoms, and network stability of these disturbances. Expected influence (EI) was used to measure the centrality of index.Results: Altogether, 1729 clinicians were included in this study. The mean age was 37.1 [standard deviation (SD)=8.04 years], while the mean PHQ-9 total score was 8.42 (SD=3.33), mean GAD-7 total score was 6.45 (SD=3.13) and mean ISI total score was 8.23 (SD=5.26). Of these clinicians, the prevalence of comorbid anxiety symptoms (GAD-7≥ 5) was 76.8% (95% CI 74.82– 78.80%), while the prevalence of comorbid insomnia symptoms (ISI≥ 8) was 43.8% (95% CI: 41.50– 46.18%). NA revealed that nodes ISI7 (“Interference with daytime functioning”) (EI=1.18), ISI4 (“Sleep dissatisfaction”) (EI=1.08) and ISI5 (“Noticeability of sleep problem by others”) (EI=1.07) were the most central (influential) symptoms in the network model of comorbid anxiety and insomnia symptoms in clinicians. Bridge symptoms included nodes PHQ3 (“Sleep”) (bridge EI=0.55) and PHQ4 (“Fatigue”) (bridge EI=0.49). Gender did not significantly influence the network structure, but “having the experience of caring for COVID-19 patients” significantly influenced the network structure.Conclusion: Central symptoms and key bridge symptoms identified in this NA should be targeted in the treatment and preventive measures for clinicians suffering from comorbid anxiety, insomnia and depressive symptoms during the late stage of the COVID-19 pandemic.Keywords: depression, anxiety, sleep, network analysis, health personnel

Zike Sheng,1,&ast; Junjie Li,2,&ast; Tingting Chen,3 Yan Zhu,4 Xueping Yu,5 Xiuhua He,5 Yijuan Zheng,5 Cuiping Ma,6 Minghui Zheng,5 Peiyun Wang,1 Ziqiang Li,1 Yumin Xu,7 Qing Xie,1 Zhijun Su,5 Sumei Chen5 1Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Pharmacy, The First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, People’s Republic of China; 4Clinical Laboratory, The First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, People’s Republic of China; 5Department of Infectious Diseases, The First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, People’s Republic of China; 6Department of Infection Control, The First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, People’s Republic of China; 7Department of Infection Control, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhijun Su; Sumei Chen, Department of Infectious Diseases, The First Hospital of Quanzhou Affiliated to Fujian Medical University, Licheng District, Quanzhou, People’s Republic of China, Tel +86-595-22277011 ; +86-595-22277173, Fax +86-595-222781, Email su2366@sina.com; chensm561119190@sina.comPurpose: Hypervirulent Klebsiella pneumoniae (hvKP) is emerging globally and can cause various infections. This study aimed to investigate the clinical and microbiological characteristics of bloodstream infection (BSI) caused by hvKP.Patients and Methods: The clinical data of hospitalized patients with K. pneumoniae BSI were retrospectively analyzed. The K. pneumoniae strains were collected and re-identified, and antimicrobial susceptibility testing was performed using the broth microdilution method. Capsular serotypes and virulence genes were detected using polymerase chain reaction, and hvKP was defined as aerobactin positive. Molecular typing was done by multilocus sequence typing. The hvKP and classic K. pneumoniae (cKP) subgroups were compared.Results: Of the 66 nonrepetitive BSI K. pneumoniae strains included, 29 (43.9%) were hvKP. In these BSI hvKP strains, salmochelin and yersiniabactin accounted for 86.2% and 72.4%, respectively. The prevalence of rmpA, iroBCD cluster, ybtS, clbA, and allS was 89.7%, 86.2%, 72.4%, 51.7%, and 41.4%, respectively, which were all significantly different between the hvKP and cKP subgroups. Serotypes K1 and K2 were strongly associated with hypervirulence (P < 0.05). Nineteen sequence types were scattered in the 29 hvKP strains, and the most common was ST23 (24.1%). None of the hvKP strains were carbapenem resistant. Compared with cKP, hvKP was more capable of developing a liver abscess. However, the 30-day mortality rate was lower (13.8% vs 21.6%) in the hvKP subgroup than in the cKP subgroup.Conclusion: This study demonstrated a high proportion of hvKP in BSI K. pneumoniae, most of which were RmpA and siderophore producing, and of multiclonal origin.Keywords: capsular serotypes, hypervirulence, infection, mortality, sequence type

Previous work has identified synaptic eligibility traces in slice preparations. Here the authors provide demonstration of eligibility traces in vivo during reinforcement learning.

Wenqing Gao,1,&ast; Yuanyuan Li,1,&ast; Teng Zhang,1 Jianglong Lu,2 Jiasong Pan,1 Qi Qi,1 Siqi Dong,3 Xiangjun Chen,3,4 Zhipeng Su,2 Jixi Li1,4 1State Key Laboratory of Genetic Engineering, Department of Neurology, Huashan Hospital and Institute of Neurology, School of Life Sciences, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, 200438, People’s Republic of China; 2Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China; 3Department of Neurology, Huashan Hospital and Institute of Neurology, Fudan University, Shanghai, 200040, People’s Republic of China; 4National Center for Neurological Disorders, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhipeng Su; Jixi Li, Email drsuzhipeng@wmu.edu.cn; lijixi@fudan.edu.cnBackground: Glioblastoma (GBM) is the most common and aggressive brain tumor in adults, in which chemokines are often upregulated and may play pivotal roles in their development and progression. Chemokines are a large subfamily of cytokines with leukocyte chemotactic activities involved in various tumor progression. However, gene expression patterns of the chemokines on a global scale were not known in GBM.Methods: Differentially expressed chemokine genes in glioma and normal samples were screened by using The Cancer Genome Atlas (TCGA) database. Cox regression identified the prognosis-related genes in each glioma subtype. The protein expression levels of chemokines in 72 glioma tissues were detected by ELISA.Results: We found that the transcripts of seven chemokines, including CCL2, CCL8, CCL18, CCL28, CXCL1, CXCL5, and CXCL13, were highly expressed in GBM that evidenced by involving immune cell infiltration regulation and accompanied with worse outcomes of GBM patients. The prognostic nomogram construction demonstrated that CCL18 held the highest risk score in patients with GBM. Furthermore, experiments on 72 glioma tissue samples confirmed that CCL18 protein expression was positively associated with tumor grade and IDH1 status but inversely with glioma patients’ overall survival (OS).Conclusion: Our study reveals comprehensive and comparable roles of chemokine members in glioblastoma, and identified CCL18 as a critical driver of GBM malignant behaviors, therefore providing a potential target for developing prognosis and therapy in human glioblastoma.Keywords: chemokines, GBM, biomarker, overall survival, prognosis

Youxin Wang,1,&ast; Qiuyue Huang,1,&ast; Xinglei Huang,1 Huiliu Zhao,2 Bin Guan,1 Kechen Ban,3 Xuefeng Zhu,1 Zhixing Ma,1 Yanmei Tang,1 Zhaohui Su,1 Qingqing Nong1 1Department of Environmental Health, School of Public Health, Guangxi Medical University, Nanning, 530021, People’s Republic of China; 2Department of Clinical Laboratory, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, People’s Republic of China; 3Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA&ast;These authors contributed equally to this workCorrespondence: Qingqing NongDepartment of Environmental Health, School of Public Health, Guangxi Medical University, Nanning, 530021, People’s Republic of ChinaTel +86-771-5358146Fax +86-771-5350823Email nnqq@gxmu.edu.cnBackground: Protein phosphatase 2A (PP2A, a serine/threonine phosphatase) is frequently inactivated in many types of cancer, including primary liver cancer (PLC). Genetic variations in PP2A subunits have been reported to be associated with the risk of many types of cancer but rarely in PLC. This study aims to assess the association between functional polymorphisms of PP2A subunit genes and the risk of PLC in Chinese.Methods: In a case-control study with a total of 541 PLC patients and 547 controls in Guangxi province of Southern China, we genotyped six putatively functional polymorphisms (rs10421191G>A, rs11453459del>insG, rs1560092T>G, rs7840855C>T, rs1255722G>A and rs10151527A>C) of three PP2A subunit genes (PPP2R1A, PPP2R2A and PPP2R5E) using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry platform.Results: The rs11453459insG variant genotypes (ins/ins+del/ins) of PPP2R1A were found to be significantly associated with an increased risk of PLC compared with the del/del genotype (adjusted OR = 1.290, 95% CI = 1.009– 1.650), and the number of insert G allele worked in a dose-dependent manner (Ptrend= 0.007). The stratified analysis showed that the effects of rs11453459insG variant genotypes were more evident in the subgroup who drink pond-ditch water (adjusted OR = 3.051, 95% CI = 1.264– 7.364) than those never drink (P = 0.041). The carriers of rs11453459 del/ins genotype had a significantly lower level of PPP2R1A mRNA expression in liver cancer tissues than those of the del/del genotype (P = 0.021). Furthermore, we used microcystin-LR, a carcinogen presents in the pond-ditch water, to treat human peripheral blood mononuclear cells and found that the cells from carriers of rs11453459insG variant genotypes induced more DNA oxidative damages than those from the del/del genotype carriers (P < 0.001).Conclusion: These findings suggest that the PPP2R1A rs11453459del>insG polymorphism is associated with an increased risk of PLC, especially for persons with a history of drinking pond-ditch water. This insertion/deletion polymorphism may be a susceptible biomarker for PLC in Chinese.Keywords: PP2A, primary liver cancer, insertion/deletion polymorphism, pond-ditch water

Yaoji Yuan,1,2,&ast; Zhengming Su,1,2,&ast; Rui Zhu,1,2 Xiezhao Li,1,2 Guibin Xu1,2 1Department of Urology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 2Key Laboratory of Enhanced Recovery After Abdominal Surgery, Guangzhou, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guibin XuDepartment of Urology, The Fifth Affiliated Hospital of Guangzhou Medical University, 621 Gangwan Road, Guangzhou, Guangdong, People’s Republic of ChinaEmail gyxgb@163.comBackground: Bladder paraganglioma (BPG) is one of the rare neuroendocrine neoplasms that develops from neural crest cells. It categorizes into functional and non-functional types based on the catecholamines secretion. Currently, functional BPG is predicted in advance based on signs and symptoms of catecholamine excess, such as hypertension and “micturition attacks”. However, it is often overlooked because of its rareness. Misdiagnosis of a functional tumor may increase the risk of surgical intervention.Case Presentation: We reported 3 cases of BPG that they were admitted to the hospital due to abdominal pain or gross hematuria. Computed tomography (CT) scans showed space-occupying lesions in the bladders with diameters less than 3cm. There were no typical catecholamine excess symptoms before surgical intervention. Postoperative pathology confirmed BPG after removal of the tumor. We also analyze 69 cases of BPG that has been reported and found that 78.0% cases were functional among the tumors larger than 3cm.Conclusion: Bladder tumors larger than 3cm in diameter can serve as an additional predictor of functional BPG. Patients who are suspected should undergo magnetic resonance imaging (MRI) scans, 123/131 metaiodobenzylguanidine (MIBG) scan, and have their catecholamine levels tested. Once the diagnosis is confirmed, patients should be started on fluid replacement therapy and adrenergic blockade to abate the disorders associated with catecholamine excess.Keywords: bladder paraganglioma, cases report

Zhimin Su,1,2 Linbin Lu,1 Fuyu Chen,3 Jianhui Chen,4 Xiong Chen1 1Department of Oncology, 900th Hospital of PLA, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, 350024, People’s Republic of China; 2Department of Medical Oncology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, 361015, People’s Republic of China; 3Department of Substation Maintenance Center, State Grid Quanzhou Electric Power Supply Company, Quanzhou, 362000, People’s Republic of China; 4Department of Urology, Fujian Medical University Union Hospital, Fuzhou, 350024, People’s Republic of ChinaCorrespondence: Xiong ChenDepartment of Oncology, 900th Hospital of PLA, Fuzong Clinical Medical College of Fujian Medical University, 156 North Xierhuan Road, Fuzhou, 350024, People’s Republic of ChinaEmail cxiongzpc@fjmu.edu.cnIntroduction: Sunitinib-induced diarrhea seriously affects the prognosis of patients with metastatic renal cell carcinoma (mRCC) and reduces their quality of life. We aim to explore and find the relationship between sunitinib-induced diarrhea and gut microbiota.Methods: Feces were collected from 31 mRCC patients receiving sunitinib treatment. To characterize the feces gut microbiome profiles of patients, the V3-V4 region of 16S rRNA sequencing was carried out in this study.Results: Gut microbial diversity was decreased both in the severe diarrhea group and in the sunitinib-post group. The microbial composition with higher abundance of Bacteroides (mucus degrading bacteria) and lower abundance of Faecalibacterium, Oscillospira, Ruminococcaceae, Eubacterium and Coriobacteriaceae (butyrate-producing bacteria) were found in patients with diarrhea. Interestingly, the abundance of Actinobacteria was decreased in patients receiving sunitinib with severe diarrhea.Conclusion: This study reported an association between gut microbiota and sunitinib-induced diarrhea. Defects of the butyrate-producing bacteria and the increase in Bacteroides may be the physiological basis of sunitinib-induced diarrhea.Keywords: sunitinib-induced diarrhea, 16S rRNA sequencing, gut microbial diversity, butyrate-producing bacteria

Yiran Yan,1,&ast; Yan Chen,2,&ast; Zhongxun Liu,1 Feiyan Cai,3 Wanting Niu,4,5 Liming Song,1 Haifeng Liang,1 Zhiwen Su,1 Bo Yu,1 Fei Yan6 1Department of Orthopedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, People’s Republic of China; 2Department of Ultrasonic Diagnosis, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, People’s Republic of China; 3Paul C. Lauterbur Research Center for Biomedical Imaging, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, People’s Republic of China; 4VA Boston Healthcare System, Boston, MA, 02130, USA; 5Department of Orthopedics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA; 6CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fei YanShenzhen Institutes of Advance Technology, Chinese Academy of Science, 1068 Xueyuan Avenue, Shenzhen University Town, Shenzhen, Guangdong, 518055, People’s Republic of ChinaTel +86 755 86392284Fax +86 755 96382299Email fei.yan@siat.ac.cnBo YuDepartment of Orthopedics, Zhujiang Hospital, Southern Medical University, 253 Gongye Avenue, Haizhu District, Guangzhou, Guangdong, 510280, People’s Republic of ChinaTel +86 20 67282573Fax +86 20 61643010Email gzyubo@163.comBackground: Parkinson’s disease (PD) is a progressive neurodegenerative disorder. Owing to the presence of blood–brain barrier (BBB), conventional pharmaceutical agents are difficult to the diseased nuclei and exert their action to inhibit or delay the progress of PD. Recent literatures have demonstrated that curcumin shows the great potential to treat PD. However, its applications are still difficult in vivo due to its poor druggability and low bioavailability through the BBB.Methods: Melt-crystallization methods were used to improve the solubility of curcumin, and curcumin-loaded lipid-PLGA nanobubbles (Cur-NBs) were fabricated through encapsulating the curcumin into the cavity of lipid-PLGA nanobubbles. The bubble size, zeta potentials, ultrasound imaging capability and drug encapsulation efficiency of the Cur-NBs were characterized by a series of analytical methods. Low-intensity focused ultrasound (LIFU) combined with Cur-NB was used to open the BBB to facilitate curcumin delivery into the deep brain of PD mice, followed by behavioral evaluation for the treatment efficacy.Results: The solubility of curcumin was improved by melt-crystallization methods, with 2627-fold higher than pure curcumin. The resulting Cur-NBs have a nanoscale size about 400 nm and show excellent contrast imaging performance. Curcumin drugs encapsulated into Cur-NBs could be effectively released when Cur-NBs were irradiated by LIFU at the optimized acoustic pressure, achieving 30% cumulative release rate within 6 h. Importantly, Cur-NBs combined with LIFU can open the BBB and locally deliver the curcumin into the deep-seated brain nuclei, significantly enhancing efficacy of curcumin in the Parkinson C57BL/6J mice model in comparison with only Cur-NBs and LIFU groups.Conclusion: In this work, we greatly improved the solubility of curcumin and developed Cur-NBs for brain delivery of curcumin against PD through combining with LIFU-mediating BBB. Cur-NBs provide a platform for these potential drugs which are difficult to cross the BBB to treat PD disease or other central nervous system (CNS) diseases.Keywords: nanobubbles, blood–brain barrier, low-intensity focus ultrasound, curcumin, Parkinson’s disease

Yu Wu,1,2,&ast; Yuxiu Liu,3,&ast; Zhe Su,2 Songwei Sun,1 Cuiping Liu,1 Wei Ding,2 Yufang Gao2 1School of Nursing, Qingdao University, Qingdao, People’s Republic of China; 2The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 3School of Nursing, Weifang Medical University, Weifang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yufang GaoThe Affiliated Hospital of Qingdao University, Qingdao, 266000, People’s Republic of ChinaTel +86-19863737553Email gaoyufang0612@163.comPurpose: The purpose of the present study was to investigate the current status of and factors influencing the demands for telenursing-based long-term care in disabled older adults.Methods: In this cross-sectional study, data from 213 participants from five districts of Qingdao, China, were investigated using multistage stratified sampling. The assessment scale of the long-term care demands level and the questionnaire of the demands of telenursing-based long-term care for disabled older adults were used to estimate the demands for telenursing-based long-term care for older adults with disabilities in Qingdao.Results: Of the participants, 60.51% were willing to receive telenursing-based long-term care. The item with the highest score was “Internet +” information management and first aid (3.77 ± 0.71); the item with the lowest score was “Internet +” daily care (2.97 ± 0.72). Average family income (P < 0.001), age (P = 0.004) and educational level (P = 0.003) were significant factors influencing the demands for telenursing-based long-term care.Conclusion: Disabled older adults had a high demand for telenursing-based long-term care. Urgent actions are needed to integrate telenursing with long-term care as soon as possible. In the development of telenursing-based long-term care, it is necessary to fully consider the average family income, age and educational level of disabled older adults.Keywords: telenursing, long-term care, disabled older adults, demands

Qiaoping Li,1,&ast; Ziwei Huang,2,&ast; Defu Liu,3 Jingna Zheng,1 Jianhui Xie,4– 6 Jiannan Chen,1 Huifang Zeng,2 Ziren Su,1 Yucui Li1 1School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of China; 2The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, People’s Republic of China; 3School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of China; 4The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, People’s Republic of China; 5State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, People’s Republic of China; 6Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, 510120, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yucui Li; Ziren SuGuangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of ChinaTel +86 20 39358517Fax +86 20 39358390Email liyucui@gzucm.edu.cn; suziren@gzucm.edu.cnPurpose: Berberine (BBR) is an active component of Phellodendri Cortex (PC), which is a traditional Chinese medicine that has been prescribed clinically for hyperuricemia (HUA) for hundreds of years. Many studies reported the anti-inflammatory and nephroprotective properties of BBR and PC; however, the therapeutic effects of BBR on HUA have not been explored. This study aims to investigate the efficacy and mechanism of BBR for treating HUA.Methods: The mechanism of BBR in the treatment of HUA were predicted by network pharmacology. A mouse model of HUA established by potassium oxonate and hypoxanthine was used to verify the prediction. The levels of serum uric acid (UA), urea nitrogen (BUN) and creatinine (CRE) were determined by biochemical test kits. Hematoxylin and eosin staining of kidney tissues was used to observe the kidney damage. ELISA kits were applied to detect the levels of interleukin (IL)-1β and IL-18 in serum and kidney tissues. Quantitative real-time PCR and Western blotting were adopted to analyze the expression of NLRP3, ASC, Caspase1, IL-1β and URAT1. The expressions of URAT1 in the kidney tubules were visualized by immunohistochemical staining. Molecular docking was used to assess the interaction between URAT1 and BBR.Results: The network pharmacology screened out 82 genes and several inflammation-related signaling pathways related to the anti-hyperuricemia effect of BBR. In the in vivo experiment, BBR substantially decreased the level of UA, BUN and CRE, and alleviated the kidney damage in mice with HUA. BBR reduced IL-1β and IL-18, and downregulated expressions of NLRP3, ASC, Caspase1 and IL-1β. BBR also inhibited expression of URAT1 and exhibited strong affinity with this target in silico docking.Conclusion: BBR exerts anti-HUA and nephroprotective effects via inhibiting activation of NLRP3 inflammasome and correcting the aberrant expression of URAT1 in kidney. BBR might be a novel therapeutic agent for treating HUA.Keywords: berberine, hyperuricemia, URAT1, NLRP3 signaling pathway

Yuexian Li, Zhou Su, Biwei Wei, Zhihai Liang Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of ChinaCorrespondence: Zhihai LiangDepartment of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi, 530021, People’s Republic of ChinaTel +86-771-5356501Fax +86-771-5350031Email ahhai@163.comBackground: Pancreatic adenocarcinoma (PAAD) is a deadly tumor with a high recurrence rate and poor prognosis. Keratin 7 (KRT7) is a member of the keratin gene family that is involved in the regulation of cell growth, migration and apoptosis in many cancers. However, the role of KRT7 and its biological functions in PAAD remain unclear. We systemically analyzed the expression and clinical values of KRT7 in PAAD.Methods: The Gene Expression Profiling Interactive Analysis (GEPIA), Oncomine and Human Protein Atlas (HPA) databases were used to analyze the mRNA and protein expression of KRT7 in PAAD. The prognosis and subgroup analysis of KRT7 in PAAD patients was performed using the GEPIA, PROGgeneV2 and UALCAN databases. Later, the correlation between KRT7 expression and tumor immune molecules in PAAD was evaluated using the Immune Cell Abundance Identifier (ImmuCellAI) and TISIDB databases. Finally, the functional enrichment pathway of KRT7 and its coexpressed genes were analyzed by the Database for Annotation, Visualization, and Integrated Discovery (DAVID) and Metascape databases and Gene Set Enrichment Analysis (GSEA).Results: The mRNA and protein expression of KRT7 was increased in PAAD tissues compared with normal tissues. High KRT7 expression was closely associated with tumor grade, TP53 mutations and poor prognosis in PAAD patients. Cox regression analysis proved that overexpressed KRT7 was an important and independent risk factor for poor overall survival (P = 0.006, HR =1.87) and disease-free survival (P = 0.019, HR =1.793) in PAAD. Additionally, KRT7 expression was significantly associated with immune infiltration of tumor immune cells and immunomodulators. Functional enrichment analyses and GSEA indicated that KRT7 might be involved in the regulation of the p53 pathway in PAAD.Conclusion: Overexpressed KRT7 could be a promising prognostic and therapeutic target biomarker for PAAD by bioinformatics analysis.Keywords: pancreatic adenocarcinoma, KRT7, prognosis, biomarker, bioinformatics analysis

Jaffar Abbas,1,2 Dake Wang,2 Zhaohui Su,3 Arash Ziapour4 1Antai College of Economics and Management (ACEM), Shanghai Jiao Tong University (SJTU), Shanghai, 200240, People’s Republic of China; 2School of Media and Communication (SMC), Shanghai, Shanghai Jiao Tong University (SJTU), 200240, People’s Republic of China; 3School of Nursing, University of Texas, Center on Smart and Connected Health Technologies, Mays Cancer Center, UT Health San Antonio, San Antonio, TX, 78229, USA; 4Research Center for Environmental Determinants of Health (RCEDH), Health Institute, Kermanshah University of Medical Sciences, Kermanshah, 6715847141, IranCorrespondence: Dake Wang;Jaffar AbbasSchool of Media and Communication (SMC), Shanghai, Shanghai Jiao Tong University (SJTU), 200240, People’s Republic of ChinaEmail dakewang@sjtu.edu.cn; Abbas512@sjtu.edu.cnBackground: This study focuses on how educating people through social media platforms can help reduce the mental health consequences of the COVID-19 to manage the global health crisis. The pandemic has posed a global mental health crisis, and correct information is indispensable to dispel uncertainty, fear, and mental stress to unify global communities in collective combat against COVID-19 disease worldwide. Mounting studies specified that manifestly endless coronavirus-related newsfeeds and death numbers considerably increased the risk of global mental health issues. Social media provided positive and negative data, and the COVID-19 has resulted in a worldwide infodemic. It has eroded public trust and impeded virus restraint, which outlived the coronavirus pandemic itself.Methods: The study incorporated the narrative review analysis based on the existing literature related to mental health problems using the non-pharmaceutical interventions (NPIs) approach to minimize the COVID-19 adverse consequences on global mental health. The study performed a search of the electronic databases available at PsycINFO, PubMed, and LISTA. This research incorporates the statistical data related to the COVID-19 provided by the WHO, John Hopkins University, and Pakistani Ministry of Health.Results: Pakistan reported the second-highest COVID-19 cases within South Asia, the fifth-highest number of cases in Asia after Iran, India, Russia, Saudi Arabia, and the 14th highest recorded cases, as of October 14, 2020. Pakistan effectively managed the COVID-19 pandemic in the second wave. It stands at the eighth-highest number of confirmed cases in Asia, the 3rd-highest in South Asia, and the 28th-highest number of established patients globally, as of February20, 2021.Conclusion: The COVID-19 has resulted in over 108.16 million confirmed cases, deaths over 2.374 million, and a recovery of 80.16 million people worldwide, as of February 12, 2021. This study focused on exploring the COVID-19 pandemic’s adverse effects on global public health and the indispensable role of social media to provide the correct information in the COVID-19 health crisis. The findings’ generalizability offers helpful insight for crisis management and contributes to the scientific literature. The results might provide a stepping-stone for conduct future empirical studies by including other factors to conclude exciting developments.Keywords: mental health, COVID-19, health crisis, social media, social support, tele-education

Li T, Wan Y, Su Z, Li J, Han M, Zhou C. Cancer Manag Res. 2020;12:6477–6491. The Editor and Publisher of Cancer Management and Research wish to retract the published article. Concerns were raised regarding the alleged similarity in features of the western blots from Figure 8A and B with those from unrelated papers. The authors responded to our queries but were unable to provide a satisfactory explanation for the alleged similarities, nor were they able to provide original data that could adequately verify the findings. The Editor requested to retract the article and the authors do not agree with this decision. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Hongna Dong,1,* Yuqiu Hao,1,* Dapeng Li,2 Zhenzhong Su,1 Wei Li,1 Bingqing Shi,1 Peng Gao1 1Department of Respiratory Medicine, Second Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China; 2Department of Respiratory Medicine, Affiliated Hospital of Jilin Medical College, Jilin, Jilin Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Peng GaoDepartment of Respiratory, Second Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of ChinaTel/Fax +86-43181136866Email gaopeng1234@sina.comBackground: The exacerbation of chronic obstructive pulmonary disease (COPD) seriously affects the patient’s quality of life and prognosis. This multicenter cross-sectional study investigated the characteristics of stable COPD and risk factors for acute exacerbation of COPD (AECOPD) in patients in Changchun, Jilin Province, China.Methods: The study included 400 outpatients admitted to four secondary hospitals and four tertiary hospitals in Jilin Province from March 2018 to March 2019. Data on the general condition of stable COPD patients, patient self-management, COPD Assessment Test (CAT) scores, number of acute exacerbations in the past 12 months, and medications received during the study period were collected using a questionnaire.Results: Sociodemographic characteristics and clinical data were obtained from 306 patients, and drug prescription data were obtained from 329 patients. Pearson correlation analysis revealed that CAT scores were positively correlated with the number of acute exacerbations. Age, education level, smoking history, disease duration, number of comorbidities, and the presence of ischemic heart disease (IHD) were associated with AECOPD. Moreover, the level of education, disease duration, and the presence of IHD were independent risk factors for AECOPD. Poor compliance due to the lack of understanding of the disease and the high cost of treatment is a risk factor for AECOPD. In addition, increased air pollution in industrial cities and vitamin D deficiency are closely related to AECOPD.Conclusion: Low education level, long disease duration, and the presence of IHD may promote the exacerbation and poor control of COPD in patients in Jilin Province.Keywords: COPD, exacerbation, risk factors, Jilin Province

Tao Li,1,* Yingchun Wan,2,* Ziyuan Su,3 Jiayu Li,4 Minna Han,5 Changyu Zhou6 1Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin, People’s Republic of China; 2Department of Endocrinology, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin, People’s Republic of China; 3Department of Pharmacy, Changchun Second Hospital, Changchun 130062, Jilin, People’s Republic of China; 4Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin, People’s Republic of China; 5Department of Medicine, Medical School of Chinese People & Apos’s Liberation Army, Chinese People & Apos’s Liberation Army General Hospital, Beijing 100853, People’s Republic of China; 6Department of Digestion, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Changyu ZhouDepartment of Digestion, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin, People’s Republic of ChinaTel/ Fax +86-431-84995850Email drZhouCY1224@163.comObjective: Serum response factor (SRF), a sequence-specific transcription factor, is closely related to metastasis of gastric cancer, a digestive tract cancer. Herein, we probed the effect of SRF on metastasis and progression of colon cancer (CC), another digestive tract disorder, and the detailed mechanism.Methods: Microarray analysis was conducted on tumor and adjacent tissues to filter differentially expressed miRNA, followed by RT-qPCR validation in CC cell lines. The transcription factor and the target gene of microRNA-214 (miR-214) were predicted, and their binding relationships were tested by luciferase reporter assays and ChIP assays. Subsequently, SRF and protein tyrosine kinase 6 (PTK6) expression in CC patients and cells was evaluated by RT-qPCR, while JAK2 and STAT3 expression in cells by Western blot analysis. To further explore functions of miR-214, PTK6 and SRF on CC, CC cells were delivered with si-PTK6, miR-214 mimic and/or SRF overexpression.Results: miR-214 expressed poorly in CC tissues and cell lines, which related to advanced TNM staging and survival. miR-214 mimic inhibited proliferation, migration, invasion, xenograft tumor growth and metastasis of CC cells. SRF, overexpressed in CC samples and cells, suppressed the transcription of miR-214. Meanwhile, SRF upregulation counteracted the inhibitory role of miR-214 mimic in CC cell growth. miR-214 negatively regulated PTK6 expression to impair the JAK2/STAT3 pathway activation, thereby halting CC cell proliferation, migration, invasion, xenograft tumor growth and metastasis.Conclusion: Altogether, miR-214 may perform as a tumor suppressor in CC, and the SRF/miR-214/PTK6/JAK2/STAT3 axis could be applied as a biomarker and potential therapeutic target.Keywords: SRF, microRNA-214, PTK6, Colon cancer, The JAK2/STAT3 pathway

Jianping Deng,1,2 Zicong Wu,1,2 Zhenling Zhao,2,3 Chaoxi Wu,2,3 Min Yuan,1 Zhengquan Su,1 Yifei Wang,2,3 Zhiping Wang1,2 1Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Department of Pharmaceutics, Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510000, People’s Republic of China; 2Guangzhou (Jinan) Biomedical Research and Development Center, Guangzhou 510000, People’s Republic of China; 3College of Life Science and Technology, Jinan University, Guangzhou 510000, People’s Republic of ChinaCorrespondence: Yifei Wang; Zhiping Wang Email twang-yf@163.com; wzping-jshb@gdpu.edu.cnPurpose: Berberine (BBR), a major ingredient extracted from Coptis chinensis, is a natural drug with limited oral bioavailability. We developed nanostructured lipid carriers (NLCs) as a delivery system for enhanced anti-inflammatory activity of BBR against ulcerative colitis (UC).Methods: BBR-loaded nanostructured lipid carriers (BBR-NLCs) prepared via high-pressure homogenization were evaluated for particle size, zeta potential, drug entrapment efficiency, drug loading, drug release, toxicity, and cellular uptake. The anti-UC activities of free and encapsulated BBR were evaluated in a DSS-induced acute model of UC in mice.Results: Spherical BBR-NLCs were prepared with a particle size of 63.96±  0.31 nm, a zeta potential of +3.16 ±  0.05 mV, an entrapment efficiency of 101.97± 6.34%, and a drug loading of 6.00± 0.09%. BBR-NLCs showed excellent biocompatibility in vivo. Cellular uptake experiments showed that BBR-NLCs improved uptake of BBR by RAW 264.7 cells and Caco-2 cells. Oral administration of BBR-NLCs significantly alleviated colitis symptoms (DAI, colon length, spleen swelling, MPO activity) through inhibition of NF-κB nuclear translocation, decreased expression of pro-inflammatory cytokines (IL-1β, IL-6, MMP-9, CX3CR1, COX-2, TERT), and increased expression of the tight junction protein ZO-1.Conclusion: BBR-loaded NLCs improved colitis symptoms, which suggested that this may be a novel formulation for treatment of UC.Keywords: berberine, nanostructured lipid carriers, anti-inflammatory, ulcerative colitis

Zhen Su,1,* Guo-rong Zou,1,* Jie Tang,1 Xiu Yue Li,1 Fang-Yun Xie2 1Panyu Central Hospital, Cancer Institute of Panyu, Guangzhou, People’s Republic of China; 2Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fang-Yun XieDepartment of Radiation Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People’s Republic of ChinaTel +86 20 87343484Email xiefy0758@sina.comBackground: The aim of this study was to evaluate the efficacy of induction chemotherapy (IC) in nasopharyngeal carcinoma (NPC) patients with moderate-risk treated with intensity-modulated radiotherapy (IMRT).Methods: We retrospectively assessed 506 patients with T1-2N1M0 or T3-4N0-1M0 NPC (according to the 2010 UICC/AJCC staging system) who received concurrent chemoradiotherapy (CCRT) with or without IC at a single center in China between 2005 and 2010. Survival outcomes were compared between the IC + CCRT and CCRT groups using the Kaplan–Meier method, Log-rank test and a Cox regression model.Results: Among the 506 patients, CCRT alone resulted in equivalent overall survival (86.8% vs 88.5%, p=0.661), progression-free survival (79.6% vs 79.6%, p=0.756), locoregional relapse-free survival (90.2% vs 87.0%, p=0.364) and distant metastasis-free survival (88.0% vs 89.8%, p= 0.407) to IC plus CCRT. In multivariate analysis, IC did not lower the risk of death (HR 0.76, 95% CI 0.46– 1.25, p= 0.278), progression (HR 0.78, 95% CI 0.51– 1.19, p= 0.244), locoregional relapse (HR 1.06, 95% CI 0.81– 1.42, p= 0.651) or distant metastasis (HR 0.66, 95% CI 0.38– 1.15, p= 0.140) in the entire cohort; similar results were obtained in stratified analysis based on N category (N0 vs N1) and EBV DNA (< vs ≥ 4000 copies/mL).Conclusion: Addition of IC to CCRT does not improve survival outcomes in moderate-risk NPC; the use of IC should be carefully considered in these patients, though additional prospective trials are warranted to confirm the conclusions of this study.Keywords: nasopharyngeal carcinoma, induction chemotherapy, prognosis, survival

Yunfei Wang, 1, 2,* Zhengrong Li, 2,* Boxue Liu, 1, 2 Rumeng Wu, 1, 2 Haifeng Gong, 2 Zhanhai Su, 2 Shoude Zhang 1, 2 1State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining, Qinghai 810016, People’s Republic of China; 2Medical College of Qinghai University, Xining, Qinghai 810016, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shoude ZhangState Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, 251# Ningda Road, Xining, Qinghai 810016, People’s Republic of ChinaTel +86-971-5366433Fax +86-971-5201533Email shoude.zhang@qhu.edu.cnPurpose: Isoborneol has been used in the treatment of cardiovascular disease for several years in China. However, the mechanism is still unclear. The aim of this study was to identify the novel mechanism of isoborneol for its application in atherosclerotic disease.Materials and Methods: The whole-genome gene expression profiles of MCF-7 cells treated with/or without isoborneol were detected by mRNA microarray analysis. The degree of similarity between the gene expression profiles was compared with the Connectivity Map (CMAP) database. An MTT assay was used to assess the toxicity of isoborneol on RAW 264.7 cells. Oil red O staining and a Dil-ox-LDL uptake assay in RAW 264.7 cells were also used to detect the accumulation of lipids in the macrophages and the uptake of oxidized low-density lipoprotein (ox-LDL).Results: Isoborneol was proved to have mRNA expression profiles similar to that of ikarugamycin which can inhibit the uptake of ox-LDL. This process has proved to be an important cause of foam cell formation and early atherosclerotic lesions. It is speculated, therefore, that isoborneol may show similar activity to that shown by ikarugamycin. Subsequently, it was shown that RAW 264.7 cells reduced the absorption of ox-LDL and the accumulation of intracellular lipids after treatment with different concentrations of isoborneol.Conclusion: The results indicate that isoborneol inhibits macrophage consumption of ox-LDL, thereby preventing the accumulation of lipids in the macrophages. These results provide evidence for the application of isoborneol in atherosclerotic disease.Keywords: isoborneol, ikarugamycin, connectivity map, ox-LDL, atherosclerosis, macrophage

Zhan Su,1,2 Duanqin Liu,1,2 Liying Chen,2 Jun Zhang,1,2 Lu Ru,2 Zhiyu Chen,2 Zhennan Gao,1,2,* Xuxia Wang1,2,* 1Shandong Provincial Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, Shandong 250012, People’s Republic of China; 2Department of Oral and Maxillofacial Surgery, School of Stomatology, Shandong University, Jinan, Shandong 250012, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhennan Gao;Xuxia WangDepartment of Oral and Maxillofacial Surgery, School of Stomatology, Shandong University, 44-1 West Wenhua Road, Jinan, Shandong 250012, People’s Republic of ChinaTel +86 531 15169070891; +86 531 13906410670Email zngao@sdu.edu.cn; wxx@sdu.edu.cnBackground: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignant tumor in the world. Studies in recent years have demonstrated that cancer stem cells (CSCs) are present in many tumor tissues, including HNSCC, and CSCs are the root cause of tumor recurrence and metastasis. Thus, taking new treatment measures to target the killing of CSCs that are resistant to chemotherapy and radiotherapy is key to the success of cancer treatment.Methods: We explored a method for preparing anti-CD44 antibody-modified superparamagnetic iron oxide nanoparticles (SPIONPs). Biocompatibility was evaluated by a CCK-8 assay. The CSCs were obtained by a 3D cell culture technique from Cal-27 (human oral squamous cell carcinoma) cells, and then the CSCs were identified by quantitative real-time polymerase chain reaction (qRT-PCR). The targeting efficiency of the CD44-SPIONPs to CSCs was confirmed by Prussian blue staining and visualized by laser scanning confocal microscopy (LSCM). Flow cytometry was used to detect the apoptosis of CSCs after alternating magnetic field (AMF) treatment. The efficacy of tumor growth inhibition by CD44-SPIONP-mediated magnetic hyperthermia therapy was evaluated with tumor xenografts in nude mice.Results: The CD44-SPIONPs exhibited no negative effect on CSCs, indicating good biocompatibility. After SPIONPs were cocultured with stem cells, the majority of CD44-SPIONPs labeled with FITC penetrated the cell membrane into the cytoplasm. After AMF treatment, CD44-SPIONPs induced CSCs to undergo programmed death. The inhibitory ratio of the treated group was 33.43%, and necrotic areas in the tumor tissue were mainly distributed around the magnetic fluid.Conclusion: These results demonstrate that it is possible to kill CSCs using targeted magnetic nanoparticles and an AMF and that magnetic fluid hyperthermia significantly inhibited the growth of grafted Cal-27 tumors in mice.Keywords: magnetic nanoparticles, cancer stem cells, alternating magnetic field, tumor targeting

Lin He,1,* Qian Wu,1,* Jing Xiong,2 Zhumin Su,3 Biyuan Zhang,4 Yuhua Song11Breast Center B Ward, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, People’s Republic of China; 2Department of Geriatrics, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, People’s Republic of China; 3Department of Neurology, The People’s Hospital of China Medical University, Shenyang, Liaoning Province, People’s Republic of China; 4Department of Radiotherapy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, People’s Republic of ChinaCorrespondence: Yuhua SongBreast Center B ward, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Laoshan District, Qingdao, Shandong Province, People’s Republic of ChinaTel +86 1 369 869 1275Email qdsongyh@126.com*These authors contributed equally to this workPurpose: To assess the overall survival (OS) of early human epidermal growth factor receptor 2 (HER2)-enriched breast cancer patients after receiving neoadjuvant trastuzumab (NAT) compared to adjuvant trastuzumab (AT) treatment and the difference in local-regional relapse (LRR) rate with this tumor and treatment between women after mastectomy and women after breast-conserving therapy (BCT).Methods: Articles were retrieved from PubMed, Embase, Web of Science, and Cochrane Library. A pooled odds ratio (OR) with a 95% confidential interval (CI) was calculated. The StataSE version 12.0 software was employed for meta-analysis.Results: Twelve available clinical studies containing 2366 subjects were included. The OS of NAT compared with that of AT was not significantly different (pooled OR=1.04; 95% CI, 0.47–2.33). There was a significantly lower LRR rate for patients with mastectomy compared to those with BCT (pooled OR=0.58; 95% CI, 0.38–0.89); however, subgroup analysis revealed that the significant advantage of LRR for mastectomy compared to BCT was only represented in women without trastuzumab treatment (pooled OR=0.52; 95% CI, 0.31–0.88) compared to those who received trastuzumab treatment (pooled OR=0.71; 95% CI, 0.34–1.49).Conclusion: Early stage HER2-overexpression breast cancer patients benefit with an equivalent OS from NAT treatment compared to AT. Patients who underwent mastectomy and BCT experienced a similar LRR rate if they received anti-HER2 targeted therapy of trastuzumab, but the LRR rate was discernibly reduced in patients who received mastectomy compared to BCT if they did not also receive trastuzumab treatment.Keywords: human epidermal growth factor receptor 2, trastuzumab, mastectomy, breast conserving therapy, breast cancer

Kunyan He,1 Haitao Ran,2,3 Zhongzhen Su,1 Zhigang Wang,2,3 Maoping Li,4 Lan Hao3 1Ultrasound Department, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, People’s Republic of China; 2Ultrasound Department, The second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, People’s Republic of China; 3The Institute of Ultrasound Imaging, Chongqing Medical University, Chongqing 400010, People’s Republic of China; 4Ultrasound Department, The First Affiliated Hospital, Chongqing Medical University, Chongqing 400010, People’s Republic of China Purpose: The objective of this study was to develop a multifunctional contrast agent for bioimaging and synergistic high-intensity focused ultrasound (HIFU) therapy to achieve theranostic.Materials and methods: A novel type of perfluorohexane-encapsulated fullerene (PFH-C60) nanosphere was successfully developed via a vacuum ultrasonic emulsification and centrifugation method and subsequently used in ultrasound/computed tomography (CT) dual-modality and HIFU ablation of dissected bovine livers. In addition, transmission electron microscopic examination was employed to detect structural changes in the target tissue for HIFU ablation.Results: The use of composite nanospheres effectively enhanced ultrasound and CT imaging. Moreover, the HIFU ablation of dissected bovine livers was also significantly enhanced.Conclusion: Composite nanospheres demonstrate potential theranostic application as a multifunctional contrast agent for dual-modality biological imaging and highly efficient synergistic imaging-guided HIFU ablation. Keywords: microbubble, noninvasive therapy, double modal imaging, sonodynamic effects, synergistic ablation efficiency

Neuromodulatory systems are essential for remodeling glutamatergic connectivity during experience-dependent cortical plasticity. This permissive/enabling function of neuromodulators has been associated with their capacity to facilitate the induction of Hebbian forms of long-term potentiation (LTP) and depression (LTD) by affecting cellular and network excitability. In vitro studies indicate that neuromodulators also affect the expression of Hebbian plasticity in a pull-push manner: receptors coupled to the G-protein Gs promote the expression of LTP at the expense of LTD, and Gq-coupled receptors promote LTD at the expense of LTP. Here we show that pull-push mechanisms can be recruited in vivo by pairing brief monocular stimulation with pharmacological or chemogenetical activation of Gs- or Gq-coupled receptors to respectively enhance or reduce neuronal responses in primary visual cortex. These changes were stable, inducible in adults after the termination of the critical period for ocular dominance plasticity, and can rescue deficits induced by prolonged monocular deprivation.

Renling Yang,1,2 Anxin Wang,3–6 Li Ma,2 Zhaoping Su,7 Shuohua Chen,8 Yilong Wang,3–6 Shouling Wu,8 Chen Wang1,2 1Department of General Practice, School of General Practice and Continuing Education, Capital Medical University, Beijing, China; 2Department of General Practice, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; 3Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; 4China National Clinical Research Center for Neurological Diseases, Beijing, China; 5Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China; 6Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China; 7Department of Epidemiology and Health Statistics, Academy of Public Health and Management, Weifang Medical University, Weifang, China; 8Department of Cardiology, Kailuan Hospital, North China University of Science and Technology, Tangshan, China Background and purpose: Whether higher hematocrit levels could increase the incidence of stroke has always been full of controversy. This study aimed to explore the association between hematocrit and the incidence of stroke in the Chinese population.Subjects and methods: The Kailuan study is a prospective longitudinal cohort study on risk factors and events of chronic diseases. Using a multivariable Cox proportional hazards analysis, we examined the association between baseline hematocrit values and the incidence of stroke in the Kailuan cohort (93,299 participants).Results: A total of 3,624 participants developed stroke during the 9-year follow-up period. In Cox regression models adjusted for demographic information and for clinical variables, there was a significant association between baseline hematocrit levels and the incidence of stroke. The highest hematocrit quartile (quartile 5: men, hematocrit >48.6%; women, hematocrit >43.2%) was associated with a higher incidence of stroke (HR 1.17, 95% CI 1.04–1.31, P for trend =0.0016) compared with the lowest hematocrit quartile (quartile 1: men, hematocrit

Yao-Xing Dou,1,2,* Jiang-Tao Zhou,3,4,* Tong-Tong Wang,2 Yan-Feng Huang,1 Vicky Ping Chen,5 You-Liang Xie,1 Zhi-Xiu Lin,6 Jian-Sheng Gao,7 Zi-Ren Su,1 Hui-Fang Zeng2 1Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2Department of Pharmacy, The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 3School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 4Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, Shanxi Medical University, Taiyuan, People’s Republic of China; 5Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA; 6School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, People’s Republic of China; 7Guangzhou Baiyunshan Mingxing Pharmaceutical Co. Ltd., Guangzhou, People’s Republic of China *These authors contributed equally to this work Background: Bruceine D (BD) is a major bioactive component isolated from the traditional Chinese medicinal plant Brucea javanica which has been widely utilized to treat dysentery (also known as ulcerative colitis [UC]). Methods: To improve the water solubility and absolute bioavailability of BD, we developed a self-nanoemulsifying drug delivery system (SNEDDS) composing of MCT (oil), Solutol HS-15 (surfactant), propylene glycol (co-surfactant) and BD. The physicochemical properties and pharmacokinetics of BD-SNEDDS were characterized, and its anti-UC activity and potential mechanism were evaluated in TNBS-induced UC rat model. Results: The prepared nanoemulsion has multiple beneficial aspects including small mean droplet size, low polydispersity index (PDI), high zeta potential (ZP) and excellent stability. Transmission electron microscopy showed that nanoemulsion droplets contained uniform shape and size of globules. Pharmacokinetic studies demonstrated that BD-SNEDDS exhibited enhanced pharmacokinetic parameters as compared with BD-suspension. Moreover, BD-SNEDDS significantly restored the colon length and body weight, reduced disease activity index (DAI) and colon pathology, decreased histological scores, diminished oxidative stress, and suppressed TLR4, MyD88, TRAF6, NF-κB p65 protein expressions in TNBS-induced UC rat model. Conclusion: These results demonstrated that BD-SNEDDS exhibited highly improved oral bioavailability and advanced anti-UC efficacy. In conclusion, our current results provided a foundation for further research of BD-SNEDDS as a potential complementary therapeutic agent for UC treatment. Keywords: bruceine D, self-nanoemulsifying drug delivery system, physicochemical properties, pharmacokinetics, anti-inflammation, anti-colitis activity

Xiaoliang Chen,1,* Yueying Yang,2,* Yong Cao,1,* Changjun Wu,3 Shuxian Wu,3 Zhan Su,1 Hongwei Jin,1 Dongli Wang,1 Gengxin Zhang,3 Wei Fan,4 Jinbo Lin,5 Yunhong Zeng,3 Dongsheng Hu6 1The Center for Chronic Disease Control and Prevention, Shenzhen Guangming District Center for Disease Control and Prevention, Shenzhen, China; 2Science and Education Department, Shenzhen School of the Affiliated High School of Renmin University of China, Shenzhen, China; 3Department of Oncology, Guangming District People’s Hospital of Shenzhen, Shenzhen, China; 4Division of Digestive and Liver Disease, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 5Department of Oncology, Longgang Central Hospital of Shenzhen Affiliated to Zunyi Medical College, Shenzhen, China; 6School of Medicine, Shenzhen University, Shenzhen, China *These authors contributed equally to this work Purpose: Long noncoding RNA PVT1 is dysregulated in some human tumors and has been found to increase the risk of tumor progression and poor prognosis. This study aimed to reanalyze the effect of PVT1 on tumorous prognosis.Materials and methods: The effect of PVT1 on metastasis and survival were analyzed by univariate logistic regression and Cox proportional hazards model for 32 types of cancer in the Cancer Genome Atlas database (TCGA), and the relationship between PVT1 level and expression of relative genes was assessed by Pearson correlation analysis. RevMan5.3 and STATA14.0 were used to estimate pooled effects of PVT1 on cancer prognosis with data from TCGA and published studies.Results: In TCGA data, high PVT1 expression tended to increase the risk of TNM progression and decreased the overall survival (OS) time in most of cancers. The pooled effect of PVT1 on TNM (pooled-OR=1.46, 95% CI: 1.29–1.65) and OS (pooled HR=1.32, 95% CI: 1.22–1.43), calculated from 37 and 48 cohorts, identified that high PVT1 expression promoted the metastasis and poor prognosis of cancer. Furthermore, the pooled ORs of 2.77 (95% CI: 1.65–4.66), 4.32 (95% CI: 1.99–9.36), 1.35 (95% CI: 1.01–1.80), 1.62 (95% CI: 1.21–2.18) and 1.48 (95% CI: 1.02–2.15) provided evidence that PVT1 played a role in lymph node metastasis, depth of invasion, distant metastasis, differentiation and lymphatic invasion; while the expression of 24 identified target genes was significantly associated with PVT1 level, and high PVT1 expression dependently decreased the OS time under the influence of co-expression genes (OR=1.29, 95% CI: 1.25–1.32) in high-throughput RNA sequencing merging data. In addition, the expression of PVT1 could be upregulated by smoking, with the pooled OR being 1.09 (95% CI 1.01–1.16).Conclusion: PVT1 is a dependent biomarker for tumorous prognosis surveillance. However, the reference value of PVT1 needs further study. Keywords: PVT1, Cancer, biomarker, survive, metastasis

Yong Huang,1,* Guiqin Song,1,* Xiaotong Chang,1 Zhenhui Wang,2 Xuejiao Zhang,1 Shuguang Han,3 Zhuobin Su,4 Hejie Yang,5 Dongdong Yang,6 Xiaojun Zhang7 1College of Lab Medicine, Hebei North University, Zhangjiakou, China; 2Department of Nuclear Medicine, People’s Liberation Army No 251 Hospital, Zhangjiakou, China; 3Institute of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China; 4The First Affiliated Hospital, Hebei North University, Zhangjiakou, China; 5State Key Laboratory for Mechanical Behavior of Materials, Xi’an Jiaotong University, Xi’an, China; 6School of Physics and Optoelectronic Engineering, Ludong University, Yantai, China; 7Department of Physics, Fourth Military Medical University, Xi’an, China *These authors contributed equally to this work Background: Poor mechanical properties, undesirable fast dissolution rate, and lack of antibacterial activity limit the application of hydroxyapatite (HA) as an implant coating material. To overcome these limitations, a hybrid coating of Ag+-substituted fluorhydroxyapatite and titania nanotube (TNT) was prepared.Methods: The incorporation of silver into the HA-TiO2 hybrid coating improves its antimicrobial properties. The addition of F as a second binary element increases the structural stability of the coating. The TNT/F-and-Ag-substituted HA (FAgHA) bilayer coating on the Ti substrate was confirmed by X-ray diffraction, scanning electron microscope, energy-dispersive X-ray spectroscopy (EDS), and X-ray photoelectron spectroscopy (XPS).Results: The results indicate that the FAgHA/TNT nanocomposite coating has a dense and uniform morphology with a nano-rod-like structure. The solubility measurement result shows that the substitution of F- ions into the AgHA structure has a positive effect on the dissolution resistance of HA. The adhesion strength of FAgHA/TNT has significantly increased because of the interlocking of the roughened surface with nano-rod-like particles that entered into the voids of the TiO2 nanotubes. Compared with that of the bare Ti, the corrosion current density of FAgHA/TNT-coated Ti substrate decreased from 3.71 to 0.18 µA, and its corrosion resistance increased by almost two orders of magnitude. Moreover, despite pure HA, the FAgHA killed all viable Staphylococcus aureus after 24 hours of incubation. Although the fabricated FAgHA/TNT coating is hydrophobic, it induced deposition of the typical spherical apatite when immersed in a simulated body fluid (SBF); the osteoblasts spread very well on the surface of the coating. In addition, in vitro cell culture tests demonstrated cell viability and alkaline phosphatase (ALP) similar to pure HA, which indicated good cytocompatibility. Interestingly, compared with bare Ti, FAgHA/TNT-coated Ti surface was innocent for cell vitality and even more beneficial for cell osteogenesis in vitro.Conclusion: Enhancing the osseointegration and preventing infection in implants, the FAgHA/TNT-coated Ti makes implants more successful. Keywords: titania nanotube, silver, fluorhydroxyapatite, bactericidal effects, osteoin­ductivity

Louise S Roper,1–3 Peter Nightingale,4 Zhangjie Su,5,6 James L Mitchell,1–3 Antonio Belli,5,6 Alexandra J Sinclair1–3 1Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, 2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, 3Department of Neurology, 4Wolfson Computer Laboratory, University Hospital Birmingham NHS Foundation Trust, 5Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, 6Health Research Surgical Reconstruction and Microbiology Research Centre, Birmingham, UK Background: Posttraumatic headache (PTH) occurs in up to 82% of patients with traumatic brain injury (TBI). Posttraumatic stress disorder (PTSD) occurs in 39% of those with PTH. This study evaluates whether PTSD affects PTH disability. Methods: Eighty-six patients with TBI were prospectively evaluated in a secondary care trauma center. Headache disability was assessed using the Headache Impact Test version 6 and signs indicative of PTSD using the PTSD Check List Civilian version. Results: Increased PTSD-type symptoms were significantly associated with increased headache disability (p

The reserve of tin-bearing iron ores is very large in China. However, they have not been utilized sufficiently so far due to the complex embedded relationship between iron- and tin-bearing minerals. In the present work, the behavior of tin in the tin-bearing iron concentrates during a reduction sintering process (RSP) were studied using XRD, SEM-EDS, chemical valence state analysis and morphology analysis. The results show that there is about 30 mass% tin deprived from the tinbearing iron concentrates by the RSP. The tin-bearing phases remained in the finished sinters exist as the form of stannic (Sn4+), stannous (Sn2+) compounds and metallic Sn (Sno). The atmosphere in the sinter bed during the RSP is theoretically suitable for the volatilization of SnO(g). However, the gas composition and temperature of the sintering gas flow are changeable, which bring about adverse effect to the deprivation of tin.

Ling Zhao,1 Wei Wang,1 Jiwen Zhong,1 YaYun Li,1 YanZi Cheng,1 Zhenjiao Su,1 Wei Zheng,1 Xiang-Dong Guan2 1Department of Critical Care Medicine, Zhuhai People’s Hospital, Zhuhai, Guangdong, 2Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China Purpose: To evaluate the clinical effects of magnesium sulfate in the treatment of diffuse axonal injury (DAI).Patients and methods: This study was a randomized, double-blind, placebo-controlled trial conducted in the First Affiliated Hospital of Sun Yat-sen University, Guangzhou and Zhuhai People’s Hospital, Zhuhai, two trauma center hospitals. A total of 128 patients suffered from DAI, with initial Glasgow coma scale (GCS) scores of 3–8. They were randomly divided into two groups: magnesium sulfate treatment (MST) group (n=64) and control group (n=64). The MST group received 250 µmol/kg magnesium sulfate intravenously 20 minutes after admission, followed by 750 µmol/kg magnesium sulfate intravenously daily for 5 days. The control group received standard management without MST. GCS scores and serum neuron-specific enolase values were measured and recorded at admission, and on days 3 and 7 after injury. Outcomes were determined by Glasgow outcome scale scores at discharge and at 3 months’ follow-up, respectively.Results: After the 7-day treatment, patients in the MST group, compared with those in the control group, had a lower serum neuron-specific enolase level (25.40±6.66 vs 29.58±7.32, respectively, P=0.001) and higher GCS score (8.23±2.72 vs 7.05±2.64, respectively, P=0.016). Although the length of stay and mortality did not differ between the groups in the intensive care unit, Glasgow outcome scale score was significantly lower in the MST group at discharge (3.30±1.35 vs 3.90±1.10, P=0.004) and 3 months after discharge (2.95±1.48 vs 3.66±1.44, P=0.009).Conclusion: Early treatment with magnesium sulfate resulted in a significant improvement in DAI outcome. Further studies are needed to confirm the clinical significance of treatment of DAI patients with magnesium sulfate. Keywords: diffuse axonal injury, magnesium sulfate, outcome