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Ruijie Zhang,1,* Xinran Dong,2,* Lu Zhang,1,* Xinao Lin,1 Xuefeng Wang,1 Yan Xu,3 Chuyan Wu,4 Feng Jiang,1 Jimei Wang1 1Department of Neonatology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, People’s Republic of China; 2Center for Molecular Medicine, Children’s Hospital of Fudan University, Shanghai, People’s Republic of China; 3Department of Neurology, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, People’s Republic of China; 4Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jimei Wang; Feng Jiang, Department of Neonatology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, People’s Republic of China, Email wjm821920@163.com; dxyjiang@163.comBackground: Neonatal sleep is pivotal for their growth and development, yet manual interpretation of raw images is time-consuming and labor-intensive. Quantitative Electroencephalography (QEEG) presents significant advantages in terms of objectivity and convenience for investigating neonatal sleep patterns. However, research on the sleep patterns of healthy neonates remains scarce. This study aims to identify QEEG markers that distinguish between different neonatal sleep cycles and analyze QEEG alterations across various sleep stages in relation to postmenstrual age.Methods: From September 2023 to February 2024, full-term neonates admitted to the neonatology department at the Obstetrics and Gynecology Hospital of Fudan University were enrolled in this study. Electroencephalographic (EEG) recordings were obtained from neonates aged 37– 42 weeks, within 1– 7 days post-birth. The ROC curve was employed to evaluate QEEG features related to amplitude, range EEG (rEEG), spectral density, and connectivity across different sleep stages. Furthermore, regression analyses were performed to investigate the association between these QEEG characteristics and postmenstrual age.Results: The alpha frequency band’s spectral_diff_F3 emerged as the most potent discriminator between active sleep (AS) and quiet sleep (QS). In distinguishing AS from wakefulness (W), the theta frequency’s spectral_diff_C4 was the most effective, whereas the delta frequency’s spectral_diff_P4 excelled in differentiating QS from W. During AS and QS phases, there was a notable increase in entropy within the delta frequency band across all monitored brain regions and in the spectral relative power within the theta frequency band, correlating with postmenstrual age (PMA).Conclusion: Spectral difference showcases the highest discriminative capability across awake and various sleep states. The observed patterns of neonatal QEEG alterations in relation to PMA are consistent with the maturation of neonatal sleep, offering insights into the prediction and evaluation of brain development outcomes.Keywords: quantitative EEG, neonates, sleep, postmenstrual age

Shaoqiu Zhang,1,&ast; Qun Zhang,2,&ast; Jian Wang,1,3,&ast; Yifan Pan,4 Zhiyi Zhang,5 Yu Geng,1 Bei Jia,1 Bing Tian,2 Yali Xiong,1 Xiaomin Yan,1 Jie Li,1,3– 5 Huali Wang,6 Rui Huang,1,3– 5 Chao Wu1,3– 5 1Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China; 2Department of Infectious Diseases, Affiliated Zhongda Hospital of Southeast University, Nanjing, Jiangsu, People’s Republic of China; 3Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, People’s Republic of China; 4Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 5Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 6Department of General Practice, Nanjing Second Hospital, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chao Wu; Rui Huang, Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, No. 321 Zhongshan Road, Nanjing, Jiangsu, 210008, People’s Republic of China, Tel +86-25-83105890, Fax +86-25-83307115, Email dr.wu@nju.edu.cn; doctor_hr@126.comBackground: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging epidemic infectious disease with high mortality rate. This study aimed to investigate the association of red blood cell distribution width (RDW) and mortality risk in hospitalized SFTS patients.Methods: Clinical data of SFTS patients was retrospectively collected from three hospitals between October 2010 and August 2022. Cox proportional hazards model was used to identity the risk factors for fatal outcome. The predictive value of RDW for fatal outcome was evaluated by the receiver operating characteristic (ROC) analysis and Kaplan–Meier methods.Results: Of 292 patients, the median age was 61.5 years. Non-survivors showed higher RDW value than survivors (13.6% vs.13.0%, P < 0.001). The mortality rate was 44.8% in patients with elevated RDW compared to 18.4% of patients with normal RDW, with a relative risk (RR) of 2.439. Elevated RDW was an independent risk factor of mortality (hazards ratio: 1.167, P = 0.019). Patients with elevated RDW had a higher cumulative mortality than patients with normal RDW. The area under the ROC curve (AUC) of RDW for the prediction of mortality was 0.690 (P < 0.001).Conclusion: Elevated RDW was associated with higher mortality risk for patients hospitalized for SFTS. RDW may be helpful for risk stratification in SFTS patients.Keywords: severe fever with thrombocytopenia syndrome, red blood cell distribution width, prognosis, survival

Guanxiong Liu,&ast; Duo Zhu,&ast; Quansheng He,&ast; Churen Zhou, Li He, Zhengran Li, Zaibo Jiang, Mingsheng Huang, Boyang Chang, Chun Wu Department of Interventional Radiology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Boyang Chang; Chun Wu, Email changby3@mail.sysu.edu.cn; wuch26@mail.sysu.edu.cnPurpose: This study aimed to assess the effectiveness and safety of combining hepatic arterial infusion chemotherapy (HAIC) with lenvatinib (LEN) and PD-1 inhibitors in treating arterioportal shunt (APS) in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT).Patients and Methods: Conducted retrospectively, the study enrolled 54 HCC patients with APS and PVTT treated with HAIC, LEN, and PD-1 inhibitors at our center between January 2021 and October 2023. APS improvement, APS recanalization, tumor response, PVTT response rate, overall survival (OS), intrahepatic progression-free survival (InPFS), and adverse events were evaluated.Results: APS improvement was observed in 42 patients (77.8%), with all improvement occurring within two treatment sessions. Complete APS occlusion was achieved in 40 patients (74.1%), and no recanalization occurred. The best objective response rate (ORR) and ORR after two HAIC sessions were 74.1% and 66.7%, respectively. The best PVTT response and PVTT response after two HAIC sessions were 98.1% and 94.4%, respectively. The median OS and InPFS were 10.0 months and 5.0 months, respectively. OS and InPFS were longer in patients with APS occlusion compared to those without (OS 12.1 vs 4.4 months, P< 0.001, InPFS 6.2 vs 2.3 months, P=0.049). ALBI grade, extrahepatic spread, APS disappearance were potential prognostic factors for OS, while APS grade and extrahepatic spread being independently associated with InPFS. No treatment-related mortality occurred.Conclusion: Combining HAIC with LEN and PD-1 inhibitors proves to be both effective and safe in managing APS in HCC with PVTT, potentially improving patient survival.Keywords: hepatocellular carcinoma, shunt, portal vein tumor thrombus, hepatic arterial infusion chemotherapy, combination therapy

Yuying Ge,1,&ast; Yuepeng Xie,2,&ast; Junlei Chai,3,&ast; Weifeng Ji,4,&ast; Xiulong Lou,1 Kun Tian,2 Ronghua Bao,3 Chengliang Wu,1 Hongfeng Ruan1 1Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, People’s Republic of China; 2The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3Hangzhou Fuyang Hospital of TCM Orthopedics and Traumatology, Hangzhou, People’s Republic of China; 4Department of Orthopaedics, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongfeng Ruan; Chengliang Wu, Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310053, People’s Republic of China, Fax +86 571 86613684, Email rhf@zcmu.edu.cn; wcl@zcmu.edu.cnBackground: Intervertebral disc (IVD) degeneration (IVDD) is highly prevalent among the elderly population and stands as a leading cause of low back pain. Our prior studies have highlighted the therapeutic potential of Liuwei Dihuang decoction (LWDHD) and its component Cornus officinalis (CO)-derived compounds in alleviating IVDD and osteoarthritis, suggesting beneficial effects of CO in treating degenerative osteoarthropathies. However, uncertainty remains regarding the optimal CO dosage within LWDHD and its potential mechanism for effectively treating IVDD.Objective: To ascertain the optimal dosage of CO within LWDHD for enhancing its therapeutic efficacy in treating IVDD, through a comparison of its effects across varied dosages using a mouse IVDD model.Methods: Eight-week-old male C57BL/6J mice were subjected to a lumbar spine instability surgery to induce an IVDD model and received a modified LWDHD formulation containing varied dosages of CO (original dose of CO, or 5- or 10-time dose of CO (referred to as 1 × CO, 5 × CO, and 10 × CO)) for 8 weeks. The therapeutic efficacy on IVDD was evaluated through changes in lumbar spine function, histopathological morphology, extracellular matrix metabolism, nucleus pulposus cell viability, sensory nerve ingrowth, and nucleus pulposus (NP) cell pyroptosis.Results: Augmenting CO levels in LWDHD led to a dose-dependent increase in the levels of CO-sourced active compounds in the plasma of mice. The modified LWDHD formulations, particularly the 5 × CO, exhibited a favorable pharmacological effect on lumbar function, structural integrity, ECM composition, NP cell viability, and sensory nerve ingrowth. Importantly, all 3 formulations notably mitigated NP cell pyroptosis by activating NRF2/KEAP1 pathway, with the 5 × CO formulation exhibiting superior efficacy. Additionally, a comprehensive score analysis indicated that 5 × CO formulation achieved the highest score.Conclusion: These data underscore that elevating the dosage of CO to a specific threshold can enhance the effectiveness of LWDHD in treating IVDD.Keywords: intervertebral disc degeneration, liuwei dihuang decoction, nucleus pulposus cell, pyroptosis, Cornus officinalis

Weihua Han,1,&ast; Peiyao Zhou,2,&ast; Chun Chen,3,&ast; Chunyang Wu,2 Li Shen,1 Cailing Wan,4 Yanghua Xiao,4 Jiao Zhang,2 Bingjie Wang,1 Junhong Shi,1 Xinru Yuan,1 Haojin Gao,1 Hongxiu Wang,1 Ying Zhou,1 Fangyou Yu1 1Department of Clinical Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China; 2Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 3Cancer Center, Department of Pulmonary and Critical Care Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, People’s Republic of China; 4School of Public Health, Nanchang University, Nanchang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying Zhou; Fangyou Yu, Email 18702195157@163.com; wzjxyfy@163.comBackground: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections are a great threat to public health worldwide. Ceftazidime-avibactam (CZA) is an effective β-lactam/β-lactamase inhibitors against CRKP. However, reports of resistance to CZA, mainly caused by Klebsiella pneumoniae carbapenemase (KPC) variants, have increased in recent years. In this study, we aimed to describe the resistance characteristics of KPC-12, a novel KPC variant identified from a CZA resistant K. pneumoniae.Methods: The K. pneumoniae YFKP-97 collected from a patient with respiratory tract infection was performed whole-genome sequencing (WGS) on the Illumina NovaSeq 6000 platform. Genomic characteristics were analyzed using bioinformatics methods. Antimicrobial susceptibility testing was conducted by the broth microdilution method. Induction of resistant strain was carried out in vitro as previously described. The G. mellonella killing assay was used to evaluate the pathogenicity of strains, and the conjugation experiment was performed to evaluate plasmid transfer ability.Results: Strain YFKP-97 was a multidrug-resistant clinical ST11-KL47 K. pneumoniae confers high-level resistance to CZA (16/4 μg/mL). WGS revealed that a KPC variant, KPC-12, was carried by the IncFII (pHN7A8) plasmids (pYFKP-97_a and pYFKP-97_b) and showed significantly decreased activity against carbapenems. In addition, there was a dose-dependent effect of blaKPC-12 on its activity against ceftazidime. In vitro inducible resistance assay results demonstrated that the KPC-12 variant was more likely to confer resistance to CZA than the KPC-2 and KPC-3 variants.Discussion: Our study revealed that patients who was not treated with CZA are also possible to be infected with CZA-resistant strains harbored a novel KPC variant. Given that the transformant carrying blaKPC-12 was more likely to exhibit a CZA-resistance phenotype. Therefore, it is important to accurately identify the KPC variants as early as possible.Keywords: carbapenem-resistant Enterobacterales, Klebsiella pneumoniae, ceftazidime-avibactam, KPC-12, carbapenemase

Ciming Wu,1,&ast; Ming Ling,2,&ast; Qiong Chen,3 Hui Chai,1 Huan Chen1,4 1Zhejiang Chinese Medical University, College of Life Science, Hangzhou, Zhejiang, 310012, People’s Republic of China; 2Jinhua Institute for Food and Drug Control, Jinhua, Zhejiang, People’s Republic of China; 3Hangzhou First People’s Hospital, Hangzhou, Zhejiang, People’s Republic of China; 4Hangzhou Digital-Micro Biotech Co, Ltd, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huan Chen; Hui Chai, Email chenhuan7809@gmail.com; christychai@zcmu.edu.cnAbstract: Methicillin-resistant Staphylococcus aureus (MRSA) is a predominant nosocomial infection-causing bacteria. The aim of this study was to develop a novel single-bacteria multiplex digital PCR assays (SMD-PCR), which is capable of simultaneously detecting and discriminating Methicillin-sensitive Staphylococcus aureus (MSSA) and MRSA. This protocol employed TaqMan probes to detect SAOUHSC_00106 and mecA genes, with the latter being linked to methicillin resistance. A total of 72 samples from various specimen types were evaluated. The accuracy rates for the sputum samples, pus samples, swab samples, ear secretion samples, and catheter samples were 94.44%, 100%, 92%, 100%, and 100%, respectively. Our results showed that the clinical practicability of SMD-PCR has applicability to the rapid detection of MRSA without DNA extraction or bacterial culture, and can be utilized for the rapid detection of Staphylococcus aureus and the timely identification of MRSA in clinical samples, thereby providing an advanced platform for the rapid diagnosis of clinical MRSA infection.Keywords: MSSA, MRSA, droplet digital PCR, SMD-PCR

Cantao Li,&ast; Chenxi Wu,&ast; Fenfen Li, Wenjing Xu, Xiaoxi Zhang, Yan Huang, Daozong Xia School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Daozong Xia, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Baichuan Street, Fuyang District, Hangzhou, Zhejiang Province, People’s Republic of China, Email xdz_zjtcm@hotmail.comAbstract: Gouty arthritis (GA) is an immune-mediated disorder characterized by severe inflammation due to the deposition of monosodium urate (MSU) crystals in the joints. The pathophysiological mechanisms of GA are not yet fully understood, and therefore, the identification of effective therapeutic targets is of paramount importance. Neutrophil extracellular traps (NETs), an intricate structure of DNA scaffold, encompassing myeloperoxidase, histones, and elastases - have gained significant attention as a prospective therapeutic target for gouty arthritis, due to their innate antimicrobial and immunomodulatory properties. Hence, exploring the therapeutic potential of NETs in gouty arthritis remains an enticing avenue for further investigation. During the process of gouty arthritis, the formation of NETs triggers the release of inflammatory cytokines, thereby contributing to the inflammatory response, while MSU crystals and cytokines are sequestered and degraded by the aggregation of NETs. Here, we provide a concise summary of the inflammatory processes underlying the initiation and resolution of gouty arthritis mediated by NETs. Furthermore, this review presents an overview of the current pharmacological approaches for treating gouty arthritis and summarizes the potential of natural and synthetic product-based inhibitors that target NET formation as novel therapeutic options, alongside elucidating the intrinsic challenges of these inhibitors in NETs research. Lastly, the limitations of HL-60 cell as a suitable substitute of neutrophils in NETs research are summarized and discussed. Series of recommendations are provided, strategically oriented towards guiding future investigations to effectively address these concerns. These findings will contribute to an enhanced comprehension of the interplay between NETs and GA, facilitating the proposition of innovative therapeutic strategies and novel approaches for the management of GA. Keywords: neutrophils, neutrophil extracellular traps, gouty arthritis, inflammation, NETs inhibitor

Shasha Zhang,1,&ast; Jianhua Wu,2,&ast; Yue Zhao,3 Jingjing Zhang,1 Xiaoyun Zhang,1 Chensi Wu,3 Zhidong Zhang,4 Zhanjun Guo1 1Department of Immunology and Rheumatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, People’s Republic of China; 2Animal Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, People’s Republic of China; 3Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, People’s Republic of China; 4Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhidong Zhang, Department of Surgery, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, 050011, People’s Republic of China, Email zzd407@163.com Zhanjun Guo, Department of Immunology and Rheumatology, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, 050011, People’s Republic of China, Tel +86 311 86095734, Email zjguo5886@aliyun.comPurpose: Immune checkpoint inhibitors (ICIs) have significantly improved the outcomes of patients with cancer; however, these agents may initiate immune-related adverse events (irAEs). Previous studies have demonstrated a robust correlation between disease prognosis and the occurrence of irAEs, specifically skin or endocrine irAEs. Herein, we aimed to evaluate the correlation between irAE-related adrenal insufficiency (AI) and ICI treatment efficacy.Patients and methods: Patients diagnosed with gastrointestinal, respiratory, head and neck, urological, skin and gynecologic cancers treated with anti-programmed cell death 1 (PD-1)/anti-programmed cell death ligand 1 (PD-L1) antibody as monotherapy or combined therapy (combined with chemotherapy or targeted therapy) were divided into irAE-A (patients with irAE-related AI), irAE-B (patients with other irAEs) and non-irAE groups. Immunotherapy efficacy was assessed based on the disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Survival probabilities were estimated using the Kaplan–Meier method with the log–rank test.Results: Of the 192 patients enrolled in our study, 17 developed irAE-related AI and 83 developed other irAEs. The DCR of the irAE-A and irAE-B groups were higher than that of the non-irAE group (P< 0.05). Multiple extended Cox regression analyses showed that irAE status (irAE-A vs non-irAE, P=0.008; irAE-B vs non-irAE, P=0.020), Eastern Cooperative Oncology Group (ECOG) status (P=0.045), tumor-node-metastasis (TNM) stage (P=0.000), and treatment line (P=0.002) were independent predictors of PFS. Contrarily, irAE status (irAE-A vs non-irAE, P=0.009; irAE-B vs non-irAE, P=0.013), ECOG status (P=0.007), TNM stage (P=0.035), treatment line (P=0.001) and treatment modality (P=0.008) were independent predictors for OS.Conclusion: IrAE-related AI was significantly associated with ICI treatment efficacy in patients with cancer, which could be a potentially predictable marker. Due to the destruction of adrenal tissue by T cells with enhanced activity, AI reflects enhanced T cell activity to some extent.Keywords: endocrine adverse event, malignancies, monoclonal antibody therapy, immune-related side effects, treatment efficacy

Yinghong Li,1,&ast; Fanwu Wu,1,&ast; Jianbo Zhang,1 Ye Xu,1 Hong Chang,1 Yueyue Yu,1 Chunhua Jiang,1 Xiujuan Gao,1 Huijuan Liu,1 Zhen Chen,2 Chenxi Wu,1 Ji-An Li1,3 1Hebei Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diabetes and Its Complications, College of Traditional Chinese Medicine, North China University of Science and Technology, Tangshan, People’s Republic of China; 2Oriental Herbs KFT, Budapest, Hungary; 3School of Public Health, North China University of Science and Technology, Tangshan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chenxi Wu; Ji-An Li, Tel +86-15930951086, Fax +86-03158805765, Email chenxi.wu@ncst.edu.cn; JianLi@ncst.edu.cnPurpose: Type 2 diabetes mellitus (T2DM) is associated with reduced insulin uptake and glucose metabolic capacity. Potentilla discolor Bunge (PDB) has been used to treat T2DM; however, the fundamental biological mechanisms remain unclear. This study aimed to understand the active ingredients, potential targets, and underlying mechanisms through which PDB treats T2DM.Methods: Components and action targets were predicted using network pharmacology and molecular docking analyses. PDB extracts were prepared and validated through pharmacological intervention in a Cg>InRK1409A diabetes Drosophila model. Network pharmacology and molecular docking analyses were used to identify the key components and core targets of PDB in the treatment of T2DM, which were subsequently verified in animal experiments.Results: Network pharmacology analysis revealed five effective compounds made up of 107 T2DM-related therapeutic targets and seven protein–protein interaction network core molecules. Molecular docking results showed that quercetin has a strong preference for interleukin-1 beta (IL1B), IL6, RAC-alpha serine/threonine-protein kinase 1 (AKT1), and cellular tumor antigen p53; kaempferol exhibited superior binding to tumor necrosis factor and AKT1; β-sitosterol demonstrated pronounced binding to Caspase-3 (CASP3). High-performance liquid chromatography data quantified quercetin, kaempferol, and β-sitosterol at proportions of 0.030%, 0.025%, and 0.076%, respectively. The animal experiments revealed that PDB had no effect on the development, viability, or fertility of Drosophila and it ameliorated glycolipid metabolism disorders in the diabetes Cg>InRK1409A fly. Furthermore, PDB improved the body size and weight of Drosophila, suggesting its potential to alleviate insulin resistance. Moreover, PDB improved Akt phosphorylation and suppressed CASP3 activity to improve insulin resistance in Drosophila with T2DM.Conclusion: Our findings suggest that PDB ameliorates diabetes metabolism disorders in the fly model by enhancing Akt activity and suppressing CASP3 expression. This will facilitate the development of key drug targets and a potential therapeutic strategy for the clinical treatment of T2DM and related metabolic diseases. Keywords: Potentilla discolor Bunge, T2DM, network pharmacology, molecular docking, Drosophila

Ronglin Ma,1,2,&ast; Chunya Ji,1,&ast; Mengdan Shen,2 Shujuan Xu,2 Guojia Fan,3 Chengcheng Wu,1 Qiang Yu,2 Linliang Yin1 1Center for Medical Ultrasound, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, 215002, People’s Republic of China; 2Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, 215002, People’s Republic of China; 3Center for Cytotoxicity Testing, Sanitation & Environment Technology Institute, Soochow University, Suzhou, Jiangsu, 215006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qiang Yu, Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Jiangsu, People’s Republic of China, Tel +86 512 62362045, Email yuqiang0102sz@163.com Linliang Yin, Center for Medical Ultrasound, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Jiangsu, People’s Republic of China, Tel +86 13382183478, Email yllsznthello@hotmail.comBackground: Radionuclides have important roles in clinical tumor radiotherapy as they are used to kill tumor cells or as imaging agents for drug tracing. The application of radionuclides has been developing as an increasing number of nanomaterials are used to deliver radionuclides to tumor areas to kill tumor cells. However, promoting the efficient combination of radionuclides and nanocarriers (NCs), enhancing radionuclide loading efficiency, and avoiding environmental pollution caused by radionuclide overuse are important challenges that hinder their further development.Methods: In the present study, a new small molecule compound (3-[[(2S)-2-hydroxy-3-(4-hydroxyphenyl)-1-carbonyl] amino]-alanine, abbreviation: HN, molecular formula: C12H16N2O5) was synthesized as a linker between radionuclide iodine-125 (125I) and NCs to enable a more efficient binding between NCs and radionuclides.Results: In vitro evidence indicated that the linker was able to bind 125I with higher efficiency (labeling efficiency > 80%) than that of tyrosine, as well as various NCs, such as cellulose nanofibers, metal oxide NCs, and graphene oxide. Single-photon emission computed tomography/computed tomography imaging demonstrated the biological distribution of 125I-labeled NCs in different organs/tissues after administration in mice.Conclusion: These results showed an improvement in radionuclide labeling efficiency for nanocarriers and provided an approach for nanocarrier image tracing.Keywords: nanocarriers, radionuclide labeling, radionuclide 125i, SPECT/CT imaging

Chenjiao Wu,1,&ast; Yi Hao Loh,2,&ast; Hangkai Huang,3 Chengfu Xu3 1Department of Nursing, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, People’s Republic of China; 2Medical Bachelor and Bachelor of Surgery (MBBS), Zhejiang University School of Medicine, Hangzhou, 310003, People’s Republic of China; 3Department of Gastroenterology, Zhejiang Provincial Clinical Research Centre for Digestive Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chengfu Xu, Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, People’s Republic of China, Tel +86-571-87236863, Email xiaofu@zju.edu.cnBackground: In previous studies, the ZJU index was reported to be a superior predictor of nonalcoholic fatty liver disease in the Chinese population compared to the Fatty Liver Index. However, whether the ZJU Index is significantly associated with diabetes among Asian populations has not been determined.Methods: The NAGALA study was carried out at Murakami Memorial Hospital (Gifu, Japan) beginning in 1994. This study included the data of the subjects who underwent health check-ups from 2004 to 2015. The ZJU Index comprises body mass index (BMI), fasting plasma glucose, triglyceride, and alanine aminotransferase-to-aspartate aminotransferase (ALT) levels and an adjustment point for females. We conducted Cox proportional hazard regression to evaluate the association between quartiles of the ZJU Index and the risk of incident diabetes.Participants: A total of 15,464 individuals who underwent health check-ups were included in this study.Results: A total of 373 cases of incident diabetes were documented during 93,350 person-years of follow-up. As the ZJU index increased, the incidence of diabetes gradually increased (P < 0.001). According to the multivariable model adjusted for metabolic covariates, the fourth quartile of the ZJU Index was positively associated with the risk of diabetes compared to the first quartile (HR=2.519, 95% CI=1.297− 4.891). Subgroup analysis revealed that the association between the ZJU index and diabetes risk was significant in subjects aged younger than 40 years (HR=3.327, 95% CI=1.544− 7.171), in females (HR=4.480, 95% CI=1.302− 15.419), in individuals with a BMI< 25 kg/m2 (HR=3.812, 95% CI=1.992− 7.293) and in individuals with a nonregular exercise (HR=2.479, 95% CI=1.193− 5.152).Conclusion: We observed a positive association between the ZJU Index and incident diabetes in the general population.Keywords: ZJU index, diabetes, epidemiology

Cheng Chen,1,&ast; Nandi Chen,2,3,&ast; Yan Qi,1,&ast; Meng Lyu,2 Chaoyan Wu,4,&ast; Conghua Xie,1 Haijun Yu1 1Department of Radiation and Medical Oncology, Hubei Province Cancer Clinical Study Center, Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China; 2Department of Gastrointestinal Surgery & Department of Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, 518020, People’s Republic of China; 3Analysis and Testing Center, Shenzhen Technology University, Shenzhen, 518118, People’s Republic of China; 4Department of Integrated Traditional Chinese Medicine and Western Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haijun Yu; Conghua Xie, Email haijunyu@whu.edu.cn; chxie_65@whu.edu.cnBackground: Radiotherapy is an indispensable part of the multidisciplinary treatment of breast cancer (BC). Due to the potential for serious side effects from ionizing radiation in the treatment of breast cancer, which can adversely affect the patient’s quality of life, the radiation dose is often limited. This limitation can result in an incomplete eradication of tumors.Methods: In this study, biomimetic copper single-atom catalysts (platelet cell membrane camouflaging, PC) were synthesized with the aim of improving the therapeutic outcomes of radiotherapy for BC. Following guidance to the tumor site facilitated by the platelet cell membrane coating, PC releases a copper single-atom nanozyme (SAzyme). This SAzyme enhances therapeutic effects by generating reactive oxygen species from H2O2 and concurrently inhibiting the self-repair mechanisms of cancer cells through the consumption of intracellular glutathione (GSH) within the tumor microenvironment. PC-augmented radiotherapy induces immunogenic cell death, which triggers an immune response to eradicate tumors.Results: With the excellent biocompatibility, PC exhibited precise tumor-targeting capabilities. Furthermore, when employed in conjunction with radiotherapy, PC showed impressive tumor elimination results through immunological activation. Remarkably, the tumor suppression rate achieved with PC-enhanced radiotherapy reached an impressive 93.6%.Conclusion: Therefore, PC presents an innovative approach for designing radiosensitizers with tumor-specific targeting capabilities, aiming to enhance the therapeutic impact of radiotherapy on BC.Keywords: platelet cell membrane, single-atom nanozyme, radiotherapy, radioimmunotherapy, breast cancer

Xing Li, Zhuyuan Zhang, Wen Cai, Xuexin Zhou, Yan Zhang, Cailiang Wu, Xianming Xu, Hao Wu Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, People’s Republic of ChinaCorrespondence: Hao Wu; Xianming Xu, Email zhuwy2007@126.com; xuxm11@163.comBackground: The relationship of iron deficiency and thyroid hormone has been researched a lot among pregnant or other healthy population. However, invisible iron deficiency, namely shortage of serum ferritin (sFer) level, has been barely investigated among Chinese pregnant women. This study aimed to explore the effects of sFer status on thyroid function and pregnancy outcomes in a population-based upper first-class hospital.Methods: A total of 781 singleton pregnant women of gestation in Shanghai General Hospital took part in this retrospective cohort study. The participants were divided into four groups by quartiles of serum ferritin levels (Q1– 4). Binary logistic regressions were used to examine the strength of association between the different traits and the serum ferritin (sFer) quartiles separately, where Q1 (lowest ferritin quartile) was taken as the base reference. One-way ANOVA was adopted to compare the averages of the different variables across sFer quartiles. Categorical measures were compared by Fisher exact test or chi-square test.Results: As the sFer concentration rises, incidence of premature birth (15.8%vs 12.3% vs 9.20% vs 6.20% p = 0.016) as well as threatened miscarriage (14.8% vs 7.2% vs 8.70% vs 6.70% p = 0.021) presented a downward trend. Compared with the other sFer group, subjects of the low sFer group were older, more often to be found to have lower serum γT3 and FT4 levels in early pregnancy but not in middle pregnancy.Conclusion: sFer concentration in the first trimester can affect thyroid function. The correction of invisible iron deficiency with inadequate sFer status prior to pregnancy or during early pregnancy is imperative, not only to prevent anemia, but also for maintaining optimum thyroid function and normal fetal development. For clinicians, sFer status of pregnant women should be attached great importance apart from attention to iron level.Keywords: serum ferritin, thyroid hormone, subclinical hypothyroidism, thyroid-stimulating hormone, pregnant women

Xing Zhang,1,&ast; Yuanyuan Song,1,&ast; Hongyang Gong,1,&ast; Chunyan Wu,1 Binquan Wang,1 Wenxuan Chen,2 Jiawei Hu,2 Hanhui Xiang,2 Ke Zhang,1 Mingkuan Sun1 1Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2The Second Clinical Medical School, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mingkuan Sun, Department of Toxicology, School of Public Health, Nanjing Medical University, No. 101 Longmian Avenue, Jiangning District, Nanjing, 211166, People’s Republic of China, Email sunmk@njmu.edu.cnAbstract: The increasing use of titanium dioxide nanoparticles (TiO2 NPs) across various fields has led to a growing concern regarding their environmental contamination and inevitable human exposure. Consequently, significant research efforts have been directed toward understanding the effects of TiO2 NPs on both humans and the environment. Notably, TiO2 NPs exposure has been associated with multiple impairments of the nervous system. This review aims to provide an overview of the documented neurotoxic effects of TiO2 NPs in different species and in vitro models. Following exposure, TiO2 NPs can reach the brain, although the specific mechanism and quantity of particles that cross the blood-brain barrier (BBB) remain unclear. Exposure to TiO2 NPs has been shown to induce oxidative stress, promote neuroinflammation, disrupt brain biochemistry, and ultimately impair neuronal function and structure. Subsequent neuronal damage may contribute to various behavioral disorders and play a significant role in the onset and progression of neurodevelopmental or neurodegenerative diseases. Moreover, the neurotoxic potential of TiO2 NPs can be influenced by various factors, including exposure characteristics and the physicochemical properties of the TiO2 NPs. However, a systematic comparison of the neurotoxic effects of TiO2 NPs with different characteristics under various exposure conditions is still lacking. Additionally, our understanding of the underlying neurotoxic mechanisms exerted by TiO2 NPs remains incomplete and fragmented. Given these knowledge gaps, it is imperative to further investigate the neurotoxic hazards and risks associated with exposure to TiO2 NPs. Keywords: TiO2 NPs, neurotoxic effects, oxidative stress, neuronal damage, neurotoxic mechanisms

Chenkai Yang,1,&ast; Xiangqian Cao,1,&ast; Lei He,2,3,&ast; Cong Wu,2,&ast; Mengxin Zhao,2 Fei Duan,2 Zhiwen Qiu,2 Xiaodong Zhu,2 Yilin Yan,1 Shengzhou Li,1 Wei Li,2 Bing Shen1 1Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Nanomedicine & Shanghai Key Laboratory of Cell Engineering, Naval Medical University, Shanghai, People’s Republic of China; 3School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Li, Department of Nanomedicine & Shanghai Key Laboratory of Cell Engineering, Naval Medical University, 800 Xiangyin Road, Yangpu District, Shanghai, 200433, People’s Republic of China, Tel +86 21 81871644, Fax +86 21 81870801, Email liwei_dds@163.com Bing Shen, Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 85 Wujin Road, Hongkou District, Shanghai, 200080, People’s Republic of China, Tel/Fax +86 18017181979, Email urodrshenbing@shsmu.edu.cnIntroduction: Insufficient tumor permeability and inadequate nanoparticle retention continue to be significant limitations in the efficacy of anti-tumor drug therapy. Numerous studies have focused on enhancing tumor perfusion by improvement of tumor-induced endothelial leakage, often known as the enhanced permeability and retention (EPR) effect. However, these approaches have produced suboptimal therapeutic outcomes and have been associated with significant side effects. Therefore, in this study, we prepared tumor cell membrane-coated gold nanorods (GNR@TM) to enhance drug delivery in tumors through homogeneous targeting of tumor cell membranes and in situ real-time photo-controlled therapy.Methods: Here, we fabricated GNR@TM, and characterized it using various techniques including Ultraviolet-Visible (UV-Vis) spectrophotometer, particle size analysis, potential measurement, and transmission electron microscopy (TEM). The cellular uptake and cytotoxicity of GNR@TM were analyzed by flow cytometry, confocal laser scanning microscopy (CLSM), TEM, CCK8 assay and live/dead staining. Tissue drug distribution was determined by inductively coupled plasma mass spectrometry (ICP-MS) and immunofluorescence staining. Furthermore, to evaluate the therapeutic effect, mice bearing MB49 tumors were intravenously administered with GNR@TM. Subsequently, near-infrared (NIR) laser therapy was performed, and the mice’s tumor growth and body weight were monitored.Results: The tumor cell membrane coating endowed GNR@TM with extended circulation time in vivo and homotypic targeting to tumor, thereby enhancing the accumulation of GNR@TM within tumors. Upon 780 nm laser, GNR@TM exhibited excellent photothermal conversion capability, leading to increased tumor vascular leakage. This magnification of the EPR effect induced by NIR laser further increased the accumulation of GNR@TM at the tumor site, demonstrating strong antitumor effects in vivo.Conclusion: In this study, we successfully developed a NIR-triggered nanomedicine that increased drug accumulation in tumor through photo-controlled therapy and homotypic targeting of the tumor cell membrane. GNR@TM has been demonstrated effective suppression of tumor growth, excellent biocompatibility, and significant potential for clinical applications. Keywords: intratumor drug accumulation, photo-controlled therapy, homotypic targeting, tumor cell membrane, gold nanorods

Arbuscular mycorrhizal fungi (AMF) play an important role on litter decomposition, which is increasing suffering the negative impact of acid deposition. In this study, we investigated the AMF effects on litter decomposition via suppressing AMF and simulating acid deposition in a subtropical Cinnamomum camphora forest. The results showed that acid deposition and AMF suppression decelerated C. camphora leaf litter decomposition, especially at late decomposition stage; soil water content was the main factor restricting early-stage decomposition. The inhibiting effect of acid deposition was enhanced with acid intensity increase and AMF suppression aggravated the negative effect of acid stress on decomposition. Nitrogen-cycling enzymatic activity was significantly higher in later than in early decomposition stage, and acid deposition and AMF suppression significantly decreased microbial activity. Despite the seasonal effect was overwhelming, we still detected the effects of acid deposition and AMF suppression on litter nutrient release. Without or under low acid deposition, AMF suppression significantly increased organic matter and decreased alkali-hydrolyzable nitrogen content of detritusphere soil. Acid deposition significantly reduced soil organic matter content, while high acid deposition intensity increased alkali-hydrolyzable nitrogen content after 2- and 12-month decomposition, and decreased it at other months. Both acid deposition and AMF suppression decreased available phosphorus content, but did not affect phosphatase activity. AMF effects on invertase and nitrogen-release enzyme activities, and alkali-hydrolyzable nitrogen and available phosphorus contents of detritusphere soil were highly sensitive to acid deposition. Our results revealed that AMF effects on microbial activity and nutrient release during litter decomposition are sensitive to acid deposition.

Qian Song,1,&ast; Ying Chen,2,3,&ast; JianQing Ma,1 Wei Zhou,4 JunYan Song,1 ChunFu Wu,5 Jie Liu2 1Department of Medical Laboratory, North China Medical & Health Group Xingtai General Hospital, Orthopedic Hospital of Xingtai, Xingtai, People’s Republic of China; 2BGI Genomics, BGI-Shenzhen, Shenzhen, People’s Republic of China; 3College of Life Sciences, University of Chinese Academy of Sciences, Beijing, People’s Republic of China; 4China National Genebank, BGI-Shenzhen, Shenzhen, People’s Republic of China; 5Yantai Harbor Hospital, Yantai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Liu, BGI Genomics, BGI-Shenzhen, Shenzhen, 518083, People’s Republic of China, Email liujie8@genomics.cn ChunFu Wu, Yantai Harbor Hospital, Yantai, 264000, People’s Republic of China, Email tjnk2009@126.comPurpose: Psoriasis is a chronic, multi-system skin disease that can be influenced by immunological, environmental, and genetic factors. Plasma metabolomic analysis can provide a great deal of information on potential diagnostic biomarkers, pathogenesis and personalized treatment. However, the role of metabolites in psoriasis is unknown.Patients and Methods: We performed an untargeted metabolomic analysis of plasma based on high-resolution liquid chromatography mass spectrometry from 10 plaque psoriasis patients and 10 healthy controls.Results: A total of 301 differential metabolites were detected, of which 10 metabolites were possible potential biomarkers, including vitamins, amino acids, and lipids. At the same time, KEGG pathway enrichment analysis was performed for all detected differential metabolites, and it was found that protein digestion and absorption, amino acid metabolism and lipid metabolism may be jointly involved in regulating the pathogenesis of psoriasis. In addition, the proteins ESR1, OPRM1 and HSD11B1 were identified as possible potential topical therapeutic targets for psoriasis through analysis of the metabolite-protein interaction network.Conclusion: In this study, we identified 10 differential metabolites as possible potential combinatorial biomarkers for the diagnosis of psoriasis. 12 metabolic pathways were significantly enriched that may be closely related to the occurrence and development of psoriasis. Three proteins, ESR1, OPRM1, and HSD11B1, were identified as possible potential therapeutic targets for psoriasis.Keywords: psoriasis, metabolomics, biomarker, KEGG pathway, therapeutic target

Yan Lu, Chaoxiang Ren, Chaolong Wu Clinical Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, 322100, People’s Republic of ChinaCorrespondence: Yan Lu, Clinical Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, 60 West Wuning Road, Dongyang, Zhejiang, 322100, People’s Republic of China, Tel +86 18367815795, Email luyan11219@hotmail.comPurpose: Studies on the prognosis of critically ill older adult patients admitted to the emergency department (ED) but requiring immediate admission to the intensive care unit (ICU) remain limited. This study aimed to develop an in-hospital mortality prediction model for critically ill older adult patients transferred from the ED to the ICU.Patients and Methods: The training cohort was taken from the Medical Information Mart for Intensive Care IV (version 2.2) database, and the external validation cohort was taken from the Affiliated Dongyang Hospital of Wenzhou Medical University. In the training cohort, class balance was addressed using Random Over Sampling Examples (ROSE). Univariate and multivariate Cox regression analyses were performed to identify independent risk factors. These were then integrated into the predictive nomogram. In the validation cohort, the predictive performance of the nomogram was evaluated using the area under the curve (AUC) of the receiver operating characteristic curve, calibration curve, clinical utility decision curve analysis (DCA), and clinical impact curve (CIC).Results: In the ROSE-balanced training cohort, univariate and multivariate Cox regression analysis identified that age, sex, Glasgow coma scale score, malignant cancer, sepsis, use of mechanical ventilation, use of vasoactive agents, white blood cells, potassium, and creatinine were independent predictors of in-hospital mortality in critically ill older adult patients, and were included in the nomogram. The nomogram showed good predictive performance in the ROSE-balanced training cohort (AUC [95% confidence interval]: 0.792 [0.783– 0.801]) and validation cohort (AUC [95% confidence interval]: 0.780 [0.727– 0.834]). The calibration curves were well-fitted. DCA and CIC demonstrated that the nomogram has good clinical application value.Conclusion: This study developed a predictive model for early prediction of in-hospital mortality in critically ill older adult patients transferred from the ED to the ICU, which was validated by external data and has good predictive performance.Keywords: nomogram, Medical Information Mart for Intensive Care IV database, random over sampling examples, external validation, prognosis

Yu Hu,1– 3 Hui Guo,1– 3 Shuai Cheng,1– 3 Junpeng Sun,2,4 Jiaqun Du,2,4 Xiaobang Liu,2,4 Ying Xiong,5 Liqing Chen,6 Chang Liu,3,6 Chao Wu,2,4 He Tian1– 3 1School of Basic Medicine, Jinzhou Medical University, Jinzhou, Liaoning, 121001, People’s Republic of China; 2Liaoning Provincial Collaborative Innovation Center for Medical Testing and Drug Research, Jinzhou Medical University, Jinzhou, Liaoning, 121001, People’s Republic of China; 3Key Laboratory of Medical Tissue Engineering of Liaoning Province, Jinzhou Medical University, Jinzhou, Liaoning, 121001, People’s Republic of China; 4Pharmacy School, Jinzhou Medical University, Jinzhou, Liaoning, 121001, People’s Republic of China; 5Laboratoire Catalyse et Spectrochimie (LCS), Normandie Université, ENSICAEN, UNICAEN, CNRS, Caen, 14050, France; 6Department of Endocrinology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 121000, People’s Republic of ChinaCorrespondence: He Tian; Chao Wu, Email tianhe@jzmu.edu.cn; wuchao@jzmu.edu.cnBackground: Oxidative stress induced reactive oxygen species (ROS) and aggregation of amyloid β (Aβ) in the nervous system are significant contributors to Alzheimer’s disease (AD). Cerium dioxide and manganese oxide are known as to be effective and recyclable ROS scavengers with high efficiency in neuroprotection.Methods: A hollow-structured manganese-doped cerium dioxide nanoparticle (LMC) was synthesized for loading Resveratrol (LMC-RES). The LMC-RES were characterized by TEM, DLS, Zeta potential, and X-ray energy spectrum analysis. We also tested the biocompatibility of LMC-RES and the ability of LMC-RES to cross the blood-brain barrier (BBB). The antioxidant effects of LMC-RES were detected by SH-SY5Y cells. Small animal live imaging was used to detect the distribution of LMC-RES in the brain tissue of AD mice. The cognitive abilities of mice were tested by water maze and nesting experiments. The effects of LMC-RES in reducing oxidative stress and protecting neurons was also explored by histological analysis.Results: The results showed that LMC-RES had good sustained release effect and biocompatibility. The drug release rate of LMC-RES at 24 hours was 80.9 ± 2.25%. Meanwhile, LMC-RES could cross the BBB and enrich in neurons to exert antioxidant effects. In Aβ-induced SH-SY5Y cells, LMC-RES could inhibits oxidative stress through the Nrf-2/HO-1 signaling pathway. In AD model mice, LMC-RES was able to reduce ROS levels, inhibit Aβ-induced neurotoxicity, and protect neurons and significantly improve cognitive deficits of AD mice after drug administration.Conclusion: LMC-RES can effectively across the BBB, reduce oxidative stress, inhibit Aβ aggregation, and promote the recovery of neurological function.Keywords: cerium dioxide nanoparticles, manganese, oxidative stress, resveratrol, Alzheimer’s disease

Yi Gao,1,&ast; Yuqing Li,1,&ast; Xiaolin Chen,1,&ast; Chen Wu,2 Ziqiang Guo,1 Geng Bai,1 Tong Liu,1 Guangping Li1 1Tianjin Key Laboratory of Logic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, the Second Hospital of Tianjin Medical University, Tianjin, 300211, People’s Republic of China; 2Department of Emergency Medicine, The Second Hospital of Tianjin Medical University, Tianjin, 300211, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guangping Li; Tong Liu, Tel +86-022-88328648, Fax +86-022-28261158, Email tic_tjcardiol@126.com; liutong@tmu.edu.cnBackground: Systemic inflammation index (SII: neutrophil count &ast; platelet count/lymphocyte count) is a new inflammatory marker that can reflect the degree of systemic inflammatory response after coronary artery disease (CAD). However, the predictive value of the SII for clinical prognosis in patients with initially diagnosed acute coronary syndrome (ACS) has yet to be thoroughly studied.Patients and Methods: Patients with initially diagnosed ACS who underwent primary coronary angiography in our hospital from January 2019 to April 2021 were included in this study. 757 patients with ACS who underwent primary coronary angiography were enrolled. According to the baseline SII level, the patients were divided into a high SII group and a low SII group. The primary endpoint was major cardiovascular events (MACEs), defined as cardiac death, non-fatal myocardial infarction (MI), and non-fatal stroke.Results: At a median follow-up of 33.9 months, 140 (18.5%) MACEs were recorded. Receiver operating characteristic (ROC) curve analysis showed that SII’s best cut-off value for predicting MACEs was 713.9&ast;109/L. Kaplan-Meier survival curve analysis showed that the survival rate of the low SII group was higher than the high SII group (P< 0.001). Compared with the low SII group, the risk of MACEs was significantly increased in the high SII group (89 cases (33.3%) vs.51 patients (10.4%), P< 0.001). Univariate and multivariate Cox regression analysis manifested that high SII level was independently associated with the occurrence of MACEs in patients with ACS undergoing primary coronary angiography (adjusted hazard ratio [HR]: 2.915, 95% confidence interval (CI%): 1.830– 4.641, P< 0.001). Adding SII to the conventional risk factor model improved the predictive value of MACEs.Conclusion: This study showed that elevated SII was associated with adverse cardiovascular prognosis in patients with ACS undergoing primary coronary angiography, making SII a valuable predictor of poor prognosis in patients with ACS undergoing primary coronary angiography.Keywords: systemic inflammation index, immune response, coronary angiography, acute coronary syndrome, clinical prognosis

Hongmei Yao,1 Yongqiang Pang,2 Yubin Chen,2 Nilu Si,2 Chao Wu,2 Zijing Wang,2 Yi Ren3 1Department of Cardiology, the First Hospital of Shanxi Medical University, TaiYuan City, 030001, People’s Republic of China; 2Department of Internal Medicine, Shanxi Medical University, TaiYuan City, 030001, People’s Republic of China; 3Department of Endocrinology, the First Hospital of Shanxi Medical University, TaiYuan City, 030001, People’s Republic of ChinaCorrespondence: Yi Ren, Department of Endocrinology, the First Hospital of Shanxi Medical University, No. 85, Jiefang South Road, Yingze District, TaiYuan City, 030001, People’s Republic of China, Tel +86-351-4639756, Email drrenyi@126.comIntroduction: Previous studies have identified diabetes as a risk factor for coronary heart disease. This study determined the correlation between the IL-6 gene − 572 G/C polymorphism and the incidence and severity of coronary heart disease in patients with diabetes.Methods: One hundred four patients with diabetes who were admitted to our hospital from January 2019 to December 2020 were retrospectively enrolled in the current study. These patients were divided into a diabetes only group (group A, 27 patients) and a diabetes complicated by coronary heart disease group (group B, 77 patients). Seventy patients in the latter group were further divided into low, medium, and high Syntax score groups based on coronary angiography results. A correlation analysis between IL-6, blood lipids, and the IL-6 − 572 G/C gene levels was performed.Results: The serum IL-6 level in patients with the IL-6-572G/C-GG genotype was higher than patients with the GC and CC genotypes. In patients with diabetes, the presence of the IL-6-572G/C-GG and GC genotypes was associated with a significantly increased risk of developing coronary heart disease. Patients with the IL-6-572G/C-GG genotype and diabetes were shown to have more severe coronary artery lesions compared to patients with the CC genotype. Moreover, the G allele of the IL-6-572G/C gene was linked to a higher risk of coronary heart disease and more severe coronary artery lesions in patients with diabetes compared to the C allele.Conclusion: The IL-6-572G/C gene polymorphism is associated with the incidence and severity of coronary heart disease in patients with diabetes.Keywords: IL-6, diabetes, coronary heart disease, gene polymorphism, coronary artery lesions

Lan Chen,1,&ast; Ying Zhou,2,&ast; Shanshan Wang,1 Chunyang Wu,3 Peiyao Zhou,4 Bingjie Wang,2 Zhu Chen,5 Fangyou Yu2 1Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, 315010, People’s Republic of China; 2Department of Clinical Laboratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200082, People’s Republic of China; 3Department of Respiratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China; 4Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 5Department of Clinical Laboratory Medicine, Ningbo No. 2 Hospital, Ningbo, Zhejiang, 315010, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhu Chen; Fangyou Yu, Email mars853234@163.com; wzjxyfy@163.comBackground: Carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) has become a clinical crisis and is associated with significant morbidity and mortality. The prevalence of CR-hvKP has trended upward since 2010. This study aims to describe the clinical and genomic characteristics of CR-hvKP collected from a tertiary hospital in eastern China, from August 2020 to October 2021.Methods: We tested the susceptibility to common antibiotics in these isolates to feature the antibiotic-resistant phenotypes. We also applied whole-genome sequencing and core-genome phylogenetic to analysis the genetic features of these isolates. Plasmid replicons were identified by using the PlasmidFinder database, and core-genome phylogenetic analysis by Parsnp database.Results: All these strains isolated from the patients with serious underlying diseases and poor prognosis. We found all CR-hvKp isolates exhibited a multidrug-resistant (MDR) phenotype. These results revealed that blaKPC-2 was the predominant carbapenemases gene (n = 53, 84.1%), and ST11-KL64 CR-hvKP strains dominated, forming a single cluster, and differed by an average of 26 core SNPs. We only found eight ST15 isolates containing KL24 and KL112 type capsules, with the main carbapenem resistance genes being blaOXA-232 and blaKPC-2. All ST11-KL64 strains had a series of resistance and virulence genes, along with IncHIB-FIB virulence plasmids and IncFII resistance plasmids, while the prevalence of resistance plasmids like the IncFII plasmid was absence in ST15 isolates.Conclusion: This suggests that ST11-KL64 CR-hvKP has emerged as the most prevalent hypervirulence and carbapenem-resistant K. pneumoniae and may contribute to hospital outbreaks of infection, which required most clinical attention.Keywords: carbapenem-resistant, hypervirulence, Klebsiella pneumoniae, whole-genome sequencing, antimicrobial resistance, virulence genes

Junwang Gu,&ast; Qi Wang,&ast; Xuanhui Wu, Han Zhang, Chunmei Wu, Wei Qiu School of Public Health and Health Management, Gannan Medical University, Ganzhou, Jiangxi Province, 341000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Qiu; Chunmei Wu, Tel/Fax +86-7978169236, Email qw21046@163.com; wuchunmei82@qq.comBackground: Comorbidity is a common problem among elderly people, significantly damaging individuals’ health and healthcare systems. However, observational studies may be susceptible to residual confounding factors and bias. The present study aimed to assess the causal effect of common chronic disease comorbidity using the Mendelian randomization (MR) approach.Methods: Data for the present study were obtained from a community survey conducted between 2018 and 2020 in four counties in Ganzhou City, southern China. A cross-sectional survey was conducted using a multi-stage stratified random sampling method. A total of 1756 valid questionnaires were collected to analyze common chronic disease comorbidities. Genetic variants associated with hypertension, diabetes, stroke, and hyperlipidemia-related factors were selected as instrumental variables for univariate and multivariate MR analyses.Results: The self-reported prevalence of chronic disease in the older adult population in Southern China was 68.1%, with hypertension (46.1%), diabetes (10.5%), and hyperlipidemia (8.5%) being the three most common conditions. The prevalence of chronic disease comorbidity was 20.7% among the 12 chronic diseases studied. Hypertension was identified as a predictor of diabetes (OR [95% CI]: 1.114 [1.049, 1.184], p < 0.001), and diabetes mellitus was equally identified as a risk factor for hypertension (OR [95% CI]: 1.118 [1.069, 1.187], p < 0.001). Furthermore, high triglyceride levels were identified as a risk factor for hypertension (OR [95% CI]: 1.262 [1.129, 1.411], p < 0.001). In contrast to intracranial hemorrhages, hypertension had a significant impact on ischemic stroke (OR [95% CI]: 1.299 [1.161, 1.454], p < 0.001).Conclusion: The causal association between multiple cardiovascular and metabolism-related diseases is mediated by hypertension, with a bidirectional cause-and-effect relationship between hypertension and diabetes. Hypertension is a risk factor for ischemic stroke, and the hyperlipidemia-related factor triglycerides (TG) influence hypertension. Therefore, prioritizing hypertension prevention and control in the elderly is critical for effective chronic disease management.Keywords: hypertension, diabetes, hyperlipidemia, stroke, causal, mendelian randomization

Yiwei Zhou,1 Yu Huang,2 Chunhua Wu,2 Hongsheng Yang,2 Chunyan Shan,2 Zumu Zhou2 1Business School, University of Shanghai for Science and Technology, Shanghai, People’s Republic of China; 2The Affiliated Kangning Hospital of Wenzhou Medical University Zhejiang Provincial Clinical Research Center for Mental Disorders, Wenzhou, People’s Republic of ChinaCorrespondence: Zumu Zhou, The Affiliated Kangning Hospital of Wenzhou Medical University Zhejiang Provincial Clinical Research Center for Mental Disorders, 1 Shengjin Road, Huanglong Residential District, Wenzhou, 325007, People’s Republic of China, Tel +86-13857709701, Fax +86-577-88789117, Email zhouzumu@126.comBackground: Coronavirus disease (COVID-19) mainly caused by the Omicron virus strain currently is still prevalent worldwide, and many medical institutions have experienced COVID-19 outbreaks in the past three years.Objective: This article reported COVID-19 outbreak among health care workers in a mental hospital to clarify the epidemiological and clinical characteristics of COVID-19 outbreak in a medical institution, to assess the susceptible factors related to COVID-19 among these personnel and to evaluate the effect of COVID-19 vaccine on the medical workers.Methods: A uniform questionnaire was used to investigate all employees, including age, gender, department, time of onset, clinical symptoms, vaccination status. At the same, the results of laboratory testing, chest computed tomography (CT) and/or X-ray examination were collected.Results: Among 1047 hospital employees, 842 cases were diagnosed as COVID-19, with a total attack rate of 80.42%. The attack rate of doctors, nurses, medical technicians, and administrators (83.50– 90.67%) was higher than that of logistics departments (56.81%). Out of the 842 patients, 9 were hospitalized; 833 were non-hospitalized patients who belong to mild or moderate cases. No deaths were reported. The full vaccination rate and booster rate of COVID-19 vaccine were 78.26% and 80.87%, respectively. There was no significant correlation between the attack rate and COVID-19 vaccine (χ2 = 3.41 P > 0.05).Conclusion: This is an outbreak of COVID-19 with a high attack rate among employees in a mental hospital. The attack rate of medical personnel is higher than that of logistics personnel, which may be related to opportunities and duration of contact with infected individuals. COVID-19 vaccine has no significant protective effect on patients with mild or moderate symptoms 13 months after the full vaccination. It is suggested that they should be timely boostered with COVID-19 vaccine to maintain their immunity to the disease.Keywords: COVID-19, outbreak, health care workers, mental hospital

Zhiqiang He,1 Huan Yang,1 Yufan Gu,1 Yuhan Xie,1 Jianan Wu,1 Chen Wu,1 Jiawei Song,1 Maofang Zhao,2,3 Da Zong,1 Wenlong Du,1 Jiaju Qiao,1 Yipeng Pang,1– 3 Yi Liu1– 3 1Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China; 2School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China; 3Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of ChinaCorrespondence: Yi Liu; Yipeng Pang, Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China, Tel/Fax +86-0516-83262084, Email cbpeliuyinew@163.com; pangyipeng.xzmu@foxmail.comPurpose: Herein, an emerging drug delivery system was constructed based on zeolite imidazole backbone (ZIF-8) to improve antibacterial defects of nanosilver (AgNPs), such as easily precipitated and highly cytotoxic.Methods: The homogeneous dispersion of AgNPs on ZIF-8 was confirmed by UV-Vis spectroscopy, FTIR spectroscopy, particle size analysis, zeta potential analysis, and SEM. The appropriate AgNPs loading ratio on ZIF-8 was screened through the cell and antibacterial experiments based on biosafety and antibacterial performance. The optimal environment for AgNPs@ZIF-8 to exert antibacterial performance was probed in the context of bacterial communities under different acid-base conditions. The potential mechanism of AgNPs@ZIF-8 to inhibit the common clinical strains was investigated by observing the biofilm metabolic activity and the level of reactive oxygen species (ROS) in bacteria.Results: The successful piggybacking of AgNPs by ZIF-8 was confirmed using UV-Vis spectroscopy, FTIR spectroscopy, particle size analysis, zeta potential analysis, and SEM characterization methods. Based on the bacterial growth curve (0– 24 hours), the antibacterial ability of AgNPs@ZIF-8 was found to be superior to AgNPs. When the mass ratio of ZIF-8 and AgNPs was 1:0.25, the selection of AgNPs@ZIF-8 was based on its superior antimicrobial efficacy and enhanced biocompatibility. Notably, under weakly acidic bacterial microenvironments (pH=6.4), AgNPs@ZIF-8 demonstrated a more satisfactory antibacterial effect. In addition, experiments on biofilms showed that concentrations of AgNPs@ZIF-8 exceeding 1×MIC resulted in more than 50% biofilm removal. The nanomedicine was found to increase ROS levels upon detecting the ROS concentration in bacteria.Conclusion: Novel nanocomposites consisting of low cytotoxicity drug carrier ZIF-8 loaded with AgNPs exhibited enhanced antimicrobial effects compared to AgNPs alone. The pH-responsive nano drug delivery system, AgNPs@ZIF-8, exhibited superior antimicrobial activity in a mildly acidic environment. Moreover, AgNPs@ZIF-8 effectively eradicated pathogenic bacterial biofilms and elevated the intracellular level of ROS.Graphical Abstract: Keywords: MOF, ZIF-8, AgNPs, nanocomplex, ROS, pathogenic biofilm

Wan He,1,&ast; Changbu Wu,2,3,&ast; Guanping Chen,2– 4 Guili Zhang,2,3 Zihan Zhao,2,3 Shu’an Wen,2,3 Yuan Zhou,2,3 Xue Deng,2,3 Yu Feng,2,3 Lan-Lan Zhong,2,3 Guo-Bao Tian,2– 4 Min Dai1 1School of Laboratory Medicine, Chengdu Medical College, Chengdu, 610500, People’s Republic of China; 2Department of Immunology and Microbiology, Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China; 3Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, People’s Republic of China; 4Department of Immunology, School of Medicine, Sun Yat-Sen University, Shenzhen, 518107, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Min Dai, School of Laboratory Medicine, Chengdu Medical College, Chengdu, Sichuan Province, People’s Republic of China, Tel +86 28-62739128, Email daimin1015@163.com Guo-Bao Tian, Department of Immunology and Microbiology, Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, People’s Republic of China, Tel/Fax +86 20 87335387, Email tiangb@mail.sysu.edu.cnBackground: The emergence and spread of hypervirulent carbapenem-resistant Klebsiella pneumoniae (hv-CRKP) is a potential epidemiological threat that needs to be monitored. However, the transmission and pathogenic characteristics of hv-CRKP in China remain unclear. We investigated the epidemiological characteristics of gut colonized hv-CRKP in a hospital in Guangdong Province, China.Methods: A total of 46 gut colonized hv-CRKP isolates were collected from Sun Yat-Sen Memorial Hospital (Guangzhou, China) from August 31st to December 31st, 2021. Minimum inhibitory concentrations (MICs) were obtained for 15 antibiotics for 46 hv-CRKP isolates. BALB/C mice infection model and mucoviscosity assay was used to evaluate the virulence of the isolates. The characteristics of genome, phylogenetic relationship and the structure of the plasmid of 46 gut colonized hv-CRKP isolates were compared with pathogenic isolates from GeneBank based on whole-genome data.Results: The hv-CRKP isolation rate of all gut colonized carbapenem-resistant Klebsiella pneumoniae was 17% (46/270), and the intestinal colonization rate of hv-CRKP was irrelevant to the sex, age, department of hospitalization, and history of antibiotic use of the host. The gut colonized hv-CRKP showed pandrug resistance and hypervirulence. The gut colonized hv-CRKP and pathogenic hv-CRKP prevalent in China were mainly ST11 hv-CRKP and had two major epidemic clades. The similarities in genomic characteristics between gut colonized hv-CRKP and pathogenic hv-CRKP were consistent. The gut colonized hv-CRKP carried an incomplete structure pK2044 virulence plasmid from hypervirulent K. pneumoniae NTUH-K2044 by analyzing the virulence plasmid structure.Conclusion: Our results suggest that the gut colonized ST11 hv-CRKP may serve as a reservoir for the clinical pathogenic ST11 HV-CRKP. It is necessary to further strengthen the monitoring of gut colonized hv-CRKP and research the potential mechanism of infection caused by gut colonized hv-CRKP.Keywords: K. pneumoniae, intestinal colonization, hypervirulent, genomic characterization, carbapenemase

Suling Jiang,1,&ast; Jian Wang,2,3,&ast; Zhiyi Zhang,4,&ast; Jie Zhan,1 Ruifei Xue,1 Yuanwang Qiu,5 Li Zhu,6 Shaoqiu Zhang,2 Yifan Pan,1 Xiaomin Yan,2 Yuxin Chen,3,7 Jie Li,1– 4 Xingxiang Liu,8 Chuanwu Zhu,6 Rui Huang,1– 4 Chao Wu1– 4 1Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China; 3Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, People’s Republic of China; 4Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 5Department of Infectious Diseases, The Fifth People’s Hospital of Wuxi, Wuxi, Jiangsu, People’s Republic of China; 6Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China; 7Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China; 8Department of Clinical Laboratory, Huai’an No. 4 People’s Hospital, Huai’an, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chao Wu, Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, No. 321 Zhongshan Road, Nanjing, Jiangsu, 210008, People’s Republic of China, Tel +86-25-83105890, Fax +86-25-83307115, Email dr.wu@nju.edu.cn Rui Huang, Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, No. 321 Zhongshan Road, Nanjing, Jiangsu, 210008, People’s Republic of China, Email doctor_hr@126.comBackground: Noninvasive diagnosis of liver inflammation is important for patients with chronic hepatitis B (CHB). This study aimed to develop a nomogram to predict significant liver inflammation for CHB patients.Methods: CHB patients who underwent liver biopsy were retrospectively collected and randomly divided into a development set and a validation set. The least absolute shrinkage and selection operator regression and logistic regression analysis were used to select independent predictors of significant liver inflammation, and a nomogram was developed. The performance of nomogram was assessed by receiver operating characteristic (ROC) curves, calibration curves and decision curve analysis (DCA).Results: A total of 1019 CHB patients with a median age of 39.0 years were included. Alanine aminotransaminase (ALT, P = 0.018), gamma-glutamyl transpeptidase (P = 0.013), prothrombin time (P < 0.001), and HBV DNA level (P = 0.030) were identified as independent predictors of significant liver inflammation in the development set. A model namely AGPD-nomogram was developed based on the above parameters. The area under the ROC curve in predicting significant inflammation was 0.765 (95% CI: 0.727– 0.803) and 0.766 (95% CI: 0.711– 0.821) in the development and validation sets, which were significantly higher than other indexes. The AGPD-nomogram had a high predictive value in patients with normal ALT. Moreover, the nomogram was proven to be clinically useful by DCA.Conclusion: A visualized AGPD-nomogram which incorporated routine clinical parameters was proposed to facilitate the prediction of significant liver inflammation in CHB patients. This nomogram had high accuracy in the identification of significant liver inflammation and would be a useful tool for the better management of CHB patients, especially for those with normal ALT.Keywords: chronic hepatitis B, liver inflammation, prediction, nomogram, alanine aminotransferase

Haiyang Chen,1,&ast; Chenlin Wu,2,&ast; Qin Lv,2 Mingjie Li,1 Lu Ren2,3 1Department of Acupuncture and Moxibustion, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China; 2Graduate School, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China; 3Mental Disorders Research Laboratory, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lu Ren, Email lnzxkc@sina.comBackground: Depression is a common mental health disorder characterized by persistent feelings of sadness, loss of interest or pleasure, and a range of physical and cognitive symptoms. It affects people of all ages and can significantly impact their daily functioning and quality of life. Mitochondrial homeostasis plays an important role in the pathogenesis of depression. Mitochondrial homeostasis includes mitophagy, mitochondrial oxidative stress, mitoptosis, mitochondrial biogenesis, and mitochondrial dynamics. The regulation of mitochondrial homeostasis is the key link in the prevention and treatment of depression.Methods: In this article, we focus on the core link of depression-mitochondrial homeostasis and summarize the research progress of acupuncture targeting mitochondrial homeostasis in the treatment of depression in recent years, so as to provide ideas and experimental basis for the research and formulation of more appropriate depression treatment strategies.Results: Acupuncture has been found to regulate mitochondrial homeostasis (by modulating mitochondrial autophagy, reducing mitochondrial oxidative stress, inhibiting mitochondrial fission, inducing mitochondrial biogenesis, and maintaining mitochondrial dynamics), alleviate depression-like behavior, and regulate signal pathways and key proteins.Conclusion: Here, we highlight the role of acupuncture in the treatment of depression. A comprehensive exploration of the impact of acupuncture on mitochondrial homeostasis could potentially present a novel mechanism for treating depression and offer fresh perspectives for the treatment of patients with clinical depression.Keywords: depression, mitochondria, homeostasis, acupuncture, mitophagy, review

Chongwu Xu,1 Weizhen Xi,2 Chen Wu,2 Ling Liu,2 Lingling Wang2 1Department of Endoscopy Center, Yijishan Hospital, Wannan Medical College, Wuhu, 241000, People’s Republic of China; 2Department of Gastroenterology, Yijishan Hospital, Wannan Medical College, Wuhu, 241000, People’s Republic of ChinaCorrespondence: Weizhen Xi, Department of Gastroenterology, Yijishan Hospital, Wannan Medical College, No. 2 Zheshan West Road, Jinghu District, Wuhu, 241000, People’s Republic of China, Tel +86 13955363461, Email xiweizhen2023@163.comPurpose: To explore the clinical effects of continuous nursing on patients with inflammatory bowel disease (IBD).Methods: Patients with IBD in the digestive department of the hospital from January 2020 to August 2021 were selected as the research participants and divided into an observation and control group by the random number table method. The patients were treated with a routine nursing intervention (control group) or routine plus continuous nursing interventions (observation group). The disease uncertainty, coping strategies, sleep and quality of life before and after the interventions were compared between the two groups.Results: After 6 months of the intervention, the disease uncertainty score of the observation group was significantly lower than that of the control group (p < 0.05). Medical coping style score: There was no significant difference in the three dimensions of medical coping style between the two groups before the intervention (p > 0.05). After 6 months of the intervention, the facial score of the observation group was significantly higher, and the avoidance and yield scores were significantly lower compared with the control group (p < 0.05). Sleep quality and quality of life score: There was no significant difference in the sleep quality score between the two groups before the intervention (p > 0.05). After 6 months of the intervention, the observation group’s sleep quality and quality of life scores were significantly higher compared with the control group (p < 0.05).Conclusion: Compared with routine nursing, continuous nursing can reduce the disease uncertainty of patients with IBD, help them to adopt an active coping style, as well as improve their sleep quality and quality of life to relieve physical and mental pain and better restore health.Keywords: continuing care, inflammatory bowel disease, quality of life, sleep quality, coping style

Jun Li,1,&ast; Yangyang Yang,2,&ast; Xiumin Han,3,&ast; Jing Li,2 Mengxiao Tian,1 Wenjing Qi,1 Huniu An,3 Chuanchuan Wu,1 Yao Zhang,1 Shuai Han,4 Liping Duan,4 Weisi Wang,4 Wenbao Zhang1 1State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China; 2Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China; 3Qinghai Provincial People’s Hospital, Xining, Qinghai, People’s Republic of China; 4NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Centre for Tropical Diseases, National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenbao Zhang; Weisi Wang, Tel +86 991 4366319 ; +86 21 64377008, Email wenbaozhang2013@163.com; wangws@nipd.chinacdc.cnBackground: Alveolar echinococcosis (AE) is a lethal parasitic disease caused by infection with the metacestode of the dog/fox tapeworm Echinococcus multilocularis, which primarily affects the liver. Although continued efforts have been made to find new drugs against this orphan and neglected disease, the current treatment options remain limited, with drug delivery considered a likely barrier for successful treatment.Methods: Nanoparticles (NPs) have gained much attention in the field of drug delivery due to their potential to improve delivery efficiency and targetability. In this study, biocompatible PLGA nanoparticles encapsulating a novel carbazole aminoalcohol anti-AE agent (H1402) were prepared to promote the delivery of the parent drug to liver tissue for treating hepatic AE.Results: H1402-loaded nanoparticles (H1402-NPs) had a uniform spherical shape and a mean particle size of 55 nm. Compound H1402 was efficiently encapsulated into PLGA NPs with a maximal encapsulation efficiency of 82.1% and drug loading content of 8.2%. An in vitro uptake assay demonstrated that H1402-NPs rapidly penetrated the in vitro cultured pre-cyst wall and extensively accumulated in the pre-cysts of E. multilocularis within only 1 h. The biodistribution profile of H1402-NPs determined through ex vivo fluorescence imaging revealed significantly enhanced liver distribution compared to unencapsulated H1402, which translated to improved therapeutic efficacy and reduced systemic toxicity (especially hepatotoxicity and cytotoxicity) in a hepatic AE murine model. Following a 30-day oral regimen (100 mg/kg/day), H1402-NPs significantly reduced the parasitic burden in both the parasite mass (liver and metacestode total weight, 8.8%) and average metacestode size (89.9%) compared to unmedicated infected mice (both p-values < 0.05); the treatment outcome was more effective than those of albendazole- and free H1402-treated individuals.Conclusion: Our findings demonstrate the advantages of encapsulating H1402 into PLGA nanoparticles and highlight the potential of H1402-NPs as a promising liver-targeting therapeutic strategy for hepatic AE.Graphical Abstract: Keywords: alveolar echinococcosis, Echinococcus multilocularis, PLGA, nanoparticles, liver targeting, oral administration

Liwei Wang,1,&ast; Yinyin Qu,1,&ast; Ying Deng,1 Jun Li,1 Yanqing Liu,2 Changyi Wu1 1Department of Anesthesiology, Peking University Third Hospital, Peking University, Beijing, 100191, People’s Republic of China; 2Department of Orthopaedics, Peking University Third Hospital, Peking University, Beijing, 100191, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Changyi Wu, Department of Anesthesiology, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, People’s Republic of China, Tel +86-13522028771, Email wuchangyitougao@sina.com Yanqing Liu, Department of Orthopaedics, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing, 100191, People’s Republic of China, Tel +86-13611346532, Email yanqing_liu@sohu.comPurpose: The location of the sciatic nerve deep within the thigh tissue makes it challenging to locate while the patient is in a supine position. The posterior intermuscular septum of the thigh, which encircles the posterior surface of the adductor magnus muscle (AMM), is where the sciatic nerve is located. Our hypothesis was that administering local anesthetic injections into this area could block the sciatic nerve. Therefore, our aim was to evaluate the effectiveness of sciatic nerve block achieved by injecting local anesthetic into the posterior intermuscular septum of the thigh, named the AMM approach.Methods: Twenty-six patients undergoing total knee arthroplasty were included in the study. We performed an ultrasound-guided sciatic nerve block by injecting 20 mL of 0.25% ropivacaine into the posterior surface of the adductor magnus muscle, using the AMM approach. Additionally, we administered a femoral nerve block with 20 mL of 0.4% ropivacaine. We assessed the sensory and motor effects of the blockade in the operated lower limb and recorded postoperative pain scores at 0, 4, 8, 12, 24, and 48 hours after the operation.Results: The AMM approach successfully block the sciatic nerve in all 26 patients. The onset of the sensory and motor blockades was achieved within 5.4 ± 1.9 min and 8.7 ± 3.5 min, respectively. We achieved a satisfactory position with the first puncture in 19 of 26 patients (73.1%). The muscle strength of the tibialis anterior immediately after surgery was 4 (ranging from 2 to 5). Additional rescue analgesics were required in 5 of the 26 patients (19.2%) during the first 24 hours postoperatively.Conclusion: The AMM approach is an innovative and effective method for sciatic nerve block. When combined with simultaneous femoral nerve block in patients undergoing total knee arthroplasty, it provides a useful analgesic treatment option.Keywords: sciatic nerve block, adductor magnus muscle, tibialis anterior, femoral nerve block

Changdong Wu,&ast; Ping Wang,&ast; Bin Wang, Muyesai Nijiati, Ming Hou Xinjiang Emergency Center, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, 830001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ming Hou, Xinjiang Emergency Center, People’s Hospital of Xinjiang Uygur Autonomous Region, No. 91, Tian-chi Road, Tianshan District, Urumqi, 830001, People’s Republic of China, Tel +86-9918563596, Email houming199@sina.comPurpose: To investigate the optimal target temperature of cooling intervention in heat stroke (HS) rats and explore the potential mechanisms of cooling intervention in alleviating heat stroke-induced damage.Materials and Methods: A total of 32 Sprague-Dawley rats were randomly divided into 4 groups (n=8/group), including control, HS[core body temperature (Tc)], HS(Tc-1°C) and HS(Tc+1°C) group. Heat stroke model was established in rats of HS(Tc), HS(Tc-1°C) and HS(Tc+1°C) group. Rats in HS(Tc) group were cooled to baseline core body temperature after establishing heat stroke model, HS(Tc-1°C) group to baseline core body temperature minus 1°C and HS(Tc+1°C) group to baseline core body temperature plus 1°C. We compared the histopathological changes of lung, liver and renal tissue, as well as cell apoptosis and expression of critical proteins in phosphatidylinositol 3´-kinase (PI3K)/Akt signaling pathway.Results: Heat stroke caused the histopathological damage and cell apoptosis of lung, liver and renal tissue, which could be alleviated by cooling intervention to a certain extent. Notably, HS(Tc+1°C) group demonstrated a better effect on alleviating cell apoptosis although the differences were not significant. Heat stroke lead to the elevated expression of p-Akt, which subsequently induced the elevated expression of Caspase-3 and Bax, as well as the decreased expression of Bcl-2. Cooling intervention could reverse this trend. Notably, the expression level of Bax in lung tissue of HS(Tc+1°C) group was significantly lower than that of HS(Tc) and HS(Tc-1°C) group.Conclusion: The mechanisms of cooling intervention in alleviating heat stroke-induced damage were associated with the expression changes of p-Akt, Caspase-3, Bax and Bcl-2. The better effect of Tc+1°C might be associated with low expression of Bax.Keywords: heat stroke, cooling intervention, target temperature, histopathological damage, cell apoptosis, PI3K/Akt signaling pathway

Chenyu Wu, Jianzhong Zhang, Yan Zhao Department of Dermatology, People’s Hospital of Peking University, Beijing, People’s Republic of ChinaCorrespondence: Yan Zhao, Email 13311373780@163.comAbstract: Hypereosinophilic dermatitis (HED) is a subtype of hypereosinophilic syndrome. HED is characterized by eosinophilic granulocytes increased in peripheral blood and bone marrow and infiltrated in skin. The clinical manifestations of HED are diffussed by erythema, papule and maculopapule with severe itching. The etiology of HED is unknown. At present, in addition to HED with FIP1L1-PDGFRA fusion gene positive, whose treatment is tyrosine kinase inhibitor, other types of HED first-line treatment are oral glucocorticoids, supplemented by antihistamines and immunosuppressants. Dupilumab is a human monoclonal antibody, which inhibits the IL-4 and IL-13 signaling by binding to the IL-4R-α and IL-13R-α-1 subunits of the receptor. We report a 76-year-old male patient with HED whose peripheral blood eosinophils decreased from 20.7% to 4.1% after 8 weeks of dupilumab, and his pruritus was completely relieved. Dupilumab was discontinued after 6 months of treatment. It is exciting that the patient has not experienced relapse for 17 months after the discontinuation. No adverse event was reported.Keywords: hypereosinophilic dermatitis, hypereosinophilic syndrome, dupilumab

Cuiyun Wu,1 Jiehong Lu,1 Lijin Ruan,2 Jie Yao1 1Department of Clinical Laboratory, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, Guangdong, People’s Republic of China; 2Department of Radiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, People’s Republic of ChinaCorrespondence: Jie Yao, Department of Clinical Laboratory, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde) Foshan, Guangdong, People’s Republic of China, No. 1, Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong Province, 528308, People’s Republic of China, Tel +86 0757 22318169, Email jie.yao413@yahoo.comObjectives: Multi-drug resistance (MDR) emerged as a serious threat in intensive care unit (ICU) settings. Our study aimed to investigate the major pathogens in ICU and identify the risk factors for MDR infection.Methods: We performed a retrospective analysis of patients admitted to the ICU. Multivariate logistic regression was applied to identify the independent predictors, and then a nomogram to predict the probability of MDR infection.Results: A total of 278 patients with 483 positive cultures were included. 249 (51.55%) had at least one MDR pathogen, including extensively drug-resistant (XDR) 77 (30.92%) and pan drug-resistant (PDR) 39 (15.66%), respectively. Klebsiella pneumonia was the most frequently isolated pathogen. We identified the number of bacteria (OR 2.91, 95% CI 1.97– 4.29, P < 0.001), multiple invasive procedures (OR 2.23, 95% CI 1.37– 3.63, P = 0.001), length of stay (LOS) (OR 1.01, 95% CI 1.00– 1.02, P = 0.007), Hemoglobin (Hb) (OR 0.99, 95% CI 0.98– 1.00, P = 0.01) were independent risk factors for MDR infection. Our nomogram displayed good discrimination with curve AUC was 0.75 (95% CI: 0.70– 0.81). The decision curves also indicate the clinical utility of our nomogram. Additionally, the in-hospital mortality with MDR pathogens was independently associated with XDR (HR, 2.60; 95% CI: 1.08– 6.25; P = 0.03) and total protein (TP) (HR, 0.95; 95% CI: 0.91– 0.99; P = 0.03).Conclusion: The number of bacteria, multiple invasive procedures, LOS, and Hb were the independent predictors associated with MDR pathogens. Our nomogram is potentially useful for predicting the occurrence of MDR infection. Besides, we also identify XDR and TP as the independent risk factors for in-hospital mortality with MDR infection. The current prevalence of MDR strains was also described. The results will contribute to the identification and preventive management of patients at increased risk of infection.Keywords: multi-drug resistance, intensive care unit, risk factors, nomogram

Junying Zhang,1,* Yiwen Zhang,1,* Hufang Wang,1 Wenlin Chen,1 Aiyu Lu,1 Hailiang Li,1 Lifeng Kang,2 Chunyong Wu3 1Department of TCMs Pharmaceuticals, China Pharmaceutical University, Nanjing, People’s Republic of China; 2School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Pharmacy and Bank Building A15, Camperdown, Australia; 3Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lifeng Kang, Email lifeng.kang@sydney.edu.au; Chunyong Wu, Email cywu@cpu.edu.cnBackground: Curcumin (CUR) is a functional ingredient from the spice turmeric. It has attracted considerable attention recently, owing to its diverse biological activities. However, curcumin has low water solubility, which limited its applications. Some sugar molecules were found to be able to solubilise poorly water-soluble compounds by forming micelles in aqueous solutions.Purpose: To improve the water solubility and oral absorption of CUR, using a non-nutritive natural sweetener, namely, Mogroside V (Mog-V).Methods: A solid dispersion of CUR in Mog-V was prepared using a solvent evaporation method. The solid dispersion was characterised by using X-ray diffraction and differential scanning calorimetry. The solid dispersion can dissolve in water to form micelles with a diameter of ~160 nm, which were characterised by using dynamic light scattering. To find out the mechanism of solubilisation, the aggregation behaviour of Mog-V molecules in aqueous solution was investigated using nuclear magnetic resonance spectroscopy. Finally, oral absorption of CUR in the solid dispersion was evaluated using a rodent model.Results: A solid dispersion was formed in a ratio of 1 CUR to 10 Mog-V by weight. Upon dissolution into water, CUR laden micelles formed via self-assembly of Mog-V molecules, which increased the solubility of CUR by nearly 6000 times compared with pure CUR crystals. In rats, the solid dispersion increased the oral absorption of CUR by 29 folds, compared with CUR crystals. In terms of solubilisation mechanism, it was found that Mog-V self-assembled into micelles with a core-shell structure and CUR molecules were incorporated into the hydrophobic core of the Mog-V micelles.Conclusion: Mog-V can form a solid dispersion with CUR. Upon dissolution in water, the Mog-V in the solid dispersion can self-assemble into micelles, which solubilise CUR and increase its oral absorption.Graphical Abstract: Keywords: Mogroside V, curcumin, micelle, solubilisation, bioavailability, solid dispersion

Biao Li,1 Xiao Hu,2 Litao Chen,3 Chuyi Wu4 1School of Education Science, Guangxi Science and Technology Normal University, Laibin, People’s Republic of China; 2Department of Education, Shiyuan College of Nanning Normal University, Nanning, People’s Republic of China; 3College of Music, Guangxi Normal University, Guilin, People’s Republic of China; 4School of Education Science, Guangxi Minzu University, Nanning, People’s Republic of ChinaCorrespondence: Xiao Hu, Department of Education, Shiyuan College of Nanning Normal University, Nanning, People’s Republic of China, Email huxiaoiris@gmail.comPurpose: The school climate, which refers to the quality and character of school life, is associated with a wide range of developmental outcomes. Although researchers have shown considerable interest in uncovering the links between school climate and prosocial behavior, the mechanisms underlying this association remain unclear. Therefore, the current study was designed to investigate the mediating role of gratitude between school climate and adolescents’ prosocial behavior.Methods: A sample of 632 Chinese adolescents (363 girls and 269 boys; Mage = 16.83 years at time 1, SD = 0.68 years) completed a battery of sociometric and self-report questionnaires that measured school climate, gratitude, and prosocial behavior in three waves.Results: Correlation analysis showed that school climate, gratitude, and prosocial behavior were all significantly and positively intercorrelated across the three waves. Importantly, gratitude completely mediated the relationship between school climate and prosocial behavior (β = 0.005 [95% confidence interval = 0.001, 0.013]) in the three-wave longitudinal mediation model.Conclusion: As a positive disposition, gratitude fosters prosocial behavior and serves as a mediator between school climate and prosocial behavior. This study provides a theoretical explanation for cultivating adolescents’ prosocial behavior and theoretical guidelines for interventions of schools and other socializing agents.Keywords: prosocial behavior, gratitude, school climate, adolescents, longitudinal mediation model

During the continuous casting process, the residual oxygen in the tundish can be significantly reduced by argon blowing from the tundish cover (ABTC). As a result, the effect of protective casting can be obviously improved, which helps to reduce the reoxidation of molten steel in the tundish. In the present work, numerical models for the ABTC of a six-strand continuous casting machine were established and verified by the measured oxygen mass fraction in the tundish during the ABTC. The results indicate that the best conditions for ABTC are to install the argon pipes on either side of the tundish cover holes, seal the baking holes, and keep the stopper rod holes open. The argon flow rate should be ≥120 m3/h during the period of empty tundish and ≥60 m3/h during the period of normal casting. Based on the calculation results, industrial testsof ABTC were carried out. The results indicated that the increased nitrogen content in steel(Δw[N]) decreased by 21.5% from 8.78×10- 6 to 6.89×10-6 , from the end of RH to tundish, and the amount of inclusions except for MnS in bloom (scanned size: 8 mm × 8 mm) decreased by 21.3% from 13.43 to 10.57, and the average size of inclusions decreased by 19.0% from 9.27 μm to 7.51 μm.

Yuelian Sun,1– 4 Jesper Padkær Petersen,5 Chunsen Wu,6,7 Julie Werenberg Dreier,3,8 Rikke Damkjær Maimburg,9– 11 Tine Brink Henriksen,5 Jakob Christensen1,2 1Department of Neurology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 3National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark; 4Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus University, Aarhus, Denmark; 5Department of Paediatrics, Clinical Institute, Aarhus University, Aarhus University Hospital, Aarhus, Denmark; 6Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 7Department of Gynaecology and Obstetrics, Odense University Hospital, Odense, Denmark; 8Centre for Integrated Register-Based Research (CIRRAU), Aarhus University, Aarhus, Denmark; 9Department of Clinical Medicine, Aarhus University, Denmark; Department of Occupational Health, Aarhus University Hospital, Aarhus, Denmark; 10Department of Midwifery, University College of Northern Denmark, Hjørring, Denmark; 11School of Nursing and Midwifery, Western Sydney University, Blacktown, NSW, AustraliaCorrespondence: Yuelian Sun, Department of Neurology, Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark, Email ys@clin.au.dkPurpose: Phototherapy is the standard treatment for neonatal hyperbilirubinemia. It is important to collect data on phototherapy to support research related to the efficacy and safety of phototherapy. We explored the registration of phototherapy in the Danish National Patient Registry (DNPR) and the clinical characteristics of neonates treated with phototherapy.Methods: We identified children born alive in Denmark from 1 January 2000 through 30 November 2016 from the DNPR (N=1,044,502). We calculated the proportion of children registered that received phototherapy during the neonatal period and examined temporal trends, both nationwide and at the level of individual hospitals. In a sub-cohort of children born at Aarhus University Hospital (AUH) in 2002– 2016 (N=71,781), we analyzed the proportions of children registered that received phototherapy, according to sex, gestational age, birth weight, and neonatal characteristics, like Apgar score, birth asphyxia, and infections.Results: We identified 11,295 (1.1%) registered that received phototherapy. The proportions of children registered that received phototherapy differed among hospitals (range: 0 to 4.1%). Nationwide registration was low during the study period, but it increased to 1.8% in 2016. For the AUH sub-cohort the proportion of children registered with phototherapy averaged 4.4% (N=3182, range:3.9– 5.1%). The proportion of children registered with phototherapy was inversely correlated with gestational age and birth weight, and positively correlated with neonatal characteristics, including low Apgar score, birth asphyxia, and infections.Conclusion: Phototherapy was under-reported in the DNPR and the proportions of children registered that received phototherapy differed among hospitals. The non-compulsory policy for reporting treatment and care in hospitals to the DNPR might explain the variation. The most consistent reporting was observed among children born in an university hospital, where 4.4% of children registered that received phototherapy, and phototherapy was inversely associated with gestational age, birth weight, and positively associated with clinical characteristics like birth asphyxia, and infections.Keywords: Danish National Patient Registry, health administrative data, neonates, hyperbilirubinemia, neonatal jaundice, phototherapy

Qingping Zhou,1,&ast; Chunyang Wu,2,&ast; Peiyao Zhou,3 Ji Zhang,1 Zhanghua Xiong,4 Ying Zhou,5 Fangyou Yu5 1Department of Neurology, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, People’s Republic of China; 2Department of Respiratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China; 3Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China; 4Department of Clinical Laboratory Medicine, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, People’s Republic of China; 5Department of Clinical Laboratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200082, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying Zhou, Email 18702195157@163.comBackground: Patients with neurological disorders were easier to develop severe intracranial infections caused by hypervirulent and carbapenem-resistant K. pneumoniae, leading to a distressing clinical outcome. In this study, eight hv-CRKP were isolated from neurological patients, to clarify the resistant and virulent features.Methods: We tested the susceptibility of common antibiotics in these isolates to feature the antibiotic-resistant phenotypes. We also detected the key virulence factors, including mucoviscosity, siderophores production, biofilm formation in vitro, and further evaluated the virulence potential with serum killing model. We also used whole-genome sequencing (WGS) to investigate the molecular mechanisms.Results: We observed that ST11-KL64 hv-CRKP (6/8) has an overwhelming epidemic dominance in these hypervirulent and carbapenem-resistant K. pneumoniae. Though the acquirement of virulence plasmid made no influence to the maintain of multidrug-resistant phenotype of these isolates, only the ST11-KL64 strains fully exhibited the hypervirulent features. Compared with ST11-KL47 and ST15-KL24 strains, ST11-KL64 hv-CRKP were more advantages in productions of capsule polysaccharide, biofilm, and siderophores. The virulence potential of ST11-KL64 hv-CRKP was further confirmed by using serum killing model. Previous studies have demonstrated that IncFII plasmid could act as a helper plasmid to mobile the non-conjugative IncFIB/IncHIB virulence plasmids. We could only observe the co-existence of IncFII resistance plasmid and IncFIB/IncHIB virulence plasmids in ST11-KL64 isolates. The co-existence of such two plasmids facilitated the formation of ST11-KL64 hv-CPKP, which then become nosocomial epidemic under the antibiotic stress.Conclusion: Overall, we observed the ST11-KL64 hv-CRKP dominated in the isolates from neurological patients, and required most clinical attention.Keywords: Klebsiella pneumoniae, KPC-2, virulence plasmid, carbapenem resistance, hypervirulent

Chenggang Zhang,&ast; Guanxin Wei,&ast; Xiuxian Zhu,&ast; Xiang Chen, Xianxiong Ma, Peng Hu, Weizhen Liu, Wenchang Yang, Tuo Ruan, Weikang Zhang, Chuanqing Wu, Kaixiong Tao Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Kaixiong Tao; Chuanqing Wu, Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, Hubei Province, 430022, People’s Republic of China, Tel +86 13507155452 ; +86 13995598966, Email kaixiongtao@hust.edu.cn; wucq2014@hust.edu.cnBackground: Circular RNAs (circRNAs) are endogenous noncoding RNAs that play vital roles in many biological processes, particularly in human cancer. Recent studies indicate that circRNAs play an important role in tumor progression through exosomes. However, the specific functions of gastric cancer-derived exosomes and the role of circSTAU2 in gastric cancer (GC) remain largely unknown.Methods: Differentially expressed circRNAs in GC were identified by circRNA microarrays analysis and quantitative real-time polymerase chain reaction (qRT-PCR). The role of circSTAU2 in GC was verified by circSTAU2 knockdown and overexpression with functional assays both in vitro and in vivo. Fluorescence in situ hybridization (FISH), immunofluorescence, RNA immunoprecipitation (RIP), dual-luciferase reporter assay, qRT-PCR and Western blot were adopted to evaluate the expression and regulatory mechanism of MBNL1, circSTAU2, miR-589 and CAPZA1. Furthermore, the role of exosomes was demonstrated by transmission electron microscopy and nano-sight particle tracking analysis.Results: CircSTAU2, mainly localized in the cytoplasm, was significantly downregulated in GC. CircSTAU2 overexpression inhibited GC cell proliferation, invasion and migration both in vitro and in vivo, while circSTAU2 knockdown had the inverse effect. CircSTAU2 could be wrapped in exosomes and delivered to recipient cells, and functioned as a sponge for miR-589 to relieve its inhibitory effect on CAPZA1, thus inhibiting GC progression. Furthermore, MBNL1 acted as the upstream RNA-binding protein of circSTAU2 and significantly influenced the circularization and expression of circSTAU2.Conclusion: Exosome-delivered circSTAU2 may act as a tumor suppressor that restrains GC progression via miR-589/CAPZA1 axis, which demonstrates a potential therapeutic target for GC.Keywords: exosomes, circ-RNAs, bioinformatics, gastric cancer, cancer progression

Hongli Yang,1,&ast; Fajuan Rui,2,&ast; Rui Li,3,&ast; Shengxia Yin,4 Qi Xue,1 Xinyu Hu,5 Yayun Xu,5 Chao Wu,4 Junping Shi,6 Jie Li2,4 1Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Ji’nan, People’s Republic of China; 2Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing, People’s Republic of China; 3Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, People’s Republic of China; 4Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China; 5Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Ji’nan, People’s Republic of China; 6Department of Infectious Disease, The Affiliated Hospital of Hangzhou Normal University, Wenzhou Road, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Li, Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, People’s Republic of China, Email lijier@sina.com Junping Shi, Department of Infectious Disease, The Affiliated Hospital of Hangzhou Normal University, Wenzhou Road, Hangzhou, Zhejiang, People’s Republic of China, Email 20131004@hznu.edu.cnAbstract: Background and Aims: Changes in living standards and diet structure, non-alcoholic fatty liver disease (NAFLD) is prevalent globally, including in Asia, where chronic hepatitis B (CHB) is endemic. As such, cooccurrence of NAFLD with CHB is common in Asia. However, the pathogenesis underlying the onset of fatty liver in CHB prognosis has not been fully elucidated. Therefore, we aimed to investigate the effects and mechanisms of lipotoxicity on hepatitis B virus (HBV) DNA replication.Methods: The expression of adenosine deaminase acting on RNA-1 (ADAR1) and miR-122 was evaluated in liver tissues from patients with CHB concurrent NAFLD. Palmitic acid-treated HepG2.2.15 cells were used as the cell model. The effect of lipotoxicity on HBV DNA replication was evaluated in vitro by transfecting the ADAR1 overexpression or knockdown lentiviral vector into HepG2.2.15 cells, respectively. qRT-PCR, western blotting and immunofluorescence were performed to determine ADAR1 expression.Results: The expression of ADAR1 in the liver tissues of CHB patients with concurrent NAFLD was significantly down-regulated compared with that in CHB patients. Enforced expression of ADAR1 inhibited the HBV DNA replication, whereas ADAR1 knockdown resulted in increased HBV DNA expression in palmitic acid - treated HepG2.2.15 cells. Additionally, ADAR1 inhibited the HBV DNA replication by upregulating miR-122, which is most abundant in the liver and mainly inhibits HBV DNA replication.Conclusions: ADAR1 may act as a suppressor of HBV replication in palmitic acid -treated HepG2.2.15 cells by increasing miR-122 levels. Thus, ADAR1 may serve as a potential biomarker and therapeutic target for CHB with concurrent NAFLD.Graphical Abstract: Keywords: chronic hepatitis B, non-alcoholic fatty liver disease, ADAR1, miR-122, HBV DNA

Yuying Xu,1,&ast; Jintao Huang,2,&ast; Yapei Fan,1 Haiyue Long,1 Minting Liang,1 Qunjie Chen,1 Zhiping Wang,2 Chaoxi Wu,1 Yifei Wang1 1Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, People’s Republic of China; 2Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chaoxi Wu; Yifei Wang, Email chaoxiw@gmail.com; twang-yf@163.comAim: This study focuses on constructing of an anti-inflammatory drug delivery system by encapsulation of berberine in the β-glucan nanoparticles and evaluates its effect on treating ulcerative colitis.Methods: β-Glucan and the anti-inflammatory drug berberine (BER) are self-assembled into nanoparticles to construct a drug delivery system (GLC/BER). The interaction between the drug and the carrier was characterized by circular dichroism, ultraviolet-visible spectroscopy, and dynamic light scattering. The anti-inflammatory effect of the GLC/BER was evaluated through a lipopolysaccharide (LPS)-induced RAW264.7 macrophage inflammation model and a sodium sulfate (DSS)-induced C57BL/6 mouse ulcerative colitis model.Results: The GLC/BER nanoparticles have a particle size of 80– 120 nm and a high encapsulation efficiency of 37.8± 4.21%. In the LPS-induced RAW264.7 macrophage inflammation model, GLC/BER significantly promoted the uptake of BER by RAW264.7 cells. RT-PCR and ELISA assay showed that it could significantly inhibit the inflammatory factors including IL-1β, IL-6 and COX-2. Furthermore, GLC/BER shows inhibiting effect on the secretion of pro-inflammatory factors such as IL-1β and IL-6, down-regulating the production of nitrite oxide; in animal studies, GLC/BER was found to exert a relieving effect on mice colitis.Conclusion: The study found that GLC/BER has an anti-inflammatory effect in vitro and in vivo, and the GLC carrier improves the potency and bioavailability of BER, providing a new type of nanomedicine for the treatment of colitis.Keywords: β-glucan, chiral, drug carrier, immunoregulation, anti-inflammation

Zhiguo Zhang,1,2,&ast; Fangda Fu,1,2,&ast; Yishan Bian,1,2,&ast; Huihao Zhang,1,2 Sai Yao,1,2 Chengcong Zhou,1,2 Yuying Ge,2 Huan Luo,3 Yuying Chen,4 Weifeng Ji,1 Kun Tian,1 Ming Yue,5 Weibin Du,6 Hongting Jin,1 Peijian Tong,1 Chengliang Wu,1,2 Hongfeng Ruan1,2 1Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, People’s Republic of China; 2The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 4The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 5Department of Physiology, College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 6Research Institute of Orthopedics, The Affiliated Jiangnan Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongfeng Ruan; Chengliang Wu, Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310053, People’s Republic of China, Fax +86 571 86613684, Email rhf@zcmu.edu.cn; wcl@zcmu.edu.cnBackground: With the rapid growth of the elderly population, the incidence of osteoarthritis (OA) increases annually, which has attracted extensive attention in public health. The roles of dietary intake in controlling joint disorders are perhaps one of the most frequently posed questions by OA patients, while the information about the interaction between dietary intake and OA based on scientific research is limited. α-Chaconine is the richest glycoalkaloid in eggplants such as potatoes. Previous evidence suggests that α-Chaconine is a toxic compound to nervous and digestive systems with potentially severe and fatal consequences for humans and farm animals, but its effect on OA development remains obscure.Objective: To determine whether α-Chaconine deteriorates OA progression through sensory innervation and chondrocyte pyroptosis via regulating nuclear factor-κB (NF-κB) signaling, providing evidence for a possible linkage between α-Chaconine and OA progression.Methods: We established a mouse OA model by destabilization of medial meniscus (DMM) surgery and then intra-articular injection of 20 or 100 μM α-Chaconine into the OA mice for 8 and 12 weeks. The severity of OA progression was evaluated by histological staining and radiographic analyses. The expressions of matrix metabolic indicators, Col2, Mmp3, and Mmp13, as well as pyroptosis-related proteins, Nlrp3, Caspase-1, Gsdmd, IL-1β, IL-18, were determined by immunohistochemistry. And the changes in sensory nerve ingrowth and activity of NF-κB signaling were determined by immunofluorescence.Results: We found that α-Chaconine could exacerbate mouse OA progression, resulting in subchondral sclerosis, osteophyte formation, and higher OARSI scores. Specifically, α-Chaconine could augment cartilage matrix degradation and induce chondrocyte pyroptosis and nerve ingrowth. Mechanistical analysis revealed that α-Chaconine stimulated NF-κB signaling by promoting I-κB α phosphorylation and p65 nuclear translocation.Conclusion: Collectively, our findings raise the possibility that α-Chaconine intake can boost chondrocyte pyroptosis and nerve ingrowth to potentiate OA progression by activating NF-κB signaling.Graphical Abstract: Keywords: α-Chaconine, osteoarthritis, pyroptosis, nerve ingrowth, NF-κB signaling

Yuying Ge,1,&ast; Yuying Chen,2,&ast; Chijiao Guo,1,&ast; Huan Luo,3 Fangda Fu,1,4 Weifeng Ji,1,4 Chengliang Wu,1,4 Hongfeng Ruan1,4 1The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China; 2The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 4Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chengliang Wu, Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310053, People’s Republic of China, Email wcl@zcmu.edu.cn Hongfeng Ruan, Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310053, People’s Republic of China, Email rhf@zcmu.edu.cnAbstract: Low back pain (LBP) is a common problem worldwide, resulting in great patient suffering and great challenges for the social health system. Intervertebral disc (IVD) degeneration (IVDD) is widely acknowledged as one of the key causes of LBP. Accumulating evidence suggests that aberrant pyroptosis of IVD cells is involved in the pathogenesis of IVDD progression, however, the comprehensive roles of pyroptosis in IVDD have not been fully established, leaving attempts to treat IVDD with anti-pyroptosis approaches questionable. In this review, we summarize the characteristics of pyroptosis and emphasize the effects of IVD cell pyroptosis on the pathological progression of IVDD, including secretion of cytokines, nucleus pulposus cell apoptosis and autophagy, accelerated extracellular matrix degradation, annulus fibrosus rupture, cartilage endplate calcification, vascularization, sensory and sympathetic fiber neoinnervation, and infiltrating lymphatic vessels. Finally, we discuss several interventions used to treat IVDD by targeting pyroptosis. This review provides novel insights into the crucial role of IVD cell pyroptosis in IVDD pathogenesis, and could be informative for developing novel therapeutic approaches for IVDD and LBP.Keywords: low back pain, intervertebral disc degeneration, pyroptosis, inflammasome, anti-pyroptotic approach

Wei Wang,1,&ast; Jinyu Gu,1,&ast; Yanxia Liu,2 Xiaoxu Liu,1 Lei Jiang,1 Changfen Wu,1 Jing Liu3 1Department of Obstetrics and Gynecology, Shijiazhuang Maternal and Child Health Care Hospital, Shijiazhuang, Hebei, 050000, People’s Republic of China; 2Department of Pediatrics, Shijiazhuang Maternity and Child Health Care Hospital, Shijiazhuang, Hebei, 050000, People’s Republic of China; 3Department of Reproductive Medicine, Shijiazhuang Maternity and Child Health Care Hospital, Shijiazhuang, Hebei, 050000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jing Liu, Department of Reproductive Medicine, Shijiazhuang Maternity and Child Health Care Hospital, No. 396 South Friendship Street, Shijiazhuang, Hebei, 050000, People’s Republic of China, Email jingll127@tom.comBackground: The novel CRP–albumin–lymphocyte (CALLY) index is an improved immunonutritive scoring system, based on serum C-reactive protein (CRP), serum albumin, and the lymphocyte count. It has been determined as a prognostic index for patients with hepatocellular carcinoma. This study was conducted to explore the prognostic value of the CALLY index in patients with epithelial ovarian cancer (EOC) undergoing surgery.Methods: Patients with EOC treated with surgery as an initial therapy were enrolled to form the training and validation cohorts. The effect of the CALLY index on overall survival (OS) and disease-free survival (DFS) was analyzed using Kaplan–Meier method and Cox proportional hazards model. The CALLY index was calculated as: (Albumin × Lymphocyte)/ (CRP × 104).Results: There were 190 patients in the training cohort and 120 in the validation cohort, respectively. With a cut-off value of 3, patients were classified into the CALLY < 3 and CALLY ≥ 3 groups. The CALLY index ≥ 3 was associated with better survival outcomes both in the training and validation cohorts. The univariate and multivariate COX analysis revealed that FIGO stage, lymphatic metastasis, and CALLY index were the prognostic factors for both OS and DFS.Conclusion: The CALLY index is a novel prognostic biomarker for patients with EOC after surgery. The novel CALLY index could select appropriate patients with poor prognosis for postoperative adjuvant therapy.Keywords: epithelial ovarian cancer, CALLY index, biomarker, survival

Huaiji Wang,1,&ast; Zihan Zhao,2,&ast; Chenghao Wu,3,&ast; Xiaowen Tong,3 Yuling Shi,2 Shunjie Chen1 1Department of Nephrology, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China; 2Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, 200443, People’s Republic of China; 3Department of Obstetrics and Gynecology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shunjie Chen, Department of Nephrology, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China, Email chenshunjie77csj@163.comIntroduction: Transdermal drug delivery provides a desirable alternative method of penetrating the skin for psoriasis treatment, by virtue of its ability to dampen the overactivation of immune cells and inflammation, while attenuating the detrimental effects of systemic administration. Lymph nodes (LNs), as a critical organ of the lymphatic and the acquired immune system, are suitable sites for drug homing to suppress the immune cells.Methods: In this context, we developed a microneedle (MN) patch that delivers nanodrugs locally to LNs for improving the antipsoriatic treatment. In this study, human serum albumin nanoparticles carrying methotrexate (HM) were synthesized and loaded into hyaluronic acid (HA)-based microneedles (HM/MN).Results: The patch showed an excellent ability to pierce the skin, which enhanced drug delivery. In a mouse model of psoriasis, the HM/MN patch significantly prevented the erythema with decreased skin thickness, thus inhibiting the progression of psoriasis. Further analysis for immune cells in LNs, the percent of dendritic cells (DC) and T cells reduced after the local treatment with HM/MN. Notably, the feasibility of targeted delivery of methotrexate to LNs using nanoparticles was verified by detecting increased accumulation of methotrexate in LNs. In addition, the HM/MN patch pronouncedly decreased the levels of tumor necrosis factor α and interleukin 6 in the skin.Conclusion: The results suggested the high efficacy of using the HM/MN patch to treat psoriasis, and provided new insight into the mechanism of the transdermal drug delivery system.Keywords: microneedles, transdermal drug delivery, psoriasis, lymph node homing, nanodrug

Feng Gu,1,2,&ast; Shan Hu,3,&ast; Yunjian Wu,4,&ast; Changyu Wu,4 Ying Yang,5 Bing Gu,6 Hong Du1 1Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, People’s Republic of China; 2Department of Laboratory Medicine, Xuzhou Central Hospital, Xuzhou, 221000, People’s Republic of China; 3Department of Laboratory Medicine, Xuzhou Tumor Hospital, Xuzhou, 221005, People’s Republic of China; 4School of Medical Imaging, Xuzhou Medical University, Xuzhou, 221004, People’s Republic of China; 5Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing Key Laboratory of New Molecular Diagnosis Technologies for Infectious Diseases, Beijing, 100850, People’s Republic of China; 6Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hong Du; Ying Yang, Email hong_du@126.com; y_ying_77@163.comPurpose: Candida infection has a high mortality rate, and the increasing prevalence of non-Candida albicans drug resistance in recent years poses a potential threat to human health. Non-Candida albicans has long culture cycles, and its firm cell walls making it difficult to isolate DNA for sequencing.Materials and Methods: Fe3O4@PEI (PEI, polyvinyl imine) was mixed with clinical samples to form Fe3O4@PEI@non-Candida albicans and enriched them with magnets. Triangular silver nanoplates enhanced the surface-enhanced Raman scattering (SERS) signal. SERS was used to detect the fingerprint spectrum of non-Candida albicans. Then, orthogonal partial least squares discriminant analysis (OPLS-DA) was used to analyze the drug resistance of non-Candida albicans.Results: SERS combined with OPLS-DA could well analyze the drug resistance of non-Candida albicans. Through 10-fold-cross validation, the accuracy of training and test data is greater than 99%, indicating that the model has good classification ability. We used SERS for the first time to detect the drug resistance of non-Candida albicans directly.Conclusion: This approach can be utilized without causing damage to the cell wall and can be accomplished in as little as 90 minutes. It can provide timely guidance for the treatment of patients with good clinical application potential.Keywords: non-Candida albicans, SERS, drug resistance, OPLS-DA

Hongxiang Wei,1,&ast; Fei Chen,1,&ast; Jinyuan Chen,2,&ast; Huangfeng Lin,1 Shenglin Wang,1 Yunqing Wang,1 Chaoyang Wu,1 Jianhua Lin,1 Guangxian Zhong1 1Department of Orthopaedics, Fujian Institute of Orthopaedics, the First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, People’s Republic of China; 2The Centralab, the First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guangxian Zhong; Jianhua Lin, Tel/Fax +86 591 87981029, Email zhongguangxian@163.com; jianhual@126.comPurpose: The objective of this study was to investigate the antitumor activity, targeting capability, and mechanism of the developed nanodrug consisting of doxorubicin and exosome (Exo-Dox) derived from mesenchymal stem cells in vitro and in vivo.Methods: The exosomes were isolated with Exosome Isolation Kit, and the Exo-Dox was prepared by mixing exosome with Dox-HCl, desalinizing with triethylamine and then dialyzing against PBS overnight. The exosome and Exo-Dox were examined by nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). The antitumor activity, targeting capability, and mechanism of the developed Exo-Dox were evaluated by cell viability assay, histological and immunofluorescence analysis and in vivo imaging system.Results: NTA results showed the size of the exosomes had increased from 141.6 nm to 178.1 nm after loading with doxorubicin. Compared with free Dox, the Exo-Dox exhibited higher cytotoxicity against osteosarcoma MG63 cells, HOS cells, and 143B cells than free Dox, the half-maximal inhibitory concentrations (IC50) of Dox, Exo-Dox were calculated to be 0.178 and 0.078 μg mL− 1 in MG63 cells, 0.294 and 0.109μg mL− 1 in HOS cells, 0.315 and 0.123 μg mL− 1 in 143B cells, respectively. The in vivo imaging showed that MSC derived Exo could serve as a highly efficient delivery vehicle for targeted drug delivery. The immunohistochemistry and histology analysis indicated that compared with the free Dox group, the Ki67-positive cells and cardiotoxicity in Exo-Dox group were significantly decreased.Conclusion: Our results suggested that MSC-derived Exo could be excellent nanocarriers used to deliver chemotherapeutic drug Dox specifically and efficiently in osteosarcoma, resulting in enhanced toxicity against osteosarcoma and less toxicity in heart tissue. We further demonstrated the targeting capability of Exo was due to the chemotaxis of MSC-derived exosomes to osteosarcoma cells via SDF1-CXCR4 axis.Keywords: targeted therapy, exosome, doxorubicin, osteosarcoma, nanocarrier

Caihua Wu,1 Yongmin Liu,2 Kexing Wan,2 Yuye Lan,2 Min Jia,3 Lixue Lin,4 Shan Gao,1 Ke Chen,1 Jinmei Yang,1 Hui-Lin Pan,5 Man Li,2 Hongrong Mao1 1Department of Acupuncture, Wuhan First Hospital, Wuhan, Hubei Province, 430030, People’s Republic of China; 2Department of Neurobiology, School of Basic medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, People’s Republic of China; 3Clinical Laboratories, Wuhan First Hospital, Wuhan, Hubei Province, 430030, People’s Republic of China; 4Department of Rehabilitation, Wuhan First Hospital, Wuhan, Hubei Province, 430030, People’s Republic of China; 5Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USACorrespondence: Hongrong Mao, Department of Acupuncture, Wuhan First Hospital, 215 Zhongshan Avenue, Wuhan, Hubei Province, 430030, People’s Republic of China, Tel +86-13277912052, Email 1838269751@qq.comPurpose: The ultrapotent transient receptor potential vanilloid 1 (TRPV1) agonist resiniferatoxin (RTX) induces small-fiber sensory neuropathy, which has been widely used model of postherpetic neuralgia to study mechanisms of neuropathic pain and new analgesics. The long non-coding RNA (lncRNA) and mRNA expression profiles in spinal dorsal horn tissues of rats six weeks after RTX injection to identify new RNAs related to neuropathic pain.Methods: Microarray technology was applied to determine lncRNA expressions in spinal dorsal horn samples of adult rats 6 weeks after treatment with RTX or vehicle. The lncNA/mRNA co-expression network was constructed, and differential expression patterns of lncRNA and mRNA in RTX-treated rats were identified. Differential expressions of lncRNAs and mRNAs between RTX-treated samples and control samples were examined by RT-qPCR.Results: Microarray analyses showed that 745 mRNA and 139 lncRNAs were upregulated, whereas 590 mRNA and 140 lncRNAs were downregulated in spinal dorsal horn tissues after RTX exposure. TargetScan was used to predict mRNA targets for these lncRNAs, which showed that the transcripts with multiple predicted target sites were related to neurologically important pathways. In addition, differential expressions of lncRNA (ENSRNOG00000022535, ENSRNOG00000042027, NR_027478, NR_030675) and Apobec3b mRNA in spinal cord tissue samples were validated, which confirmed the microarray data. The association between NR_030675 and Apobec3b levels was confirmed, which may be related to neuropathic pain.Conclusion: Our study reveals lncRNA and mRNA of molecule targets that are enriched in the spinal cord dorsal horn and provides new information for further investigation on the mechanisms and therapeutics of neuropathic pain.Keywords: postherpetic neuralgia, lncRNAs, microarray, spinal dorsal horn

Cuiyun Wu,1 Lin Zheng,1 Jie Yao2 1Department of Clinical Laboratory, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, Guangdong, People’s Republic of China; 2Department of Laboratory Medicine and Medical Research Center, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, Guangdong, People’s Republic of ChinaCorrespondence: Jie Yao, Department of Laboratory Medicine and Medical Research Center, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), No. 1, Jiazi Road, Lunjiao, Shunde District, Foshan City, Guangdong Province, 528308, People’s Republic of China, Tel +86 757 22318169, Email jie.yao413@yahoo.comBackground: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infection is associated with high mortality and has become a major public problem threatening patients. This study aimed to explore risk factors for death in patients with Klebsiella pneumoniae (KP) and identify risk factors for CRKP infection.Methods: The study retrospectively analyzed clinical characteristics and microbiological data from patients infected with KP from January 2019 to October 2021 to identify risk factors and mortality, using multivariate logistic regression analysis and Cox regression analysis.Results: A total of 214 KP inpatients were enrolled in our study. The in-hospital mortality rate was significantly higher in patients infected with CRKP (13/68, 19.12%) than carbapenem-susceptible KP (CSKP) (2/146, 1.37%) and the difference was statistically significant (P= 0.03). Multivariate Cox regression analysis showed CRKP isolation (HR 12.26, 95% CI 2.43– 61.68, P = 0.002), lower TP (HR 10.50, 95% CI 1.33– 82.76, P = 0.03), antibiotic days of therapy > 15 (HR 0.08, 95% CI 0.01– 0.56, P= 0.01) and length of stay (LOS) (HR 0.03, 95% CI 0.002– 0.61, P= 0.02) were independent risk factors for death from KP. Additionally, intensive care unit (ICU) stay (OR 21.69, 95% CI 4.50– 118.76, P< 0.001) and previous carbapenem exposure (OR 5.26, 95% CI 1.38– 21.19, P= 0.02) are independent risk factors for CRKP.Conclusion: Our findings showed that patients infected with CRKP have a higher in-hospital mortality rate. Identifying the independent risk factors for CRKP infection may contribute to the management of CRKP and reduce the mortality of KP patients.Keywords: carbapenem-resistant, Klebsiella pneumoniae, risk factors, mortality