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Zhiwei Huang,1,* Jiatong Chen,1,* Shenglu Liu,1 Xin Xiang,2 Yang Long,3 Peng Tan,1,4 Wenguang Fu1,4 1Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, People’s Republic of China; 2Department of General Surgery, The First People’s Hospital of Neijiang, Neijiang, 641000, People’s Republic of China; 3Department of Endocrinology and Metabolism, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, People’s Republic of China; 4Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory of Luzhou City, Academician (Expert) Workstation of Sichuan Province, Department of General Surgery (Hepatopancreatobiliary surgery), The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Peng Tan; Wenguang Fu, Department of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, People’s Republic of China, Email tanpeng@swmu.edu.cn; fuwg@swmu.edu.cnBackground: Nonalcoholic steatohepatitis (NASH) has recently garnered increased attention due to immune infiltration. However, the role of membrane-associated protein 17 (MAP17) in NASH remains unclear, which prompted this study to explore its relationship with immune infiltration and its regulatory mechanisms.Methods: We employed weighted correlation network analysis (WGCNA) to construct a gene co-expression network aimed at identifying key genes associated with NASH progression. Our further analyses included differential expression evaluation, protein-protein interaction (PPI) network analysis, and Venn diagram analysis to discover novel targets. The CIBERSORT algorithm assessed the correlation between MAP17 and immune cell infiltration within the tumor microenvironment (TME), while the TIDE algorithm predicted responses to immunotherapy. Additionally, we conducted gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) to elucidate the mechanisms by which MAP17 operates. The expression of MAP17 was validated using liver tissues obtained from NASH patients and mice with diet-induced NASH or CCl4-induced liver fibrosis.Results: Our findings identified MAP17 as a novel target in the progression of NASH. Correlation analyses demonstrated a positive association between MAP17 and M1 macrophage infiltration, as well as a negative association with M2 infiltration. TIDE results positioned MAP17 as a potential biomarker for predicting responses to immune checkpoint blockade. Mechanistic studies revealed that MAP17 induced oxidative stress, which subsequently activated the p53, PI3K-AKT, and Wnt signaling pathways. Validation analyses confirmed that MAP17 levels significantly increased in liver tissues of mice with diet-induced NASH or CCl4-induced liver fibrosis, as well as in NASH patients.Conclusion: MAP17 is a novel biomarker linked to macrophage infiltration and immunotherapy responses in NASH patients. The oxidative stress induced by MAP17 activates the p53, PI3K-AKT, and Wnt pathways, all of which contribute to the progression of NASH.Keywords: NASH, MAP17, macrophage infiltration, immunotherapy response, oxidative stress

Jiabei Li,1,2 Wuchang Fu,3 Na Wang,1 Sisi Zeng,1 Xuechao Li,1 Jixiang Wan,1 Fangjun Wang1 1Department of Anesthesiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, People’s Republic of China; 2Department of Anesthesiology, Meishan City People’s Hospital, Meishan, People’s Republic of China; 3Department of Anesthesiology, The Second Clinical Medical College of North Sichuan Medical College (Nanchong Central Hospital), Nanchong, People’s Republic of ChinaCorrespondence: Fangjun Wang, Department of Anesthesiology, Affiliated Hospital of North Sichuan Medical College, No. 1 Maoyuan South Road, Nanchong, Sichuan, 637000, People’s Republic of China, Tel +86 13458253172, Email wfjlxy006@126.comPurpose: To determine the effect of dexmedetomidine on the ED50 and ED95 of sufentanil in patient-controlled intravenous analgesia (PCIA) after cesarean section.Patients and Methods: Parturients who underwent elective cesarean section (n = 80) were randomly assigned to either the sufentanil group (S group) or the dexmedetomidine-sufentanil combination group (DS group). Patients in the S group received a combination of sufentanil, 5 mg of tropisetron, and saline, whereas patients in the DS group were administered 1.5μg/kg of dexmedetomidine in addition to sufentanil, 5 mg of tropisetron, and saline. The ED50 and ED95 of sufentanil were determined by Dixon sequential method. We used probit regression to calculate the ED50, ED95, and 95% confidence intervals for sufentanil in each group.Results: The ED50 and ED95 for sufentanil in the S group were 1.634 (95% CI: 1.476– 1.810)μg/kg and 2.035 (95% CI: 1.841– 3.312)μg/kg, respectively. The ED50 and ED95 for sufentanil in the DS group were 1.275 (95% CI: 1.187– 1.353)μg/kg and 1.503 (95% CI: 1.406– 1.824)μg/kg. The VAS scores with rest at t5 and with movement at t4- t5 were lower in the DS group (P< 0.05). The t2-t5 Ramsay scores in the DS group were higher than those in the S group (P< 0.05). The doses of sufentanil and tramadol were markedly reduced in the DS group, while the onset of first lactation occurred significantly earlier in the DS group (P< 0.05). Compared with the S group, the DS group had a lower incidence of nausea, vomiting, and skin itching (P< 0.05), and lower frequency of patient-controlled analgesia (PCA) episodes (P< 0.05), and better postoperative pain satisfaction (P< 0.05).Conclusion: The 1.5μg/kg dexmedetomidine can significantly decrease the ED50 and ED95 of sufentanil in patient-controlled intravenous analgesia after cesarean section, provide good postoperative analgesia and sedation, and promote the earlier occurrence of first lactation.Keywords: dexmedetomidine, sufentanil, cesarean section, postoperative analgesia, ED50, ED95

Yunfan He,1,2 Jun Liang,3– 5 Wenguang Fu,6 Yongcheng Liu,7 Fangyu Yang,8 Shunjing Ding,9 Jianbo Lei10– 12 1School of International Relations and Public Affairs, Fudan University, Shanghai, People’s Republic of China; 2National Institute of Intelligent Evaluation and Governance, Fudan University, Shanghai, People’s Republic of China; 3Department of AI and IT, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 4Center for Health Policy Studies, School of Public Health, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 5Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 6Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 7Netease Group, Hangzhou, Zhejiang, People’s Republic of China; 8School of Nursing, Capital Medical University, Beijing, People’s Republic of China; 9Department of Cardiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 10Clinical Research Center, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 11School of Medical Informatics and Engineering, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 12Center for Medical Informatics, Health Science Center, Peking University, Beijing, People’s Republic of ChinaCorrespondence: Jianbo Lei, Center for Medical Informatics, Peking University, Beijing, 100191, People’s Republic of China, Tel +86 (10) 8280-5901, Fax +86 (10) 8280-5900, Email jblei@hsc.pku.edu.cn Shunjing Ding, Department of Cardiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China, Email dsj6890@sina.comBackground: Online health-related misinformation poses a serious threat to public health. As the coronavirus disease 2019 (COVID-19) pandemic aggravated the spread of misinformation regarding COVID-19, relevant research has surged.Objective: To systematically summarize Chinese and English articles regarding health-related misinformation about COVID-19 on social media and quantitatively describe research progress.Methods: Using bibliometrics, we systematically analyzed and compared the characteristics of scientific articles in English and Chinese, examining article numbers, journals, authors, countries, institutions, funding, and research topics, and compared changes in popular research topics.Results: This study analyzed 1,294 articles, revealing a significant increase in article numbers and citations during the COVID-19 pandemic (1.94 times and 2.95 times, respectively, compared to pre-pandemic data). However, high-impact articles were scarce and the field lacked a core group of authors and collaborative networks. China had the largest number of papers (n=266) and funds (n=292), but articles in English exceeded by far those in Chinese (1,131 vs 163, respectively). Regarding article topics, the transformation from qualitative small-data analyses to quantitative empirical big-data research has been realized.Conclusion: With the maturity of natural language processing technology, in-depth mining of massive user-generated content has become a hot spot. The outbreak of the COVID-19 pandemic has prompted the research focus to shift from misinformation-related health problems to social problems involving the sources, content, channels, audiences, and effects of communication networks. Using artificial intelligence technology like machine learning to deeply mine large amounts of user-generated content on social media will be a future research hot spot.Keywords: misinformation, online health information, social media, COVID-19, Chinese, English

Xudong Che, Baixue Wu, Hongxia Zhang, Dengzhi Jiang, Wenqiao Fu, Zhaohui He Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Zhaohui He, Email geno_he@163.comBackground: Hemoglobin decrement is a common complication after aneurysmal subarachnoid hemorrhage (aSAH) and is associated with poor outcome. However, the mediating variables on the causal pathway between hemoglobin decrement and poor outcome in aSAH are not clear.Methods: This is a single-center retrospective observational study containing all consecutive patients with aSAH admitted to our hospital between January 1, 2019, and June 30, 2022. Hemoglobin decrement was defined as the hemoglobin at admission minus the minimum hemoglobin during hospitalization. Calculation of cutoff value using ROC curve Youden index. The main exposure of interest was a hemoglobin decrement greater than the cutoff value. The primary outcome was poor outcome at 3 months (mRS 4– 6).Results: A total of 480 patients with aSAH were included in the study, 414 (71.1%) had a favorable and 66 (28.9%) had a poor outcome at 3 months. The cut-off value for calculating the degree of hemoglobin decrease using the ROC curve was 12.5 g/l. Hemoglobin decrement greater than the cutoff value was significantly associated with pneumonia (OR 3.12; 95% CI 1.78– 5.57; p < 0.001), cerebral infarction (OR 3.06; 95% CI 1.80– 5.30; p < 0.001), and poor prognosis (OR 2.88; 95% CI 1.44– 5.92; p = 0.003) at 3 months. The mediation effect was significant for both pneumonia and cerebral infarction, with the average causal mediation effect (ACME) were 0.04 (95% CI 0.02– 0.08; p < 0.05) and 0.05 (95% CI 0.02– 0.08; p < 0.001), respectively.Conclusion: Hemoglobin decrement during hospitalization was significantly associated with poor prognosis after aSAH, and the increased risk of cerebral infarction and pneumonia might mediate this effect. Avoiding hemoglobin decrement greater than 12.5g/l may improve the prognosis of patients with aSAH.Keywords: aneurysmal subarachnoid hemorrhage, hemoglobin decrement, cerebral infarction, pneumonia

Mei Song, Meng Zhang, Jia Han, Wenjiang Fu Department of Infectious Diseases, Jiashan County First People’s Hospital, Jiashan, Zhejiang, 314100, People’s Republic of ChinaCorrespondence: Mei Song; Wenjiang Fu, Department of Infectious Diseases, Jiashan County First People’s Hospital, Jiashan, Zhejiang, 314100, People’s Republic of China, Email songmeiarticle@163.com; fwjtjh168@sina.comBackground: The present study aimed to construct and validate a nomogram based on clinical metrics to identify CPTB.Patients and Methods: The present study retrospectively recruited pulmonary tuberculosis (PTB) patients admitted to Jiashan County First People’s Hospital in China from November 2018 to September 2023. PTB patients were classified into the CPTB group and the non-CPTB group based on chest computed tomography findings, and were randomly allocated to the training set (70%) and the validation cohort (30%). The training set and validation set were used to establish and validate nomogram, respectively. Multivariate logistic regression analysis (MLSA) was used to identify the independent risk factors for CPTB in patients with PTB. Statistically significant variables in the MLSA were then used to construct a nomogram predicting CPTB in patients with PTB. The receiver operating characteristic (ROC) curve, calibration curve analysis (CCA), and decision curve analysis (DCA) were used for the evaluation of the nomogram.Results: A total of 293 PTB patients, including 208 in the training set (85 CPTB) and 85 in the validation set (33 CPTB\), were included in this study. Stepwise MLSA showed that sputum smear (≥ 2+), smoking(yes), glycosylated hemoglobin A1c(HbA1c), hemoglobin (HB), and systemic inflammatory response index (SIRI) were independent risk factors for the development of cavitation in patients with PTB. The nomogram identifying the high-risk CPTB patients was successfully established and showed a strong predictive capacity, with area under the curves (AUCs) of 0.875 (95% CI:0.806– 0.909) and 0.848 (95% CI:0.751– 0.946) in the training set and validation set respectively. In addition, the CCA and DCA corroborated the nomogram’s high level of accuracy and clinical applicability within both the training and validation sets.Conclusion: The constructed nomogram, consisting of sputum smear positivity, smoking, HbA1C, HB, and SIRI, serves as a practical and effective tool for early identification and personalized management of CPTB.Keywords: pulmonary tuberculosis, cavitation, nomogram

Lina Zhang,1– 3,&ast; Ruibin Wu,2,3,&ast; Tenghui Ma,2,3 Wenwen Fu,2,3 Jiamin Chen,2,3 Lingling Li,2,3 Qing He2,3 1The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, 510080, People’s Republic of China; 2Department of Clinical Nutrition and Microbiome; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, People’s Republic of China; 3Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qing He, Email heqing5@mail.sysu.edu.cnObjective: To explore the active substances and targets of Danbie Capsules in Endometriosis therapy.Methods: This study was conducted through TCMSP and published literature screened and obtained 183 active substances of Danbie Capsules, combined and intersected with Endometriosis target genes collected and screened in the GEO database, obtained 24 target genes for Endometriosis treatment, and mapped the target network map of Danbie Capsules active substances against Endometriosis. The network was analyzed with the aid of Cytoscape version 3.9.1. With the aid of the platform of the STRING data analysis, PPI network analysis was conducted on 24 anti-Endometriosis targets of the Danbie Capsules.Results: The research results obtained three critical active substances, namely, Quercetin, β-sitosterol, and Luteolin. Seven critical targets were identified, and two representative genes (TP53 and AKT1) have been verified in Macromolecular docking and immunohistochemical verification.Conclusion: The active substances of Danbie Capsules in the treatment of Endometriosis are Quercetin, β-sitosterol and Luteolin, and the main targets are TP53 and AKT1.Keywords: danbie capsules, endometriosis, network pharmacology

Wanlan Fu,1 Yunxiang Cao,2 Jian Liu,2 Chuanbing Huang,2 Kaiyan Shu,1 Nanfei Zhu1 1First Clinical Medical College, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, People’s Republic of China; 2Department of Rheumatology, First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, 230031, People’s Republic of ChinaCorrespondence: Yunxiang Cao, Department of Rheumatology, First Affiliated Hospital of Anhui University of Chinese Medicine, 117 Meishan Road, Shushan District, Hefei, Anhui, 230031, People’s Republic of China, Tel +86-13514984395 ; +0551-62838591, Email cyx800805@163.comPurpose: This study probed the mechanism of action of Xinfeng Capsule (XFC) in myocardial injury in rats with adjuvant arthritis (AA) via the growth arrest-specific transcript 5 (GAS5)/microRNA-21 (miR-21)/Toll-like receptor 4 (TLR4) axis.Methods: Rats were injected with Freund’s complete adjuvant to establish a rat model of AA. Then, some modeled rats were given normal saline or drugs only, and some modeled rats were injected with adeno-associated viruses or necrosulfonamide (NSA; a pyroptosis inhibitor) before drug administration. Toe swelling and arthritis index (AI) were calculated. Pathological and morphological changes in synovial and myocardial tissues were analyzed with hematoxylin-eosin staining, and pyroptotic vesicles and the ultrastructural changes of myocardial tissues were observed with transmission electron microscopy. The serum levels of interleukin (IL)-1β, IL-18, IL-6, and tumor necrosis factor (TNF)-α were detected, and lactate dehydrogenase (LDH) release was measured in myocardial tissues, accompanied by the examination of GAS5, miR-21, TLR4, nuclear factor-kB (NF-κB) p65, nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), Caspase-1, and Gasdermin D (GSDMD) expression in myocardial tissues.Results: After AA modeling, rats presented with significantly increased toe swelling and AI scores, synovial and myocardial tissue damage, elevated pyroptotic vesicles, and markedly enhanced serum levels of IL-1β, IL-18, IL-6, and TNF-α, accompanied by significantly diminished GAS5 expression, substantially augmented miR-21, TLR4, NF-κB p65, NLRP3, Caspase-1, and GSDMD expression, greatly increased LDH release in myocardial tissues. XFC treatment significantly declined toe swelling, AI scores, synovial and myocardial tissue damage, and the serum levels of IL-1β, IL-18, IL-6, and TNF-α in AA rats. Additionally, XFC treatment markedly elevated GAS5 expression and substantially lowered LDH release and miR-21, TLR4, NF-κB p65, NLRP3, Caspase-1, and GSDMD expression in myocardial tissues of AA rats. Moreover, the above effects of XFC in AA rats were further promoted by GAS5 overexpression or NSA treatment.Conclusion: XFC alleviated myocardial injury in AA rats by regulating the GAS5/miR-21/TLR4 axis and inhibiting pyroptosis and pro-inflammatory cytokine secretion.Keywords: adjuvant arthritis, myocardial injury, GAS5/miR-21/TLR4 axis, pyroptosis, Xinfeng Capsule

Yujian Shao,1,2 Yonglu Chen,2 Mingyue Zhu,3 Yuanyuan Liu,2 Chen Fang,3 Minjun Wang,2 Peng Sun,3 Weiling Fu,2 Jing Huang,3 Shimei Sheng,2 Yanshan Huang2 1Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Innovative Drug Discovery and Development, Zhejiang Doer Biologics Co., Ltd, Hangzhou, Zhejiang, People’s Republic of China; 3First Research Institute, Zhejiang Heze Pharmaceutical Technology Co., Ltd, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Yanshan Huang, Department of Innovative Drug Discovery and Development, Zhejiang Doer Biologics Co., Ltd, Hangzhou, Zhejiang, People’s Republic of China, Email yanshanhuang@doerbio.comIntroduction: Diabetes and obesity are momentous risk factors threatening people’s lives and health. Currently available incretin analogue glucagon-like peptide 1 (GLP-1) possesses huge hypoglycemic effect with the unsatisfactory effect of weight loss. Co-agonists targeting GLP-1R plus glucagon receptor (GCGR) or gastric inhibitory polypeptide receptor (GIPR) show synergistic benefits in glycaemic control and weight loss. Here, we describe a novel dual GIP and GLP-1 receptor agonist, DR10627, and performed a preclinical assessment of it.Methods: The agonistic ability of DR10627 was indirectly assessed by inducing cAMP accumulation in Chinese hamster ovary (CHO) cells transfected with GLP-1R or GIPR in vitro. The plasma pharmacokinetics of DR10627 were analysed in cynomolgus monkeys. The OGTTs were performed in Sprague‑Dawley (SD) rats. The glucose lowering effects were evaluated by repeated administration of DR10627 in diabetic (db/db) mice for 4 weeks. The effects of anti-obesity and improving metabolism of DR10627 were evaluated by repeated administration of DR10627 in diet-induced obesity (DIO) mice for 57 days.Results: DR10627 had the capacity to activate both GLP-1R and GIPR in vitro. The terminal half-life of DR10627 was found to be approximately 4.19– 5.8 h in cynomolgus monkeys. DR10627 had a great improvement in oral glucose tolerance in SD rats. Moreover, DR10627 had a potent glucose-lowering effect in db/db mice, and the hypoglycemic effect of 18 nmol/kg DR10627 was better than that of 50 nmol/kg liraglutide. In addition, 10 and 30 nmol/kg DR10627 possessed the ability of potentiating the weight-loss, lipid-lowing efficacy and improving metabolism to a greater extent than 80 nmol/kg liraglutide.Conclusion: Preclinical assessment demonstrated that administration of DR10627 resulted in glucose lowering in SD rats and db/db mice, and substantial body weight reduction and metabolism improvement in DIO mice. DR10627 is a promising agent deserving further investigation for the treatment of type 2 diabetes and obesity.Keywords: glucagon-like peptide-1, gastric inhibitory polypeptide receptor, obesity, type 2 diabetes, inflammation

Wenxian Fu,1– 4 Xinyi Li,1– 4 Sifan Ji,1– 4 Tingting Yang,1,3– 5 Lu Chen,1,3– 5 Yaru Guo,1,3– 5 Kongliang He1– 5 1Affiliated Psychological Hospital of Anhui Medical University, Hefei Fourth People’s Hospital, Hefei, 230022, People’s Republic of China; 2School of Mental Health and Psychological Sciences, Anhui Medical University, Hefei, 230022, People’s Republic of China; 3Anhui Mental Health Center, Hefei Fourth People’s Hospital, Hefei, 230022, People’s Republic of China; 4Psychiatry Department, Hefei Fourth People’s Hospital, Hefei, 230022, People’s Republic of China; 5Psychological Counseling department, Hefei Fourth People’s Hospital, Hefei, 230022, People’s Republic of ChinaCorrespondence: Kongliang He, Affiliated Psychological Hospital of Anhui Medical University, Hefei Fourth People’s Hospital, Hefei, 230022, People’s Republic of China, Tel +8613966721862, Email hefei413@126.comObjective: Non-suicidal self-injury (NSSI) behavior is very common in adolescents with depression, and childhood trauma is considered one of the distal risk factors for its exacerbation. Rumination caused by adverse traumatic experiences, which can be transferred through NSSI behavior, can alleviate symptoms of depression in adolescents. The current research focuses on the relationship between the three, further exploring whether rumination is a mediator in the relationship between childhood trauma and NSSI behavior on the basis of previous studies, and provides some suggestions for future early intervention for adolescents with depression.Methods: A total of 833 adolescent patients with depression who met the DSM-5 criteria for depressive episode were recruited from 12 hospitals in China. The Chinese version of the Function Assessment of Self-mutilation, Childhood Trauma Questionnaire, and Rumination Inventory were used as research tools.Results: The scores of childhood trauma and rumination in adolescents with depression in the NSSI group were higher than those in the non-NSSI group. A Pearson’s correlation analysis showed that childhood trauma was positively correlated with rumination (r=0.165, P< 0.01), different types of childhood trauma were significantly positively correlated with rumination and its three factors, and these results were statistically significant. Rumination partially mediated the relationship between childhood trauma and NSSI behavior in depressed adolescent patients (effect size=0.002), and the effect in female participants (effect size=0.003), was greater than that in male participants (effect size=0.002).Conclusion: Childhood trauma and rumination were key factors for NSSI behavior in adolescents with depression. Childhood trauma not only has a direct effect on NSSI behavior in adolescent depression, but also plays an indirect effect on NSSI behavior through rumination.Keywords: adolescents, childhood trauma, rumination, non-suicidal self-injury

Tianli Zheng,1,2 Weiwei Fu,1,2 Shuang Jiang,3 Xiaodong Yang1,2 1School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China; 2Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou, Jiangsu, People’s Republic of China; 3The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, People’s Republic of ChinaCorrespondence: Xiaodong Yang, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, No. 88, Keling Road, Suzhou, Jiangsu Province, 215000, People’s Republic of China, Email xiaodong.yang@sibet.ac.cnPurpose: The prevalence of obesity and myopia in young people is increasing worldwide; however, the association between body mass index (BMI) and myopia remains controversial. This study aimed to assess the association between BMI and myopia in Chinese schoolchildren.Patients and Methods: In this study, the open data for analysis were obtained from DATADRYAD website (www.datadryad.org). A total of 3658 children were enrolled in this study. Logistic regression model was used to analyze the relationship between BMI and myopia.Results: Compared with individuals with lower BMI Q1 (less than 25 kg/m2), the adjusted odds ratios (ORs) for BMI and myopia were 2.15 (95% confidence interval [CI]: 1.62– 2.86) in Q2 (25.0– 29.9 kg/m2) and 2.39 (95% CI: 1.37– 4.18) in Q3 (30.0 kg/m2 or more). Moreover, the association between BMI and myopia exhibited an inverted L-shaped curve (nonlinear; p < 0.001). When the BMI was < 25 kg/m2, an increased BMI was significantly associated with a higher risk of myopia (OR = 1.244 [95% CI: 1.211– 1.277], p < 0.001). However, when the BMI was ≥ 25 kg/m2, the association lost its significance (OR = 1.063 [95% Cl: 0.964– 1.171], p = 0.219).Conclusion: This study found an inverted L-shaped association between BMI and myopia in Chinese schoolchildren. A higher BMI was associated with a higher risk of myopia reaching 25 kg/m2, after which an increase in BMI was no longer associated with an increased risk of myopia.Keywords: myopia, body mass index, cross-sectional, schoolchildren, logistic regression

Wenying Yi,1,2 Haibo Wu,1,2 Weibin Fu,1,2 Huimei Feng,1,2 Jie Huang,1,2 Haijing Li,1,2 Zhen Song,1,2 Yuwei Chen,1,2 Yingjun Zheng,1,2 Shenglin She1,2 1Department of Psychiatry, the Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China Guangzhou Medical University, Guangzhou, People’s Republic of ChinaCorrespondence: Shenglin She, Department of Psychiatry, the Affiliated Brain Hospital of Guangzhou MedicalUniversity, No. 36 Mingxin Road, Liwan District, Guangzhou, People’s Republic of China, Tel +86-13825154669, Fax +86-20-82068107, Email shenglinshe@gzhmu.edu.cnBackground: To assess the prevalence and risk factors of NAFLD in non-obese patients with schizophrenia in a public psychiatric hospital in China.Methods: A total of 1,305 adult inpatients with schizophrenia in 2019 were included in this retrospective study. Body mass index (BMI) ≥ 25 kg/m2 was considered obese, and BMI < 25 kg/m2 was considered non-obese. We obtained the data from electronic records of the Affiliated Brain Hospital of Guangzhou Medical University.Results: A total of 1,045 non-obese patients and 260 obese patients were included in this study. The prevalence of NAFLD in non-obese patients was 25.0%, and it was much lower that in the obese patients (25.0% vs 64.6%, p < 0.001). Among the non-obese patients, there were significant differences in age, BMI, alanine aminotransferase (ALT), metabolic indices, and the prevalence of diabetes and hypertension between patients with NAFLD and patients without NAFLD. According to the results of binary logistic regression analysis, age, BMI, ALT, triglyceride (TG) and diabetes were significantly related to NAFLD among non-obese patients with schizophrenia. In contrast, HDL-C was was negatively associated with NAFLD among non-obese patients.Conclusion: This study suggested that NAFLD was common in patients with schizophrenia, even in non-obese patients with schizophrenia. In non-obese patients with schizophrenia, age, BMI, ALT, TG and diabetes are significantly associated with NAFLD. Moreover, HDL-C level was an independent protective factor against NAFLD. Given the adverse outcomes of NAFLD, it is necessary to increase awareness of NAFLD in patients with schizophrenia, especially in non-obese patients with schizophrenia.Keywords: schizophrenia, NAFLD, non-obese, obese, risk factors, China

Rui Zhao, Jing Zhao, Yichuan Song, Wenxuan Fu, Qingtao Wang, Rui Zhang Department of Clinical Laboratory, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Qingtao Wang; Rui Zhang, Department of Clinical Laboratory, Beijing Chao-yang Hospital, Capital Medical University, No. 8, Gongtinan Road, Chao-Yang District, Beijing, 100020, People’s Republic of China, Tel +86 1085231660, Email wqt36@163.com; zr189169@163.comPurpose: Outcomes after autologous stem cell transplantation (ASCT) are quite variable and difficult to predict. Second-generation flow, second-generation sequencing, and other tests are invasive and expensive for patients. In this study, we aimed to analyze laboratory data before and after transplantation to look for laboratory indicators that could predict disease progression in patients with newly diagnosed multiple myeloma (NDMM) patients underwent ASCT.Patients and Methods: Standard complete blood count (CBC) parameters, clinical biochemical, and immunological indicators on day -5 and day 90 after ASCT were obtained. Receiver-operating characteristic (ROC) curve was used to determine the cutoff values, we evaluated the predictive abilities of laboratory parameters for progression-free survival (PFS). Univariate and multivariate analyses were performed to evaluate the prognostic significance of variables associated with the PFS of 166 NDMM who underwent ASCT.Results: At day-5, a low absolute monocyte count (AMC, p=0.001), systemic inflammation response index< 1.56 (SIRI, P=0.03), serum calcium (p=0.02), and albumin (p=0.006) can predict for superior PFS. At Day +90, a high absolute neutrophil count (ANC, p = 0.008) and lymphocyte-to-monocyte ratio (LMR, p = 0.02), a low neutrophil-to-lymphocyte ratio (NLR, p =0.02) and SIRI< 0.41 (p=0.02) predicted for superior PFS.Conclusion: There are inflammation-related indicators derived from peripheral blood cell count (WBCC) – ANC, NLR, SIRI, and LMR - which can serve as potential biomarkers for predicting PFS of NDMM patients underwent ASCT.Keywords: multiple myeloma, autologous stem cell transplantation, SIRI, lymphocyte-to-monocyte ratio

Chunhui Shu,1,&ast; Jiaqiang Zhou,2,&ast; Hongqiong Yu,1 Weijing Fu,1 Jiayi Shen,1 Linchun Liang,3 Lisi Zheng,4 Lin Mao,5 Xuyan Fu,4 Tao Lv,4,6 Yunbo Chen4 1Department of Laboratory Medicine, Ningbo Mingzhou Hospital, Ningbo, People’s Republic of China; 2Department of Neurosurgery, Ningbo Mingzhou Hospital, Ningbo, People’s Republic of China; 3Department of Oncology, Ningbo Mingzhou Hospital, Ningbo, People’s Republic of China; 4State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 5Department of Rehabilitation Medicine, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 6Jinan Microecological Biomedicine Shandong Laboratory, Jinan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tao Lv; Yunbo Chen, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China, Tel/Fax +86 571-87236756, Email xifan_lvtao@163.com; chenyunbo@aliyun.comBackground: Clostridioides difficile is an important pathogen causing approximately 20– 30% of the cases-with antibiotic-associated diarrhea and 90% of those with Pseudomembranous enteritis. However, limited surveillance of C. difficile infections (CDI) in China is done at present, especially in terms of multi-hospital epidemiological reports.Methods: Between June 2020 and November 2020, we conducted a prospective study addressing antimicrobial susceptibility profiles and genomic epidemiology of C. difficile strains isolated from inpatients with diarrhea in seven tertiary hospitals in the same city.Results: In total, 177 strains of toxin-producing C. difficile were isolated, and the dominant toxin gene profiles were tcdA+tcdB+ (84.2%, 149/177) and tcdA-tcdB+ (15.8%, 28/177). Furthermore, 130 isolates were successfully analyzed for antimicrobial susceptibility phenotype in which the rates of resistance to clindamycin, erythromycin, levofloxacin, and moxifloxacin were higher than to other antibiotics. All strains were susceptible to metronidazole and vancomycin. Fluoroquinolone-associated mutations (such as gyrA) were the most frequently found ones in the analyzed genomes. Moreover, 24 different sequence types (STs) were identified in the 130 isolates, and the most prevalent types were ST3 (26.2%, 34/130) followed by ST54 (16.9%, 22/130) and ST2 (10%, 13/130). The so-called highly virulent strain ribotyping 027 (B1/NAP1/ST1) was not identified. In addition, we also compared single nucleotide polymorphisms (SNPs) among the isolates and carried out genomic epidemiological studies on the isolates. We found that ST3 and ST54 could cause transmission in both intra- and inter-hospital settings.Conclusion: Although it is the so-called hypervirulent epidemic strain, ribotyping 027 (ST1), was not detected. ST3 and ST54 can be transmitted through different hospitals. Therefore, it is necessary to conduct further molecular epidemiological monitoring of C. difficile and screening of patients admitted to key departments.Keywords: Clostridioides difficile infection, genomic analysis, toxin gene, antibiotic resistance, transmission

Shouying Li,1,&ast; Jiaxin Feng,2,&ast; Haiyan Weng,1 Feng Zhao,3 Guohui Cui,1 Wenkui Fu,1 Xiaorong Lin,4 Hai Hu1,5 1Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 2The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 3Research and Development Department, Guangzhou BioBlue Technology Co. Ltd, Guangzhou, People’s Republic of China; 4Diagnosis and Treatment Center of Breast Diseases, Shantou Central Hospital, Shantou, People’s Republic of China; 5Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaorong Lin; Hai Hu, Email clarelynn_lin@163.com; huhai@mail.sysu.edu.cnPurpose: For better understanding of radiotherapy resistance and its potential mechanism.Methods: We established radioresistance cell lines of non-small cell lung cancer (NSCLC) followed by microarray analysis. 529 differentially expressed genes (DEGs) were then screened between radiation resistant cell lines compared with the sensitive cell lines. The biological functions and enrichment pathways of the above DEGs were identified using Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) enrichment analyses. Gene Set Enrichment Analysis (GSEA) revealed that the radiation resistance group had the most gene sets enriched in altered immune response, such as TNF signaling pathway, when compared to the radiation sensitive group. Protein-protein interaction (PPI) network was carried out through the STRING database, and then five hub genes (CXCL10, IFIH1, DDX58, CXCL11, RSAD2) were screened by Cytoscape software. RT-PCR confirmed the expression of the above hub genes. ChIP-X Enrichment Analysis showed that STAT1 might be the transcription factor of the above hub genes. Considering that PD-L1 could be activated by STAT1 in a variety of tumors and ultimately lead to immune exhaustion, RT-PCR and Western blot verified the expression level of PD-L1.Results: Five hub genes (CXCL10, IFIH1, DDX58, CXCL11, RSAD2) were screened and verified to be highly expressed in radioresistance group, STAT1 might be the transcription factor of the above hub genes. Our study found that the expression level of PD-L1 was increased after radiotherapy resistance.Conclusion: Although immune system activation occurs followed by radiation resistance, we hypothesized that the upregulation of PD-L1 expression caused by STAT1 activation might be one of the mechanisms of radiotherapy resistance.Keywords: NSCLC, radioresistance, DEGs, hub gene, STAT1

Jia Zhou,1,&ast; Yi Chen,1,&ast; Yi Xu,2,&ast; Bin Liao,3 Wenguang Fu4 1School of Humanities and Management Science, Southwest Medical University, Luzhou, SiChuan, 646000, People’s Republic of China; 2Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, People’s Republic of China; 3Department of Cardiovascular Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, SiChuan, 646000, People’s Republic of China; 4Department of Hepatobiliary Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenguang Fu, Department of Hepatobiliary Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China, Tel +86-13982770568, Email fuwg@swmu.edu.cn Bin Liao, Department of Cardiovascular Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, SiChuan, 646000, People’s Republic of China, Tel +86-0830-3162306, Email liaobin@swmu.edu.cnPurpose: This study explored the relationship between emotion and death-thought accessibility (DTA) in individuals experiencing true mortality salience (MS), specifically, patients with cancer.Patients and Methods: The study included 255 participants; among them, 132 patients had cancer and represented the MS group, and 123 had dental pain and served as a control group. Participants completed the Projective Diseases Attitude Assessment Questionnaire to induce priming, completed an affect scale, completed one of four calculation tasks as manipulation of cognitive load (all four were done over several sessions), and performed a Pinyin-Chinese characters exercise to measure DTA.Results: MS was associated with strong negative emotional arousal. When these negative emotions are generated, they enter an individual’s consciousness and activate proximal defense mechanisms. At this point, DTA can be measured. Patients with cancer had significantly higher levels of DTA in the high-frequency cognitive load condition than in the other three conditions (no task, simple delay task, and single cognitive load task). Patients with dental pain had significantly higher levels of DTA in the no task and simple delay conditions than in the single cognitive load or high-frequency cognitive load conditions. This study also found that negative experiences without MS (specifically, dental pain) are associated with higher levels of DTA.Conclusion: These findings suggest that in addition to death-related events, both negative and stress-inducing events can produce DTA.Keywords: mortality salience, cancer, terror management theory, proximal defense mechanisms

Danni Zheng,1,&ast; Weida Fu,1,&ast; Lingli Jin,1,&ast; Xiaofang Jiang,2 Wenjie Jiang,1 Yaoyao Guan,3 Rutian Hao1 1Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 3Department of Plastic Surgery, Sir Run-Run Hospital Affiliated to Zhejiang University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yaoyao Guan, 3 Qingchun East Road, Jianggan District, Hangzhou, Zhejiang, People’s Republic of China, Tel +86 571-86006618, Fax +86 571-86044817, Email gyykq748@163.com Rutian Hao, South White Elephant Warm hospital first New Area, Ouhai District, Wenzhou, Zhejiang, People’s Republic of China, Tel +86 577 5557, Fax +86 577-55578033, Email hrtwenzhou@163.comPurpose: To explore the mechanism of AP1S1 in breast cancer.Methods and Results: In different datasets, we found that AP1S1 is more highly expressed in breast tumors, which was furthermore verified in our local cohort.Immune infiltration analysis showed that AP1S1 was related to a variety of immune cells. The higher AP1S1 expression was negatively correlated with a variety of immune infiltrating cells, suggesting that AP1S1 may affect cellular immunity.Clinical analysis showed that patients with higher AP1S1 expression had higher estrogen receptor gene expression and were more prone to distant metastasis and lymph node metastasis.The overall survival rate, disease-specific survival rate, and progression-free interval time were worse in the group with higher AP1S1 expression. AP1S1 may be a potential oncogene of breast cancer, and overexpression is related to the poor prognosis of breast cancer.Therefore, a nomogram was constructed, along with correlated gene analysis and functional analysis to further explore the carcinogenic mechanism, practical clinical issues, and value of AP1S1.Conclusion: AP1S1 is a potential oncogene of breast cancer.Keywords: breast cancer, AP1S1, immune infiltration, prognosis, oncogene

Weida Fu,&ast; Shurong Zheng,&ast; Jieyu Zhou, Kangkang Lu, Yiqiao Lu, Guilong Guo Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guilong Guo, Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China, Tel/Fax +86-13867709361, Email guoguilong@sina.comAbstract: Male breast carcinoma metastatic to the choroid is very rare and often related to poor prognosis. Herein, we report the findings in a Chinese male breast cancer patient who developed choroidal metastasis, and give opinions on systemic treatments. A 45-year-old Chinese male represented with difficulty breathing and visual impairment in the left eye 6 years after his breast cancer surgery and postoperative adjuvant treatment. PET/CT revealed multi-organs metastasis of the patient. The IHC indicated the lung lesion to be originated from the breast (ER+/PR+/HER2-). Eye examination provided evidence for breast cancer choroidal metastasis. Two cycles of TX (docetaxel + capecitabine) followed by two courses of GP (gemcitabine + cis-platinum) were applied as salvage chemotherapy. Metastases in his lung and bone remained stable. As for choroidal metastasis, a regimen of CDK4/6 inhibitor (Palbociclib) plus fulvestrant was recommended to the patient, which led to a good response. Notably, CDK4/6 inhibitor combined with endocrine therapy may be considered as an effective treatment for hormonal receptor-positive breast cancer patients with choroidal metastasis. We recommend that eye examination should not be neglected in breast cancer patients.Keywords: choroidal metastasis, male breast cancer, systemic therapy, CDK4/6 inhibitor, case report

Di Zhang, Yi Li, Heping Li, Weifeng Fu, Jing Zeng, Xi Zeng Department of Rehabilitation Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, Henan Province, People’s Republic of ChinaCorrespondence: Xi ZengDepartment of Rehabilitation Medicine, The First Affiliated Hospital of Zhengzhou University, Huiji District, Zhengzhou City, Henan Province, People’s Republic of China, Tel +861 359 250 5588, Email zengxikangfu@126.comPurpose: This study investigated the factors that influence the prognosis of swallowing function rehabilitation therapy in patients with dysphagia after medullary infarction.Patients and Methods: This retrospective study was conducted using the clinical data of 51 patients who were diagnosed with dysphagia after medullary infarction and hospitalized at our institution between January 2019 and January 2021. As per the water swallow test (WST) grade at 1 month after rehabilitation treatment, patients were classified into the good prognosis group and the poor prognosis group. Univariate analysis as well as univariate and multivariate logistic regression analysis were used to analyze factors that influence the prognosis of swallowing function rehabilitation therapy in patients with dysphagia after medullary infarction. Receiver operating characteristic (ROC) curves were then used to test the predictive ability of the significant parameters to predict the prognosis of the rehabilitation therapy in these patients.Results: Univariate analysis and univariate logistic regression analysis showed that previous stroke (odds ratio [OR] = 1.361), dysarthria (OR = 3.771), disease course (OR = 1.112), National Institutes of Health Stroke Scale (NIHSS) score at admission (OR = 2.596), and infarct site (OR = 11.071) were all significantly correlated with the prognosis of swallowing function rehabilitation therapy in patients with dysphagia after medullary infarction (P < 0.05). Multivariate logistic regression analysis showed that dysarthria (OR = 5.519, 95% confidence interval (CI) 1.413– 21.566), infarct site (OR = 18.634, 95% CI 1.696– 204.73), and the NIHSS score (OR = 1.001, 95% CI 1.536– 4.820) were independent influencing factors of the prognosis of swallowing function rehabilitation therapy in these patients. The ROC curve showed that the area under the curve for the combined prediction of the three indicators was 0.943.Conclusion: The NIHSS score, dysarthria, and infarct site are independent influencing factors for the prognosis of swallowing function rehabilitation therapy in patients with dysphagia after medullary infarction.Keywords: medullary infarction, dysphagia, rehabilitation, prognosis, influencing factors

Hao Ren,1,2,&ast; Jie Liu,1,3,&ast; Jiwei Zhang,4 Baixi Zhuang,5 Weiguo Fu,6 Danming Wu,7 Feng Wang,8 Yu Zhao,9 Pingfan Guo,10 Wei Bi,11 Shenming Wang,12 Wei Guo1,3 1Medical School of Chinese PLA, Beijing, 100853, People’s Republic of China; 2Department of Vascular Surgery, Dalian Municipal Central Hospital, Dalian, 116033, People’s Republic of China; 3Department of Vascular and Endovascular Surgery, Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China; 4Department of Vascular Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200120, People’s Republic of China; 5Department of Vascular Surgery, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100080, People’s Republic of China; 6Department of Vascular Surgery, Zhongshan Hospital Fudan University, Shanghai, 200032, People’s Republic of China; 7Department of Vascular Surgery, The People’s Hospital of Liaoning Province, Shenyang, 110016, People’s Republic of China; 8Department of Interventional Therapy, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People’s Republic of China; 9Department of Vascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400042, People’s Republic of China; 10Department of Vascular Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, People’s Republic of China; 11Department of Vascular Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050073, People’s Republic of China; 12Department of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510055, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei GuoDepartment of Vascular and Endovascular Surgery, Chinese PLA General Hospital, Beijing, 100853, People’s Republic of ChinaTel +86-10-66938049Fax +86-10-66938149Email Guoweiplagh@sina.comObjective: To evaluate the long-term outcomes after drug-coated balloon (DCB) angioplasty dissection in patients with complex femoropopliteal artery disease.Methods: Two hundred patients with femoropopliteal peripheral artery disease were enrolled in the AcoArt I trial and randomly assigned to either the DCB or percutaneous transluminal angioplasty (PTA) group. A total of 86 patients with post-balloon angioplasty dissection were reanalyzed. The primary endpoint was clinically driven target lesion revascularization (CD-TLR) over five years. Kaplan–Meier curve estimates were used to evaluate the association between the treatment and CD-TLR. Interaction and stratified analyses were also performed.Results: Over five years, patients treated with DCB angioplasty demonstrated an acceptable effect with a numerically higher but not statistically significant rate of freedom from CD-TLR compared with those treated by PTA (Kaplan–Meier estimate of 77.6% vs 64.4%; log-rank P = 0.08). Among the patients who underwent TLR, the mean time from intervention to TLR in the DCB group was significantly prolonged compared to the PTA group (P < 0.001). The stratified analysis showed that the Rutherford classification played an interactive role in the association between the DCB angioplasty and low CD-TLR rate at five years. No significant difference in the all-cause mortality was found in the patients with post-balloon angioplasty dissection between the two treatment groups.Conclusion: The five-year follow-up outcomes of the post-balloon angioplasty dissection in the AcoArt I trial demonstrated that DCB angioplasty is more trustworthy than PTA, with a higher rate of freedom than CD-TLR and sustained improvement in clinical symptoms. However, the all-cause mortality rate in patients with femoropopliteal lesions is similar after both DCB angioplasty and PTA.Clinical Trial Registration: http://www.clinicaltrials.gov.Unique Identifier: NCT01850056.Keywords: balloon angioplasty, dissection, femoropopliteal artery disease, long-term outcomes, drug-coated balloon, percutaneous transluminal angioplasty

Yuanchun Li,1,&ast; Qingdong Wang,2,&ast; DongWei Wang,2 Weihua Fu3 1Department of General Surgery, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, Heilongjiang Province, People’s Republic of China; 2Department of Anesthesiology, First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang, People’s Republic of China; 3Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: DongWei WangDepartment of Anesthesiology, First Affiliated Hospital of Jiamusi University, No. 348, Dexiang Street, Jiamusi, Heilongjiang Province, 154002, People’s Republic of ChinaTel +86-0454-8605850Email mhnhua@163.comWeihua FuDepartment of General Surgery, Tianjin Medical University General Hospital, No. 154, Anshan Road, Tianjin, 300052, People’s Republic of ChinaTel +022-60363901Email tjmughgs_fwh@163.comPurpose: Elucidating the mechanism of gastric cancer progression is of great importance for the discovery of new therapy targets against gastric cancer. In this study, we investigated the function of Kruppel-like factor 7 (KLF7) in gastric cancer.Methods: qPCR and Western blot were performed to determine the expression of ANTXR1 after KLF7 inhibition. CCK-8, colony formation, apoptosis analysis, cell cycle analysis and transwell assay were performed to determine KLF7 functions in cellular proliferation, migration, apoptosis and cell cycle. Tumour xenograft experiments were performed to examine cell growth in vivo.Results: The results showed that KLF7 was upregulated in gastric cancer. The proliferation and migration of gastric cancer cells were suppressed by depletion of KLF7. In vivo tumour progression was also attenuated following the downregulation of KLF7. Meanwhile, overexpression of KLF7 promoted the proliferation and migration of gastric cancer cells. The results of the mechanistic analysis showed that KLF7 promoted gastric carcinogenesis via upregulation of ANTXR cell adhesion molecule 1 (ANTXR1).Conclusion: Therefore, this study may provide a theoretical foundation for further clinical therapy of gastric cancer.Keywords: KLF7, gastric cancer, ANTXR1, proliferation, migration

Wenfan Fu,&ast; Jian Zhao,&ast; Weimin Hu, Lu Dai, Zeyong Jiang, Shengpeng Zhong, Boyun Deng, Yun Huang, Wenjie Wu, Jun Yin Departments of Chest Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun Yin Email 153144068@qq.comBackground: Radioresistance is the main reason for the failure of radiotherapy in non-small-cell lung cancer (NSCLC); however, the molecular mechanism of radioresistance is still unclear.Methods: An RNA-Seq assay was used to screen differentially expressed long non-coding RNAs (lncRNAs) and genes in irradiation-resistant NSCLC cells. RT-PCR and Western blotting assays were performed to analyze the expressions of lncRNAs and genes. The chromosome conformation capture (3C) assay was performed to measure chromatin interactions. Cell cytotoxicity, cell apoptosis, sphere formation and Transwell assays were performed to assess cellular function.Results: In this study, it was found that LINC01224 increased during the induction of radioresistance in NSCLC cells. LINC01224 was located within the enhancer of ZNF91, and LINC01224 could affect the transcription of ZNF91 by regulating the long-range interactions between the ZNF91 enhancer and promoter. Moreover, upregulation of LINC01224 and ZNF91 could promote irradiation resistance by regulating the stem cell-like properties of NSCLC cells. In addition, high expression levels of LINC01224 and ZNF91 in tissue samples were associated with radioresistance in NSCLC patients.Conclusion: Our findings demonstrated that LINC01224/ZNF91 drove radioresistance regulation by promoting the stem cell-like properties in NSCLC.Keywords: non-small cell lung cancer, radioresistance, LINC01224, ZNF91, stem cell-like properties

Cheng Wang,1 Hong Wang,2 Luming Dai,1 Jianqing Zhang,1 Lizhou Fang,1 Ling Liu,1 Weiping Fu,1 Dang Tang3 1Second Department of Respiratory Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, People’s Republic of China; 2Department of Burns Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, People’s Republic of China; 3First Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, People’s Republic of ChinaCorrespondence: Dang Tang Email tangdangdemao@126.comBackground: Chronic obstructive pulmonary disease (COPD) is often combined with type 2 diabetes mellitus (T2DM) in clinical, and with poor prognosis. In recent years, research shows that inflammation is a common characteristic of COPD and T2DM. T-helper 17 cell (Th17)/regulatory T-cell (Treg) balance controls inflammation and may be important in the pathogenesis of COPD combined with T2DM patients. This study investigated the characteristics of Th17, Treg and related inflammatory factors in COPD combined with T2DM patients and the potential mechanism.Methods: Application of flow cytometry technology, real-time fluorescent quantitative PCR and ELISA to detect the changes in peripheral blood of Th17 and Treg number and the expression of key transcription factors and related cytokines in COPD combined T2DM patients were performed.Results: Patients with COPD combined with T2DM revealed significant increase in peripheral Th17, Th17 related cytokines (IL-17A, IL-17F, IL-21, IL-23, IL-6) and transcription factor (RORγt) levels and significant decrease in Treg, Treg-related cytokines (IL-10, TGFβ 1) and transcription factor (Foxp3) as compared with patients with COPD, T2DM and healthy controls.Conclusion: Th17/Treg functional imbalance exists in patients with COPD combined with T2DM, indicating a potential role of Th17/Treg imbalance in the formation and progression of COPD combined with T2DM.Keywords: COPD combined with T2DM, Th17/Treg, cytokine, transcription factor

En Liang,1 Xiaojun Li,2 Wenjun Fu,2 Changtong Zhao,1 Baoying Yang,3 Zhonghua Yang2 1Department of Neurosurgery, The Affiliated Hexian Memorial Hospital of Southern Medical University, Guangzhou, People’s Republic of China; 2Centre for Integrative Medicine, School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 3Department of Neurosurgery, Guangdong Sanjiu Brain Hospital, Guangzhou, People’s Republic of ChinaCorrespondence: Baoying YangDepartment of Neurosurgery, Guangdong Sanjiu Brain Hospital, No. 578 Shatai Nan Road, Baiyun District, Guangzhou, 510510, People’s Republic of ChinaEmail yby7899@163.comZhonghua YangCentre for Integrative Medicine, School of Basic Medical Science, Guangzhou University of Chinese Medicine, No. 232 Waihuan Dong Road, Panyun District, Guangzhou, 510006, People’s Republic of ChinaEmail yangzhonghua@gzucm.edu.cnBackground: The suppressor of cytokine signaling 3 (SOCS3) is a specific negative regulator of signal transducer and activator of transcription 3 (STAT3) signaling, which is predominantly activated to induce neuroinflammatory response in microglia and functions essential roles during cerebral ischemia-reperfusion (I/R) injury. Constitutive photomorphogenesis 9 (COP9) signalosome (CSN) is a signaling platform controlling protein stability by remodeling of cullin-RING ubiquitin ligases, which is recently reported to specifically recognize proteins with SOCS-box domains. However, whether SOCS3 is related to COP9 signalosome in neuroinflammation during cerebral I/R injury is completely unclear.Methods: Mice subjected to transient middle cerebral artery occlusion (MCAO) and reperfusion, and BV2 microglia cells treated with oxygen-glucose deprivation and reoxygenation (OGD/R) were used to mimic cerebral I/R injury. Western blot, qRTPCR, immunofluorescence, and co-Immunoprecipitation assays were performed to explore the regulatory mechanism of SOCS3 on neuroinflammation and the relationship of SOCS3 and COP9 signalosome during cerebral I/R injury.Results: SOCS3 expression is significantly upregulated in microglia during OGD/R treatment, and overexpression of SOCS3 suppresses OGD/R-induced STAT3 activation and inflammatory factor expression. Furthermore, we find that COP9 signalosome subunit 3 (CSN3) interacts with SOCS3 protein to enhance its stability, thereby resulting in restricting OGD/R-induced STAT3 activation and inflammatory response. Moreover, we find that knockdown of CSN3 evidently accelerates STAT3 activation, and aggravates cerebral I/R injury in vivo.Conclusion: CSN3 restricts neuroinflammatory responses during cerebral I/R injury through stabilizing SOCS3 protein and indicates that CSN3 a potential therapeutic target for cerebral I/R injury.Keywords: cerebral ischemia-reperfusion injury, neuroinflammation, suppressor of cytokine signaling 3, constitutive photomorphogenesis 9 signalosome, signal transducer and activator of transcription 3

Wei Fu, Shanshan Xu, Xiang Dong, Qing Xie, Yadong Gao Department of Allergology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of ChinaCorrespondence: Yadong Gao; Wei FuDepartment of Allergology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of ChinaTel +86 15071384536Email gaoyadong@whu.edu.cn; fuwei0511@163.comAbstract: Aspirin is clinically widely used to inhibit platelet aggregation after coronary intervention. Herein we describe a case of aspirin-induced thrombocytopenia that may be related to allergy to aspirin. A 47‐year‐old man developed a delayed hypersensitivity reaction to aspirin, with pruritus, purpura and thrombocytopenia, increased peripheral blood eosinophils and enlarged inguinal lymph node. All the symptoms disappeared in 2 years after stopping aspirin. Aspirin-induced thrombocytopenia related to allergy is rarely reported. Aspirin hypersensitivity should be taken into consideration in case of unexplained thrombocytopenia in patients taking aspirin. Aspirin “allergy”-induced thrombocytopenia may involve both aspirin related IgG and IgE antibodies.Keywords: aspirin, allergy, thrombocytopenia, platelets

Li Y, Wang Q, Wang D, Fu W. Cancer Manag Res. 2021;13:5547–5557. At the authors request, the Editor and Publisher of Cancer Management and Research wish to retract the published article. Concerns were raised regarding the alleged duplication of western blot and flow cytometry images in Figures 2 and 3 with comparable images from Liu et al, 2021 (https://www.ijbs.com/v17p3401.htm). Specifically, Figures 2B and 2D, AGS and HGC27, β-actin bands, appear to show unexpected similarities with comparable images from Figure 2H, BCPAP and K1, β-actin bands, respectively, from Liu et al, 2021. Figure 3C, AGS, siKLF7-2, appears to show unexpected similarities with a comparable image from Figure 3C, BCPAP, shMARCH6#2 from Liu et al, 2021. The authors were unable to provide a satisfactory explanation for the alleged duplication, nor were they able to provide supporting information that would verify the integrity of the published findings. The Editor determined that the reported findings were unreliable and agreed to the authors retraction request. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

Siyi Lu,1,* Zhenzhen Liu,1,* Xin Zhou,1 Bingyan Wang,1 Fei Li,1 Yanpeng Ma,1 Wendong Wang,1 Junren Ma,1 Yuxia Wang,2 Hao Wang,2 Wei Fu1 1Department of General Surgery, Peking University Third Hospital, Beijing 100191, People’s Republic of China; 2Department of Radiotherapy, Peking University Third Hospital, Beijing 100191, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei FuDepartment of General Surgery, Peking University Third Hospital, 49 Huayuan North Road, Haidian District, Beijing 100191, People’s Republic of ChinaEmail fuwei@bjmu.edu.cnHao WangDepartment of Radiotherapy, Peking University Third Hospital, 49 Huayuan North Road, Haidian District, Beijing 100191, People’s Republic of ChinaEmail wanghaobysy@bjmu.edu.cnBackground: Inflammatory response and nutritional status are associated with cancer development and progression. The purpose of this study was to explore whether the preoperative fibrinogen-albumin ratio index (FARI) is related to prognosis and chemoradiotherapy outcome of radical surgery after neoadjuvant chemoradiotherapy (NCRT) in patients with locally advanced rectal cancer (LARC).Methods: In total, 123 patients with LARC who underwent radical surgery after NCRT between June 2012 and December 2018 were collected in this study. Time-dependent receiver operating characteristic (ROC) curve analysis was made to evaluate the ability of the markers for forecasting prognosis. The correlation between FARI and clinicopathological parameters was analyzed. The Kaplan–Meier survival analysis, univariate and multivariate analysis based on Cox proportional hazards models, and subgroup analysis were performed to evaluate overall survival (OS) and disease-free survival (DFS). A nomogram was constructed to evaluate the predictive role of FARI in DFS.Results: The ROC curve analysis showed that the ability of FARI on DFS prediction was superior to those of other inflammatory markers and carcinoembryonic antigen (CEA) (P< 0.05). Based on the Youden’s index, the optimal cut-off value of FARI was 8.8%. High FARI patients (> 8.8%) showed a poor response to NCRT and a decreased DFS rate (P< 0.05). In addition, multivariate analysis revealed that FARI (HR=3.098, P=0.033), neutrophil-to-lymphocyte ratio (NLR), and postoperative T stage were independent prognostic factors for DFS in TNM stage III LARC patients. However, FARI failed to distinguish patients with poor OS. Harrell’s concordance index (C-index) of the nomogram containing FARI (0.807) was obviously higher than that without it (0.732) among LARC patients who underwent radical surgery after NCRT. Moreover, multivariate analysis revealed FARI (OR=3.044, P=0.012) as an independent predictor for response to NCRT.Conclusion: Among LARC patients who underwent radical surgery after NCRT, preoperative FARI is an independent prognostic factor for DFS and an independent predictor for response to NCRT.Keywords: rectal cancer, fibrinogen-albumin ratio index, prognosis, tumor regression grade

Wei Fu,1– 3 Yujin Ma,1– 3 Liping Li,1– 3 Jie Liu,1– 3 Liujun Fu,1– 3 Yu Guo,1– 3 Zhiyin Zhang,1– 3 Jiaxi Li,1– 3 Hongwei Jiang1– 3 1Department of Endocrinology, The First Affiliated Hospital and Clinical Medicine College, Henan University of Science and Technology, Luoyang 471003, People’s Republic of China; 2National Center for Clinical Research of Metabolic Diseases, Luoyang Center for Endocrinology and Metabolism, Luoyang 471003, People’s Republic of China; 3Diabetic Nephropathy Academician Workstation of Henan Province, Luoyang 471003, People’s Republic of ChinaCorrespondence: Hongwei JiangEndocrinology Department, The First Affiliated Hospital and Clinical Medicine College, Henan University of Science and Technology, Luoyang 471003, People’s Republic of ChinaTel +86 13653880139Email jianghw@haust.edu.cnBackground: Artemether, a commonly used artemisinin derivative, has been shown to possess potential antidiabetic activities. However, only limited information is available on the mechanisms of artemether in type 2 diabetes. Therefore, in this study, we examined some of the possible mechanisms of artemether (ATM) upon glycolipid metabolism in the db/db mouse model of diabetes.Materials and Methods: Male C57BL/KsJ-db/db and C57BL/KsJ-db/+ mice at 4 weeks of age were divided into four groups (N=6/group): (1) NC (normal control – db/+ mice, 1% methylcellulose, intragastric administration), (2) DM (diabetic model – db/db mice, 1% methylcellulose, intragastric administration), (3) ATM 100 (DM + 100 mg/kg of artemether) and (4) ATM 200 (DM + 200 mg/kg of artemether). A number of assays related to diabetes were then performed following a 4-week period of these treatments.Results: Artemether at both doses significantly reduced rates of weight gain and fasting blood glucose levels, improved islet function and insulin resistance and reduced serum lipid levels to varying degrees in db/db mice. Artemether exerted a positive effect on islet vacuolar degeneration and hepatic steatosis, and increased expressions of AMP-activated protein kinase, glucose transporter 4 and Insulin receptor β protein in the liver of these db/db mice. With the use of liver protein chip detection, we found that artemether significantly improved the immune microenvironment, down-regulated the expression of inflammatory factors and activated the cytokine-mediated signaling pathway through cytokine–cytokine receptor interactions.Conclusion: Artemether may regulate glycolipid metabolism in db/db mice by improving the immune microenvironment. The results of this study provide important new information that can serve as the foundation for future research into the use of artemether as a means to improve glycolipid metabolism.Keywords: artemether, glycolipid metabolism, immune microenvironment, AMPK, type 2 diabetes

Bingyan Wang,1,* Siyi Lu,1,* Zhiqiang Song,2 Fei Li,1 Junren Ma,1 Yanpeng Ma,1 Xin Zhou,1 Wei Fu1 1Department of General Surgery, Peking University Third Hospital, Beijing, People’s Republic of China; 2Department of Gastroenterology, Peking University Third Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei FuDepartment of General Surgery, Peking University Third Hospital, Beijing 100191, People’s Republic of ChinaEmail fuwei@bjmu.edu.cn zhouxinasd@sina.cnAim: Obstructive colon cancer can be treated by self-expanding metal stents (SEMS) prior to definitive surgery. However, the oncological outcome remains controversial, especially regarding whether stent placement or obstruction results in more perineural invasion (PNI) or lymphovascular invasion (LVI). This study aimed to compare clinical outcomes of emergency surgery (ES) and stent as bridge to surgery (SBTS) in patients with obstructive colon cancer. The pathological characteristics were also compared between obstructive and nonobstructive cancer.Methods: This study included 880 patients (including 47 ES and 45 SBTS) admitted to Peking University Third Hospital from January 2010 to December 2018. Short-term and long-term outcomes were compared. The pathological differences between an equal number of obstructive and nonobstructive patients matched using propensity scores were investigated.Results: SBTS patients had less intraoperative blood loss (P < 0.001), shorter ICU stay time (P = 0.007), lower incidence of colostomy (P < 0.001), and higher laparoscopic achievement (P < 0.001) than did ES patients. No pathological difference was found between the two groups. SBTS patients showed better overall survival (86.7% vs 68.1%, P = 0.029), but not disease-free survival (68.9% vs 59.6%, P = 0.211) than did ES patients. PNI was significantly higher in obstructive cancer than in nonobstructive cancer (29.3% vs 16.3%, P = 0.035).Conclusion: SBTS had a lower incidence of short-term complications and did not affect long-term prognosis compared with that of ES, indicating that SBTS is a safe and effective treatment. Further, PNI may be associated with obstruction, but not with stent insertion.Keywords: colon obstruction, stenting, bridge to surgery, perineural invasion

Gong S, Zhang J, Guo Z, Fu W. Drug Des Devel Ther. 2018;12:1865–1879. The Editor and Publisher of Drug Design, Development and Therapy wish to retract the published article. Concerns were raised regarding the alleged duplication of flow cytometry images in Figures 3A, 4E, 7C and 9E. The authors responded to our queries but were unable to provide a satisfactory explanation for the alleged duplication nor were they able to provide the original flow cytometry data for their study. The Editor determined the results of the study were invalid and requested for the article to be retracted. The authors agreed with this decision. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”. This retraction relates to this paper

Fu G, Wang H, Cai Y, Zhao H, Fu W. Drug Des Devel Ther. 2018;12:1609–1619. The Editor and Publisher of Drug Design, Development and Therapy wish to retract the published article. Concerns were raised regarding the alleged duplication of western blot bands in Figure 3D. The authors explained that an error had been made by the journal which led to the unintended duplication of the Caspase-1 and IL-1β bands in Figure 3D. The journal accepts an error was made, however further investigation found the authors were unable to provide adequate original western blot data and could no longer verify the validity of the reporting findings. The decision was made to retract the article and the authors do not agree with this. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”. This retraction relates to this paper

Qining Yang, Yongwei Zhou, Pengfei Cai, Weicong Fu, Jinhua Wang, Qiang Wei, Xiaofei LiDepartment of Joint Surgery, Jinhua Municipal Central Hospital, Jinhua, Zhejiang 321000, People’s Republic of ChinaBackground: Osteoarthritis (OA) is a common joint disease, which is characterized by degradation of articular cartilage. Evidence indicated that miR-23b-3p was upregulated in cartilage tissues of a patient with OA. However, the mechanism by which miR-23b-3p regulates the occurrence and development of OA remains unclear. Thus, this study aimed to investigate the role of miR-23b-3p in the progression of OA.Methods: In this study, qRT-PCR was used to measure the expression of miR-23b-3p in OA tissue samples and normal controls, respectively. Western blotting assay was performed to detect the levels of collagen II, aggrecan, Bax and active caspase 3 in CHON-001 cells. In addition, the dual-luciferase reporter system assay was used to detect the interaction between miR-23b-3p and COL11A2 in OA.Results: The levels of miR-23b-3p were upregulated, while the expressions of collagen II and aggrecan were decreased in OA tissues and in IL-1β-treated CHON-001 cells. In addition, IL-1β significantly induced apoptosis of CHON-001 cells via increasing the levels of Bax and active caspase 3. However, downregulation of miR-23b-3p markedly inhibited IL-1β-induced apoptosis in CHON-001 cells via increasing the collagen II and aggrecan levels and decreasing Bax and active caspase 3 expressions. Meanwhile, dual-luciferase assay showed that COL11A2 was the direct target of miR-23b-3p in CHON-001 cells. Overexpression of miR-23b-3p markedly decreased the level of COL11A2 in cells. Moreover, downregulation of miR-23b-3p alleviated synovitis/cartilage destruction and reduced Osteoarthritis Research Society International scores and subchondral bone thickness in vivo.Conclusion: Downregulation of miR-23b-3p could alleviate the progression of OA through upregulating COL11A2 in vivo and in vitro. Therefore, downregulation of miR-23b-3p might be a potential therapeutic strategy for the treatment of OA.Keywords: microRNA-23b-3p, osteoarthritis, IL-1β, COL11A2

Guanglei Fu,1 Hua Wang,2 Youli Cai,2 Hui Zhao,2 Wenjun Fu2 1Department of Neurology, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China; 2School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China Objective: Intracerebral hemorrhage (ICH) is one of the most common acute cerebrovascular diseases with high mortality. Numerous studies have shown that inflammatory response played an important role in ICH-induced brain injury. Theaflavin (TF) extracted from black tea has various biological functions including anti-inflammatory activity. In this study, we investigated whether TF could inhibit ICH-induced inflammatory response in rats and explored its mechanism.Materials and methods: ICH rat models were induced with type VII collagenase and pretreated with TF by gavage in different doses (25 mg/kg–100 mg/kg). Twenty-four hours after ICH attack, we evaluated the rats’ behavioral performance, the blood–brain barrier (BBB) integrity, and the formation of cerebral edema. The levels of reactive oxygen species (ROS) and inflammatory cytokines were examined by 2',7'-dichlorofluorescin diacetate and enzyme-linked immunosorbent assay. Nissl staining and transferase dUTP nick end labeling (TUNEL) were aimed to detect the neuron loss and apoptosis, the mechanism of which was explored by Western blot.Results: It was found that in the pretreated ICH rats TF significantly alleviated the behavioral defects, protected BBB integrity, and decreased the formation of cerebral edema and the levels of ROS as well as inflammatory cytokines (including interleukin-1 beta [IL-1β], IL-18, tumor nectosis factor-alpha, interferon-γ, transforming growth factor beta, and (C-X-C motif) ligand 1 [CXCL1]). Nissl staining and TUNEL displayed TF could protect against the neuron loss and apoptosis via inhibiting the activation of nuclear transcription factor kappa-β-p65 (NF-κβ-p65), caspase-1, and IL-1β. We also found that phorbol 12-myristate 13-acetate, a nonspecific activator of NF-κβ-p65, weakened the positive effect of TF on ICH-induced neural defects and neuron apoptosis by upregulating NF-κβ-related signaling pathway.Conclusion: TF could alleviate ICH-induced inflammatory responses and brain injury in rats via inhibiting NF-κβ-related pathway, which may provide a new way for the therapy of ICH. Keywords: cerebral hemorrhage, theaflavin, inflammatory response, NF-κβ-p65

Shenglan Gong,1 Jin Zhang,2 Zhouke Guo,3 Wenjun Fu1 1South China Research Center for Acupuncture and Moxibustion, School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, People’s Republic of China; 2Department of Anatomy, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, People’s Republic of China; 3Department of Neurology and Psychology, Shenzhen Affiliated Hospital of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, People’s Republic of China Background: Depression is characterized by a pathological injury to the hippocampal neurons. Senkyunolide A (SenA) is one of the major active components of Dan-zhi-xiao-yao-san, which is widely used in the treatment of depression-related disorders.Materials and methods: In the present study, it was hypothesized that the antidepressant effect of Dan-zhi-xiao-yao-san depended on the function of SenA and the authors attempted to reveal the molecular mechanism associated with the treatment. An in vitro depression model was induced using corticosterone (Cort), and the effect of SenA on the cell viability, apoptosis, and protein phosphatase 2A/α-synuclein (PP2A/α-syn) signaling was detected. To validate the mechanism driving the therapeutic effect of SenA, activity of PP2A and α-syn was modulated and the effect on neural cells was evaluated.Results: The results showed that SenA protects Cort-induced cell apoptosis in PC12 cells. In addition, SenA increased Cort-induced reduction of PP2A activity, while it decreased the expression of p-PP2A, α-syn, and p-α-syn (Ser129). Further, modulation of PP2A activity with specific inhibitor okadaic acid (OA) increased Cort-induced cell apoptosis, while PP2A activator D-erythro-sphingosine (SPH) exhibited an opposite effect. The neuroprotective effects of SenA on neural cells also depended on inhibition of α-syn function, the regulation of which would influence the activity of PP2A in a negative loop.Conclusion: Collectively, the results suggested that the neuroprotective effects of SenA were exerted by modulating activities of PP2A activities and α-syn. The findings partially explained the mechanism associated with the neuroprotective effect of SenA. Keywords: α-synuclein, corticosterone, depression, neuroprotection, protein phosphatase 2A, senkyunolide A

Haixin Li,1,* Ying Huang,2,* Xian Wu,3 Ting Wu,1 Ying Cao,1 Qimei Wang,1 Yuchang Qiu,1 Weiming Fu,1 Qun Zhang,4 Jianxin Pang1 1Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, People’s Republic of China; 3Department of Pharmacy, The Third Affiliated Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 4Good Clinical Practice Development, The Third Affiliated Hospital, Southern Medical University, Guangzhou, People’s Republic of China *These authors contributed equally to this work Objective: Hemocoagulase agkistrodon (HCA), a thrombin-like enzyme (TLE) from the venom of the Chinese moccasin snake (Deinagkistrodon acutus), has been used in clinical practice as a hemostatic compound. The aim of this study was to further investigate the pharmacological properties of HCA. Materials and methods: Sodium dodecyl sulfate or native polyacrylamide gel electrophoresis (SDS- or N-PAGE) as well as enzyme linked immunosorbent assays (ELISAs) were conducted to study the effects of HCA on the human plasma fibrinogen and prothrombin levels, as well as its in vitro interactions with some coagulation factors. In addition, the bleeding time effects of HCA in the mouse tail-bleeding model as well as its effects on the fibrinogen levels in rabbits were determined in vivo. Results: In vitro results revealed that HCA exerts its procoagulant activities by hydrolyzing fibrinogen into segments that are easier to be absorbed, reducing the risk of thrombus formation. Besides, HCA could significantly inhibit the activation of prothrombin at the concentration of 0.3 μM. Unexpectedly, we also found that HCA was able to strongly bind to factor X/Xa (in a ratio of 1:1) and thus inhibit the acceleration of active factor X to tissue plasminogen activator-catalyzed plasminogen activation, demonstrating that it could be less likely to lead to thrombus formation. Finally, in vivo results indicated that HCA could significantly shorten the bleeding time in the mouse tail-bleeding model and had no effect on the fibrinogen levels in rabbits. Conclusion: In summary, HCA, a unique and new family member of TLEs, may become a new clinical drug for the prevention and treatment of hemorrhage due to its unique and complex interactions with the blood system. Clarification of these features will enable us to further understand the mechanism of action of HCA and then promote its further application in clinical practice as a therapeutic drug. Keywords: thrombin-like enzymes, TLEs, coagulation factors, procoagulant activity, anticoagulant activity, FXa, t-PA

Chao Liu,1,* Jie Hu,1,* Zhi Mao,1,* Hongjun Kang,1 Hui Liu,1 Wanlei Fu,2 Yangfan Lv,2 Feihu Zhou1 1Department of Critical Care Medicine, Chinese People’s Liberation Army General Hospital, Beijing, People’s Republic of China; 2Department of Pathology, Xinqiao Hospital, Third Military Medical University, Chongqing, People’s Republic of China *These authors contributed equally to this work Background: Recently, the D-galactose (D-gal)-induced mimetic aging rat model has been widely used in studies of age-associated diseases, which have shown that chronic D-gal exposure induces premature aging similar to natural aging in rats. With the increasing rate of sepsis in the geriatric population, an easy-access animal model for preclinical studies of elderly sepsis is urgently needed. This study investigates whether a sepsis model that is established in D-gal-induced aging rats can serve as a suitable model for preclinical studies of elderly patients with sepsis.Objective: To investigate the acute kidney injury (AKI) and inflammatory response of sepsis following cecal ligation and puncture (CLP) in D-gal-induced aging rats.Methods: Twelve-week-old male Sprague Dawley rats were divided into low-dose D-gal (L D-gal, 125 mg/kg/d), high-dose D-gal (H D-gal, 500 mg/kg/d), and control groups. After daily subcutaneous injection of D-gal for 6 weeks, the CLP method was used to establish a sepsis model.Results: The mortality was 73.3%, 40%, and 33.3% in the H D-gal, L D-gal, and control groups, respectively. Blood urea nitrogen, creatinine, plasma neutrophil gelatinase-associated lipocalin, interleukin-6, interleukin-10, and tumor necrosis factor-α were markedly increased in the H D-gal group after establishment of the sepsis model (H D-gal vs control, P

Jianming Wu,1–3,* Xiao Ke,2,* Na Ma,2 Wei Wang,2 Wei Fu,2 Hongcheng Zhang,2 Manxi Zhao,2 Xiaoping Gao,2 Xiaofeng Hao,2 Zhirong Zhang3 1Laboratory of Chinese Materia Medica, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 2Post-Doctoral Research Station, Kanghong Pharmaceutical Group, 3Post-Doctoral Mobile Station, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, People’s Republic of China *These authors contributed equally to this work Background: It has been reported that formononetin (FMN), one of the main ingredients from famous traditional Chinese medicine “Huang-qi” (Astragalus membranaceus [Fisch] Bunge) for Qi-tonifying, exhibits the effects of immunomodulation and tumor growth inhibition via antiangiogenesis. Furthermore, A. membranaceus may alleviate the retinal neovascularization (NV) of diabetic retinopathy. However, the information of FMN on retinal NV is limited so far. In the present study, we investigated the effects of FMN on the hypoxia-induced retinal NV and the possible related mechanisms.Materials and methods: The VEGF secretion model of acute retinal pigment epithelial-19 (ARPE-19) cells under chemical hypoxia was established by the exposure of cells to 150 µM CoCl2 and then cells were treated with 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1, a potent HIF-1ɑ inhibitor, 1.0 µg/mL) or different concentrations of FMN (0.2 µg/mL, 1.0 µg/mL, and 5.0 µg/mL). The supernatants of cells were collected 48 hours later to measure the VEGF concentrations, following the manufacturer’s instruction. The mRNA expressions of VEGF, HIF-1ɑ, PHD-2, and β-actin were analyzed by quantitative reverse transcription polymerase chain reaction, and the protein expressions of HIF-1ɑ and PHD-2 were determined by Western blot analysis. Furthermore, the rats with retinopathy were treated by intraperitoneal administration of conbercept injection (1.0 mg/kg) or FMN (5.0 mg/kg and 10.0 mg/kg) in an 80% oxygen atmosphere. The retinal avascular areas were assessed through visualization of the retinal vasculature by adenosine diphosphatase staining and hematoxylin and eosin staining.Results: FMN can indeed inhibit the VEGF secretion of ARPE-19 cells under hypoxia, downregulate the mRNA expression of VEGFA and PHD-2, and decrease the protein expression of VEGF, HIF-1ɑ, and PHD-2 in vitro. Furthermore, FMN can prevent hypoxia-induced retinal NV in vivo.Conclusion: FMN can ameliorate retinal NV via the HIF-1ɑ/VEGF signaling pathway, and it may become a potential drug for the prevention and treatment of diabetic retinopathy. Keywords: formononetin, angiogenesis, oxygen-induced retinopathy, vascular endothelial growth factor, hypoxia-inducible factor-1

Weitao Fu,1,* Lingfeng Chen,1,* Zhe Wang,1 Chengwei Zhao,1 Gaozhi Chen,1 Xing Liu,1 Yuanrong Dai,2 Yuepiao Cai,1 Chenglong Li,1,3 Jianmin Zhou,1 Guang Liang1 1Chemical Biology Research Center, School of Pharmaceutical Sciences, 2Department of Respiratory Medicine, the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 3Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, OH, USA *These authors contributed equally to this work Abstract: It is recognized that myeloid differentiation protein 2 (MD-2), a coreceptor of toll-like receptor 4 (TLR4) for innate immunity, plays an essential role in activation of the lipopolysaccharide signaling pathway. MD-2 is known as a neoteric and suitable therapeutical target. Therefore, there is great interest in the development of a potent MD-2 inhibitor for anti-inflammatory therapeutics. Several studies have reported that xanthohumol (XN), an anti-inflammatory natural product from hops and beer, can block the TLR4 signaling by binding to MD-2 directly. However, the interaction between MD-2 and XN remains unknown. Herein, our work aims at characterizing interactions between MD-2 and XN. Using a combination of experimental and theoretical modeling analysis, we found that XN can embed into the hydrophobic pocket of MD-2 and form two stable hydrogen bonds with residues ARG-90 and TYR-102 of MD-2. Moreover, we confirmed that ARG-90 and TYR-102 were two necessary residues during the recognition process of XN binding to MD-2. Results from this study identified the atomic interactions between the MD-2 and XN, which will contribute to future structural design of novel MD-2-targeting molecules for the treatment of inflammatory diseases. Keywords: myeloid differentiation 2, xanthohumol, binding mode, inflammation, molecular dynamics simulation

Xiaomin He,1,* Bei Feng,1,2,* Chuanpei Huang,1 Hao Wang,1 Yang Ge,1 Renjie Hu,1 Meng Yin,1 Zhiwei Xu,1 Wei Wang,1 Wei Fu,1,2 Jinghao Zheng1 1Department of Pediatric Cardiothoracic Surgery, 2Institute of Pediatric Translational Medicine, Shanghai Children’s Medical Center School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Electrospinning has recently received considerable attention, showing notable potential as a novel method of scaffold fabrication for cartilage engineering. The aim of this study was to use a coculture strategy of chondrocytes combined with electrospun gelatin/polycaprolactone (GT/PCL) membranes, instead of pure chondrocytes, to evaluate the formation of cartilaginous tissue. We prepared the GT/PCL membranes, seeded bone marrow stromal cell (BMSC)/chondrocyte cocultures (75% BMSCs and 25% chondrocytes) in a sandwich model in vitro, and then implanted the constructs subcutaneously into nude mice for 12 weeks. Gross observation, histological and immunohistological evaluation, glycosaminoglycan analyses, Young’s modulus measurement, and immunofluorescence staining were performed postimplantation. We found that the coculture group formed mature cartilage-like tissue, with no statistically significant difference from the chondrocyte group, and labeled BMSCs could differentiate into chondrocyte-like cells under the chondrogenic niche of chondrocytes. This entire strategy indicates that GT/PCL membranes are also a suitable scaffold for stem cell-based cartilage engineering and may provide a potentially clinically feasible approach for cartilage repairs. Keywords: electrospinning, nanocomposite, cartilage tissue engineering, nanomaterials, stem cells

Wei Fu,1,2,* Zhenling Liu,1,* Bei Feng,1,2 Renjie Hu,1 Xiaomin He,1 Hao Wang,1 Meng Yin,1 Huimin Huang,1 Haibo Zhang,1 Wei Wang11Department of Pediatric Cardiothoracic Surgery, 2Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China*These authors contributed equally to this workAbstract: Electrospun hybrid nanofibers prepared using combinations of natural and synthetic polymers have been widely investigated in cardiovascular tissue engineering. In this study, electrospun gelatin/polycaprolactone (PCL) and collagen/poly(l-lactic acid-co-ε-caprolactone) (PLCL) scaffolds were successfully produced. Scanning electron micrographs showed that fibers of both membranes were smooth and homogeneous. Water contact angle measurements further demonstrated that both scaffolds were hydrophilic. To determine cell attachment and migration on the scaffolds, both hybrid scaffolds were seeded with human umbilical arterial smooth muscle cells. Scanning electron micrographs and MTT assays showed that the cells grew and proliferated well on both hybrid scaffolds. Gross observation of the transplanted scaffolds revealed that the engineered collagen/PLCL scaffolds were smoother and brighter than the gelatin/PCL scaffolds. Hematoxylin and eosin staining showed that the engineered blood vessels constructed by collagen/PLCL electrospun membranes formed relatively homogenous vessel-like tissues. Interestingly, Young's modulus for the engineered collagen/PLCL scaffolds was greater than for the gelatin/PCL scaffolds. Together, these results indicate that nanofibrous collagen/PLCL membranes with favorable mechanical and biological properties may be a desirable scaffold for vascular tissue engineering.Keywords: electrospinning, gelatin, collagen, polycaprolactone, poly(l-lactic acid-co-ε-caprolactone)