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Yuwei Jiang,1,2,* Wenjun Dang,3,* Lirong Sui,1 Tianci Gao,1 Xiangying Kong,1 Jin Guo,1 Shuang Liu,1 Hong Nie,3 Zhimei Jiang1,2 1College of Rehabilitation Medicine, Jiamusi University, Jiamusi City, Hei longJiang Province, People’s Republic of China; 2Pediatric Cerebral Palsy Prevention and Treatment Center of Heilongjiang Province, Jiamusi City, Hei longJiang Province, People’s Republic of China; 3College of Jiamusi, HeiLongJiang University of Chinese Medicine, Jiamusi City, Hei longJiang Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhimei Jiang; Shuang Liu, Email 15704601990@163.com; 307692456@qq.comAbstract: We conducted an umbrella evaluation to quantitatively synthesize previous systematic reviews and meta-analyses, thereby collating evidence on the association between vitamin D and core symptoms in people with autism in anticipation of informing clinical vitamin D supplementation. Based on the pre-established protocol, we ended up with 9 studies. Based on rigorous analysis, we found that vitamin D deficiency early in life is a risk factor for the development of ASD and that vitamin D supplementation improves the core symptoms of ASD. Our study concludes that vitamin D supplementation is beneficial for individuals with autism, that vitamin D deficiency early in embryonic life increases the risk of ASD, and that our study supports the idea that prevention begins with vitamin D supplementation early in life. At the same time, we must recognize that our current conclusions support the benefits of vitamin D supplementation for children with ASD, but we are unable to determine the causal relationship, ie, how vitamin D works in ASD, and we need more basic research to explore the mechanisms involved.Keywords: autism spectrum disorders, vitamin D, core symptoms, 25(OH)D, umbrella review

Huifang Nie,1 Jinwen Ge,1,2 Kailin Yang,1 Zhuli Peng,1 Haihui Wu,1 Tong Yang,1 Zhigang Mei1 1Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People’s Republic of China; 2Hunan Academy of Chinese Medicine, Changsha, Hunan, 410006, People’s Republic of ChinaCorrespondence: Zhigang Mei; Jinwen Ge, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People’s Republic of China, Email meizhigang@hnucm.edu.cn; 001267@hnucm.edu.cnBackground: Ischemic stroke (IS) is a leading cause of mortality worldwide. Naotaifang III is a new Chinese herbal formula to treat IS. Previous studies have shown that Astragali Radix, Puerariae Lobatae Radix, Chuanxiong Rhizoma, and Rhei Radix Et Rhizoma in Naotaifang III were able to regulate the imbalance of intestinal microbiota during cerebral ischemia injury.Methods: Rats were randomly divided into sham operation group, normal control group, middle cerebral artery occlusion (MCAO) group, intestinal microbiota imbalance MCAO group, Naotaifang III group, and normal bacteria transplantation group, with 15 rats in each group. Then, neurological function scores and cerebral infarction volume were detected; haematoxylin and eosin staining and Golgi silver staining were used to observe morphological changes in brain tissue. Meanwhile, the lipopolysaccharide (LPS) and cerebral cortex interleukin (IL)-1β were detected by enzyme-linked immunosorbent assay (ELISA); the expressions of Toll-like receptor (TLR)-4 and nuclear factor kappa-B (NF-κB) proteins were detected by immunofluorescence and Western blot. The cecal flora was detected by 16S rDNA. The results showed that gut dysbiosis aggravated cerebral ischemic injury and significantly increased the expression of LPS, TLR4, NF-κB, and IL-1β, which could be significantly reversed by Naotaifang III or normal bacterial transplantation. Naotaifang III may exert a protective effect on neuroinflammatory injury after MCAO through the LPS/TLR4 signaling pathway in the microbe-gut-brain axis. In summary, Naotaifang III may induce anti-neuroinflammatory molecular mechanisms and signaling pathways through the microbe-gut-brain axis.Results: The results showed that gut dysbiosis aggravated cerebral ischemic injury and significantly increased the expression of LPS, TLR4, NF-κB, and IL-1β, which could be significantly reversed by Naotaifang III or normal bacterial transplantation. Naotaifang III may exert a protective effect on neuroinflammatory injury after MCAO through the LPS/TLR4 signaling pathway in the microbe-gut-brain axis.Conclusion: Naotaifang III may induce anti-neuroinflammatory molecular mechanisms and signaling pathways through the microbe-gut-brain axis. Keywords: Naotaifang III, ischemic stroke, intestinal microbiota, LPS/TLR4 signaling pathway, microbiota–gut–brain axis

Xi Yang,1 Linlin Wen,1 Jinqian Zheng,1 Huijuan Nie,1 Shengli Liu,1 Chengqun Chen,1 Fangying Si,1 Xiaojian Zhang,1,2 Jian Kang,1,2 Shuzhang Du,1 Zhao Yin1 1Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Henan Drug Clinical Comprehensive Evaluation Center, Zhengzhou, People’s Republic of ChinaCorrespondence: Zhao Yin; Shuzhang Du, Email yinzhao0601@163.com; dushuzhang911@163.comObjective: The study explores the psychological state and related influences of hospital pharmacists enclosed in extreme work environments in the post-epidemic era, and also explores potential measures to alleviate negative emotions.Methods: An embedded mixed research methodology was used. In the qualitative research phase, semi-structured interviews were carried out with 30 pharmacists consistently confined to their work environments. The data were managed and analyzed using NVivo12 software. In the quantitative research phase, 146 pharmacists with experience in extreme work environments were selected, and the data were collected through questionnaires (GAD-7 and CD-RISC-25) and self-administered questions generated during the qualitative phase. The Shapiro–Wilk test was utilized to assess data normality. Spearman correlation was conducted to evaluate correlations among self-designed questions, resilience, and anxiety.Results: The results from interviews with 30 pharmacists revealed four factors influencing the psychological state of pharmacists in the post-epidemic era: personal factors, interpersonal relationships, environmental factors, and policy and public opinion. Mitigation measures for negative emotions encompass material security, life adjustment, epidemic prevention policy, public opinion information, and organizational management. The results of a quantitative study of 146 pharmacists showed that only 1% had severe anxiety, but the psychological resilience scores were generally low, and 62% had poor psychological resilience, with scores below 73. Simultaneously, it was observed that, except religious beliefs, factors influencing psychological status in extreme work environments were significantly negatively correlated with personal anxiety levels and significantly positively correlated with psychological resilience.Conclusion: Our study holds significance in unraveling the psychological aspects of pharmacists as healthcare workers. It also offers insights into how healthcare organizations respond to the negative emotions experienced by healthcare workers in emergencies or extreme environments.Keywords: mixed study, hospital pharmacists, post-pandemic era, psychological state

Lini Wang,&ast; Yi Wang,&ast; Li Ma,&ast; Yiting Wang, Xiaoxiao Mu, Zhaoxu Huang, Ziyu Zheng, Huang Nie Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huang Nie; Ziyu Zheng, Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Changle West Road 127, Xi’an, Shaanxi, 710032, People’s Republic of China, Email niehuang@163.com; zhengziyu@126.comPurpose: This study aimed to compare the cardiopulmonary safety of remimazolam and propofol in patients undergoing cervical conization.Methods: This was a single-blind, parallel, randomized controlled study. A total of 204 patients scheduled for day surgery of cold knife cervical conization received either remimazolam-alfentanil anesthesia (remimazolam group) or propofol-alfentanil anesthesia (propofol group). The primary outcome was the incidence of intraoperative cardiopulmonary adverse events (a composite outcome of hypotension, bradycardia and hypoxemia). The occurrence of hypotension, bradycardia, hypoxemia and the degree of body movement were secondary outcomes, as well as the moment at which consciousness was lost, the interval between the end of anesthesia and the operating room’s release of the patient, and the overall dosage of alfentanil administered during the procedure.Results: The incidence of intraoperative cardiopulmonary adverse events was 45 (44.1%) in the remimazolam group and 72 (70.6%) in the propofol group (absolute risk difference [95% CI], − 26.47% [− 39.55% to − 13.39%]; odds ratio (OR) [95% CI], 0.43 [0.28 to 0.65]; P < 0.001). The remimazolam group showed lower incidences of hypotension and hypoxemia compared to the propofol group (P = 0.01 for both). No significant differences were observed in the overall alfentanil dosages administered, bradycardia, bodily movement, or time to losing consciousness between the two groups.Conclusion: In patients who underwent cold knife cervical conization, remimazolam-alfentanil anesthesia was associated with a reduced incidence of intraoperative cardiopulmonary adverse events compared with propofol-alfentanil anesthesia.Keywords: adverse events, alfentanil, cervical conization, general anesthesia, propofol, remimazolam

Hui Nie,1,2 Fei Wang,1 Xiaoli Zeng,2 Hairong Bao,2 Xiaoju Liu2 1The First Clinical Medical College of Lanzhou University, Lanzhou, People’s Republic of China; 2Department of Gerontal Respiratory Medicine, the First Hospital of Lanzhou University, Lanzhou, People’s Republic of ChinaCorrespondence: Xiaoju Liu, Department of Gerontal Respiratory Medicine, the First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, 730000, People’s Republic of China, Email liuxj@lzu.edu.cnBackground: Chronic obstructive pulmonary disease (COPD) patients with osteoporosis (OP) usually experience more frequent exacerbations, worse quality of life, and heavier economic burden, however, few studies have investigated common molecular mechanisms of COPD and OP.Objective: To explore the relationship between COPD and OP through bioinformatics analysis.Methods: The miRNA microarray data of COPD and OP were retrieved from the Gene Expression Database (GEO), and the differentially expressed microRNAs (DEmiRNAs) were screened and the intersection was obtained. The Targetscan, miRDB, and miRWalk databases were used to predict the target genes of DEmiRNA, and the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the R package clusterProfiler, the STRING database was used to analyze the target protein–protein interaction network (PPI) and screens to determine the core modules and core genes.Results: Two DEmiRNAs (miR-23a-5p, miR-194-3p) have been found in COPD and OP, which have predicted 76 and 114 target genes, respectively. GO functional annotations of miR-23a-5p were significantly enriched in CD40 signaling pathway, ubiquitin-conjugating enzyme activity, etc; KEGG pathways of miR-23a-5p were significantly enriched in ubiquitin-mediated proteolysis, folate biosynthesis, and regulation of actin cytoskeleton. GO function annotations of miR-194-3p were significantly enriched in T cell activation regulation, ubiquitin protein ligase activity, and DNA transcription factor binding; KEGG pathways of miR-194-3p were significantly enriched in cell adhesion molecules, intercellular tight junctions, and lysosomal pathway. PPI analysis found target coding proteins formed complex regulatory networks. Ten core genes (TP53, SRC, PXN, CHD4, SYK, TNRC6B, PML, KAT5, BRD1 and IGF2) were picked out among them, then we used the MCODE plugin found three core subnetworks.Conclusion: Two identical DEmiRNAs (miR-23a-5p, miR-194-3p) exist in the peripheral blood of COPD and OP patients, which are important biomarkers for COPD patients with OP and may represent novel targets for diagnosis and treatment of COPD patients with OP.Keywords: chronic obstructive pulmonary disease, osteoporosis, bioinformatics, microRNA

Jianguo Sun,1,&ast; Huiling Nie,2,&ast; Panpan Pan,3,&ast; Qin Jiang,2,&ast; Chang Liu,1 Min Wang,1 Yonghui Deng,3,4 Biao Yan1 1Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, People’s Republic of China; 2The Affiliated Eye Hospital and The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, People’s Republic of China; 3Department of Chemistry, Fudan University, Shanghai, People’s Republic of China; 4Department of Gastroenterology and Hepatology, Zhongshan Hospital, Institute of Biomedical Sciences, Fudan University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yonghui Deng; Biao Yan, Email yhdeng@fudan.edu.cn; biao.yan@fdeent.orgBackground: Ocular vascular diseases are the major causes of visual impairment, which are characterized by retinal vascular dysfunction and robust inflammatory responses. Traditional anti-angiogenic or anti-inflammatory drugs still have limitations due to the short-acting effects. To improve the anti-angiogenic or anti-inflammatory efficiency, a dual-drug nanocomposite formulation was proposed for combined anti-angiogenic and anti-inflammatory treatment of ocular vascular diseases.Methods: : CBC-MCC@hMSN(SM) complex nanoformulation was prepared by integrating conbercept (CBC, an anti-angiogenic drug) and MCC950 (MCC, an inhibitor of inflammation) into the surface-modified hollow mesoporous silica nanoparticles (hMSN(SM)). CBC-MCC@hMSN(SM) complex nanoformulation was then characterized by Fourier transform infrared spectroscopy, transmission electron microscopy, zeta potentials, and nitrogen adsorption-desorption measurement. CBC and MCC release profile, cytotoxicity, tissue toxicity, anti-angiogenic effects, and anti-inflammatory effects of CBC-MCC@hMSN(SM) were estimated using the in vitro and in vivo experiments.Results: CBC-MCC@hMSN(SM) complex had no obvious cytotoxicity and tissue toxicity and did not cause a detectable ocular inflammatory responses. CBC-MCC@hMSN(SM) complex was more effective than free CBC or MCC in suppressing endothelial angiogenic effects and inflammatory responses in vitro. A single intraocular injection of CBC-MCC@hMSN(SM) complex potently suppressed diabetes-induced retinal vascular dysfunction, choroidal neovascularization, and inflammatory responses for up to 6 months.Conclusion: : Combined CBC and MCC nanoformulation provides a promising strategy for sustained suppression of pathological angiogenesis and inflammatory responses to improve the treatment outcomes of ocular vascular diseases.Keywords: combined nanocomposite formulation, mesoporous silica nanoparticle, anti-angiogenesis, anti-inflammation, ocular vascular disease

Qinglin Zhang,&ast; He Nie,&ast; Jiadong Pan, Haoran Xu, Qiang Zhan Department of Gastroenterology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214023, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qinglin Zhang; Qiang Zhan, Email zhang517068@126.com; ryzhanqiang@163.comBackground: FMNL3 (Formin-like protein 3) is involved in the tumorigenesis of multiple cancers. The critical role of FMNL3 in malignancies has been preliminarily explored, but its immunological correlation is not clear.Methods: A pan-cancer analysis was performed to investigate the expressions, prognostic values, and immunological roles of FMNL3 across cancer types in The Cancer Genome Atlas (TCGA) database. Next, the correlations between FMNL3 and immunological features in the tumor microenvironment (TME) of pancreatic cancer (PAAD) were assessed. Besides, the role of FMNL3 in predicting the clinical characteristics and the responses to various therapies in PAAD was evaluated as well. Besides, the correlations between FMNL3 and the emerging immune-related biomarkers were also evaluated.Results: The pan-cancer analysis uncovered inconsistent expression status and prognostic values in several cancers. Besides, FMNL3 exhibited positive correlations with a majority of immunomodulators and tumor-infiltrating immune cells (TIICs) in several cancer types, including PAAD. In addition, FMNL3 was associated with an inflamed phenotype in the TME and predicted significantly higher responses to multiple anti-cancer therapies. In addition, FMNL3 was notably correlated with immune-related microbiota and N6-methyladenosine (m6A) genes.Conclusion: In summary, FMNL3 predicts an immuno-hot phenotype, which could be a promising indicator for identifying high immunogenicity in PAAD.Keywords: FMNL3, PAAD, tumor microenvironment, bioinformatics analysis, formin

Lini Wang,&ast; Yiting Wang,&ast; Yumei Ma, Xiaoxiao Mu, Zhen Zhang, Huan Wang, Ziyu Zheng, Huang Nie Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huang Nie, Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Changle West Road 127, Xi’an, Shaanxi, 710032, People’s Republic of China, Email niehuang@163.comPurpose: This retrospective study evaluated the efficacy, opioid consumption, and safety profile of two patient-controlled intravenous analgesia (PCIA) regimens (sufentanil combined with nalbuphine vs sufentanil alone) after cesarean section (CS).Patients and Methods: Parturients (n = 1808) received sufentanil combined with nalbuphine (SN group) or sufentanil alone (S group) as PCIA after CS. The primary outcome was the numeric rating scale (NRS) pain score with movement (NRS-M) at 24 h after CS. Secondary outcomes were NRS scores at rest (NRS-R) at 24 and 48 h after CS, NRS-M at 48 h after CS, cumulative PCIA bolus times, and opioid consumption during the first 24 and 48 h postoperatively, which was measured in morphine-equivalent doses.Results: The population comprised 993 and 815 subjects in the SN and S groups, respectively. At 24 and 48 h after CS, the respective NRS-M scores of the SN group (4.62, 3.37) were each significantly lower than those of the S group (5.18, 4.01; P < 0.01 for both). The corresponding NRS-S scores were similarly lower in the SN group (0.96, 0.19) than in the S group (2.05, 0.92; P < 0.01 for both). After adjusting for covariates, the SN group still had lower NRS-M than the S group at 24 h after CS (estimate adjusted = 0.565, P < 0.001). The PCIA bolus times were significantly lower in the SN group than in the S group. The rates of bradycardia and respiratory depression were lower in the SN group than in the S group. However, the rates of dizziness and postoperative hypotension were slightly higher in the SN group, and those of nausea/vomiting were comparable.Conclusion: Compared with sufentanil alone, sufentanil combined with nalbuphine for PCIA provided superior analgesia in parturient women after CS.Keywords: nalbuphine, sufentanil, patient-controlled intravenous analgesia, cesarean section

Ruoyao Xu,1 Jie Wang,1 Huimin Nie,1 Danyi Zeng,1 Chengyu Yin,1 Yuanyuan Li,1 Huina Wei,1 Boyu Liu,1 Yan Tai,2 Qimiao Hu,1 Xiaomei Shao,1 Jianqiao Fang,1 Boyi Liu1 1Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou, 310053, People’s Republic of China; 2Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of ChinaCorrespondence: Boyi Liu; Jianqiao Fang, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou, 310053, People’s Republic of China, Email boyi.liu@foxmail.com; fangjianqiao7532@163.comBackground: Chronic postsurgical pain (CPSP) is common among patients receiving major surgeries. CPSP produces suffering in patients, both physically and mentally. However, the mechanisms underlying CPSP remain elusive. Here, a genome-wide expression profiling of ipsilateral spinal cord dorsal horn (SCDH) was performed to identify potential genes related with CPSP.Methods: A rat skin/muscle incision and retraction (SMIR) model was established to induce CPSP. Immunostaining was used to study glial cell and neuron activation in ipsilateral SCDH of SMIR model rats. RNA sequencing (RNA-Seq), combined with bioinformatics analysis, was undertaken to explore gene expression profiles. qPCR was applied to validate the expression of some representative genes.Results: The SMIR model rats developed persistent mechanical allodynia in ipsilateral hindpaw for up to 14 days. Ipsilateral SCDH of SMIR rats showed remarkable glial cell and neuron activation. A number of differentially expressed genes (DEGs) were identified in ipsilateral SCDH of SMIR rats by RNA-Seq. qPCR confirmed expression of some representative DEGs. Bioinformatics indicated that chemical synaptic transmission, sensory perception of pain and neuroactive ligand-receptor interaction were predominant functions. We compared our dataset with human pain-related genes and found that several genes exclusively participate in pain modulation and mechanisms.Conclusion: Our study provided novel understandings of the molecular mechanisms possibly contributing to CPSP. These findings may offer new targets for future treatment of CPSP.Keywords: postsurgical pain, spinal cord dorsal horn, RNA-Seq, microglia, genome

Hui Chen,1,&ast; Na Li,1,2,&ast; Xiang Zhan,1,&ast; Ting Zheng,1 Xinzhou Huang,1 Qianglin Chen,1 Zihao Song,1 Fei Yang,1,3 Hao Nie,1,3 Yanxiang Zhang,3 Bing Zheng,1,3 Quan Gong1,3 1Department of Immunology, School of Medicine, Yangtze University, Jingzhou, People’s Republic of China; 2Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, People’s Republic of China; 3Clinical Molecular Immunology Center, School of Medicine, Yangtze University, Jingzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bing Zheng; Quan GongDepartment of Immunology, School of Medicine, Yangtze University, Jingzhou, People’s Republic of ChinaEmail hxzheng@yangtzeu.edu.cn; gongquan1998@163.comPurpose: Capsaicin (8-methyl-N-geranyl-6-nonamide; CAP) is an alkaloid isolated from chili peppers, which has complex pharmacological properties, including beneficial effects against various diseases. The aim of this study was to investigate the role of CAP in lipopolysaccharide (LPS)-induced acute lung injury (ALI), and the possible underlying mechanisms.Materials and Methods: ALI was induced by intranasal administration of LPS (0.5 mg/kg), and CAP (1 mg/kg) injected intraperitoneally 3 days before exposure to LPS. Then, the histopathological changes were evaluated by hematoxylin and eosin staining. Enzyme-linked immunosorbent assay and qPCR were used to detect pro-inflammatory cytokines in serum and lung tissue. The expressions of HMGB1/NF-κB, PI3K/AKT/mTOR signaling pathways and apoptosis-associated molecules were determined by Western blot and/or qPCR. In addition, the lung cell apoptosis was analyzed by TUNEL staining, and the expression and location of cleaved caspase-3 were detected by immunofluorescence analysis.Results: CAP pretreatment significantly protected mice from LPS-induced ALI, with reduced lung wet/dry weight ratio, lung histological damage, myeloperoxidase (MPO) activity, malondialdehyde (MDA) content and pro-inflammatory cytokine levels, and significant increased superoxide dismutase (SOD) activity. In addition, CAP pretreatment significantly inhibited the high-mobility group protein B1 (HMGB1) expression, nuclear factor-kappa B (NF-κB) activation, and the PI3K/AKT/mTOR signaling pathway. Furthermore, mice pre-treated with CAP exhibited reduced apoptosis of lung tissues, with associated down-regulation of caspase-3, cleaved caspase-3, and BAX expression, and up-regulation of BCL-2.Conclusion: Our data demonstrate that CAP can protect against LPS-induced ALI by inhibiting oxidative stress, inflammatory responses and apoptosis through down-regulation of the HMGB1/NF-κB and PI3K/AKT/mTOR pathways.Keywords: capsaicin, acute lung injury, HMGB1/NF-κB, PI3K/AKT/mTOR, apoptosis, inflammation

Huimin Nie,1,&ast; Boyu Liu,1,&ast; Chengyu Yin,1 Ruixiang Chen,1 Jie Wang,1 Danyi Zeng,1 Yan Tai,2 Jingdun Xie,3 Dongwei He,4 Boyi Liu1 1Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou, 310053, People’s Republic of China; 2Academy of Chinese Medicine Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China; 3Department of Anesthesiology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Collaborative Innovation for Cancer Medicine, Guangzhou, Guangdong, 510060, People’s Republic of China; 4Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Boyi LiuDepartment of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou, 310053, People’s Republic of ChinaEmail boyi.liu@zcmu.edu.cnDongwei HeLaboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, People’s Republic of ChinaEmail dongweihe@hebmu.edu.cnBackground: Mirror-image pain (MIP), which develops from the healthy body region contralateral to the actual injured site, is a mysterious pain phenomenon accompanying many chronic pain conditions, such as complex regional pain syndrome (CRPS). However, the pathogenesis of MIP still remains largely unknown. The purpose of this study is to perform an expression profiling to identify genes related to MIP in an animal model of CRPS-I.Methods: We established a rat chronic post-ischemic pain (CPIP) model to mimic human CRPS-I. RNA-sequencing (RNA-Seq), bioinformatics, qPCR, immunostaining, and animal behavioral assays were used to screen potential genes in the contralateral dorsal root ganglia (DRG) that may be involved in MIP.Results: The CPIP model rats developed robust and persistent MIP in contralateral hind paws. Bilateral DRG neurons did not exhibit obvious neuronal damage. RNA-Seq of contralateral DRG from CPIP model rats identified a total 527 differentially expressed genes (DEGs) vs sham rats. The expression changes of several representative DEGs were further verified by qPCR. Bioinformatics analysis indicated that the immune system process, innate immune response, and cell adhesion were among the mostly enriched biological processes, which are important processes involved in pain sensitization, neuroinflammation, and chronic pain. We further identified DEGs potentially involved in pain mechanisms or enriched in small- to medium-sized sensory neurons or TRPV1-lineage nociceptors. By comparing with published datasets summarizing genes enriched in pain mechanisms, we sorted out a core set of genes which might contribute to nociception and the pain mechanism in MIP.Conclusion: We provided by far the first study to profile gene expression changes and pathway analysis of contralateral DRG for the studying of MIP mechanisms. This work may provide novel insights into understanding the mysterious mechanisms underlying MIP.Keywords: RNA-Seq, pain, CRPS-I, dorsal root ganglia, inflammation, cytokine

Ziyu Liu,1,2 Leilei Huang,3,4 Liwei Sun,1 Hui Nie,3,4 Yuqi Liang,1,2 Jinwen Huang,3,4 Fanhong Wu,3,4 Xin Hu1 1The Laboratory of Cancer Biology, China-Japan Union Hospital of Jilin University, Jilin University, Changchun, Jilin, People’s Republic of China; 2Department of Biochemistry and Molecular Biology, School of Life Science, Jilin University, Changchun, Jilin, People’s Republic of China; 3Shanghai Engineering Research Center of Green Fluoropharmaceutical Technology, Shanghai, People’s Republic of China; 4Department of Pharmaceutical Engineering, School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, People’s Republic of ChinaCorrespondence: Xin Hu; Fanhong Wu Email huxin@jlu.edu.cn; wfh@sit.edu.cnPurpose: Erianin is a small chemical compound extracted from Dendrobium chrysotoxum and has excellent antineoplastic effects against a variety of cancers. Combretastatin A-4 (CA4) is the most effective member of natural phenolic stilbene compounds isolated from the African willow tree Combretum caffrum. Ecust004 (Chemical Formula: C18H21NO7S) is a drug candidate optimized from structure–activity relationship studies of the sulfamate derivatives of Erianin and CA4, which has better bioavailability and pharmacokinetic profiles than Erianin and CA4.Methods: To investigate the antitumor activity of Ecust004 in different types of breast cancer cells, MDA-MB-231 and MCF7 cells were treated with Ecust004. MTT and CCK8 were used to determine the effects of Ecust004 on cell proliferation. Wound-healing and Transwell assays were used to evaluate the migration and invasion level of cells treated with Ecust004. The expression of genes and proteins associated with epithelial–mesenchymal transition was detected by RT-PCR and Western blotting. In vivo studies further clarified the functional effects of Ecust004.Results: Ecust004 treatment decreased the growth and proliferation of MDA-MB-231 and MCF7 cells at a lower dosage than Erianin. In addition, compared to Erianin and CA4, Ecust004 can better inhibit the invasion and migration of MDA-MB-231 and MCF7 cells. Accordingly, the expression of genes associated with epithelial–mesenchymal transition, such as E-cadherin and vinculin, was increased. Finally, compared with Erianin and CA4, Ecust004 exhibited a better anti-tumor activity in vivo.Conclusion: Ecust004 inhibits the proliferation, invasion, and migration of breast cancer cells, and therefore represents a potential agent for development as an antitumor drug.Keywords: Ecust004, Erianin, breast cancer, EMT

Deliang Yu,1,&ast; Xiaoyong Wu,1,&ast; Xuzhao Li,1,&ast; Xiaonan Liu,1 Kun Jiang,2 Qingchuan Zhao,1 Huang Nie3 1Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi, 710032, People’s Republic of China; 2Information Center, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, Shaanxi, People’s Republic of China; 3Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, 710032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qingchuan Zhao Tel +86-29-84771503Email zhaoqcxjh@163.comHuang Nie +86-29-84775343Email niehuang@163.comAim: Enhanced recovery after surgery (ERAS) gradually shortens the length of stay but increases the rate of unplanned readmission after discharge. Currently, objective discharge criteria for patients after radical gastrectomy is lacking. This study aimed to construct and validate a nomogram for estimation of the possibility of safe discharge on the fifth-day post radical gastrectomy.Methods: We enrolled 496 consecutive patients undergoing radical gastrectomy as the development cohort. After the fifth day of surgery, patients were assigned to the postoperative complication group and no postoperative complication group. Multivariate logistic regression analyses were performed for both groups. Then, we constructed the risk prediction model of postoperative severe complications (PSCs) and applied it to evaluate whether the patient could be discharged safely. The external validation cohort comprised 245 patients, whom we used to evaluate the capability of our model to predict the risk of PSCs. The primary measure was the negative predictive rate (NPR) and the area under the curve (AUC).Results: Through multivariate analysis, gender, maximum body temperature on the 4th postoperative day (POD4), oral intake and ambulatory duration on POD4, the proportion of neutrophils (≥ 75% or < 75%) and pain score (≥ 4 or < 4) on POD5, and defecation with 5 days after the procedure (yes or no) were identified as independent predictors for PSCs. Upon incorporation of these variables, the nomogram demonstrated a good NPR of 0.957 and 0.916 and AUC of 0.918 and 0.719 in the two cohorts, respectively. With a nomogram score of 110, patients were stratified into low and high risk of PSCs.Conclusion: The nomogram demonstrated good predictive potential for low-risk patients. It could serve as an objective safe discharge approach for patients after the fifth day of radical gastrectomy.Keywords: gastric cancer, radical gastrectomy, postoperative complications, safe discharge, perioperative management

Hanxiao Nie, Tao He, Li Wang, Ling Zhang Department of Hepatobiliary Surgery,The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450008, People’s Republic of ChinaCorrespondence: Hanxiao NieDepartment of Hepatobiliary Surgery, The Affiliated Cancer Hospital of Zhengzhou University, 127 Dongming Road, Jinshui District, Zhengzhou, 450008, People’s Republic of ChinaTel +8615290055861Email nie911653213@163.comLing ZhangDepartment of Hepatobiliary Surgery, The Affiliated Cancer Hospital of Zhengzhou University, 127 Dongming Road, Jinshui District, Zhengzhou, 450008, People’s Republic of ChinaTel/Fax +86 371 6558 7787Email zhanglily561@126.comAim: To explore the difference in tumor-infiltrating lymphocytes (TILs) and programmed death-ligand (PD-L1) in primary hepatocellular carcinoma (HCC) and its adjacent tissues, and to evaluate their effect on HCC prognosis.Methods: Liver cancer and paracancerous tissue samples were collected from 72 patients who underwent radical hepatectomy between December 15, 2017 and January 9, 2019. Flow cytometry was used to detect the distribution of TILs and PD-L1, analyze the correlation between the expression of CD8/CD3 and PD-L1 and clinical-pathological parameters, and evaluate their effect on the prognosis of HCC patients.Results: The distribution proportion of CD3+T cells, CD4+T cells, and PD-L1 in liver cancer were significantly higher than in paracancerous tissues, while the distribution proportion of CD8+T cells was significantly lower (all P< 0.05). In HCC, the distribution proportion of CD8+T cells was related to tumor size and stage, while the PD-L1 expression was related to the tumor stage only (all P < 0.05). Univariate analysis showed that tumor differentiation, TNM stage, expression of CD8/CD3, and PD-L1 in tumor tissue were related to disease-free survival (DFS)(P < 0.05); multivariate Cox regression analysis showed that tumor differentiation, TNM stage, CD8/CD3, and PD-L1 expression were independent influencing factors of postoperative DFS (P < 0.05). Kaplan–Meier survival curve analysis showed that the DFS of CD8/CD3 high expression group was significantly higher than that of the low expression group, and the DFS of PD-L1 low expression group was significantly higher than that of the high expression group (all P < 0.05).Conclusion: There are significant differences in the distribution of TILs and PD-L1 in HCC and paracancerous tissues. The expression of CD8/CD3 and PD-L1 in tumor-infiltrating lymphocytes in HCC may help evaluate the immunological indexes of prognosis after radical resection of HCC and to further the study of immunotherapy in patients with HCC.Keywords: liver cancer, TILs, PD-L1, DFS

Tao Wang,1,* Yifei Chen,1,* Hanxiang Nie,2 Yi Huang,2 Yang Zhao,2 Jiong Yang1 1Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China; 2Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, China *These authors contributed equally to this work Introduction: Non-small-cell lung cancer (NSCLC) accounts for more than half of all lung cancer cases. Cytokines play an important role in NSCLC, including IL-27. IL-27 inhibits NSCLC progression; however, the mechanism is not clear. The purpose of this study is to investigate the effects of IL-27 on NSCLC cell proliferation and metastasis. Materials and methods: NSCLC cells were treated with IL-27 or transfected with miR-935, and the cell proliferation was assayed by Cell Counting Kit-8 (CCK-8) and colony formation. Cell metastasis was analyzed by Transwell chamber system and wound healing assay. IL-27 protein in the medium was analyzed by ELISA. IL-27 mRNA expression was measured by quantitative reverse transcriptase-PCR. Results: We found that IL-27 played an inhibiting role in NSCLC cell proliferation and metastasis. The molecular mechanism of the suppressing role of IL-27 in NSCLC was regulated by miR-935. IL-27 expression was negatively associated with miR-935 in the clinical NSCLC samples. Conclusion: The study revealed that IL-27 decreased lung cancer cell proliferation and metastasis via miR-935. Keywords: non-small cell lung cancer, IL-27, miR-935

Xuxue Guo,1,* Hanxiang Nie,1,* Qianhui Chen,1 Shuo Chen,1 Nishan Deng,1 Ruiyun Li,1 Xuhong Ding,1 Suping Hu,1 Ailing Wang2 1Department of Respiratory Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China; 2Nursing Department, Wuhan University School of Health Sciences, Wuhan 430071, Hubei Province, China *These authors contributed equally to this work Introduction: Acute exacerbation of COPD (AECOPD) and left heart failure (LHF) commonly exist together in clinical practice. However, the identification of AECOPD concurrent with LHF is currently challenging. Our study aimed to investigate the role of plasma N-terminal brain natriuretic pro-peptide (NT-proBNP) in diagnosing elderly patients with AECOPD associated with LHF. Methods and results: LHF was diagnosed in patients with AECOPD according to echocardiographic criteria, and the levels of NT-proBNP in plasma were measured by quantitative electrochemiluminescence assay. Among the 655 patients with AECOPD, 158 (24.1%) had comorbid LHF, whether systolic (n=108, 68.4%) or diastolic (n=50, 31.6%). The plasma concentrations of NT-proBNP in elderly patients with AECOPD associated with LHF were markedly elevated, compared with those with only AECOPD (4,542.5 and 763.0 ng/L, respectively, P

OBJECTIVE: Sophorae Flavescentis Radix (Kuh-seng, SFR), a Traditional Chinese Medicine (TCM), is widely used alone or within a TCM formula to treat pruritus, especially histamine-independent intractable itching. In the previous study, potential antipruritic active components of the SFR were screened based on cell membrane immobilized chromatography (CMIC), revealing oxymatrine (OMT) as an antipruritic agent. However, the low oral bioavailability (OB) of OMT cannot explain the antipruritic effect of SFR when administered orally in clinic. In this study, we investigated the antipruritic effects and underlying mechanisms of orally administered SFR. MATERIALS AND METHODS: A network pharmacology and molecular docking were employed to screen the active components of SFR and predict their binding to disease-related target proteins, while the potential mechanisms were explored with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The binding energy between components and target proteins was calculated by molecular docking. RESULTS: The SFR-components-targets-intractable itching Protein-Protein Interactions (PPI) network was established, and 22 active components and 42 targets were screened. The GO enrichment analysis showed that the key target genes of SFR were related to nuclear receptors, transcription factors, and steroid hormone receptors. The results of the KEGG enrichment pathway analysis include Hepatitis B, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance, advanced glycation nd product (AGE)-receptor for AGE (RAGE) signaling pathway in diabetic complications, etc. Molecular docking showed that three key target proteins in the network, the vascular endothelial growth factor A (VEGFA), epidermal growth factor receptor (EGFR) and caspase-3 (CASP3), have higher binding activities with inermine, phaseolin and kushenol O, respectively; the binding energy of each pair is stronger than that of the target protein-corresponding inhibitors. CONCLUSIONS: The complexity of the SFR-components-targets-intractable itching network demonstrated the holistic treatment effect of SFR on intractable itching. The partial coherence between results screened by CMIC in the previous study and network pharmacology demonstrated the potential of network pharmacology in active component screening. Inermine screened from both CMIC and network pharmacology is a VEGFA inhibitor, which possibly accounts for the antipruritic effect of orally administered SFR. [ABSTRACT FROM AUTHOR]

ObjectivesQuantitatively assess the severity and predict the mortality of interstitial lung disease (ILD) associated with Rheumatoid arthritis (RA) was a challenge for clinicians. This study aimed to construct a radiomics nomogram based on chest computed tomography (CT) imaging by using the ILD-GAP (gender, age, and pulmonary physiology) index system for clinical management.MethodsChest CT images of patients with RA-ILD were retrospectively analyzed and staged using the ILD-GAP index system. The balanced dataset was then divided into training and testing cohorts at a 7:3 ratio. A clinical factor model was created using demographic and serum analysis data, and a radiomics signature was developed from radiomics features extracted from the CT images. Combined with the radiomics signature and independent clinical factors, a nomogram model was established based on the Rad-score and clinical factors. The model capabilities were measured by operating characteristic curves, calibration curves and decision curves analyses.ResultsA total of 177 patients were divided into two groups (Group I, n = 107; Group II, n = 63). Krebs von den Lungen-6, and nineteen radiomics features were used to build the nomogram, which showed favorable calibration and discrimination in the training cohort [AUC, 0.948 (95% CI: 0.910–0.986)] and the testing validation cohort [AUC, 0.923 (95% CI: 0.853–0.993)]. Decision curve analysis demonstrated that the nomogram performed well in terms of clinical usefulness.ConclusionThe CT-based radiomics nomogram model achieved favorable efficacy in predicting low-risk RA-ILD patients.