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Jingxin Zhou,1,&ast; Can Cao,1,&ast; Tonghua Liu,2 Lili Wu,2 Juan Miao1 1Department of Nephrology and Endocrinology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 101121, People’s Republic of China; 2Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lili Wu; Juan Miao, Email qingniao_566@163.com; 77915183@qq.comBackground: Thyroid dysfunction is more common in other endocrine disorders such as diabetes mellitus (DM). Carcinoembryonic antigen (CEA), a common tumor biomarker, is found elevated in patients with thyroid dysfunction. However, the relationship between thyroid hormone levels and CEA levels remains unclear.Methods: In total, 663 patients with type 2 diabetes at the Tongzhou Branch of Dongzhimen Hospital were enrolled in this retrospective study. Data were collected from inpatient electronic files between December 2011 and December 2019. Laboratory indices were statistically analyzed using logistic regression and Spearman correlation analyses.Results: In our study, total triiodothyronine (TT3), free triiodothyronine (FT3), serum albumin(ALB), total protein (TP), and triglyceride (TG) levels were significantly higher in the T2DM patients with normal values of CEA than T2DM patients who had abnormal values of CEA, whereas alkaline phosphatase (ALP), Glucose (GLU), and HbA1c levels were significantly increased in the T2DM patients with abnormal CEA level. Binary logistic regression analysis demonstrated that FT3, GLU, HbA1c, and TG levels remained as independent risk factors for CEA in patients with T2DM (β=− 0.907, P =0.004; β =− 1.009, P=0.004; β =0.090, P = 0001; β= 0.336, P < 0.001; β= − 0.293, P =0.009, resp). Spearman correlation analysis showed that CEA level was significantly positively correlated with HbA1c and GLU (rs value: 0.265, P < 0.001; rs value: 0.270, P < 0.001, resp.) and negatively correlated with FT3 and TG levels (rs value: − 0.139, P < 0.001; rs value: − 0.103 P =0.008, resp). Furthermore, multivariate logistic regression analysis indicated that the FT3 quartiles were significantly associated with CEA levels before and after adjusting for confounding factors.Conclusion: Our study determined that FT3 remained an independent risk factor for CEA in patients with T2DM and was significantly negatively correlated with CEA levels.Keywords: retrospective study, free triiodothyronine, carcinoembryonic antigen, thyroid function, type 2 diabetes mellitus

Ran Li,1,2,&ast; Yanwei Li,1,2,&ast; Zijian Song,1,2 Yixuan Gu,1,2 Xiaofeng Jiao,1,2 Chaoqiong Wan,1,2 Tiantian Liu,1,2 Rongrong Zhang,1,2 Ruifang Gao,1,2 Xiangyu Wang1,2 1Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, 030001, People’s Republic of China; 2Department of Pediatric and Preventive Dentistry, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, 030001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ran Li; Xiangyu Wang, Email lraner@163.com; wangxiangyu76@163.comPurpose: Chemotherapy is one of the most commonly used treatments for oral squamous cell carcinoma (OSCC), but its use is limited by drug resistance and severe systemic toxicity. To eliminate these side effects and improve anti-tumor efficacy, several therapeutic approaches have been developed for use with chemotherapy. In this study, we developed a graphene-based lipid modulation nanoplatform (NSD) that carries SB-204990, a small molecule inhibitor specific for ATP citrate lyase (ACLY), and doxorubicin (DOX), a chemotherapeutic agent, and the trio enables synergistic treatment of OSCC with lipid starvation, chemotherapy, and photothermal therapy.Methods: We first determined whether ACLY expression was upregulated in OSCC, and then assessed the growth inhibitory effects of SB-204990 on SCC-15 cells and changes in lipid (acetyl coenzyme A, free fatty acids, and cholesterol) levels. We characterized NSD and then evaluated the stability, photothermal properties, drug loading, and release ability of NSD. Finally, the therapeutic effects of NSD on OSCC were investigated by in vitro and in vivo experiments, and the changes in lipid levels in OSCC tissues after ACLY inhibition were further evaluated.Results: The results showed that ACLY was highly expressed in OSCC, and ACLY inhibition produced reproductive suppression and decreased lipid levels in SCC-15 cells. The NSD nanoplatform possessed good stability, photothermal properties, high drug loading capacity and controlled release. In addition, the triple therapy achieved satisfactory anticancer effects in both in vivo and in vitro assays, and the inhibition rate of tumors was as high as 99.4% in the NSD+Laser treatment group.Conclusion: The changes in tumor cell lipid levels and cell proliferation arrest induced by ACLY inhibition suggest that ACLY may be a promising target for lipid starvation therapy and resistance to chemoresistance, and its inhibitors are expected to become new anticancer drugs. The NSD nanocarrier system enables synergistic treatment with lipid starvation, chemotherapy, and photothermal therapy, which represents an innovative approach to combating tumors. Keywords: starvation therapy, ACLY, nanotechnology, chemotherapy resistance, OSCC

Zheng Wan,1 Tianyi Liu,1 Ning Xu,1 Wenhao Zhu,2 Xiaoyu Zhang,2 Qin Liu,1 Haifeng Wang,2 Honglei Wang1 1Department of Neurovascular Surgery, The First Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China; 2Department of Neurotrauma, The First Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of ChinaCorrespondence: Haifeng Wang; Honglei Wang, Email hfwang@jlu.edu.cn; wanghongl@jlu.edu.cnIntroduction: Extracellular vesicles (EVs) are nanosized membrane vesicles that are naturally secreted by almost all cells and have gained considerable attention. Many studies have applied EVs to the treatment of brain diseases and validated their effectiveness. Although only a few EVs can penetrate the blood‒brain barrier (BBB) into the brain after administration, it has been proven that EVs and their cargos exert their effects by interacting with brain cells. PKH dyes are commonly used to stain EVs for distribution studies. However, systematic investigations of imaging characteristics of the PKH-labeled EVs distributed in the brain are still scarce.Methods: We stained EVs derived from mesenchymal stem cells with PKH26 or PKH67. PKH26-labeled EVs and PKH67-labeled EVs were administered at the same time into each mouse while PKH26-labeled EVs were given through tail veins and PKH67-labeled EVs were given through intraperitoneal injection. Confocal microscopy was used to explore the distribution difference of two types of EVs given via different routes in the brain.Results: The fluorescence of PKH26 and PKH67 had nearly identical distributions in brain slices after 1 h, 6 h, 12 h and 1 day of EV administration. Under the same confocal parameters, brain slices without EVs administration demonstrated the same result. However, liver slices from mice administered with labeled EVs showed obviously different distributions of two types PKH fluorescence.Discussion: These findings raise questions about the ability of PKH dyes as labels for EVs when explore the EV brain distribution observed via confocal microscopy.Keywords: extracellular vesicles, PKH dyes, brain distribution

Shiya Zeng,1,&ast; Yanyue Tan,1,2,&ast; Zhiwei Cao,3 Yunhao Zheng,1 Tiqian Liu,1 Yifei Deng,1 Xin Xiong1 1State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Nursing, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3School of Stomatology, Tianjin Medical University, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xin Xiong, State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 15, West Section 3, Second Ring Road, Chengdu, Sichuan, 610041, People’s Republic of China, Tel +86 028 85501425, Email drxiongxin@scu.edu.cnObjective: Growing researches explore vitamin D’s role in temporomandibular disorders (TMDs), but the link between vitamin D and TMDs remains debated. To clarify the causal relationship, we conducted a Mendelian randomization (MR) analysis using data from genome-wide association studies (GWAS).Subjects and Methods: The GWAS dataset of vitamin D (GWAS ID: ukb-d-30890_irnt; sample size: 329247) was obtained from the IEU Open GWAS project. And that of TMDs (GWAS ID: finn-b-TEMPORO; sample size: 134280), initiated on August 25th, 2017 and publicly released on December 18th, 2023, was extracted from the FinnGen dataset, whose cases were diagnosed based on the revised International Classification of Diseases, 10th Edition (ICD-10) code K07.6. Both datasets were obtained from the European population. According to three assumptions of MR analysis, a bi-directional MR analysis was performed to measure the causal relationship, with Inverse variance weighted (IVW) as the primary method and MR Egger and Weighted median as supplement. Moreover, diverse sensitivity analyses, including Cochran’s Q test, MR Egger intercept, Mendelian randomized polymorphism RESidual Sum and Outlier (MR-PRESSO), and leave-one-out analysis, were used to verify the stability of the findings.Results: The MR analysis supported causal effects of vitamin D levels on TMDs risks within the European population using IVW method [odds ratio = 1.316; 95% confidence interval = 1.086 to 1.595; P = 0.005], supported by MR Egger and Weighted median. While there was no indication that TMDs have a direct impact on vitamin D levels [β: − 0.00738, standard error = 0.00665; P = 0.568].Conclusion: The study revealed that within the European population higher levels of vitamin D led to higher risks of developing temporomandibular disorders, but found no obvious evidence that TMDs are causally associated with vitamin D. The conclusion should be cautiously interpreted, given the selection bias of TMDs patients sample.Keywords: Mendelian randomization analysis, temporomandibular joint disorders, vitamin D, 25-hydroxyvitamin D

Jia-wei Xu,1,2,&ast; Fang-fang Chen,1,&ast; Ying-hui Qv,1,&ast; Cong-cong Sun,1 Dong Zhang,1,2 Zhi Guo,1 Yu-jiao Wang,3 Jun-fei Wang,4 Tian Liu,4 Liang Dong,1,2 Qian Qi1,2 1Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Shandong Characteristic Laboratory of Clinical Transformation of Respiratory Biological Immunity and Regenerative Medicine, Jinan, Shandong Province, 250014, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong Province, 250014, People’s Republic of China; 3Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Laboratory Medicine, Jinan, Shandong Province, 250014, People’s Republic of China; 4Department of Pulmonary and Critical Care Medicine, Qilu Hospital, Shandong University, Jinan, Shandong Province, 250012, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qian Qi, Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, &num;16766, Jingshi Road, Jinan City, Shandong Province, 250014, People’s Republic of China, Tel +86 13706380314, Email qiqianqlh@163.comPurpose: Bronchiectasis patients are prone to Pseudomonas aeruginosa infection due to decreased level of sphingosine in airway. Adiponectin receptor agonist AdipoRon activates the intrinsic ceramidase activity of adiponectin receptor 1 (AdipoR1) and positively regulates sphingosine metabolism. This study aimed to investigate the potential therapeutic benefit of AdipoRon against Pseudomonas aeruginosa infection.Methods: A mouse model of Pseudomonas aeruginosa lung infection and a co-culture model of human bronchial epithelial cells with Pseudomonas aeruginosa were established to explore the protective effect of AdipoRon. Liquid chromatography-mass spectrometry was used to detect the effect of AdipoRon on sphingosine level in lung of Pseudomonas aeruginosa-infected mouse models.Results: The down-regulation of adiponectin and AdipoR1 in airway of bronchiectasis patients was linked to Pseudomonas aeruginosa infection. By activating AdipoR1, AdipoRon reduced Pseudomonas aeruginosa adherence on bronchial epithelial cells and protected cilia from damage in vitro. With the treatment of AdipoRon, the load of Pseudomonas aeruginosa in lung significantly decreased, and peribronchial inflammatory cell infiltration was lessened in vivo. The reduced level of sphingosine in the airway of Pseudomonas aeruginosa infected mice was replenished by AdipoRon, thus playing a protective role in the airway. Moreover, AdipoRon activated P-AMPKα/PGC1α, inhibited TLR4/P-NF-κB p65, and reduced expression of pro-apoptotic bax. However, the protective effect of AdipoRon on resisting Pseudomonas aeruginosa infection was weakened when AdipoR1 was knocked down.Conclusion: AdipoRon protects bronchial epithelial cells and lung by enhancing their resistance to Pseudomonas aeruginosa infection. The mechanism might be modulating sphingosine metabolism and activating P-AMPKα/PGC1α while inhibiting TLR4/P-NF-κB p65.Keywords: AdipoRon, Pseudomonas aeruginosa, bronchiectasis, AdipoR1, sphingosine metabolism

Tongzuo Liu,1,2,&ast; Jingyi Zhang,1,2,&ast; Zhiqiang Zhao,1 Yingfei Bi,1 Ying Zheng,1 Shuai Wang,1 Xiaohua Dai,3 Jun Li,4 Qian Lin,5 Daimei Ni,6 Chenglong Wang,7 Jianguang Wu,8 Yitao Xue,9 Mingjun Zhu,10 Xianliang Wang,1,&ast; Jingyuan Mao1,&ast; 1Cardiovascular Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine/National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, People’s Republic of China; 2Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China; 3Cardiovascular Department, The First Affiliated Hospital of Anhui University of Chinese Medicine, Anhui, People’s Republic of China; 4Cardiovascular Department, Guang’anmen Hospital of China Academy of Chinese Medicine Science, Beijing, People’s Republic of China; 5Cardiovascular Department, Dongzhimen Hospital of Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 6Cardiovascular Department, Taihe Hospital of Traditional Chinese Medicine Affiliated to Anhui University of Chinese Medicine, Anhui, People’s Republic of China; 7Cardiovascular Department, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 8Cardiovascular Department, Affiliated Hospital of Jiangxi University of Chinese Medicine, Jiangxi, People’s Republic of China; 9Cardiovascular Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Shandong, People’s Republic of China; 10Cardiovascular Department, The First Affiliated Hospital of He’nan University of Traditional Chinese Medicine, Henan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jingyuan Mao; Xianliang Wang, Cardiovascular Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine/National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, People’s Republic of China, Tel +86-13820498886 ; +86-13920007825, Email jymao@126.com; xlwang1981@126.comBackground: Stable angina pectoris (SAP), as a common type of coronary heart disease (CHD), is characterized by transient retrosternal squeezing pain or suffocation induced by exercise, mood swings, or other stress. Most patients with stable angina pectoris do not benefit from interventional therapy and medication, so optimizing treatment plans has important clinical significance. Jiuxin pill is a Chinese patent medicine developed by Huatuo Chinese Medicine Co. Ltd. (Bozhou, China) to relieve the symptoms of stable angina pectoris (SAP). However, there is a lack of evidence support from high-quality clinical studies.Methods: In this randomized, double-blind, placebo-controlled, multicenter clinical trial, 170 patients with SAP were recruited from 11 centers in China. The patients were randomized to either the treatment group (Jiuxin pill, 2 pills, bid) or the control group (Jiuxin pill simulant, 2 pills, bid) without changing the original conventional western medicine. The trial was set up with a run-in period of 7 days, a treatment period of 28 ± 2 days, and a follow-up period of 28 ± 2 days. Total exercise time (TED) in the treadmill test and Seattle Angina Questionnaire (SAQ) scores were set as the main efficacy outcomes, and the 1-minute heart rate recovery (HRR1), metabolic equivalents (METs), maximum ST segment depression, Borg perceived exertion after exercise, the average number of angina attacks per week, usage of nitroglycerin, drug withdrawal and reduction rate, information scoring of four diagnostic methods in traditional Chinese medicine and incidence of major adverse cardiovascular events were set as the secondary efficacy outcomes. Adverse events were monitored throughout the trial.Discussion: In China, the use of Chinese patent medicine in the treatment of stable angina pectoris is more common. This trial evaluated the efficacy and safety of the Jiuxin pill in the treatment of patients with SAP, and the trial results provide high-quality research evidence for its clinical application.Trial Registration: This trial has been registered in the China Clinical Trial Registry on 11 June 2022 (Registration No.: ChiCTR2200060780, https://www.chictr.org.cn/showproj.html?proj=172352).Keywords: traditional Chinese medicine, Jiuxin pill, stable angina pectoris, protocol, randomized controlled trial

Ting Liu,1,* Chao Lei,1,* Qinhong Huang,2,* Weiqi Song,3 Chen Li,1 Ning Sun,4,5 Zhihua Liu6 1Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, the Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510799, People’s Republic of China; 2The First Clinical College, Guangzhou Medical University, Guangzhou, 511400, People’s Republic of China; 3Department of Public Health, Guangzhou Medical University, Guangzhou, People’s Republic of China; 4Guangzhou 11th People’s Hospital, Guangzhou Cadre and Talent Health Management Center, Guangzhou, 510530, People’s Republic of China; 5The State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, the Hong Kong Polytechnic University, 999077, Hong Kong, China; 6Department of Anorectal Surgery, the Tenth Affiliated Hospital of Southern Medical University (Dongguan People’s Hospital), Dongguan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhihua Liu; Ning Sun, Email liuzhihua83@hotmail.com; ning.sun@connect.polyu.hkIntroduction: Obesity, which is associated with gut microbiota dysbiosis, low-grade chronic inflammation and intestinal barrier dysfunction, can cause a variety of chronic metabolic diseases. Phytochemical flavonoids have a variety of biological activities, among which there may be safe and effective anti-obesity solutions.Methods: We tested a plant-derived flavonoid hesperidin and fecal microbiota transplantation (FMT) to alleviate diet-induced obesity. High-fat diet (HFD)-fed mice were treated with hesperidin (100 and 200 mg/kg BW) and FMT.Results: Results indicated that hesperidin had the effects of reducing obesity as indicated by reduction of body weight, fat accumulation and blood lipids, reducing inflammation as indicated by reduction of pro-inflammation factors including TNFα, IL-6, IL-1βand iNOS, and improving gut integrity as indicated by increasing colon length, reducing plasma gut permeability indicators iFABP and LBP, increased mRNA expression of mucus protein Muc2, tight junction p Claudin 2, Occludin and ZO-1 in the HFD-fed mice. The anti-obesity effects of hesperidin treatment have a dose-dependent manner. In addition, 16S rRNA-based gut microbiota analysis revealed that hesperidin selectively promoted the growth of Lactobacillus salivarius, Staphylococcus sciuri and Desulfovibrio C21_c20 while inhibiting Bifidobacterium pseudolongum, Mucispirillum schaedleri, Helicobacter ganmani and Helicobacter hepaticus in the HFD-fed mice. Horizontal feces transfer from the normal diet (ND)-fed mice to the HFD-fed mice conferred anti-obesity effects and transmitted some of the HFD-modulated microbes.Conclusion: We concluded that hesperidin and FMT both affect the reduction of body weight and improve HFD-related disorders in the HFD-fed mice possibly through modulating the composition of the gut microbiota.Keywords: hesperidin, high-fat diet, obesity, gut microbiota, fecal microbiota transplantation

Ting Liu,1,2 Luxu Wang,1– 3 Tuo Shi,4 Hongrui Liu,1,2 Bo Liu,5 Jie Guo,1,2 Minqi Li1,2,5 1Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, People’s Republic of China; 2Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, People’s Republic of China; 3School of Stomatology, Jinzhou Medical University, Jinzhou, People’s Republic of China; 4School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 5School of Clinical Medicine, Jining Medical University, Jining, People’s Republic of ChinaCorrespondence: Bo Liu, School of Clinical Medicine, Jining Medical University, Jining, 272067, People’s Republic of China, Tel +86-0537-6051782, Email liubo7230@mail.jnmc.edu.cn Jie Guo, Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, 250012, People’s Republic of China, Tel +86-0531-88382923, Email kqgj@sdu.edu.cnPurpose: Bone loss is a common complication of type 2 diabetes mellitus (T2DM). Circadian rhythms play a significant role in T2DM and bone remodeling. Eldecalcitol (ED-71), a novel active vitamin D analog, has shown promise in ameliorating T2DM. We aimed to investigate whether the circadian rhythm coregulator BMAL1 mediates the anti-osteoporotic effect of ED-71 in T2DM and its associated mechanisms.Methods: A T2DM mouse model was established using high-fat diet (HDF) and streptozotocin (STZ) injection, and blood glucose levels were monitored weekly. HE staining, Masson staining, and Micro-CT were performed to assess the changes in bone mass. IHC staining and IF staining were used to detect osteoblast status and BMAL1 expression and RT-qPCR was applied to detect the change of oxidative stress factors. In vitro, high glucose (HG) stimulation was used to simulate the cell environment in T2DM. RT-qPCR, Western blot, IF, ALP staining and AR staining were used to detect osteogenic differentiation and SIRT1/GSK3β signaling pathway. DCFH-DA staining was used to detect reactive oxygen species (ROS) levels.Results: ED-71 increased bone mass and promoted osteogenesis in T2DM mice. Moreover, ED-71 inhibited oxidative stress and promoted BMAL1 expression in osteoblasts The addition of STL1267, an agonist of the BMAL1 transcriptional repressor protein REV-ERB, reversed the inhibitory effect of ED-71 on oxidative stress and the promotional effect on osteogenic differentiation. In addition, ED-71 facilitated SIRT1 expression and reduced GSK3β activity. The inhibition of SIRT1 with EX527 partially attenuated ED-71’s effects, whereas the GSK3β inhibitor LiCl further enhanced ED-71’s positive effects on BMAL1 expression.Conclusion: ED-71 ameliorates bone loss in T2DM by upregulating the circadian rhythm coregulator BMAL1 and promoting osteogenesis through inhibition of oxidative stress. The SIRT1/GSK3β signaling pathway is involved in the regulation of BMAL1.Keywords: eldecalcitol, type 2 diabetic mellitus, osteoblast, BMAL1, SIRT1/GSK3β signaling pathway

Xiaolong Wang,1,2,&ast; Guanyi Wang,2,&ast; Peibin Cen,1,&ast; Hongyu Lan,1 Linfa Guo,2 Zuhaer Yisha,2 Aodun Gu,2 Guiyong Liu,3 Zijian Wang,2 Tongzu Liu,2,4– 8 Qingfeng Yu1,9– 11 1Department of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 3Department of Urology, Qianjiang Central Hospital of Hubei Province, Qianjiang, People’s Republic of China; 4Hubei Key Laboratory of Urological Diseases, Wuhan University, Wuhan, People’s Republic of China; 5Hubei Clinical Research Center for Laparoscopic/Endoscopic Urologic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 6Institute of Urology, Wuhan University, Wuhan, People’s Republic of China; 7Hubei Medical Quality Control Center for Laparoscopic/Endoscopic Urologic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 8Wuhan Clinical Research Center for Urogenital Tumors, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 9Guangdong Provincial Key Laboratory of Urological Diseases, Guangzhou Medical University, Guangzhou, People’s Republic of China; 10Guangdong Engineering Research Center of Urinary Minimally Invasive Surgery Robot and Intelligent Equipment, Guangzhou Medical University, Guangzhou, People’s Republic of China; 11Guangzhou Institute of Urology, Guangzhou Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tongzu Liu, Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China, Email liutongzu@163.com Qingfeng Yu, Department of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China, Email sunriseyu@yeah.netIntroduction: Overactive bladder (OAB) is a highly prevalent condition with limited treatment options due to poor efficacy, side effects, and patient compliance. Novel drug delivery systems that can target the bladder wall may improve OAB therapy.Methods: We explored a polydopamine (PDA)-coated lactobacillus platform as a potential carrier for localized OAB treatment. Urinary microbiome profiling was performed to identify the presence of lactobacillus in healthy and OAB groups. Lactobacillus-PDA nanoparticles were synthesized and characterized by electron microscopy and spectrophotometry. A rat bladder perfusion model and human bladder smooth muscle cell spheroids were used to assess the distribution and penetration of the nanoparticles. The efficacy of the Lactobacillus-PDA system (LPS) for delivering the antimuscarinic drug solifenacin was evaluated in an OAB rat model.Results: Urinary microbiome profiling revealed lactobacillus as a dominant genus in both healthy and OAB groups. The synthesized Lactobacillus-PDA nanoparticles exhibited uniform size and optical properties. In the rat bladder perfusion model, the nanoparticles distributed throughout the bladder wall and smooth muscle without toxicity. The nanoparticles also penetrated human bladder smooth muscle cell spheroids. In the OAB rat model, LPS facilitated the delivery of solifenacin and improved treatment efficacy.Discussion: The results highlight LPS as a promising drug carrier for targeted OAB therapy via penetration into bladder tissues. This bacteriotherapy approach may overcome limitations of current systemic OAB medications. Lactobacillus, a probiotic bacterium present in the urinary tract microbiome, was hypothesized to adhere to and penetrate the bladder wall when coated with PDA nanoparticles, making it a suitable candidate for localized drug delivery. Keywords: polydopamine, lactobacillus, nano material, drug delivery, overactive bladder

Ruijing Su,&ast; Yue Yang,&ast; Haiyan Wu, Bo Liu, Xinyuan Tian, Chaoyu Zhou, Yanxin Hu, Tianlong Liu Laboratory of Veterinary Pathology and Nanopathology, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tianlong Liu; Yanxin Hu, Email liutianlong@cau.edu.cn; huyx@cau.edu.cnBackground: A successful immune response against tumors depends on various cellular processes. Hence, there is an urgent need to construct a proficient nanoplatform for immunotherapy that can concurrently regulate the activities of various cells participating in the immune process. We have developed zeolitic imidazolate framework-8 (ZIF-8) formula, with good pH sensitivity, which is conducive to the release of drugs in the tumor site (acidic environment) and significantly improves immunotherapy. This is achieved through the coordinated action of different therapeutic agents, such as the photothermal agent polydopamine (PDA), the chemodrug camptothecin (CPT), and the immunomodulator 1-methyl-D-tryptophan (1-MT).Materials and Methods: In this study, we evaluated the antitumor effect of PDA/(CPT + 1-MT) @ZIF-8 (PCMZ) nanoparticles (NPs) in vitro and in vivo and investigated the molecular mechanism of PCMZ NPs in tumor suppression via photothermal-chemo-immunotherapy.Results: MTT and Annexin V-FITC/PI double staining apoptosis test showed that PCMZ NPs could induce apoptosis of 4T1 cell, and PCMZ NPs could cause 4T1 cell necrosis under 808 nm laser irradiation. The objective is to establish a unilateral breast cancer model in mice and investigate the effect of PCMZ NPs on tumor growth and tumor suppression in tumor bearing mice. The results showed that PCMZ NPs showed good heating effect in vivo and effectively inhibited tumor growth under 808 nm laser irradiation. In addition, PCMZ NPs could induce the immunogenic death of tumor cells, promote the maturation of DCs, inhibit IDO pathway, and finally differentiate T cells into cytotoxic T cells and helper T cells, so as to effectively activate the anti-tumor immune response.Conclusion: The PCMZ NPs, possessing good photothermal conversion capabilities due to join of PDA, effectively overcome two main challenges in immunotherapy: insufficient stimulation of the immune response and evasion of the immune system. This provides a robust platform against invasive cancer and recurrent tumors. Keywords: zeolitic imidazolate framework-8, photothermal agent polydopamine, 1-methyl-D-tryptophan, photoluminescence, camptothecin

Jing Han,1,2,&ast; Qingxun Meng,1,2,&ast; Taicheng Liu,1,2 Mengru Lv,1,2 Wenxuan Su,1,2 Beibei Liu,1,2 Jiannan Wu1,2 1Department of Oral Implantology, Tianjin Stomatological Hospital, School of Medicine, Nankai University, Tianjin, 300041, People’s Republic of China; 2Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, Tianjin, 300041, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jing Han; Jiannan Wu, Department of Oral Implantology, Tianjin Stomatological Hospital, School of Medicine, Nankai University, Tianjin, 300041, People’s Republic of China, Email hanj0203@163.com; bdxiaosier@163.comBackground: Wound healing has always been a focal point in clinical work. Bacterial infections and immune microenvironment disorders can both hinder normal wound healing. Current wound dressings only serve a covering function. Developing wound dressings with antibacterial and immunomodulatory functions is crucial for aiding wound healing. To address this issue, we have developed a hydrogel with antibacterial and immunomodulatory functions for managing infected wounds.Methods: The present study describes a photo-crosslinked antibacterial hydrogel composed of curcumin, silver nanoparticles-loaded reduced graphene oxide, and silk fibroin methacryloyl for the treatment of infected wounds. The study assessed its antibacterial properties and its capacity to induce macrophage M2 polarization through in vitro and in vivo experiments.Results: The hydrogel demonstrates robust antibacterial properties and enhances macrophage M2 polarization in both in vitro and in vivo settings. Moreover, it accelerates the healing of infected wounds in vivo by stimulating collagen deposition and angiogenesis.Conclusion: Overall, this hydrogel shows great potential in managing wound infections. Keywords: infected wound healing, silk fibroin methacryloyl, curcumin, silver nanoparticles-reduced graphene oxide, immunomodulation, antibacterial

Yuqing Li,1,&ast; Lei Wu,1,2,&ast; Rui Zhao,1,2,&ast; Yi Gao,1 Geng Bai,1 Ziqiang Guo,1 Xiaolin Chen,1 Yuanlu Chen,2 Tong Liu,1 Guangping Li1 1Tianjin Key Laboratory of Logic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, People’s Republic of China; 2TEDA International Cardiovascular Hospital, Electrophysiological Department, Tianjin, 300457, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guangping Li, Email tic_tjcardiol@126.comBackground: An electrocardiogram (ECG) was used to determine the type of acute myocardial infarction (MI) and locate the culprit vessel. Inferior wall myocardial infarction (IWMI) patients with the right coronary artery (RCA) as the culprit vessel may have a worse clinical prognosis than the left circumflex artery (LCx). We aimed to develop a new, simple, accurate scoring system to localize the RCA.Methods: From January 2018 to January 2020, patients were admitted to the Department of Cardiology of TEDA International Cardiovascular Hospital and the Second Hospital of Tianjin Medical University due to IWMI and coronary angiography confirmed that the infarct-related vessel was a single RCA or LCx. ECG of patients before percutaneous coronary intervention (PCI) was collected to quantitatively analyze the characteristics of ST-segment deviation in non-inferior wall leads (N-IWL) and establish the RCA score in N-IWL.Results: 149 patients were enrolled, including 83 in the RCA group and 66 in the LCx group. Finally, ST-segment depression (ST↓) lead I, aVR, V1, and V6, and ST↓≥ 1mm in lead V4 were found to be associated with the location of the RCA. The sensitivity, specificity, and area under the curve (AUC) of the N-IWL RCA scoring system were 77.1%, 72.7%, and 0.83, respectively. The diagnostic ability of the scoring system was better than that of other algorithms and scoring systems.Conclusion: ECG helps identify the RCA in patients with IWMI before PCI. The N-IWL RCA score may help identify the culprit vessel as the RCA in patients with IWMI.Keywords: electrocardiogram, inferior wall myocardial infarction, percutaneous coronary intervention, right coronary artery

Mingyu Shao,1 Zhaohong Liu,1 Tongtong Liu2 1Department of Child Health Care, Zibo Central Hospital, Zibo, Shandong, 255020, People’s Republic of China; 2Department of Pediatrics, Zibo Central Hospital, Zibo, Shandong, 255020, People’s Republic of ChinaCorrespondence: Tongtong Liu, Department of Pediatrics, Zibo Central Hospital, No. 54 Gongqingtuan West Road, Zhangdian District, Zibo, Shandong, 255020, People’s Republic of China, Tel +86-18560290203, Email liutongtong321@126.comIntroduction: Healthcare is essential for asthma control, however, whether family-supported healthcare improves therapeutic effects in childhood asthma remains unclear.Methods: The enrolled patients were randomly divided into control and intervention groups. The pulmonary function was evaluated by forced expiratory volume in 1 s as a percentage of forced vital capacity (FEV1/FVC) and fractional exhaled nitric oxide (FeNO). Asthma control and life quality were assessed via a childhood asthma control test and pediatric asthma quality of life questionnaire. Inflammatory cytokines interleukin-6 (IL-6) and interleukin-17 (IL-17) were determined by enzyme-linked immunosorbent assay.Results: No significant differences existed in the basic characteristics of asthma children and their parents among two groups. The increase of FEV1/FVC was higher in the intervention group versus the control group (76.47 ± 10.76% vs 69.76 ± 8.88%, p = 0.001 at the time of post-intervention), and the decrease of FeNO was greater in the intervention group (30.43 ± 6.85 bbp vs 35.64 ± 6.62 bbp, p = 0.003 at the time of post-intervention). Family-supported healthcare highly improved asthma control and quality of life in childhood asthma post-treatment. Meanwhile, the inflammatory cytokines IL-17 (118.14 ± 25.79 pg/mL in intervention group vs 142.86 ± 28.68 pg/mL in control group, p = 0.004 at the time of post-intervention) and IL-6 (103.76 ± 23.11 pg/mL in intervention group vs 119.73 ± 22.68 pg/mL in control group, p = 0.009 at the time of post-intervention) significantly decreased by family-supported healthcare intervention. Importantly, acute exacerbation (80.8% in intervention group vs 95.7% in control group, p = 0.030) and rehospitalization cases (88.5% in intervention group vs 100% in control group, p = 0.028) also decreased by family-supported healthcare intervention.Discussion: Family-supported healthcare improves pulmonary function and quality of life while alleviates inflammation, acute exacerbation, and rehospitalization in childhood asthma post-routine treatment.Keywords: asthma, family-supported healthcare, pulmonary function, IL-6, IL-17

Cuiting Wang,1,2 Tian An,1,2 Cong Lu,1,2 Tiantian Liu,1,2 Xiaomeng Shan,1,2 Zhiyao Zhu,1,2 Yanbin Gao1,2 1School of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Key Laboratory of TCM Collateral Disease Theory Research, Beijing, People’s Republic of ChinaCorrespondence: Yanbin Gao; Zhiyao Zhu, School of Traditional Chinese Medicine, Capital Medical University, No. 10 You An Men Wai, Xi Tou Tiao, Feng Tai District, Beijing, 100069, People’s Republic of China, Tel +86 10 8391 1640 ; +86 10 8391 1626, Email gyb@ccmu.edu.cn; 20120103@ccmu.edu.cnBackground: Prediabetes, characterized by a series of metabolic abnormalities, increases the risk of diabetes and cardiovascular diseases. Tangzhiping (TZP), a clinically validated traditional Chinese medicine formula, is used to treat impaired glucose tolerance. However, the underlying mechanism of TZP in intervening prediabetes is not fully elucidated.Purpose: The current study aimed to evaluate the protective effect of TZP against prediabetes mice and explore its potential mechanism.Methods: After establishing a prediabetic animal model through 12 weeks of high-fat diet (HFD) feeding, mice were subjected to TZP for 8 weeks. Various parameters related to body weight, glucose and lipid metabolism, and insulin sensitivity were measured. Histopathological examinations observed adipose cell size and liver lipid deposition. The Sable Promethion system assessed energy metabolism activity. Transcriptomic analysis of Epididymal white adipose tissue (EWAT) identified enriched pathways and genes. The key genes in the enriched pathways were identified through RT-PCR.Results: Our data revealed that the administration of TZP reduced body weight and fat mass in a prediabetes mouse model. TZP normalized the glucose and insulin levels, improved insulin resistance, and decreased plasma TC and FFA. The alleviation of adipose tissue hypertrophy and lipid deposition by TZP was demonstrated through pathological examination. Indirect calorimetry measurements indicated a potential increase in VO2 and EE levels with TZP. The results of EWAT transcription showed that TZP reversed pathways and genes related to inflammation and catabolic metabolism. RT-PCR demonstrated that the mRNA expression of inflammation and lipolysis, including Tlr2, Ccr5, Ccl9, Itgb2, Lipe, Pnpla2, Cdo1, Ces1d, Echs1, and Acad11, were changed by TZP treatment.Conclusion: TZP effectively alleviates obesity, impaired glucose and lipid metabolism, and insulin resistance. The effect of TZP might be associated with the regulation of gene expression in dysfunctional adipose tissue. Keywords: traditional Chinese medicine, Tangzhiping, prediabetes, adipose tissue, inflammation, lipolysis

Mengjie Yang, Kun Guo, Wenjing Liu, Xiuqing Fang, Ting Liu School of Nursing, Qingdao University, Qingdao, Shandong, People’s Republic of ChinaCorrespondence: Ting Liu, School of Nursing, Qingdao University, 1 Ningde Road, Qingdao, Shandong, 266073, People’s Republic of China, Tel +86 15066237573, Email liuting201516@163.comPurpose: The study aimed to explore the status of four common health problems (ie, smoking, internet addiction, physical inactivity, psychological disorder) among college students and analyze the relationship between psychological resilience, coping tendency and health problems.Participants and Methods: The convenience sampling method was used to recruit 500 college students from four universities. The General Information Questionnaire, Adolescent Psychological Resilience Scale, Simplified Coping Style Questionnaire and Health Risk Behavior Questionnaire were used for survey.Results: Among the students, there were 71 smokers (15.4%) and 61 internet addicts (13.2%). Over a third of the students reported physical inactivity (35.9%) and a minority had psychological disorder (6.3%). The psychological resilience score differed between students who smoked, had internet addiction, physical inactivity, psychological disorder and those without these health-risk behaviors. Logistic regression analysis showed that negative coping tendency was the common contributing factor of physical inactivity, internet addiction and psychological disorder. Coping tendency played a partial mediating effect in the relationship between psychological resilience and health problems, with a mediating effect of 37.93%.Conclusion: Psychological resilience can not only affect health problems directly but also influence health problems indirectly through coping tendency. Educators and administrators in universities can apply effective measures to improve psychological resilience and positive coping to prevent or reduce health problems among undergraduates.Keywords: undergraduates, psychological resilience, coping, health problems, mediating effect

Xin Liu,1,&ast; Ruofan Xi,1,&ast; Xinran Du,1 Yi Wang,1 Linyan Cheng,1 Ge Yan,1 Hanzhi Lu,1 Te Liu,2 Fulun Li1 1Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Te Liu; Fulun Li, Email liute1979@shutcm.edu.cn; drlifulun@163.comBackground: Psoriasis is a common chronic inflammatory skin condition. The emergence of psoriasis has been linked to dysbiosis of the microbiota on the skin surface and an imbalance in the immunological microenvironment. In this study, we investigated the therapeutic impact of topical thymopentin (TP5) on imiquimod (IMQ)-induced psoriasis in mice, as well as the modulatory influence of TP5 on the skin immune milieu and the skin surface microbiota.Methods: The IMQ-induced psoriasis-like lesion mouse model was used to identify the targets and molecular mechanisms of TP5. Immunofluorescence was employed to identify differences in T-cell subset expression before and after TP5 therapy. Changes in the expression of NF-κB signaling pathway components were assessed using Western blotting (WB). 16S rRNA sequencing and network pharmacology were used to detect changes in the skin flora before and after TP5 administration.Results: In vivo, TP5 reduced IMQ-induced back inflammation in mice. H&E staining revealed decreased epidermal thickness and inflammatory cell infiltration with TP5. Masson staining revealed decreased epidermal and dermal collagen infiltration after TP5 administration. Immunohistochemistry showed that TP5 treatment dramatically reduced IL-17 expression. Results of the immunoinfiltration analyses showed psoriatic lesions with more T-cell subsets. According to the immunofluorescence results, TP5 dramatically declined the proportions of CD4+, Th17, ROR+, and CD8+ T cells. WB revealed that TP5 reduced NF-κB pathway expression in skin tissues from IMQ-induced psoriasis model mice. 16S rRNA sequencing revealed a significant increase in Burkholderia and Pseudomonadaceae_Pseudomonas and a significant decrease in Staphylococcaceae_Staphylococcus, Aquabacterium, Herbaspirillum, and Balneimonas. Firmicutes dominated the skin microbial diversity after TP5 treatment, while Bacteroidetes, Verrucomicrobia, TM7, Proteobacteria, Actinobacteria, Acidobacteria, Gemmatimonadetes, and other species dominated in the IMQ group.Conclusion: TP5 may treat psoriasis by modulating the epidermal flora, reducing NF-κB pathway expression, and influencing T-cell subsets.Keywords: psoriasis, thymopentin, 16S rRNA sequencing, T-cell subsets

Li-Mian Song,1,&ast; Du-Juan Yao,1,&ast; Lin Xia,1 Xu-Ming Wang,2 Tian Liu,2 Qian-Qian Tang,1 Jun Zhou1 1Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Pathology, Affiliated Hospital of Guilin Medical College, Guilin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun Zhou, Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China, Email bbfat51740@sina.comPurpose: To explore the effect of DSG2 on the growth of cervical cancer cells and its possible regulatory mechanism.Methods: The expression levels and survival prognosis of DSG2 and ADAM17 in cervical squamous cell carcinoma tissues and adjacent normal tissues were analyzed by bioinformatics. CCK-8 assay, colony formation assay and Transwell assay were used to detect the effects of DSG2 on the proliferative activity, colony formation ability and migration ability of SiHa and Hela cells. The effect of DSG 2 on the level of ADAM17 transcription and translation was detected by qPCR and Western blot experiments. The interaction between DSG2 and c-MYC was detected by immunocoprecipitation. c-MYC inhibitors were used in HeLa cells overexpressing DSG2 to analyze the effects of DSG2 and c-MYC on proliferation, colony formation and migration of Hela cells, as well as the regulation of ADAM17 expression.Results: DSG2 was highly expressed in cervical squamous cell carcinoma compared with normal tissues (P< 0.05), and high DSG2 expression suggested poor overall survival (P< 0.05). After DSG2 knockdown, the proliferative activity, colony formation and migration ability of SiHa and Hela cells were significantly decreased (P< 0.05). Compared with adjacent normal tissues, ADAM17 was highly expressed in cervical squamous cell carcinoma (P< 0.05), and high ADAM17 expression suggested poor overall survival in cervical cancer patients (P< 0.05). The results of immunocoprecipitation showed the interaction between DSG2 and c-MYC. Compared with DSG2 overexpression group, DSG2 overexpression combined with c-MYC inhibition group significantly decreased cell proliferation, migration and ADAM17 expression (P < 0.05).Conclusion: DSG2 is highly expressed in cervical cancer, and inhibition of DSG2 expression can reduce the proliferation and migration ability of cervical cancer cells, which may be related to the regulation of ADAM17 expression through c-MYC interaction.Keywords: cervical cancer, proliferation, migration, DSG2, c-MYC, ADAM17

Tianshu Liu, Mengfan Zhang, Jin Zhang, Naijin Kang, Linlin Zheng, Zhiying Ding School of Pharmaceutical Sciences, Jilin University, Changchun, 130021, People’s Republic of ChinaCorrespondence: Zhiying Ding, School of Pharmaceutical Sciences, Jilin University, Changchun, 130021, People’s Republic of China, Tel/Fax +86 13843180286, Email dzy@jlu.edu.cnPurpose: Ginsenoside Rg3 (Rg3) and Panax notoginseng saponins (PNS) can be used for ischemic stroke treatment, however, the lack of targeting to the ischemic region limits the therapeutic effect. To address this, we leveraged the affinity of macrophage membrane proteins for inflamed brain microvascular endothelial cells to develop a macrophage membrane-cloaked liposome loaded with Rg3 and PNS (MM-Lip-Rg3/PNS), which can precisely target brain lesion region through intranasal administration.Methods: MM-Lip-Rg3/PNS was prepared by co-extrusion method and was performed by characterization, stability, surface protein, and morphology. The cellular uptake, immune escape ability, and blood-brain barrier crossing ability of MM-Lip-Rg3/PNS were studied in vitro. The in vivo brain targeting, biodistribution and anti-ischemic efficacy of MM-Lip-Rg3/PNS were evaluated in MACO rats, and we determined the diversity of the nasal brain pathway through the olfactory nerve blockade model in rats. Finally, the pharmacokinetics and brain targeting index of MM-Lip-Rg3/PNS were investigated.Results: Our results indicated that MM-Lip-Rg3/PNS was spherical with a shell-core structure. MM-Lip-Rg3/PNS can avoid mononuclear phagocytosis, actively bind to inflammatory endothelial cells, and have the ability to cross the blood-brain barrier. Moreover, MM-Lip-Rg3/PNS could specifically target ischemic sites, even microglia, increase the cumulative number of drugs in the brain, improve the inflammatory environment of the brain, and reduce the infarct size. By comparing olfactory nerve-blocking rats with normal rats, it was found that there are direct and indirect pathways for nasal entry into the brain. Pharmacokinetics demonstrated that MM-Lip-Rg3/PNS exhibited stronger brain targeting and prolonged drug half-life.Conclusion: MM-Lip-Rg3/PNS might contribute to the accumulation of Rg3 and PNS in the ischemic brain area to improve treatment efficacy. This biomimetic nano-drug delivery system provides a new and promising strategy for the treatment of ischemic stroke. Keywords: macrophage-membrane coating, biomimetic liposome, brain targeting, ischemic stroke, intranasal delivery

Jing Luo,1,2 Yi Luo,2 Maoru Zhao,3 Yulong Liu,2 Jiayin Liu,2 Zhulin Du,2 Hong Gong,2 Lian Wang,2 Jinghui Zhao,2 Xiaqing Wang,2 Zhanjun Gu,3 Wenhui Zhao,1 Tianyao Liu,2 Xiaotang Fan2 1School of Life Sciences, Chongqing University, Chongqing, 401331, People’s Republic of China; 2Department of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, 400038, People’s Republic of China; 3Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, Institute of High Energy Physics and National Center for Nanoscience and Technology, Chinese Academy of Sciences, Beijing, 100049, People’s Republic of ChinaCorrespondence: Xiaotang Fan; Tianyao Liu, Email fanxiaotang2005@163.com; squall277@163.comBackground: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that affects social interaction and communication and can cause stereotypic behavior. Fullerenols, a type of carbon nanomaterial known for its neuroprotective properties, have not yet been studied for their potential in treating ASD. We aimed to investigate its role in improving autistic behaviors in BTBR T+Itpr3tf/J (BTBR) mice and its underlying mechanism, which could provide reliable clues for future ASD treatments.Methods: Our research involved treating C57BL/6J (C57) and BTBR mice with either 0.9% NaCl or fullerenols (10 mg/kg) daily for one week at seven weeks of age. We then conducted ASD-related behavioral tests in the eighth week and used RNA-seq to screen for vital pathways in the mouse hippocampus. Additionally, we used real-time quantitative PCR (RT-qPCR) to verify related pathway genes and evaluated the number of stem cells in the hippocampal dentate gyrus (DG) by Immunofluorescence staining.Results: Our findings revealed that fullerenols treatment significantly improved the related ASD-like behaviors of BTBR mice, manifested by enhanced social ability and improved cognitive deficits. Immunofluorescence results showed that fullerenols treatment increased the number of DCX+ and SOX2+/GFAP+ cells in the DG region of BTBR mice, indicating an expanded neural progenitor cell (NPC) pool of BTBR mice. RNA-seq analysis of the mouse hippocampus showed that VEGFA was involved in the rescued hippocampal neurogenesis by fullerenols treatment.Conclusion: In conclusion, our findings suggest that fullerenols treatment improves ASD-like behavior in BTBR mice by upregulating VEGFA, making nanoparticle- fullerenols a promising drug for ASD treatment. Keywords: fullerenols, BTBR, neurogenesis, autism spectrum disorder, hippocampus

Na Li,1 Liufu Cui,1 Gary Tse,2,3 Panagiotis Korantzopoulos,4 Konstantinos P Letsas,5 George Bazoukis,6,7 Shuohua Chen,8 Nan Zhang,2 Xuemei Yang,9 Peipei Liu,10 Lili Wu,11 Gan-Xin Yan,12,13 Gregory Yoke Hong Lip,14,15 Shouling Wu,8 Tong Liu2 1Department of Rheumatology and Immunology, Kailuan General Hospital, Tangshan, Hebei Province, People’s Republic of China; 2Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China; 3School of Nursing and Health Studies, Hong Kong Metropolitan University, Hong Kong, People’s Republic of China; 4First Department of Cardiology, University of Ioannina Medical School, Ioannina, Greece; 5Arrhythmia Unit, Laboratory of Cardiac Pacing and Electrophysiology, Onassis Cardiac Surgery Center, Athens, Greece; 6Department of Cardiology, Larnaca General Hospital, Larnaca, Cyprus; 7European University Cyprus, Medical School, Nicosia, Cyprus; 8Department of Cardiology, Kailuan General Hospital, Tangshan, Hebei Province, People’s Republic of China; 9School of Clinical Medicine, North China University of Science and Technology, Tangshan, Hebei Province, People’s Republic of China; 10School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, People’s Republic of China; 11Department of Cardiology, Shanghai Songjiang District Central Hospital, Shanghai, People’s Republic of China; 12Lankenau Medical Center and Lankenau Institute for Medical Research, Wynnewood, PA, USA; 13Department of Cardiology, Fuwai Huazhong Hospital, Zhengzhou, Henan Province, People’s Republic of China; 14Liverpool Centre for Cardiovascular Sciences, University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK; 15Danish Center for Clinical Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, DenmarkCorrespondence: Tong Liu, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China, Email liutong@tmu.edu.cn; liutongdoc@126.com Shouling Wu, Department of Cardiology, Kailuan General Hospital, Tangshan, Hebei Province, People’s Republic of China, Email drwusl@163.comObjective: This study aimed to explore the impact of a combination of hyperuricemia (HUA) and excessive high-sensitivity C-reactive protein (hs-CRP) levels on the likelihood of developing cardiac conduction block (CCB). Additionally, it sought to assess whether the influence of uric acid (UA) on CCB is mediated by hs-CRP.Methods: A prospective study was executed utilizing data from the Kailuan cohort, including 81,896 individuals initially free from CCB. The participants were categorized into four groups depending on the existence of HUA and low-grade inflammation (hs-CRP> 3 mg/L). Cox regression analysis was employed to ascertain hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of incident CCB. A mediation analysis was performed to determine if hs-CRP functioned as a mediator in the connection between UA levels and the incidence of CCB.Results: During a median observation period of 11.8 years, we identified 3160 cases of newly occurring CCB. Compared with the low UA/low CRP group, the combination of HUA and low-grade inflammation elevated the CCB risks (HR:1.56, 95% CI:1.22– 1.99), atrioventricular block (AVB) (HR:1.88, 95% CI:1.27– 2.77), and right bundle branch block (HR:1.47, 95% CI:1.02– 2.12), respectively. Mediation analysis revealed that in the HUA group, compared with the non-HUA group, the risk of CCB elevated by 14.0%, with 10.3% of the increase mediated through hs-CRP.Conclusion: HUA combined with elevated hs-CRP increased the risk of CCB, especially AVB. The connection between UA and the CCB risk was partly mediated by hs-CRP. Keywords: hyperuricemia, inflammation, cardiac conduction block, combined exposure, risk factors, mediation

Chengxue He,1,2,&ast; YanHui Guo,3,&ast; Nina Zhou,2,&ast; Zhen Wang,4,&ast; Teli Liu,2 Xiaoxia Xu,2 Feng Wang,2 Hua Zhu,2 Zhi Yang,1,2 Xianteng Yang,1,5 Lei Xia2 1Medical College, Guizhou University, Guiyang, GuiZhou Province, People’s Republic of China; 2Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China; 3Department of Radiology, Peking University Third Hospital, Beijing, People’s Republic of China; 4Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Hepato-Pancreato-Biliary Surgery, Sarcoma Center, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China; 5Department of Orthopedics, Guizhou Provincial People’s Hospital, Guiyang, GuiZhou Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lei Xia; Zhi Yang, Tel +86 010-88197852 ; +86 010-88196196, Email xialei9012288@126.com; pekyz@163.comBackground: In recent years, PD-L1 has been primarily utilized as an immune checkpoint marker in cancer immunotherapy. However, due to tumor heterogeneity, the response rate to such therapies often falls short of expectations. In addition to its role in immunotherapy, PD-L1 serves as a specific target on the surface of tumor cells for targeted diagnostic and therapeutic interventions. There is an absence of a fully developed PD-L1-targeted diagnostic and therapeutic probe for clinical use, which constrains the exploration and clinical exploitation of this target.Methods and Results: In this study, we engineered a PD-L1-targeted probe with multimodal imaging and dual therapeutic functionalities utilizing organic melanin nanoparticles. Functionalization with the WL12-SH peptide endowed the nanoprobe with specific targeting capabilities. Subsequent radiolabeling with 89Zr (half-life: 100.8 hours) and chelation of Mn2+ ions afforded the probe the capacity for simultaneous PET and MRI imaging modalities. Cellular uptake assays revealed pronounced specificity, with -positive cells exhibiting significantly higher uptake than -negative counterparts (p < 0.05). Dual-modal PET/MRI imaging delineated rapid and sustained accumulation at the neoplastic site, yielding tumor-to-non-tumor (T/NT) signal ratios at 24 hours post-injection of 16.67± 3.45 for PET and 6.63± 0.64 for MRI, respectively. We conjugated the therapeutic radionuclide 131I (half-life: 8.02 days) to the construct and combined low-dose radiotherapy and photothermal treatment (PTT), culminating in superior antitumor efficacy while preserving a high safety profile. The tumors in the cohort receiving the dual-modality therapy exhibited significantly reduced volume and weight compared to those in the control and monotherapy groups.Conclusion: We developed and applied a novel -targeted multimodal theranostic nanoprobe, characterized by its high specificity and superior imaging capabilities as demonstrated in PET/MRI modalities. Furthermore, this nanoprobe facilitates potent therapeutic efficacy at lower radionuclide doses when used in conjunction with PTT. Keywords: theranostics, PET/MRI, melanin nanoparticles, photothermal therapy

Yanling Li,&ast; Li Ji,&ast; Tian Liu, Guang Xu, Kaihe Wang, Leixin Mu, Yuying Guo, Qun Ma School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qun Ma, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, People’s Republic of China, Email maqun99@126.comBackground: Qiguiyin decoction (QGYD) is a traditional Chinese medicine (TCM) and its combined application with levofloxacin (LVFX) has been confirmed effective in the clinical treatment of multidrug-resistant Pseudomonas aeruginosa (MDR PA) infection. This study investigated the therapeutic effect and possible mechanism of QGYD in sensitizing LVFX against MDR PA infection.Materials and Methods: Pulmonary infections were induced in rats by MDR PA. The changes in pharmacokinetics-pharmacodynamics (PK-PD) parameters of LVFX after combined with QGYD were investigated in MDR PA-induced rats. Subsequently, the correlation between PK and PD was analyzed and PK-PD models were established to elucidate the relationship between QGYD-induced alterations in LVFX metabolism and its sensitization to LVFX. Antibody chip technology was used to detect the levels of inflammatory factors, suggesting the relationship between the beneficial effect of immune regulation and the sensitization of QGYD.Results: QGYD significantly enhanced the therapeutic efficacy of LVFX against MDR PA infection. The combination of QGYD changed the PK parameters of LVFX such as Tmax, t1/2, MRT, Vd/F, CL/F and PD parameters such as MIC, AUC0-24h/MIC. Predicted results from PK-PD models demonstrated that the antibacterial effect of LVFX was significantly enhanced with the combination of QGYD, consistent with experimental findings. Antibody chip results revealed that the combination of QGYD made IL-1 β, IL-6, TNF- α, IL-10, and MCP-1 levels more akin to those of the blank group.Conclusion: These findings indicated that QGYD could change the PK-PD behaviors of LVFX and help the body restore immune balance faster. This implied that a potential drug interaction might occur between QGYD and LVFX, leading to improved clinical efficacy when combined.Keywords: multidrug-resistant Pseudomonas aeruginosa infection, combination therapy, PK/PD model, Qiguiyin decoction, levofloxacin

Tingting Liu,1,&ast; Haojie Wu,1,&ast; Lin Sun,2 Jianshe Wei1 1Institute for Brain Sciences Research, School of Life Sciences, Henan University, Institute of Neurourology and Urodynamics, Huaihe Hospital of Henan University, Kaifeng, 475004, People’s Republic of China; 2College of Chemistry and Molecular Sciences, Henan University, Kaifeng, 475004, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lin Sun; Jianshe Wei, Email sunlin@vip.henu.edu.cn; jswei@henu.edu.cnBackground: The coronavirus disease 2019 (COVID-19) can lead to neurological symptoms such as headaches, confusion, seizures, hearing loss, and loss of smell. The link between COVID-19 and Parkinson’s disease (PD) is being investigated, but more research is needed for a definitive connection.Methods: Datasets GSE22491 and GSE164805 were selected to screen differentially expressed gene (DEG), and immune infiltration and gene set enrichment analysis (GSEA) of the DEG were performed. WGCNA analyzed the DEG and selected the intersection genes. Potential biological functions and signaling pathways were determined, and diagnostic genes were further screened using gene expression and receiver operating characteristic (ROC) curves. Screening and molecular docking of ibuprofen as a therapeutic target. The effectiveness of ibuprofen was verified by constructing a PD model in vitro, and constructing “COVID19-PD” signaling pathway, and exploring the role of angiotensin-converting enzyme 2 (ACE2) in PD.Results: A total of 13 DEG were screened from the GSE36980 and GSE5281 datasets. Kyoto encyclopedia of genes and genomes (KEGG) analysis showed that the DEG were mainly associated with the hypoxia-inducible factor (HIF-1), epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance, etc. After analysis, it is found that ibuprofen alleviates PD symptoms by inhibiting the expression of nuclear factor kappa-B (NF-κB), interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α). Based on signal pathway construction, the importance of ACE2 in COVID-19-induced PD has been identified. ACE2 is found to have widespread distribution in the brain. In the 1-methyl-4-phenyl-1,2,3,6-te-trahydropyridine (MPTP)-induced ACE2-null PD mice model, more severe motor and non-motor symptoms, increased NF-κB p65 and α-synuclein (α-syn) expression with significant aggregation, decreased tyrosine hydroxylase (TH), severe neuronal loss, and neurodegenerative disorders.Conclusion: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection increases the risk of PD through an inflammatory environment and downregulation of ACE2, providing evidence for the molecular mechanism and targeted therapy associated with COVID-19 and PD.Keywords: Parkinson’s disease, COVID-19, ibuprofen, nuclear factor kappa-B, angiotensin-converting enzyme 2

Yifang Tang,1,&ast; Tao Liu,2,&ast; Shibo Sun,3 Youbo Peng,1 Xiaoxiao Huang,4 Shuangquan Wang,4 Zhu Zhou1 1Department of Nephrology, the First Affiliated Hospital, Kunming Medical University, Kunming, People’s Republic of China; 2Organ Transplantation Center, the First Affiliated Hospital, Kunming Medical University, Kunming, People’s Republic of China; 3Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, People’s Republic of China; 4Department of Nephrology, Xishuangbanna Dai Autonomous Prefecture People’s Hospital, Xishuangbanna, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhu Zhou, Department of Nephrology, The First Affiliated Hospital of Kunming Medical University and Yunnan Province Clinical Research Center for Chronic Kidney Disease, No. 295, Xichang Road, Wuhua District, Kunming, People’s Republic of China, Email zhouzhu21@163.com Shibo Sun, Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, No. 295, Xichang Road, Wuhua District, Kunming, People’s Republic of China, Email shibosunky@126.comAbstract: GDF-15 is an essential member of the transforming growth factor-beta superfamily. Its functions mainly involve in tissue injury, inflammation, fibrosis, regulation of appetite and weight, development of tumor, and cardiovascular disease. GDF-15 is involved in various signaling pathways, such as MAPK pathway, PI3K/AKT pathway, STAT3 pathway, RET pathway, and SMAD pathway. In addition, several factors such as p53, ROS, and TNF-α participate the regulation of GDF-15. However, the specific mechanism of these factors regulating GDF-15 is still unclear and more research is needed to explore them. GDF-15 mainly improves the function of kidneys in CKD and plays an important role in the prediction of CKD progression and cardiovascular complications. In addition, the role of GDF-15 in the kidney may be related to the SMAD and MAPK pathways. However, the specific mechanism of these pathways remains unclear. Accordingly, more research on the specific mechanism of GDF-15 affecting kidney disease is needed in the future. In conclusion, GDF-15 may be a therapeutic target for kidney disease.Keywords: chronic kidney disease, GDF-15, biomarker, inflammation, renal protection

Chang Su,1– 3 Zeyu Wang,4 Zhen Qin,1– 3 Yan Lv,1– 3 Yachen Hou,1– 3 Ge Zhang,1– 3 Mengdie Cheng,1– 3 Xinyue Cui,1– 3 Zhiyu Liu,1– 3 Pengchong Du,1– 3 Tianding Liu,1– 3 Peiyu Yuan,1– 3 Junnan Tang,1– 3 Jinying Zhang1– 3 1Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, People’s Republic of China; 3Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, People’s Republic of China; 4Department of Cardiology, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Junnan Tang; Jinying Zhang, Department of Cardiology, First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, Henan, 450052, People’s Republic of China, Tel +86 15890696166 ; +86 13503830283, Email fcctangjn@zzu.edu.cn; jyzhang@zzu.edu.cnBackground: The triglyceride-glucose (TYG) index is a novel and reliable marker reflecting insulin resistance. Its predictive ability for cardiovascular disease onset and prognosis has been confirmed. However, for advanced chronic heart failure (acHF) patients, the prognostic value of TYG is challenged due to the often accompanying renal dysfunction (RD). Therefore, this study focuses on patients with aHF accompanied by RD to investigate the predictive value of the TYG index for their prognosis.Methods and Results: 717 acHF with RD patients were included. The acHF diagnosis was based on the 2021 ESC criteria for acHF. RD was defined as the eGFR < 90 mL/(min/1.73 m2). Patients were divided into two groups based on their TYG index values. The primary endpoint was major adverse cardiovascular events (MACEs), and the secondary endpoints is all-cause mortality (ACM). The follow-up duration was 21.58 (17.98– 25.39) months. The optimal cutoff values for predicting MACEs and ACM were determined using ROC curves. Hazard factors for MACEs and ACM were revealed through univariate and multivariate COX regression analyses. According to the univariate COX regression analysis, high TyG index was identified as a risk factor for MACEs (hazard ratio = 5.198; 95% confidence interval [CI], 3.702– 7.298; P < 0.001) and ACM (hazard ratio = 4.461; 95% CI, 2.962– 6.718; P < 0.001). The multivariate COX regression analysis showed that patients in the high TyG group experienced 440.2% MACEs risk increase (95% CI, 3.771– 7.739; P < 0.001) and 406.2% ACM risk increase (95% CI, 3.268– 7.839; P < 0.001). Kaplan-Meier survival analysis revealed that patients with high TyG index levels had an elevated risk of experiencing MACEs and ACM within 30 months.Conclusion: This study found that patients with high TYG index had an increased risk of MACEs and ACM, and the TYG index can serve as an independent predictor for prognosis.Keywords: TyG index, advanced chronic heart failure, renal dysfunction, prognosis factor

Jie Gao,1,&ast; Jie Dou,1,&ast; Hui-Hui Yang,1 Ruo-Ling Guo,1 Chao Jiang,1 Gary Tse,2– 4 Tong Liu,2 Jian-Wei Liu,5 Dong-Lei Luo6 1Chengde Medical University, Chengde, 067000, People’s Republic of China; 2Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, 300211, People’s Republic of China; 3School of Nursing and Health Studies, Hong Kong Metropolitan University, Hong Kong, 999077, People’s Republic of China; 4Epidemiology Research Unit, Cardiovascular Analytics Group, PowerHealth Limited, Hong Kong, 999077, People’s Republic of China; 5Department of Cardiothoracic Interventional Vascular Surgery, Chengde Central Hospital/Second Clinical College of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China; 6Department of Cardiology, Chengde Central Hospital / Second Clinical College of Chengde Medical University, Chengde, 067000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dong-Lei Luo, Department of Cardiology, Chengde Central Hospital / Second Clinical College of Chengde Medical University, Chengde, 067000, People’s Republic of China, Email dongleiluocn@aliyun.com Jian-Wei Liu, Department of Cardiothoracic Interventional Vascular Surgery, Chengde Central Hospital/Second Clinical College of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China, Email Ljw2112@126.comPurpose: To investigate the clinical application value of diagonal earlobe crease (DELC) in patients with chest pain for the diagnosis of coronary heart disease (CHD) and to construct a risk model by multivariate logistic regression.Patients and Methods: Our trial enrolled prospectively and consecutively 706 chest pain patients with suspected CHD between January 2021 to June 2023 from Chengde Central Hospital. According to coronary angiography results, they were categorized into the CHD (n=457) and non-CHD groups (n=249).Results: The trial demonstrated a significant positive relationship between DELC and CHD. Independent risk factors were sex, age, hypertension, diabetes mellitus, LP (a), Cys C, and DELC, whilst HDL-C was a protective factor, for CHD. Patients with-DELC were older than those in the without-DELC arm (P< 0.001) and had a higher proportion of males than females (61.6% vs 50.0%, P=0.026). After multifactorial correction, independent risk factors for CHD included DELC (OR=1.660, 95% CI:1.153 to 2.388, P=0.006), age (OR=1.024, 95% CI:1.002 to 1.045, P=0.030), gender (OR=1.702, 95% CI:1.141 to 2.539, P=0.009), hypertension (OR=1.744, 95% CI:1.226 to 2.482, P=0.002), diabetes mellitus (OR=2.113, 95% CI:1.404 to 3.179, P< 0.001), LP(a) (OR=1.010, 95% CI:1.003 to 1.017, P=0.005), Cys C (OR=3.549, 95% CI:1.605 to 7.846, P=0.002). The Hosmer and Lemeshow (H-L) test (P=0.818) suggests a high goodness of fit, and the area under the ROC curve was calculated to be 0.721 (95% CI:0.682 to 0.760, P< 0.001), which demonstrates that the model has a superior diagnostic value for CHD.Conclusion: DELC is an independent risk factor for CHD after adjusting for sex, age, hypertension, diabetes mellitus, smoking index, LP (a), Cys C, and HDL-C. Our model can be used clinically for assessing the risk of CHD.Keywords: coronary heart disease, diagonal earlobe crease, coronary angiography, model

Zhongwei Wen, Yiqiang Chen, Tangjuan Liu, Jiahui Han, Yuting Jiang, Ke Zhang Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of ChinaCorrespondence: Yiqiang Chen, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China, Email chenyiq0708@163.comIntroduction: Respiratory infections are a major global health concern, with Klebsiella pneumoniae standing out due to its evolving antibiotic resistance. This study compares the resistance profiles of hypervirulent Klebsiella pneumoniae (hvKP) and classical Klebsiella pneumoniae (cKP), aiming to shed light on their clinical implications.Methods: We analyzed 86 cases, comprising 42 hvKP and 44 cKP strains, using comprehensive antimicrobial susceptibility testing and clinical data evaluation to assess antibiotic tolerance and resistance mechanisms.Results: Our findings reveal distinct resistance patterns between hvKP and cKP, highlighting the role of chromosomal mutations and plasmid-mediated gene transfer in conferring antibiotic resistance. Notably, hvKP strains exhibited unique resistance trends, including the production of extended-spectrum β-lactamases (ESBLs) and carbapenemases, differing from those of cKP.Discussion: This research underscores the importance of continuous surveillance and the development of targeted therapies against antibiotic-resistant Klebsiella pneumoniae. It emphasizes the critical need for judicious antibiotic use and novel therapeutic approaches to combat respiratory infections caused by these increasingly resistant pathogens.Keywords: Klebsiella pneumoniae, antibiotic resistance, hypervirulent Klebsiella pneumoniae, hvKP, classical Klebsiella pneumoniae, cKP, public health

Yi Tang,1,&ast; Zhengqi Hu,2,&ast; Zhibin Liu,2 Siling Peng,2 Tiancheng Liu,2 Yaoyuan Xiao,2 Jianqiang Peng,1 Hongwei Pan,1 Zhaofen Zheng,1 Jin He1 1Department of Cardiology, Hunan Provincial People’s Hospital, the First Affiliated Hospital of Hunan Normal University, Clinical Medicine Research Center of Heart Failure of Hunan Province, Hunan Normal University, Changsha, People’s Republic of China; 2Department of Cardiology, Hunan Provincial People’s Hospital, the First Affiliated Hospital of Hunan Normal University, Changsha, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jin He, Email 394929734@qq.comPurpose: The levels of human epididymis protein 4 (HE4) is associated not only with the prognosis of patients with acute heart failure (AHF), but also with chronic kidney disease (CKD). Our study aims to understand the prediction value of HE4 on prognosis in patients with AHF combined with CKD.Patients and Methods: This study prospectively enrolled patients diagnosed with AHF combined with CKD at the Department of Cardiology of Hunan Provincial People’s Hospital from March 2019 to December 2022. Serum levels of HE4 were measured using a chemiluminescence microparticle immunoassay. The endpoint events included heart failure readmission and cardiovascular death.Results: A total of 130 patients with AHF combined with CKD were included in the stud. The median age is 73 years (interquartile range: 65– 79 years). Among the patients, 94 experienced the endpoint events. The multivariable Cox analysis reveals that LnHE4 (HR=2.280, 95% CI 1.300– 3.998, P = 0.004) and age (HR=1.024, 95% CI 1.003– 1.045, P = 0.025) are independent predictors of the endpoint events. The Kaplan-Meier survival curve demonstrates that patients with HE4 levels> 276.15 pmol/L has a significantly higher incidence of endpoint events compared to those with HE4 levels≤ 276.15 pmol/L (Log rank test: χ 2=19.689, P < 0.001). After adjusting for age and gender, the HR is 2.520 (95% CI: 1.626– 3.906, P < 0.001).Conclusion: HE4 is an independent predictor of heart failure readmission and cardiovascular death in patients with AHF combined with CKD.Keywords: Human epididymis protein 4, Acute heart failure, Chronic kidney disease, Prognosis

Qianyu Bai,1,&ast; Yichi Zhang,1,&ast; Runqiu Cai,1 Haiyan Wu,1 Huiqun Fu,2 Xuemei Zhou,2 Jie Chai,3 Xuepeng Teng,3 Tianlong Liu1 1National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agriculture University, Beijing, People’s Republic of China; 2 101 Institute of the Ministry of Civil Affairs, Beijing, People’s Republic of China; 3Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xuemei Zhou, 101 Institute of the Ministry of Civil Affairs, South Fourth Ring West Road No.188, Beijing, 100070, Email zxmcaur@126.com; Tianlong Liu, College of Veterinary Medicine, China Agriculture University, Yuanmingyuan West Road No. 2, Beijing, 100193, Email liutianlong@cau.edu.cnBackground: In the past decades, antimicrobial resistance (AMR) has been a major threat to global public health. Long-term, chronic otitis media is becoming more challenging to treat, thus the novel antibiotic alternative agents are much needed.Methods: ZnO@TiO2@AMP (ATZ NPs) were synthesized through a solvothermal method and subjected to comprehensive characterization. The in vitro and in vivo antibacterial effect and biocompatibility of ATZ NPs were evaluated. For the antibacterial mechanism exploration, we utilized the Electron Paramagnetic Resonance (EPR) Spectrometer to detect and analyze the hydroxyl radicals produced by ATZ NPs.Results: ATZ NPs exhibited a spherical structure of 99.85 nm, the drug-loading rate for ZnO was 20.73%, and AMP within ATZ NPs was 41.86%. Notably, the Minimum Inhibitory Concentration (MIC) value of ATZ NPs against Staphylococcus aureus (S. aureus), methicillin-resistant Staphylococcus aureus (MRSA), and Streptococcus pneumoniae (S. pneumoniae) were 10 μg/mL, and Minimum Bactericidal Concentration (MBC) value of ATZ NPs against S. aureus, and S. pneumoniae were 50 μg/mL. In comparison to the model group, the treatment of otitis media with ATZ NPs significantly reduces inflammatory exudation in the middle ear cavity, with no observable damage to the tympanic membrane. Both in vivo and in vitro toxicity tests indicating the good biocompatibility of ATZ NPs. Moreover, EPR spectroscopy results highlighted the superior ability of ATZ NPs to generate hydroxyl radicals (·OH) compared to ZnO NPs.Conclusion: ATZ NPs exhibited remarkable antibacterial properties both in vivo and in vitro. This innovative application of advanced ATZ NPs, bringing great promise for the treatment of otitis media.Keywords: nanoparticles, otitis media, zinc oxide, mesoporous titanium dioxide, antimicrobial peptide, antimicrobial, hydroxyl radical

Kun Li,1 Dongsheng Han,2 Ahmad Alhaskawi,3 Tingting Liu,1 Xiaojuan Wang,4 Wu Yang,1 Hui Lu,3 Xueling Fang1 1Department of Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Laboratory Medicine, the First Affiliated Hospital, Zhejiang University school of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 3Department of Orthopaedics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 4Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Xueling Fang, Department of Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79, Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, People’s Republic of China, Fax +86 571-87236838, Email 1191012@zju.edu.cn Hui Lu, Department of Orthopaedics, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79, Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, People’s Republic of China, Fax +86 571-87236121, Email HuiLu@zju.edu.cnBackground: Chromobacterium violaceum (C. violaceum) is a Gram-negative bacterium capable of causing severe infections in both humans and specific animals. Despite its infrequency, C. violaceum infections exhibit a notably high mortality rate. The timely and precise detection of this pathogen stands as a critical factor in achieving effective diagnosis and treatment. Traditional diagnostic approaches possess limitations, particularly in terms of their time-consuming nature and the range of pathogens they can identify. Metagenomic next-generation sequencing (mNGS) testing has emerged as a highly promising diagnostic tool for infectious diseases.Methods: Within this case report, we present a patient who developed a C. violaceum infection subsequent to a lower limb infection, leading to the progression of sepsis, a liver abscess, septic shock, multi-organ dysfunction, and altered mental status. Samples of the patient’s blood and tissue from the lower limb skin are collected, and the infection is swiftly diagnosed through mNGS, allowing for the immediate initiation of suitable treatment.Results: The mNGS results revealed the patient’s infection with C. violaceum. Subsequent conventional bacterial culture results were concordant with the mNGS findings. Following comprehensive management measures, including prompt and effective anti-infective treatment, the patient achieved cure and was successfully discharged.Conclusion: This case underscores the significance of employing advanced diagnostic methodologies like mNGS for the early detection of uncommon pathogens such as C. violaceum. The expedited diagnosis and timely intervention hold the potential to substantially enhance patient outcomes in cases of severe infections instigated by this bacterium.Keywords: chromobacterium violaceum, sepsis, infection, hepatapostema, liver, liver abscess, metagenomic next-generation sequencing

Mi Qi, Yajuan Cheng, Ke Liu, Jingxing Cai, Tianyu Liu, Xiaoying Wu, Huili Tang, He Huang, Qinbiao Chen, Xiaoguang Zhou The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, People’s Republic of ChinaCorrespondence: Mi Qi; Xiaoguang Zhou, Tel +86-13510794978 ; +86-18818780760, Email qimi@mail.sysu.edu.cn; gzzhouxg@163.comPurpose: Ischemic stroke is a high-incidence disease that threatens human well-being. The potent neuroprotective effects render reactive oxygen species (ROS) scavengers potential agents for acute ischemic stroke therapy. Challenges such as inadequate permeability across the blood-brain barrier (BBB), limited half-life, and adverse effects hinder the widespread utilization of small molecule and inorganic ROS scavengers. Thus, there is an urgent demand for efficacious neuroprotective agents targeting ischemic stroke. Our study discovered the superoxide dismutase (SOD)-mimetic activity of recombinant human heavy chain ferritin (rHF) nanoparticles expressed from Escherichia coli (E. coli). Subsequent investigations delved into the ROS-scavenging proficiency of rHF within neural cells, its therapeutic efficacy against ischemic stroke, and the elucidation of its neuroprotective mechanisms.Methods: rHF protein nanoparticles were expressed in E. coli and purified via size-exclusion chromatography. The superoxide anion (•O2−) scavenging SOD-mimetic activity of rHF nanoparticles was measured using a SOD detection kit. The ROS scavenging ability and protection effects against oxidative damage of rHF nanoparticles were studied in H2O2-induced PC12 cells. Therapeutic effects and neuroprotective mechanisms of rHF against ischemic stroke were investigated with transient middle cerebral artery occlusion (MCAO) reperfusion mice model.Results: rHF nanoparticles can eliminate excessive ROS in nerve cells and alleviate oxidative damage. The results of animal experiments demonstrated that rHF nanoparticles passed across BBB, reduced infarct areas in brain tissue, and lowered the neurological deficit score of ischemia-reperfusion model mice. Additionally, rHF nanoparticles mitigated neuronal apoptosis and ferroptosis, suppressed microglial activation, maintained oxygen homeostasis, and exhibited negligible organ toxicity.Conclusion: rHF nanoparticle could be developed as a new ROS scavenger for nerve cells and has therapeutic potential as a drug for cerebral ischemia-reperfusion injury. Keywords: human heavy chain ferritin, ROS scavenger, ischemic stroke, SOD-mimetic, neuroprotection

Hao Zhan,1,2 Qichun Chen,1,2 Tiantian Liu,1,2 Yuting Shi,1,2 Jinxia Pei,1,2 Liwei Zou,1,2 Longsheng Wang1,2 1Department of Radiology, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, People’s Republic of China; 2Medical Imaging Research Center of Anhui Medical University, Hefei, 230601, People’s Republic of ChinaCorrespondence: Liwei Zou; Longsheng Wang, Email zouliwei@ahmu.edu.cn; wangls1125@sina.comPurpose: The main aim of this study is to analyze the relationship between body composition indices and metabolic unhealthy phenotypes in young and middle-aged obese patients and to assess their joint predictive ability.Patients and Methods: A cross-sectional study method was used to select 207 patients who were proposed to undergo weight loss surgery for morbid obesity from March to November 2022. Total adipose tissue (TAT), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), liver fat content (LFC), cross-sectional area (CSAmuscle), and intermuscular adipose tissue (CSAIMAT) of paraspinal muscles were measured using quantitative computed tomography. Participants were categorized into two groups: metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO). The receiver operating characteristic curve comprised body composition variables that correlated with MUO, and the area under the curve (AUC) was calculated to compare their prediction capacity for MUO.Results: There were 71 patients with MHO (34.3%) and 136 patients with MUO (65.7%). The VAT, VAT/TAT ratio, LFC, and CSAmuscle was higher in MUO patients than in MHO (all P < 0.001), and SAT was lower than in MHO (P = 0.008). And all of these metrics were correlated with MUO (all P < 0.05). Inclusion of these body composition metrics in the ROC analysis showed that the AUC values for SAT, VAT, VAT/TAT ratio, LFC and CSAmuscle were 0.615, 0.663, 0.727, 0.694, 0.671, respectively, and the combination of the VAT/TAT ratio and the LFC had the ability to predict MUO best (AUC=0.746, P = 0.025).Conclusion: The combined use of VAT/TAT ratio and LFC is superior to the use of these two metrics alone in terms of their ability to predict the MUO, providing a more accurate approach to the management and prevention of obesity-related metabolic risk.Keywords: metabolically unhealthy, obesity, body composition, quantitative computed tomography

Tian Liu, Zhenkun Qin, Zhiyue Yang, Xiaoling Feng Division of General Practice, The Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of ChinaCorrespondence: Xiaoling Feng, Division of General Practice, The Fifth Affiliated Hospital of Xinjiang Medical University, No. 118, Henan West Road, Urumqi, Xinjiang Uygur Autonomous Region, 830011, People’s Republic of China, Email 1874519696@qq.comBackground: Numerous non-invasive serologic tests are available to diagnose and monitor ulcerative colitis (UC), but their accuracy levels are limited. Thus, there is a pressing need for a serologic biomarker with higher precision for clinical practice. This study aims to evaluate the predictive capacity of monocyte/HDL ratio (MHR) and neutrophil/lymphocyte ratio (NLR) for UC disease activity.Patients and Methods: We conducted a retrospective analysis of 81 UC patients and 77 age- and sex-matched healthy controls. UC patients were categorized into active and inactive groups based on the Mayo score. The Mayo endoscopic subscore classified them into mild-to-moderate and severe UC groups.Results: The optimal cut-off values for diagnosing UC were 0.34 for MHR (85.7% sensitivity, 76.0% specificity, 88.9% positive predictive value, 70.4% negative predictive value) and 2.49 for NLR (66.1% sensitivity, 88.0% specificity, 92.5% positive predictive value, 53.7% negative predictive value). The optimal MHR and NLR cut-off values to differentiate between mild-to-moderate UC and severe UC were 0.38 (92.9% sensitivity, 56.6% specificity, 53.1% positive predictive value, 93.7% negative predictive value) and 3.46 (71.4% sensitivity, 88.7% specificity, 76.9% positive predictive value, 85.5% negative predictive value), respectively.Conclusion: NLR and MHR are simple yet effective biological predictors of disease activity in UC patients.Keywords: ulcerative colitis, monocyte/HDL ratio, neutrophil/lymphocyte ratio, disease activity

Jiapei Yao,1,2 Xindie Zhou,1,3 Dongmei Xu,1 Ting Liu,1 Yuanyuan Gui,4 Yong Huang1,3 1Department of Orthopedics, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou, People’s Republic of China; 2Hunan Normal University, Changsha, People’s Republic of China; 3Changzhou Medical Center, Nanjing Medical University, Changzhou, People’s Republic of China; 4Department of Psychogeriatric Intensive Care Medicine, Xianlin Campus, Tongde Hospital of Zhejiang Province, Hangzhou, People’s Republic of ChinaCorrespondence: Yuanyuan Gui; Yong Huang, Email Guiyuanyuansltd@163.com; huangyong@njmu.edu.cnObjective: Secondary traumatic stress (STS) is stress caused by helping or wanting to help someone who has suffered a traumatic event. STS has adverse effects on nurses and their work, such as reduced career achievement, an increased staff turnover rate, inability to complete work, avoidance of contact with patients, mental exhaustion, negative emotions which seriously affect the quality of their work and life. The study to investigate secondary traumatic stress in emergency and intensive care nurses and analyze factors that influence it.Material and Methods: The study was a cross-sectional survey. Convenience sampling was used to select hospital emergency and intensive care department nurses (n=434) who met the inclusion and exclusion criteria from August to October 2021 to participate in this study. They provided demographic data and completed measures of secondary traumatic stress, emotional intelligence, anxiety and depression. Data analysis included independent samples t-tests, one-way analysis of variance, Pearson correlation analysis and multiple linear regression analysis.Results: Almost one-third (30.7%) of participants were at moderate risk for Secondary Traumatic Stress Scale or above, with high average scores on measures of anxiety (GAD-7 average = 6.05 ± 4.13), and depression (PHQ-9 average = 6.35 ± 4.85). The results of multiple linear regression analysis showed that the average daily amount of sleep in the past week, the number of night shifts in the past month, emotional intelligence, anxiety, and depression influenced secondary traumatic stress, explaining 70.8% of the variance.Conclusion: The STS of emergency and intensive care nurses in Changzhou is at a high level. Sleep time, number of night shifts and emotional intelligence are related to secondary traumatic stress and anxiety and depression significantly predicted the degree of secondary traumatic stress. Nurses need to master effective treatment methods for secondary traumatic stress, to improve their work efficiency and nursing quality and ensure nursing safety.Keywords: secondary traumatic stress, emergency and intensive care department nurses, anxiety, depression, emotional intelligence

Chao Huang,1,&ast; Jixiang Pei,1,&ast; Daisong Li,1 Tao Liu,2 Zhaoqing Li,1 Guoliang Zhang,1 Ruolan Chen,1 Xiaojian Xu,1 Bing Li,3,4 Zhexun Lian,1 Xian-Ming Chu1,5 1Department of Cardiology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266100, People’s Republic of China; 2The Affiliated Qingdao Central Hospital of Qingdao University, The Second Affiliated Hospital of Medical College of Qingdao University, Qingdao, Shandong, 266042, People’s Republic of China; 3Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, 266000, People’s Republic of China; 4Department of Dermatology, The Affiliated Haici Hospital of Qingdao University, Qingdao, 266033, People’s Republic of China; 5The Affiliated Cardiovascular Hospital of Qingdao University, Qingdao, 266071, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhexun Lian; Xian-Ming Chu, Tel +86-532-82913257, Email lianzx566@163.com; chuxianming@qdu.edu.cnPurpose: Doxorubicin-induced cardiotoxicity (DIC) is a severe side reaction in cancer chemotherapy that greatly impacts the well-being of cancer patients. Currently, there is still an insufficiency of effective and reliable biomarkers in the field of clinical practice for the early detection of DIC. This study aimed to determine and validate the potential diagnostic and predictive values of critical signatures in DIC.Methods: We obtained high-throughput sequencing data from the GEO database and performed data analysis and visualization using R software, GO, KEGG and Cytoscape. Machine learning methods and weighted gene coexpression network (WGCNA) were used to identify key genes for diagnostic model construction. Receiver operating characteristic (ROC) analysis and a nomogram were used to assess their diagnostic values. A multiregulatory network was built to reveal the possible regulatory relationships of critical signatures. Cell-type identification by estimating relative subsets of RNA transcript (CIBERSORT) analysis was used to investigate differential immune cell infiltration. Additionally, a cell and animal model were constructed to investigate the relationship between the identified genes and DIC.Results: Among the 3713 differentially expressed genes, three key genes (CSGALNACT1, ZNF296 and FANCB) were identified. A nomogram and ROC curves based on three key genes showed excellent diagnostic predictive performance. The regulatory network analysis showed that the TFs CREB1, EP300, FLI1, FOXA1, MAX, and MAZ modulated three key genes. An analysis of immune cell infiltration indicated that many immune cells (activated NK cells, M0 macrophages, activated dendritic cells and neutrophils) might be related to the progression of DIC. Furthermore, there may be various degrees of correlation between the three critical signatures and immune cells. RT‒qPCR demonstrated that the mRNA expression of CSGALNACT1 and ZNF296 was significantly upregulated, while FANCB was significantly downregulated in DOX-treated cardiomyocytes in vitro and in vivo.Conclusion: Our study suggested that the differential expression of CSGALNACT1, ZNF296 and FANCB is associated with cardiotoxicity and is also involved in immune cell infiltration in DIC. They might be potential biomarkers for the early occurrence of DIC.Keywords: doxorubicin, cardiotoxicity, biomarker, machine learning, immune infiltration

Ke Wang,1,2,&ast; Te Liu,1,&ast; Yucheng Zhang,1 Huiying Lv,1 Hua Yao,1 Ye Zhao,3 Jing Li,1 Xiuying Li1 1Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 2Gynecology and Obstetrics Department, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 3Dermatological Department, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiuying Li; Jing Li, Email lixiuying@jlu.edu.cn; lijing1029@jlu.edu.cnBackground: Diabetic nephropathy (DN) is a prevalent complication of diabetes mellitus and constitutes the primary cause of mortality in affected patients. Previous studies have shown that placental mesenchymal stem cells (PL-MSCs) can alleviate kidney dysfunction in animal models of DN. However, the limited ability of mesenchymal stem cells (MSCs) to home to damaged sites restricts their therapeutic potential. Enhancing the precision of PL-MSCs’ homing to target tissues is therefore vital for the success of cell therapies in treating DN.Methods: We developed Fe3O4 coated polydopamine nanoparticle (NP)-internalized MSCs and evaluated their therapeutic effectiveness in a mouse model of streptozotocin- and high-fat diet-induced DN, using an external magnetic field.Results: Our study confirmed that NPs were effectively internalized into PL-MSCs without compromising their intrinsic stem cell properties. The magnetic targeting of PL-MSCs notably improved their homing to the kidney tissues in mice with DN, resulting in enhanced kidney function compared to the transplantation of PL-MSCs alone. Furthermore, the anti-inflammatory and antifibrotic attributes of PL-MSCs played a role in the recovery of kidney function and structure.Conclusion: These results demonstrate that magnetically targeted therapy using PL-MSCs is a promising approach for treating diabetic nephropathy.Keywords: diabetic nephropathy, magnetic targeting, mesenchymal stem cells, iron oxide nanoparticles

Wei He,&ast; Quan Zhou,&ast; Jiaheng Lv,&ast; Yujie Shen, Hao Liu, Huilin Yang, Peng Yang, Tao Liu Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Peng Yang; Tao Liu, Department of Orthopaedics, The First Affiliated Hospital of Soochow University, No. 899 Pinhai Road, Suzhou, Jiangsu, 215006, People’s Republic of China, Tel +86-512-67781420, Fax +86-512-67781165, Email ypspine@163.com; liutao821108@163.comBackground: Few studies have focused on percutaneous kyphoplasty (PKP) in the treatment of thoracic osteoporotic vertebral compression fractures (OVCFs) with intervertebral cleft (IVC). Hence, the objective of this retrospective study was to compare the clinical and radiographic outcomes of PKP in elderly patients with thoracic OVCFs, with or without IVC.Methods: A total of 106 patients were enrolled in this study and divided into two groups: the IVC group and the NIVC group (without IVC). Radiographic measures included anterior vertebral height (AVH), thoracic kyphosis (TK), lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS). Clinical function measures included Oswestry disability index (ODI) and visual analog scale (VAS) scores.Results: There were no significant differences in the preoperative basic data between the groups classified as IVC and NIVC. However, both groups showed significant improvements in AVH and TK throughout the follow-up periods compared to the preoperative measurements (P< 0.05). The recovery of AVH in the IVC group was found to be inferior to that in the NIVC group at 3 years after operation (P< 0.05). There were no significant differences in LL, PI, PT and SS in both groups compared with the preoperative results and no statistically significant differences between the two groups at the same follow-up time (P> 0.05). The VAS and ODI scores during all follow-up periods were significantly lower than those before operation (P< 0.05). At 3 years after operation, the VAS and ODI scores of the IVC group were higher than those of the NIVC group (P< 0.05).Conclusion: PKP is an adoptable measure to treat thoracic OVCFs with or without IVC. Our study revealed that the NIVC group was superior to the IVC group in terms of improved vertebral height and pain recovery at long-term follow-up (3 years).Keywords: percutaneous kyphoplasty, thoracic, osteoporotic vertebral compression fracture, intervertebral cleft, sagittal balance

Guangyi Xu,1 Ting Liu,1 Yunxia Jiang,1 Yanhong Xu,2 Taohua Zheng,2 Xiaona Li3 1Author affiliations School of Nursing, Qingdao University, Shandong, People’s Republic of China; 2Author affiliations Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Shandong, People’s Republic of China; 3Author Affiliations Endoscopic Diagnosis and Treatment Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Qingdao, People’s Republic of ChinaCorrespondence: Ting Liu, School of Nursing, Qingdao University, 1 Ningde Road, Qingdao, Shandong, 266073, People’s Republic of China, Tel +86 15066237573, Email liuting201516@163.comPurpose: To identify the distinct profiles of psychosocial adaptation of Chinese inflammatory bowel disease (IBD) patients and the predictive factors.Patients and Methods: A cross-sectional survey method was used to recruit 263 IBD patients who were treated in a tertiary hospital in Shandong Province from July 2022 to April 2023. The general information questionnaire, Inflammatory Bowel Disease Psychosocial Adaptation Questionnaire, Resilience Scale for Inflammatory Bowel Disease, Chinese Benefit Finding Scale, and Stigma Scale for Chronic Illnesses, Medical Coping Modes Questionnaire and Inflammatory Bowel Disease-Disk were used as the instruments for investigation. Latent profile analysis was conducted with the six dimensions of the IBD Psychosocial Adaptation Questionnaire as the explicit indicators. The predictors of profile membership were analyzed by multinomial logistic regressions.Results: Four profiles of psychosocial adaptation in IBD patients were identified: Low level psychosocial adaptation (14.1%), Medium level psychosocial adaptation – High body image distress (25.5%), Medium level psychosocial adaptation – Low body image distress (30.0%) and High level psychosocial adaptation (30.4%). Compared with Low level psychosocial adaptation group, High level psychosocial adaptation group had a higher level of positive cognition (OR=2.930, 95%IC 0.017– 0.305, p< 0.001) and overall psychological resilience (OR=1.832, 95%IC 0.000– 0.016, p < 0.001), more health behaviors (OR= 2.520, 95%IC 0.191– 1.358, p=0.001), a lower level of internal stigma (OR=0.135, 95%IC 0.043– 0.420, p < 0.001) and overall stigma (OR=0.010, 95%IC 0.003– 0.118, p=0.001), less acceptance-resignation coping style (OR=0.055, 95%IC 0.209– 3.200, p < 0.001) and lower disease burden (OR=0.407, 95%IC 0.298– 0.698, p=0.006).Conclusion: About a half of IBD patients had a medium level of psychosocial adaptation. Psychological resilience, benefit finding, stigma, medical coping styles and disease burden predicted psychosocial adaptation profiles. Healthcare providers need to focus on the heterogeneity of psychosocial adaptation of IBD patients and formulate personalized intervention programs for patients with different profiles to improve their psychosocial adaptation.Keywords: inflammatory bowel disease, latent profile analysis, psychosocial adaptation, benefit finding, resilience, coping, stigma

Min Chen,1,&ast; Tao Liu,2,&ast; Wenqiang Li,3 Yingting Li,1 Puxin Zhong,1 Huanchen Yan,1 Jingyin Kong,1 Weixiang Liang2 1Department of Obstetrics and Gynecology, Department of Fetal Medicine and Prenatal Diagnosis; Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510000, People’s Republic of China; 2Department of Ultrasound; Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510000, People’s Republic of China; 3Engineering Technology Research Center for Sports Assistive Devices of Guangdong, Guangzhou Sport University, Guangzhou, 510076, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Min Chen, Email edchen99@gmail.comBackground: Cartilage-related diseases, such as hypoplastic chondrodysplasia a rare genetic disorder that affects newborns, causing abnormal cartilage development and restricted skeletal growth. However, the development of effective treatment strategies for chondrodysplasia still faces significant challenges due to limitations in the controlled drug delivery, biocompatibility, and biodegradability of nanomedicines.Methods: A biodegradable magnesium doped-silicon based-nanoplatforms based on silicon nanoparticles (MON) was constructed. Briefly, the MON was modified with sulfhydryl groups using MPTMS to form MOS. Further engineering of MOS was achieved by incorporating Mg2+ ions through the “dissolution-regrowth” method, resulting in MMOS. Ica was effectively loaded into the MMOS channels, and HA was anchored on the surface of MOS to obtain MMOS-Ica@HA nanoplatforms. Additionally, in vitro cell experiments and in vivo zebrafish embryo models were used to evaluate the effect of the nanoplatforms on cartilage differentiation or formation and the efficiency of treating chondrodysplasia.Results: A series of characterization tests including TEM, SEM, DLS, XPS, EDX, and BET analysis validate the successful preparation of MOS-Ica@HA nanoplatforms. The prepared nanoplatforms show excellent dispersion and controllable drug release behavior. The cytotoxicity evaluation reveals the good biocompatibility of MOS-Ica@HA due to the sustained and controllable release of Ica. Importantly, the presence of Ica and Mg component in MOS-Ica@HA significantly promote chondrogenic differentiation of BMSCs via the Smad5/HIF-1α signaling pathway. In vitro and in vivo experiments confirmed that the nanoplatforms improved chondrodysplasia by promoting cartilage differentiation and formation.Conclusion: The findings suggest the potential application of the developed biodegradable MMOS-Ica@HA nanoplatforms with acceptable drug loading capacity and controlled drug release in chondrodysplasia treatment, which indicates a promising approach for the treatment of chondrodysplasia.Keywords: nanoplatforms, controlled release, biocompatibility, chondrodysplasia, cartilage differentiation

Liu M, Luo G, Wang Y, et al. Int J Nanomedicine. 2017;12:6827-6840. The authors have advised due to an error that occurred inadvertently at the time of figure assembly, Figure 7B on page 6834 is incorrect. The authors have also advised the magnification in the note section is incorrect. The correct Figure 7 and caption are as follows. Figure 7 Fluorescence microscopy photographes of GFP transgenic fibroblasts on the (A) PCL/DA, (B) PCL/NS0.5, (C) PCL/NS1.0 and (D) PCL/NS2.0 films. (E) The cell viability measured using CCK8 assay at day 1, 3 and 5 post-seeding.Abbreviations: CCK8, Cell Counting Kit-8; DA, dopamine; GFP, green fluorescent protein; NS, nanosilver; PCL, polycaprolactone.Notes: Magnification ×100. *p

Zhigang Zuo,1– 3 Liu Pei,4 Tianzhi Liu,2 Xiujuan Liu,2 Yuhong Chen,1,3 Zhenjie Hu1,3 1Department of Critical Care Medicine, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, People’s Republic of China; 2Department of Critical Care Medicine, the First Hospital of Qinhuangdao, Qinhuangdao, Hebei, 066000, People’s Republic of China; 3Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Shijiazhuang, Hebei, 050011, People’s Republic of China; 4Department of Laboratory, the First Hospital of Qinhuangdao, Qinhuangdao, Hebei, 066000, People’s Republic of ChinaCorrespondence: Zhenjie Hu, Department of Critical Care Medicine, the Fourth Hospital of Hebei Medical University, No. 12 Jiankang Road, Shijiazhuang, Hebei, 050011, People’s Republic of China, Email syicuhzj@163.comBackground: Sepsis is a life-threatening organ dysfunction caused by the host’s dysfunctional response to infection, which can cause acute gastrointestinal injury (AGI). The gut microbiota is dynamic and plays a role in the immune and metabolic. The aim of this study was to investigate the composition and function of gut microbiota in patients with sepsis, as well as the gut microbiome that may be involved in the occurrence of AGI.Methods: A total of 23 stool samples from healthy control individuals and 41 stool samples from sepsis patients were collected. Patients with sepsis were followed up for one week to observe whether AGI has occurred. Finally, 41 patients included 21 sepsis complicated with AGI (referred to as Com-AGI) and 20 sepsis without complicated with AGI (referred to as No-AGI). The gut microbiota was analyzed by 16S rRNA gene sequencing, followed by composition analysis, difference analysis, correlation analysis, functional prediction analysis.Results: The diversity and evenness of gut microbiota were decreased in patients with sepsis. Compared with No-AGI, the gut microbiota of Com-AGI has higher community diversity, richness, and phylogenetic diversity. Escherichia-Shigella, Blautia and Enterococcus may be important indicators of sepsis. The correlation analysis showed that aspartate aminotransferase (AST) and Barnesiella have the most significant positive correlation. Moreover, Clostridium_innocuum_group, Christensenellaceae_R-7_group and Eubacterium were all significantly correlated with LAC and DAO. Clostridium_innocuum_group, Barnesiella, Christensenellaceae_R-7_group and Eubacterium may play important roles in the occurrence of AGI in sepsis. PICRUSt analysis revealed multiple functional pathways involved in the relationship between gut microbiota and sepsis, including starch degradation V, glycogen degradation I (bacterial), Lipoic acid metabolism and Valine, leucine and isoleucine biosynthesis. BugBase analysis showed that the gut microbiota with Aerobic phenotype may play an important role in sepsis.Conclusion: Dysfunction of gut microbiota was associated with sepsis and AGI in patients with sepsis.Keywords: sepsis, acute gastrointestinal injury, gut microbiota, PICRUSt, classification model

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

Yue Zhang, Ruoxin Pan, Duoduo Gu, Xiaoqi Meng, Tingwei Liu, Yang Xu Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, 210029, People’s Republic of ChinaCorrespondence: Yang Xu, Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing, Jiangsu Province, 210029, People’s Republic of China, Tel/Fax +86-13851856794, Email yangxu@njmu.edu.cnBackground and Aim: Clinical manifestations of rosacea include transient or persistent facial erythema, telangiectasia, papules, and pustules. The existing assessment tools primarily evaluate the facial area to assess the severity of rosacea. However, in addition to the face, telangiectasia, erythema, and flushing can occur in the ear. Here, we investigated the correlation between the dermoscopic characteristics of capillaries in the earlobe and auricle and the types and severity of rosacea.Materials and Methods: Experienced dermatologists evaluated the clinical type, medical history, severity, and distribution pattern of facial erythema. The clinical severity of rosacea was assessed using the standard grading system (SGS), clinician’s erythema assessment (CEA), and investigator’s global assessment (IGA). Relationships of the clinical types and severity with the dermoscopic characteristics of capillaries in the earlobe and auricle were further analyzed.Results: In total, 145 patients with rosacea were enrolled in this study. We found that SGS, CEA, and IGA correlated well with the dermoscopic features of capillaries in the earlobe (R = 0.357, 0.357, and 0.314, respectively) (p < 0.001) and auricle (R = 0.423, 0.443, and 0.374, respectively) (p < 0.001). However, there was no significant correlation between the features and types of rosacea.Conclusion: The dermoscopic characteristics of capillaries in the earlobe and auricle can be used as indicators of the clinical severity of rosacea, regardless of the clinical subtype.Keywords: skin conditions, ear, dermoscopy, blood vessels

Liyu Hu, Jikang Yang, Ting Liu, Jinhuan Zhang, Xingxian Huang, Haibo Yu The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of ChinaCorrespondence: Haibo Yu, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, No. 1 Fuhua Road, Futian District, Shenzhen, 518000, People’s Republic of China, Tel +8613603066098, Email 13603066098@163.comPurpose: Electroacupuncture is widely used to pain management. A bibliometric analysis was conducted to identify the hotspots and trends in research on electroacupuncture for pain.Methods: We retrieved studies published from 1994– 2022 on the topic of pain relief by electroacupuncture from the Web of Science Core Collection database. We comprehensively analysed the data with VOSviewer, CiteSpace, and bibliometrix. Seven aspects of the data were analysed separately: annual publication outputs, countries, institutions, authors, journals, keywords and references.Results: A total of 2030 papers were analysed, and the number of worldwide publications continuously increased over the period of interest. The most productive country and institution in this field were China and KyungHee University. Evidence-Based Complementary and Alternative Medicine was the most productive journal, and Pain was the most co-cited journal. Han Jisheng, Fang Jianqiao, and Lao Lixing were the most representative authors. Based on keywords and references, three active areas of research on EA for pain were mechanisms, randomized controlled trials, and perioperative applications. Three emerging trends were functional magnetic resonance imaging (fMRI), systematic reviews, and knee osteoarthritis.Conclusion: This study comprehensively analysed the research published over the past 28 years on electroacupuncture for pain treatment, using bibliometrics and science mapping analysis. This work presents the current status and landscape of the field and may serve as a valuable resource for researchers. Chronic pain, fMRI-based mechanistic research, and the perioperative application of electroacupuncture are among the likely foci of future research in this area.Keywords: bibliometrics, electroacupuncture, pain, VOSviewer, CiteSpace, blibliometrix

Yuqing Li,&ast; Geng Bai,&ast; Yi Gao,&ast; Ziqiang Guo, Xiaolin Chen, Tong Liu, Guangping Li Tianjin Key Laboratory of Logic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guangping Li, Tel + 86-22-88328648, Fax + 86-22-28261158, Email tic_tjcardiol@126.comBackground: Recently, the systemic immune inflammatory response index (SIIRI), a novel and expanded inflammatory response marker, has been an independent predictor of lesion severity in patients with acute coronary syndrome (ACS). However, its predictive role in patients with initially diagnosed coronary artery disease (CAD) remains to be explored.Patients and Methods: We evaluated 959 patients with CAD undergoing an initial coronary intervention. Each patient had laboratory measurements, including blood cell counts, taken after admission and before interventional treatment. The primary endpoint was major cardiovascular events (MACEs), defined as cardiovascular death, nonfatal myocardial infarction(MI), and nonfatal stroke. The secondary endpoints included MACEs and readmission for congestive heart failure(HF).Results: During a mean follow-up period of 33.3± 9.9 months, 229 (23.9%) MACEs were recorded. ROC curve analysis displayed that the best cut-off value of SIIRI for predicting MACEs was 247.17&ast;1018/L2. Kaplan-Meier survival curve analysis showed that the survival rate of the low SIIRI group was higher than that of the high SIIRI group (P< 0.001). Compared with the low SIIRI group, the high SIIRI group had a significantly higher risk of MACEs (187 cases (39.53%) vs.42 patients (8.64%), P< 0.001). Univariate and multivariate Cox regression analyses displayed that high SIIRI levels were independently associated with the occurrence of MACEs in patients with initially diagnosed CAD undergoing percutaneous coronary intervention (PCI) (adjusted hazard ratio [HR]: 3.808, 95% confidence interval [CI%]: 2.643– 5.486, P< 0.001). Adding SIIRI to conventional risk factor models improved the predictive value of MACEs.Conclusion: Elevated SIIRI is associated with adverse cardiovascular prognosis in patients with initially diagnosed CAD. SIIRI can be a simple and practical index to identify high-risk patients with CAD after PCI.Keywords: systemic immune inflammatory response index, coronary artery disease, inflammation, markers, blood cell count

Xiaolong Wang,1 Linfa Guo,1 Guiyong Liu,2 Tongzu Liu1,3,4 1Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Qianjiang Central Hospital of Hubei Province, Qianjiang, People’s Republic of China; 3Cancer Precision Diagnosis and Treatment and Translational Medicine Hubei Engineering Research Center, Wuhan, People’s Republic of China; 4Hubei Province Key Laboratory of Urinary System Diseases, Wuhan, People’s Republic of ChinaCorrespondence: Tongzu Liu; Guiyong Liu, Department of Urology, Cancer Precision Diagnosis and Treatment and Translational Medicine Hubei Engineering Research Center, Hubei Province Key Laboratory of Urinary System Diseases, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People’s Republic of China, Email liutongzu@163.com; nogardmd@whu.edu.cnIntroduction: Leptin is a metabolic peptide hormone produced by adipocytes, with proven roles in proliferation of prostate cancer cells and of prostate cells in animal models of benign prostatic hyperplasia (BPH). Thus, the role of leptin as a molecular link connecting BPH and lower urinary tract symptoms (LUTS) suggestive of BPH with metabolic symptoms appears feasible but is still unknown. In fact, a connection between metabolic syndrome and BPH is becoming increasingly evident from epidemiologic studies. Key factors of Lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH/LUTS) are increased prostate smooth muscle tone, and prostate enlargement. Here, we examined the effects of leptin on contraction of human prostate smooth muscle and on growth of stromal cells.Methods: We performed microarray analysis to identify genes (fold change ≥ 1.5) associated with BPH/LUTS progression, such as those involved in proliferation, apoptosis, and mitochondrial metabolism, in rat prostate tissue (data from GSE129561). We then used electric field stimulation (EFS) to induce frequency-dependent, neurogenic contractions of human prostate strips, which were enhanced by leptin. We also examined the effect of leptin on human prostate stromal cells (WPMY-1) and found increased cell proliferation and viability upon exposure. To explore the underlying mechanism, we conducted mitochondrial stress assay using near-infrared (NIR) fluorescent dye and flow cytometry (FACS) analysis and observed reduced cellular apoptosis and preserved mitochondrial membrane potential (∆ψM) after leptin treatment.Results: Microarray analysis reveals that leptin regulates prostate smooth muscle contraction and stromal cell proliferation, shedding new light on its involvement in BPH/LUTS pathogenesis and mitochondrial function. We found that leptin enhanced the proliferation rate of prostate stromal cells relative to the control group (0.67 ± 0.05 vs 0.54 ± 0.08, p-value= 0.024). Moreover, leptin (100 ng/mL) potentiated the frequency-dependent, neurogenic contractions of prostate strips elicited by EFS (p= 0.047 between leptin and control group). We also show that leptin treatment increased the mitochondrial membrane potential of prostate stromal cells and inhibited mitochondrial apoptosis.&#x00A0Discussion: Our results indicate that leptin stimulates the contractility and proliferation of smooth muscle and stromal cells in the human prostate, implying a potential role for leptin in exacerbating BPH/LUTS in obese men. Leptin modulation may be a beneficial therapeutic strategy for patients with metabolic syndrome and BPH/LUTS. Further studies are warranted to elucidate the mechanisms and implications of the leptin system in BPH/LUTS.Keywords: metabolic syndrome, leptin, prostate, contraction, mitochondrial

Ning Zhang,1,&ast; Tong Liu,1,&ast; Jianan Wang,2,&ast; Yingying Xiao,1 Ying Zhang,1 Jun Dai,1 Zhihong Ma,1,3 Donglai Ma4 1School of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, People’s Republic of China; 2Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, People’s Republic of China; 3Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Shijiazhuang, Hebei, 050200, People’s Republic of China; 4School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhihong Ma; Donglai Ma, Hebei University of Chinese Medicine, Xingyuan Road 3, Shijiazhuang, Hebei, 050200, People’s Republic of China, Tel +86 31189926238, Email mazh1969@163.com; mdl_hebei@aliyun.comBackground: Metabolic associated fatty liver disease (MAFLD) is a chronic disease characterized by excessive lipid deposition in the liver without alcohol or other clear liver-damaging factors. AMP-activated protein kinase (AMPK)/silencing information regulator (SIRT)1 signaling pathway plays an important role in MAFLD development. Si-Ni-San (SNS), a traditional Chinese medicine, has shown reducing hepatic lipid deposition in MAFLD rats, however, the underlying mechanisms of SNS are barely understood.Purpose: The aim of this research was to investigate the mechanisms of SNS in reducing hepatic lipid deposition in MAFLD rats by regulating AMPK/SIRT1 signaling pathways.Methods: The components of SNS were determined by high performance liquid chromatography with mass spectrometry (HPLC-MS) analysis. MAFLD rats were induced by high-fat and high-cholesterol diet (HFHCD), and treated by SNS. SNS-containing serum and Compound C (AMPK inhibitor) were used to treat palmitic acid (PA)-induced HepG2 cells. To elucidate the potential mechanism, lipid synthesis-related proteins (SREBP-1c and FAS), fatty acid oxidation (PPARα and CPT-1), and AMPK/SIRT1 signaling pathway (p-AMPK and SIRT1) were assessed by Western blot.Results: SNS improved serum lipid levels, liver function and reduced hepatic lipid deposition in MAFLD rats. SNS-containing serum reduced lipid deposition in PA-induced HepG2 cells. SNS could up-regulate protein expressions of PPARα, CPT-1, p-AMPK and SIRT1, and down-regulate protein expressions of SREBP-1c and FAS. Similar effects of SNS-containing serum were observed in PA-induced HepG2 cells. Meanwhile, Compound C weakened the therapeutic effects of SNS-containing serum on lipid deposition.Conclusion: SNS could reduce hepatic lipid deposition by inhibiting lipid synthesis and promoting fatty acid oxidation, which might be related with activating the AMPK/SIRT1 signaling pathway. This study could provide a theoretical basis for the clinical use of SNS to treat MAFLD.Graphical Abstract: Keywords: Si-Ni-San, MAFLD, lipid deposition, lipid synthesis, fatty acid oxidation, AMPK

Jinhong Zhao, Xue Wu, Yuan Chen, Tao Li, Yunrui Han, Tingfang Liu, Yuanli Liu School of Health Policy and Management, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, People’s Republic of ChinaCorrespondence: Tingfang Liu; Yuanli Liu, School of health policy and management, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 9, Dongdansantiao Street, Dongcheng District, Beijing, 100730, People’s Republic of China, Tel +86 13501008967 ; +86 13522592907, Fax +86 010-65105750, Email liutingfang@pumc.edu.cn; liuyuanli_pumc@163.comPurpose: To summarize the organizational and management experiences and explore the organizational theoretical model of five leading public hospitals in China.Patients and Methods: Purposive sampling was used to select five leading hospitals in different regions of China under the National Health Commission and Provincial Health Commission as study hospitals for the study. From August 2021 to March 2022, 8 leaders and 39 managers from these hospitals were surveyed using semi-structured interviews. The data and information were analyzed in four dimensions using thematic analysis and grounded theory, focused on summarizing the experiences and practices of China’s leading hospitals in organizational system, culture, operations and performance management, and employee development. This study complied with the COREQ guidelines for reporting qualitative research.Results: An organizational system model of the characteristics of hospital excellence was developed using four core attributes: organizational system, organizational culture, operations and performance management, and employee development; the model was named the System–Culture–Operation–Performance–Employee (SCOPE) model. Organization and management among leaders and managers in China’s leading hospitals are based on the SCOPE process, resulting in employees’ well-being, patients’ positive outcomes, and organizational excellence. In terms of hospital culture, while adhering to the Hippocratic Oath, the hospital is deeply influenced by traditional Chinese culture, which emphasizes “benevolence” and “love”, leading all staff to adhere to “patient-centered care and service.” In terms of operations management, a separate operations management department is responsible for hospital operations and performance assessment. As for employee development, the staff’s sense of reverence for their profession is emphasized and a reasonable salary system and good practice environment are established to promote staff motivation.Conclusion: The SCOPE model reveals the perspectives of leaders and managers in China’s leading hospitals regarding organization and management under a Chinese cultural background. These findings can complement the existing literature on hospital management systems.Keywords: hospital management, excellence, lessons, qualitative study, model

Yongde Zhou,1,&ast; Xiaoxiao Wang,2,3,&ast; Zhengqian Li,2,4 Yu Ma,5 Cuiping Yu,1 Yao Chen,1 Jian Ding,1 Jianfeng Yu,1 Rongsong Zhou,5 Ning Yang,2,4 Taotao Liu,2,4 Xiangyang Guo,2,4 Ting Fan,1 Chengmei Shi2,4 1Department of Anesthesiology, Tsinghua University Yuquan Hospital, Beijing, 100040, People’s Republic of China; 2Department of Anesthesiology, Peking University Third Hospital, Beijing, 100191, People’s Republic of China; 3Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, 100191, People’s Republic of China; 4Beijing Center of Quality Control and Improvement on Clinical Anesthesia, Beijing, 100191, People’s Republic of China; 5Department of Neurosurgery, Tsinghua University Yuquan Hospital, Beijing, 100040, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chengmei Shi, Department of Anesthesiology, Peking University Third Hospital, Beijing, 100191, People’s Republic of China, Tel +86-13811592813, Email shichengmei@bjmu.edu.cn Ting Fan, Department of Anesthesiology, Tsinghua University Yuquan Hospital, Beijing, 100040, People’s Republic of China, Tel +86-13681100715, Email 13681100715@163.comBackground: A simple, rapid, and effective cognitive screening test appropriate for fast-paced settings with limited resources and staff is essential, especially preoperatively. This study aimed to develop and validate the short versions of Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) for predicting postoperative delirium (POD) in patients with Parkinson’s disease (PD) who were scheduled for surgery.Methods: The current study was a secondary analysis of data collected from 128 inpatients scheduled for deep brain stimulation of the subthalamic nuclei (STN-DBS) lasting > 60 min, at Tsinghua University Yuquan Hospital, China. Preoperative cognitive screening was performed during the preoperative visit using the MMSE and MoCA. The optimal MMSE and MoCA cut-off scores for detecting PD-MCI was 27 and 23 respectively. The POD was assessed twice a day on the first postoperative day until discharge by the confusion assessment method. The backward conditional logistic regression analysis was used to organize the reduced versions of the MMSE or MoCA. Also, the areas under the receiver operating characteristic curves (AUCs) were examined using the DeLong test.Results: 125/128 PD patients were included in the analysis, and 27 (21.6%) developed POD. The MMSE reduced version (orientation to time, attention and calculation, and comprehension) demonstrated performance similar to the original MMSE in predicting POD (z=0.820, p=0.412). The AUC of the original MoCA and the short MoCA (visuospatial and executive attention and orientation) were 0.808 and 0.826, respectively. There was no significantly difference in the AUC values between the tests (z=0.561, p=0.575).Conclusion: Our simplified MMSE and MoCA could be efficiently used to identify patients at risk for POD. Also, short cognitive tests could be considered while predicting POD in fast-paced preoperative settings with limited resources and staff.Plain Language Summary: Routine preoperative cognitive screening is very important in predicting postoperative delirium.MMSE and MoCA are the most commonly used cognitive testing method which normally takes a long time.The short variant of MMSE and MoCA show a predictive performance similar to the original tests.Keywords: Parkinson’s disease, preoperative cognitive impairment, mini-mental state examination, Montreal Cognitive Assessment, postoperative delirium

Lingjun Wen, Can Luo, Xinyi Chen, Tianyao Liu, Xianping Li,&ast; Min Wang&ast; Department of Laboratory Medicine, The Second Xiangya Hospital of Central South University, Changsha, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Min Wang; Xianping Li, Department of Laboratory Medicine, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha, 410011, People’s Republic of China, Tel +86 13298697558, Email wangmin0000@csu.edu.cn; xianpingli2017@csu.edu.cnPurpose: We aimed to evaluate the in vitro antibacterial effects of combination of cefepime/avibactam against carbapenem-resistant Klebsiella pneumonia (CRKP) and explore the resistance mechanism of FEP/AVI.Patients and Methods: This study explored the in vitro antibacterial activities of ceftazidime/avibactam (CAZ/AVI) and cefepime/avibactam (FEP/AVI) against 40 and 76 CRKP clinical isolates. Proteomics and metabolomics were employed to investigate the resistance mechanisms of CRKP to FEP/AVI.Results: FEP/AVI (MIC50/MIC90 0.5/4-64/4 μg/mL, resistance rate 17.1%) showed better antibacterial activity against CRKP than CAZ/AVI (MIC50/MIC90 4/4-128/4 μg/mL, resistance rate 20%) in vitro. Bioinformatics analysis showed that the differentially expressed proteins (DEPs) were enriched in alanine, aspartate and glutamate metabolism, and ribosome. Remarkably, transcriptional and translational activity-related pathways were inhibited in FEP/AVI resistant CRKP. Overlap analysis suggested that H-NS might play an important role in resistance to FEP/AVI in CRKP. The mRNA levels of DEPs-related genes (adhE, gltB, purA, ftsI and hns) showed the same trends as DEPs in FEP/AVI susceptible and resistant strains. FEP/AVI resistant isolates demonstrated stronger biofilm formation capacity than susceptible isolates. Metabolomics results showed that disturbed metabolites were mainly lipids, and adenine was decreased in FEP/AVI resistant CRKP.Conclusion: These results indicated that H-NS, GltB and SpoT may directly or indirectly promote biofilm formation of CRKP and led to FEP/AVI resistance, but inhibited ribosomal function. Our study provides a mechanistic insight into the acquisition of resistance to FEP/AVI in Klebsiella pneumoniae.Keywords: carbapenem-resistantKlebsiella pneumoniae, bacterial resistance, proteomics, metabolomics, cefepime/avibactam, ribosome