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Xinyue Yi,1,2,* Pengyuan Leng,1,* Supeng Wang,2 Liangle Liu,1 Bingju Xie1 1The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of China; 2Clinical Medical College, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, People’s Republic of China*These authors contributed equally to this workCorrespondence: Liangle Liu; Bingju Xie, Email liuliangle@wmu.edu.cn; xiebingju@wmu.edu.cnAbstract: Osteoarthritis (OA) is the most common degenerative joint disease, affecting more than 595 million people worldwide. Nanomaterials possess superior physicochemical properties and can influence pathological processes due to their unique structural features, such as size, surface interface, and photoelectromagnetic thermal effects. Unlike traditional OA treatments, which suffer from short half-life, low stability, poor bioavailability, and high systemic toxicity, nanotherapeutic strategies for OA offer longer half-life, enhanced targeting, improved bioavailability, and reduced systemic toxicity. These advantages effectively address the limitations of traditional therapies. This review aims to inspire researchers to develop more multifunctional nanomaterials and promote their practical application in OA treatment. Keywords: nanostructures, osteoarthritis, drug delivery systems, nanomedicine, precision medicine

Xuan Wei,1,2,* Yu Zhong,3,* Xiaofei Yi,1 Tingting Li,1 Zhougui Ling,2 Moyu Ming,2 Shuang Zhang,1 Zhiyi He1 1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, People’s Republic of China; 3Department of Emergency Medicine, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhiyi He, Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, NO. 6 Shuangyong Road, Qingxiu District, Nanning City, Guangxi Zhuang Autonomous Region, People’s Republic of China, 530000, Tel +86 187 7801 7698, Email zhiyi-river@163.comObjective: Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease with high prevalence, morbidity, and mortality. Chuankezhi (CKZ) injection, a Chinese patent medicine, has been commonly used for treating COPD. This study evaluated the clinical efficacy of CKZ injections in COPD patients and explored potential underlying mechanisms by integrating meta-analysis and network pharmacology.Research Methods: Randomized controlled trials (RCTs) were search in database by Web of Science, Cochrane Library and PubMed as of November 2022 for literature collection, and the Review Manager 5.4 was used to analyze the data. Through the network pharmacology method, the chemical components and their targets, as well as the disease targets were further analyzed.Results: A total of 15 RCTs including 1212 patients were included. The results of meta-analysis showed that CKZ injection can significantly improve the clinical effective rate (RR = 1.25, 95% CI: 1.14 to 1.36), and the clinical advantage was that it can significantly reduced acute exacerbation rate (RR = 0.29, 95% CI: 0.12 to 0.70) and COPD assessment test (CAT) scores (MD =− 4.62, 95% CI:-8.966 to-0.28). A total of 31 chemical compounds and 178 potential targets for CKZ injection were obtained from the online databases. Molecular docking revealed that most key components and targets could form stable structure.Conclusion: This systematic review with meta-analysis and network pharmacology demonstrates that CKZ could effectively improve the clinical efficacy and safety in the treatment of COPD. Such efficacy may be related to an anti-inflammatory effect and immunoregulation of CKZ via multiple components, multiple targets and multiple pathways. Keywords: meta-analysis, network pharmacology, chronic obstructive pulmonary disease, Chuankezhi injection

Min Wu,1,2,* Sining Zeng,3,* Yi Zhang,1,2,* Yanru Liu,1,2 Bingbing Li,1,2 Xuemei Yi,1,2 Yuling Shi,1,2 Xiaoping Zhu3 1Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, 200443, People’s Republic of China; 2Institute of Psoriasis, Tongji University School of Medicine, Shanghai, 200443, People’s Republic of China; 3Nursing Department, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoping Zhu, Nursing Department, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, 301 Yanchang Middle Road, Jing’an District, Shanghai, People’s Republic of China, Tel +86-021-66300588, Fax +86-021-66307542, Email xiaopingzhu0424@163.com Yuling Shi, Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, 1278 Baode Road, Jing’an District, Shanghai, People’s Republic of China, Tel +86-021-36803020, Fax +86-021-36803021, Email shiyuling1973@tongji.edu.cnBackground: Psoriasis is a chronic autoimmune inflammatory skin condition characterized by erythema, papules, and scales. It imposes a heavy psychological and social strain on both patients and their families. Surprisingly, there’s limited research delving into the disease burden and coping strategies of spouses contending with psoriasis.Objective: The objective is to explore the disease burden faced and coping strategies utilized by spouses of individuals living with psoriasis. This exploration aims to offer insights crucial for devising mental health support and intervention strategies.Methods: The research methodology employed in this study was phenomenological, a qualitative approach. A total of fifteen spouses of patients with psoriasis were selected using an objective sampling method for in-depth, semi-structured interviews. Thematic analysis was then applied to the recorded interview data to derive meaningful themes.Results: This study has identified and analyzed three core themes concerning the disease burden and coping strategies of spouses of patients with psoriasis: Overwhelming disease burden; Lack of support system; Coping strategies (Problem - centered coping strategies: Proactive acquisition of disease knowledge; Active confrontation of illness - related issues; Behavioral habit alteration; and Emotional - centered coping strategies: Active acceptance and normalization; Passive acceptance and internalized stigma; Avoidance of disease - related problems).Conclusion: This study adds valuable insights into comprehending the disease burden encountered by spouses of patients with psoriasis and sheds light on the coping strategies they employ. Healthcare providers should proactively recognize and address the burden experienced by spouses early on. Establishing a robust support network is crucial, and promoting adaptive coping strategies can significantly aid spouses in effectively navigating and managing the complexities associated with psoriasis.Keywords: psoriasis, spouse, disease burden, coping strategies, qualitative research

Xuan Yi,1 Xinxing Wan,1 Md Asaduzzaman Khan,2,3 Xiaoying Sun,1 Zhouqi Wang,1 Ke Chen,1 Lin Peng4 1Department of Endocrinology, The Third Xiangya Hospital of Central South University, Changsha, People’s Republic of China; 2Research Division, Nature Study Society of Bangladesh, Dhaka, 1000, Bangladesh; 3Pulmonary Department, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, 02118, USA; 4Department of Nephrology, The First Hospital of Changsha, Changsha, People’s Republic of ChinaCorrespondence: Lin Peng, Department of Nephrology, The First Hospital of Changsha, Changsha, People’s Republic of China, Tel +86-731-8466-7510, Email plin1018@163.com Ke Chen, Department of Endocrinology, The Third Xiangya Hospital of Central South University, Changsha, People’s Republic of China, Tel +86-731-8861-8239, Email chenke520@yeah.netPurpose: Adipogenesis is one of the major pathways for generating obesity or overweight that can cause a range of metabolic disorders. Circular RNAs (circRNAs), a specific type of RNAs, have a significant influence on metabolic disorders. This study aims to find differentially expressed circRNAs (DECs) during human subcutaneous adipose tissue (SATs) adipogenesis.Patients and Methods: The human adipose tissue-derived stromal cells (hADSCs) were isolated from human SATs (n = 3), and then induced into adipocytes. Total RNAs were extracted from hADSCs and adipocytes, and he DECs were detected using circRNA microarray. The GO and KEGG pathways of DECs were analyzed by bioinformatic methods, and partial DECs were further validated by quantitative polymerase chain reaction (qPCR).Results: Our study detected a total of 1987 DECs, among which, 1134 were found upregulated and 853 were downregulated. GO analysis showed that the upregulated DECs have catalytic activity in intracellular organelle and cytoplasms, whereas downregulated DECs are enriched in organelle lumen, and are involved in positive regulation of developmental process. In addition, pathway results demonstrated that upregulated DECs are involved in platinum drug resistance and cellular senescence, and downregulated DECs are enriched in proteoglycans in cancer and focal adhesion pathway. Two circRNAs, namely has_circ_0001600 and has_circ_0001947 were validated to be significantly upregulated in adipocytes compared to hADSCs.Conclusion: Our study explored DECs between hADSCs derived from SATs and adipocytes, and report that two circRNAs named has_circ_0001600 and has_circ_0001947 might be important factors involved in human adipogenesis, however, the molecular mechanism should be further explored.Keywords: circRNA microarray, subcutaneous adipose tissue, human adipose tissue-derived stromal cells, adipogenesis, SAT

Hongjie Yuan,1 Xiaobin Yi2 1Department of Pain Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Pain Division, Department of Anesthesiology, Washington University in St Louis, St Louis, MO, USACorrespondence: Xiaobin Yi, Email yix@wustl.eduBackground: Lumbar spinal stenosis (LSS) is a common pain condition that causes lumbar back pain, radiating leg pain, and possible functional impairment. MILD is an emerging minimally invasive treatment for LSS. It is an image-guided percutaneous procedure designed to debulk hypertrophied ligamentum flavum. However, the exact short- and long-term efficacy, safety profile, indication criteria, and certain procedure details reported in medical literature vary.Objective: This narrative review was to elucidate efficacy, safety profile, certain procedure details, advantages, and limitations of MILD.Study Design: This is a narrative review.Setting: All included articles are clinic trials including analytic studies and descriptive studies.Methods: PubMed, Cochrane Library, and Scopus were searched. Only clinical trials of MILD procedure were included. Information of indications, contraindications, VAS scores, ODI scores, effective rate, efficacy durations, and certain procedure details was focused on.Results: According to the literature, for the MILD procedure, the VAS score could be reduced from a pre-treatment level of 6.3– 9.6 to a post-treatment level of 2.3– 5.8. The ODI score could be reduced from a pre-treatment level of 38.8– 55.3 to a post-treatment level of 27.4– 39.8. The effective rate of the MILD procedure was reported to be 57.1%– 88%. A 2-year postoperative stability of efficacy was also supported. One RCT study testified superior efficacy of MILD over epidural steroid injection.Limitations: There is few high-quality literature in the review. Moreover, the long-term efficacy of MILD cannot be revealed according to the current literature.Conclusion: Based on the reviewed literature, MILD is an effective and safe procedure. MILD can reduce pain intensity and improve functional status significantly. Therefore, it is a preferable option for LSS patients who failed conservative treatments, but not for those who require immediate invasive decompression surgery.Keywords: lumbar spinal stenosis, minimally invasive lumbar decompression, mild ®, low back pain, lumbar radiculopathy, neurogenic claudication, ligamentum flavum

Shuping Cai,1,2,* Jingyuan Gao,3,* Xiaomin Liu,3,* Junhao Yang,3,* Dingyun Feng,1 Guijun Li,2 Sijia Li,1 Hailing Yang,1 Zhang Wang,3 Xinzhu Yi,3 Yuqi Zhou1 1Department of Pulmonary and Critical Care Medicine, Institute of Respiratory Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guang Dong, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, the Seventh Affiliated Hospital of SUN YAT-SEN University, Shenzhen, Guang Dong, People’s Republic of China; 3Institute of Ecological Sciences, School of Life Sciences, South China Normal University, Guangzhou, Guang Dong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xinzhu Yi; Yuqi Zhou, Email labxz@hotmail.com; zhouyuqi@mail.sysu.edu.cnIntroduction: Increasing evidence suggests that seasonal changes can trigger the alternation of airway microbiome. However, the dynamics of the upper airway bacterial ecology of chronic obstructive pulmonary disease (COPD) patients across different seasons remains unclear.Methods: In this study, we present a 16S ribosomal RNA survey of the airway microbiome on 72 swab samples collected in different months (March, May, July, September, and November) in 2019 from 18 COPD patients and from six resampled patients in November in 2020.Results: Our study uncovered a dynamic airway microbiota where changes appeared to be associated with seasonal alternation in COPD patients. Twelve clusters of temporal patterns were displayed by differential and clustering analysis along the time course, systematically revealing distinct microbial taxa that prefer to grow in cool and warm seasons, respectively. Moreover, the upper airway microbiome composition was relatively stable in the same season in different years.Discussion: Given the tight association between airway microbiome and COPD disease progression, this study can provide useful information for clinically understanding the seasonal trend of disease phenotypes in COPD patients.Graphical Abstract: Keywords: chronic obstructive pulmonary disease, upper airway microbiome, seasonal variation

Qingqing Huang,1 Qin Shi,2 Xiaobo Yi,1 Jingzheng Zeng,2 Xuemei Dai,1 Lu Lin,1 Yanling Yang,1 Xiao Wu,2 Gu Gong1 1Department of Anesthesiology, The General Hospital of Western Theater Command, Chengdu, People’s Republic of China; 2Department of Anesthesiology, North Sichuan Medical College, Nanchong, People’s Republic of ChinaCorrespondence: Gu Gong, Department of Anesthesiology, The General Hospital of Western Theater Command, 270 Tianhui Road, Rongdu Avenue, Jinniu District, Chengdu, Sichuan, 610083, People’s Republic of China, Tel +8617360137572, Fax +86 28570423, Email gonggu68@163.comObjective: Postoperative delirium is common after general anesthesia in older patients. However, there are currently no effective preventive measures. This study investigated the effect of repeated intranasal administration of different insulin doses before surgery on postoperative delirium in older patients with esophageal cancer, and the possible mechanism for its efficacy.Methods: In this randomized, placebo-controlled, double-blind, parallel-group study, 90 older patients were randomly assigned to either a Control (normal saline), Insulin 1 (20 U/0.5 mL intranasal insulin), or Insulin 2 (30 U/0.75 mL intranasal insulin) group. Delirium was assessed on postoperative days 1 (T2), 2 (T3), and 3 (T4) using the Confusion Assessment Method for the Intensive Care Unit. Serum τ and Aβ protein levels were measured at T0 (before insulin/saline administration), T1 (end of surgery), T2, T3 and T4.Results: The Insulin 2 group had a significantly lower prevalence of delirium compared to the Control and Insulin 1 groups three days after surgery. Compared to baseline, τ and Aβ protein levels increased significantly at T1–T4. Compared to the Control group, the Insulin 1 and 2 groups had significantly lower τ and Aβ protein levels at T1–T4, and the Insulin 2 group had significantly lower levels than the Insulin 1 group at T1–T2.Conclusion: The administration of 30 U of intranasal insulin twice daily, from 2 days preoperatively until 10 minutes preanesthesia on the day of surgery, can significantly reduce postoperative delirium in older patients undergoing radical esophagectomy. It can also decrease postoperative τ and Aβ protein expression without causing hypoglycemia.Clinical Trial Registration: This study was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn, with the unique identifier: ChiCTR2100054245; December 11, 2021).Keywords: postoperative delirium, intranasal insulin, τ protein, Aβ protein, aged

Xiaoying Sun,1 Xinxing Wan,1 Md Asaduzzaman Khan,2 Keke Zhang,1 Xuan Yi,1 Zhouqi Wang,1 Ke Chen1 1Department of Endocrinology, The Third Xiangya Hospital of Central South University, Changsha, People’s Republic of China; 2The Research Centre for Preclinical Medicine, Southwest Medical University, Luzhou, People’s Republic of ChinaCorrespondence: Ke Chen, Department of Endocrinology, The Third Xiangya Hospital of Central South University, Changsha, People’s Republic of China, Tel +86-731-8861-8239, Email chenke520@yeah.netPurpose: Brown adipose tissue (BAT) can rapidly generate heat and improve energy metabolism. Circular RNAs (circRNAs) are cellular endogenous non-coding RNAs, which can regulate the development and progress of different diseases. However, the role of circRNAs in human BAT is not fully understood. Here, we analyzed the differentially expressed circRNAs (DECs) in human BAT, as well as in white adipose tissue (WAT), and identified new biomarkers of BAT.Patients and Methods: Three human BAT and three human subcutaneous WAT samples were selected, and circRNA microarray was performed. Additionally, quantitative real-time polymerase chain reaction (qRT-PCR) was applied to determine the expression of six circRNAs. Finally, the functional analysis was performed by bioinformatics.Results: Compared to WAT, 152 upregulated circRNAs and 201 downregulated circRNAs were identified in BAT. The DECs were further subjected to GO and KEGG enrichment analysis. Several circRNAs, for example, hsa_circ_0006168, hsa_circ_26337 and hsa_circ_0007507 were found upregulated and hsa_circ_0030162 was found downregulated in human BAT compared to WAT.Conclusion: This study profiles the circRNA expression in human BAT and WAT, and suggests hsa_circ_0006168, hsa_circ_26337, hsa_circ_0007507, and hsa_circ_0030162 as novel biomarkers for human BAT.Keywords: brown adipose tissue, biomarkers, circRNA microarray

Keke Zhang,1 Xinxing Wan,1 Md Asaduzzaman Khan,2 Xiaoying Sun,1 Xuan Yi,1 Zhouqi Wang,1 Ke Chen,1 Lin Peng3 1Department of Endocrinology, the Third Xiangya Hospital of Central South University, Changsha, People’s Republic of China; 2The Research Centre for Preclinical Medicine, Southwest Medical University, Luzhou, People’s Republic of China; 3Department of Nephrology, the First Hospital of Changsha, Changsha, People’s Republic of ChinaCorrespondence: Lin Peng, Department of Nephrology, the First Hospital of Changsha, Changsha, People’s Republic of China, Tel +86-731-8466-7510, Email plin1018@163.com Ke Chen, Department of Endocrinology, the Third Xiangya Hospital of Central South University, Changsha, People’s Republic of China, Tel +86-731-8861-8239, Email chenke520@yeah.netPurpose: Type 2 diabetes mellitus (T2DM) increases the incidence of diabetic nephropathy (DN) and eventually progresses to end-stage renal disease. Circular RNAs (circRNAs) are a class of non-coding RNAs that are promising as diagnostic biomarkers and therapeutic targets for human diseases. The aim of this study was to analyze the differential expression of circRNAs (DECs) in peripheral blood from patients with early type 2 diabetic nephropathy (ET2DN), T2DM and controls, which will facilitate to discover some new biomarkers for ET2DN.Patients and Methods: Twenty ET2DN patients, 20 T2DM patients, and 20 normal controls were included in this study. Blood samples from 3 random subjects of age- and sex-matched patients in each group, respectively, were used to detect circRNA expression profiles by circRNA microarray, and the circRNA expression of remaining subjects was validated by real-time quantitative polymerase chain reaction (qRT-PCR). Further functional assessment was performed by bioinformatic tools.Results: There were 586 DECs in ET2DN vs T2DM group (249 circRNAs were upregulated and 337 circRNAs were downregulated); 176 circRNAs were upregulated and 101 circRNAs were downregulated in T2DM vs control group; 57 circRNAs were upregulated and 5 circRNAs were downregulated in ET2DN vs control group. The functional and pathway enrichment of DECs were analyzed by GO and KEGG. qRT-PCR results revealed that hsa_circ_0001831 and hsa_circ_0000867 were significantly upregulated in ET2DN group compared to both of T2DM and control group. The ROC curve demonstrated that hsa_circ_0001831 and hsa_circ_0000867 have high sensitivity and specificity associated with ET2DN.Conclusion: Our study showed the expression profiles of circRNAs in ET2DN patients and demonstrated that hsa_circ_0001831 and hsa_circ_0000867 can be used as novel diagnostic biomarkers for ET2DN.Keywords: circRNAs microarray, diagnostic biomarkers, early type 2 diabetic nephropathy, inflammation

Xuanzi Yi,1,* Xu Cheng2,3,* 1Department of Medicine II, Division of Endocrinology and Diabetology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, 79106, Germany; 2Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 3Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, 79106, Germany*These authors contributed equally to this workCorrespondence: Xuanzi YiDepartment of Medicine II, Division of Endocrinology and Diabetology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, Freiburg, 79106, GermanyTel/Fax +49 761 270-73270Email xuanzi.yi@uniklinik-Freiburg.deBackground: Type 1 diabetes mellitus (T1DM), an autoimmune disease with a genetic tendency, has an increasing prevalence. Long non-coding RNA (lncRNA) and circular RNA (circRNA) are receiving increasing attention in disease pathogenesis. However, their roles in T1DM are poorly understood. The present study aimed at identifying signature lncRNAs and circRNAs and investigating their roles in T1DM using the competing endogenous RNA (ceRNA) network analysis.Methods: The T1DM expression profile was downloaded from Gene Expression Omnibus (GEO) database to identify the differentially expressed circRNAs, lncRNAs, and mRNAs. The biological functions of these differentially expressed circRNAs, lncRNAs, and mRNAs were analyzed by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Targeting relationships of circRNA-miRNA, lncRNA-miRNA, and miRNA-mRNA were predicted, and the circRNA-lncRNA-miRNA-mRNA ceRNA regulatory network was established. Finally, qRT-PCR was applied to identify the effect of hsa_circ_0002202 inhibition on the IFN-I induced macrophage inflammation.Results: A total of 178 circRNAs, 404 lncRNAs, and 73 mRNAs were identified to be abnormally expressed in T1DM samples. Functional enrichment analysis results indicated that the differentially expressed genes were mainly enriched in extracellular matrix components and macrophage activation. CeRNA regulatory network showed that circRNAs and lncRNAs regulate mRNAs through integrate multiple miRNAs. In addition, in vitro experiments showed that hsa_circ_0002202 inhibition suppressed the type I interferon (IFN-I)-induced macrophage inflammation.Conclusion: In the present study, the circRNA-lncRNA-miRNA-mRNA ceRNA regulatory network in T1DM was established for the first time. We also found that hsa_circ_0002202 inhibition suppressed the IFN-I-induced macrophage inflammation. Our study may lay a foundation for future studies on the ceRNA regulatory network in T1DM.Keywords: type 1 diabetes mellitus, ceRNA network, peripheral blood mononuclear cell, macrophage

Dong Zhang, Ying Yuan, Hao Zhang, Xinzeyu Yi, Weidong Xiao, Aixi Yu Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of ChinaCorrespondence: Aixi Yu; Weidong XiaoDepartment of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of ChinaTel +86-027-67813120; +86-18707182868Email yuaixi@whu.edu.cn; xiaoweidong@whu.edu.cnBackground: Skin avulsion injuries caused by high-energy traffic and machinery accidents are important topics in the field of repair and reconstruction. The injury generates a skin flap with uncertain vascular basis resulting in ischemic necrosis of the distal portion of the flap. Yet there is lack of reliable way for estimating the extent of blood supply in damaged tissue, which has limited the possibility of prompt surgical intervention. Recent studies have confirmed that photoacoustic microscopy imaging has a wide range of applications in the biomedical field owing to its good performance in angiography.Methods: In our study, we successfully surgically induced skin avulsion injury on mice hindlimbs. Then, we used this novel approach to image skin microcirculation and predict skin necrosis with impaired blood supply after injury in live mice.Results and Conclusion: All skin tissues in the avulsed hindlimb flap group show different levels of necrosis at the end of the observation period. The “dark zone” with impaired microcirculation in PAM images, which continuously extends over time, was seen as a prediction of necrosis of skin tissue and at 60 min after surgery was similar to the area of clinical necrosis on postoperative day 7. All these indicate that photoacoustic microscopy imaging is a feasible, precise, high-resolution, non-invasive technique for early prediction of necrosis in skin avulsion injury, providing a promising tool for surgeons to manage the injury.Keywords: skin avulsion injuries, photoacoustic microscope, monitoring microcirculation

Zhexiu Jin,1 Xue Yi,2 Jingjing Yang,1 Meili Zhou,1 Peifu Wu,1 Gen Yan3 1Department of Cardiovascular Medicine, The Second Affiliated Hospital of Xiamen Medical College, Xiamen, Fujian Province, 361023, People’s Republic of China; 2Department of Basic Medicine, Xiamen Medical College, Xiamen, Fujian Province, 361023, People’s Republic of China; 3Department of Radiology, The Second Affiliated Hospital of Xiamen Medical College, Xiamen, Fujian Province, 361023, People’s Republic of ChinaCorrespondence: Gen YanDepartment of Radiology, The Second Affiliated Hospital of Xiamen Medical College, Xiamen, Fujian Province, 361023, People’s Republic of ChinaTel +86 592 627 6910Email gyan@stu.edu.cnPurpose: A liposome-coated arsenic–manganese complex, denoted as LP@MnAsx was constructed for the targeted delivery of arsenic trioxide (ATO) against carcinoma.Methods: Arsenite, the prodrug of ATO, was encapsulated within a liposome via electrostatic interaction with the manganese ions. The as-prepared material was characterized with dynamic light scattering and transmission electron microscopy. The entrapment efficiency and drug loading of arsenic in the carrier were measured using inductively coupled plasma spectrometry. The in vitro release of arsenic was evaluated by using the dialysis bag method. Furthermore, the Fenton-like activity and in vitro cytodynamics research of LP@MnAsx were monitored in this work. And the cellular uptake study was used to investigate the in vitro entry mechanism. Furthermore, the cytotoxicity, cell apoptosis and cell cycle study were performed to evaluate the tumor-killing efficiency. Also, the pharmacokinetic and antitumor studies were investigated in HepG2 tumor-bearing nude mice.Results: The as-prepared LP@MnAsx possessed a spherical morphology, uniformly distributed hydrodynamic diameter, and excellent drug-loading efficiency. LP@MnAsx displayed robust stability and sustained-release profile under physiological environments. LP@MnAsx could degrade with high sensitivity to the pH variation in the tumor microenvironment. As such, this could lead to a burst release profile of Mn2+ and arsenite to achieve a synergistic therapy of chemodynamic therapy and chemotherapy. When compared to the carrier-free arsenate, in vitro experiments revealed that LP@MnAsx exhibited enhanced cellular uptake and tumor-killing efficiency. LP@MnAsx also demonstrated significantly enhanced tumor-specific in vivo distribution of arsenic, prolonged systemic circulation lifetime, and increased accumulation at the tumor site.Conclusion: Based on the experimental results, LP@MnAsx is an ideal arsenic-based nanodelivery system, whereby it can improve the non-specific distribution of NaAsO2 in vivo. Thus, this work can expand the research and application of arsenic trioxide against solid tumors.Keywords: arsenic–manganese complex liposome, arsenic trioxide, pH-sensitive, hepatocellular carcinoma

Fuyu Jin,1 Fei Geng,2 Dingjie Xu,3 Yaqian Li,1 Tian Li,1 Xinyu Yang,1 Shupeng Liu,1 Hui Zhang,1 Zhongqiu Wei,1 Shifeng Li,2 Xuemin Gao,2 Wenchen Cai,2 Na Mao,2 Xue Yi,4 Heliang Liu,2 Ying Sun,1 Fang Yang,2 Hong Xu1,2 1Basic Medical College, Hebei Key Laboratory for Chronic Diseases, North China University of Science and Technology, Tangshan, Hebei Province, 063210, People’s Republic of China; 2School of Public Health, Hebei Key Laboratory for Organ Fibrosis Research, North China University of Science and Technology, Tangshan, Hebei Province, 063210, People’s Republic of China; 3Traditional Chinese Medicine College, North China University of Science and Technology, Tangshan, Hebei Province, 063210, People’s Republic of China; 4Key Laboratory of Functional and Clinical Translational Medicine, Xiamen Medical College, Xianmen, Fujian Province, 361023, People’s Republic of ChinaCorrespondence: Hong Xu 21 Bohai Road, Caofeidian District, Tangshan, Hebei Province, 063210, People’s Republic of ChinaTel +86 315-8816236Email xuhong@ncst.edu.cnBackground: Silica-induced inflammatory activation is associated with silicosis and various non-respiratory conditions. The present study was designed to examine the anti-inflammatory effects of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) on lung macrophages and bone osteoclasts after silica inhalation in rats.Methods: Wistar rats and NR8383 and RAW 264.7 cell lines were used in the present study. The receptor activator of nuclear factor kappa-B ligand (RANKL) and toll-like receptor 4 (TLR4) signaling pathways was measured in the lung tissue of rats or NR8383/RAW 264.7 cells exposed to silica. The microarchitecture of the trabecular bone in the tibia and femur was evaluated in silicotic rats. Furthermore, the roles of Ac-SDKP on silicotic rats, silica-treated NR8383/RAW 264.7 cells, and RANKL-induced osteoclast differentiation were studied.Results: The data indicated that silica inhalation might activate the RANKL and TLR4 signaling pathways in lung macrophages, thus inducing the lung inflammatory and proteolytic phenotype of macrophages and osteoclasts in lung and bone. Ac-SDKP maintained the lung elastin level by inhibiting lung inflammation and macrophage activation via the RANKL and TLR4 signaling pathways. Ac-SDKP also attenuated the reduction in femoral bone mineral density in silicotic rats by inhibiting osteoclast differentiation via the RANKL signaling pathway.Conclusion: Our findings support the hypothesis that inhalation of crystalline silica induces activation of lung macrophages and bone osteoclasts via the RANKL and TLR4 signaling pathways. Ac-SDKP has the potential to stabilize lung homeostasis and bone metabolism.Keywords: silicosis, N-acetyl-seryl-aspartyl-lysyl-proline, macrophage, osteoclast

Abstract We have investigated the crystal structures and mechanical properties of osmium diboride (OsB2) based on the density functional theory. The structures of OsB2 from 0 to 400 GPa were predicted using the particle swarm optimization algorithm structure prediction technique. The orthorhombic Pmmn structure of OsB2 (oP6-OsB2) was found to be the most stable phase under zero pressure and it will transfer to the hexagonal P63/mmc structure (hP6-OsB2) around 12.4 GPa. Meanwhile, we have discovered a new stable orthorhombic Immm structure (oI12-OsB2) above 379.6 GPa. After that, a thorough and comprehensive investigation on mechanical properties of different OsB2 phases is performed in this work. Further studies showed that the hardness of oP6-OsB2 and hP6-OsB2 at zero pressure is 15.6 and 20.1 GPa, while that for oI12-OsB2 under 400 GPa is 15.4 GPa, indicating that these three phases should be potentially hard materials rather than superhard materials. Finally, the pressure–temperature phase diagram of OsB2 is constructed for the first time by using the quasi-harmonic approximation method. Our results showed that the transition pressures of oP6-OsB2 → hP6-OsB2 and hP6-OsB2 → oI12-OsB2 all decreases appreciably with the increase of temperature.

Xiaoyi Yi,1 Xiangyang Zhu,1 Yong Zhou,1 Dongmei Zhang,2 Mengmeng Li,2 Yuting Zhu,1 Xiaoming Guo1 1Deparment of Neurology, Affiliated Hospital 2 of Nantong University, Nantong, People’s Republic of China; 2Clinical Research Center, Affiliated Hospital 2 of Nantong University, Nantong, People’s Republic of ChinaCorrespondence: Xiangyang ZhuDepartment of Neurology, Affiliated Hospital 2 of Nantong University, 6 Haier-Xiang North Road, Nantong, 226000, Jiangsu, People’s Republic of ChinaFax +86 513-85061148Email zhuxxyy2092@163.comPurpose: Previous studies have shown that insulin resistance and inflammation may be associated with the pathophysiological mechanisms of mood disorders. Here, we investigated whether homeostatic model assessment of insulin resistance (HOMA-IR) and serum interleukin-1β (IL-1β) in acute ischemic stroke patients might be associated with post-stroke depression (PSD).Materials and Methods: The prospective study was conducted in China from February 2019 to September 2020. HOMA-IR and clinical data were collected at the time of admission. Serum levels of IL-1β were determined with enzyme-linked immunosorbent assays. Symptoms of depression and anxiety were screened by using the Hamilton Depression and Anxiety Scale at 6 months after stroke, and PSD was diagnosed on the basis of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criteria. The association of potential risk factors with PSD was analyzed with multivariate logistic regression analysis. Finally, the ability of HOMA-IR and IL-1β to predict PSD was assessed with receiver operating characteristic curve.Results: A total of 305 people was included in the study; 65% were male, and the median age was 69.5± 11.8 years. At the 6-month follow-up, 113 patients (37.5%) showed depressive symptoms. In multivariate logistic regression analysis, HOMA-IR and IL-1β as graded variables were associated with an increased risk of PSD (P < 0.05). Receiver operating characteristic curve analysis indicated the highest sensitivity and specificity when the HOMA-IR and IL-1β were 1.96 and 38.71 pg/mL, respectively (P < 0.001). IL-1β improved the ability of HOMA-IR to diagnose PSD combined model area under the curve (AUC): 0.78; 95% CI: 0.72– 0.83; P < 0.001).Conclusion: This study suggests that HOMA-IR and IL-1β are strongly associated with PSD at 6 months after stroke in patients with acute ischemic stroke. These two factors together improve the ability for early PSD assessment.Keywords: insulin resistance, interleukin-1β, acute ischemic stroke, post-stroke depression, inflammation

Jinchun Wu,1 Haiyan Zhou,2 Xiaoping Yi,3 Qiongzhi He,4 Tianxiang Lei,5 Fengbo Tan,5 Heli Liu,5 Bin Li1 1Department of Oncology, Xiangya Hospital, Central South University, Changsha 410008, People’s Republic of China; 2Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, People’s Republic of China; 3Department of Radiology, Xiangya Hospital, Central South University, Changsha 410008, People’s Republic of China; 4Geneplus-Beijing Institute, Beijing, People’s Republic of China; 5Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, People’s Republic of ChinaCorrespondence: Heli Liu; Bin Li Email heliliu@csu.edu.cn; bincsuxy@csu.edu.cnPurpose: NF1-deficient GISTs account for about 1% of gastrointestinal stromal tumors (GISTs) and are usually considered as a subtype of KIT/PDGFRA wild-type GISTs that have no detectable KIT and PDGFRA mutations. Some KIT/PDGFRA wild-type GISTs actually have cryptic KIT mutations (mKIT). So we investigate whether concurrent mKIT existed in NF1-associated GISTs.Patients and Methods: Three independent cohorts were retrospectively analyzed. KIT/PDGFRA wild-type GISTs in Xiangya Hospital between May 2017 and Oct 2019 were investigated by next-generation sequencing (NGS) approach targeted 1021 cancer-related genes regions. GISTs cases in Gene+ dataset from May 2017 to May 2020 were collected from the platform of this company. The genotypes of GISTs in MSKCC cohort were downloaded from cBioPortal.Results: A total of 290 cases including 23 KIT/PDGFRA wild-type GISTs in Xiangya Hospital, 136 GISTs in Gene+ database, and 131 GISTs in MSKCC were enrolled. Twenty-six cases have NF1 mutations (mNF1), and 48% (12/26) of NF1-mutated GISTs have concurrent mKIT. Compared with MSKCC (2/10, 20%), a higher ratio of mKIT in NF1-associated GISTs was detected in Xiangya Hospital (3/5, 60%) and Gene+ (7/11, 64%) (p< 0.05). No mutation hotspot existed in mNF1. Most of mKIT centered within exon 11 (7/12, 58%) and others including exon 17 (3/12, 25%), exon 9(1/12, 8%), exon 13 (1/12, 8%) and exon 21 (1/12, 8%). No differences in age, gender, and location were detected between NF1-related GISTs with mKIT and those without mKIT. Three GIST cases of type I neurofibromatosis, skin neurofibromas and micro-GISTs (≤ 1 cm) were devoid of mKIT, but all the mini-GISTs (1∼ 2 cm) and clinic GIST lesions (> 2 cm) in two cases harbored mKIT.Conclusion: mKIT was not unusual in NF1-associated GISTs, especially in Chinese populations. The gain-of-function mKIT possibly facilitated the progression of NF1-deficient lesions to clinic GISTs, however, the underlying mechanism warrants further studies.Keywords: gastrointestinal stromal tumor, NF1, KIT, deep sequencing

Binbin Deng,1,* Jianyong Deng,1,* Xuan Yi,1 Yeqing Zou,2 Chen Li1 1Department of Orthopedics, Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 2Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chen LiDepartment of Orthopedics, Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, Jiangxi Province 330006, People’s Republic of ChinaEmail tanzikoulc@163.comYeqing ZouJiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, Jiangxi Province 330006, People’s Republic of ChinaEmail zouyeqing3366@163.comBackground: Osteosarcoma (OS) is a malignant bone tumour that exhibits a high mortality. While tumours thrive in a state of malnutrition, the mechanism by which OS cells adapt to metabolic stress through metabolic reprogramming remains unclear.Methods: We analysed the expression of ROCK2 in osteosarcoma tissues by RT-qPCR and Western blot. Cell proliferation were analysed using CCK8, EdU and colony formation assays. The level of cell glycolysis was detected by glucose-6 phosphate, glucose consumption, lactate production and ATP levels.Results: Herein, our study showed that ROCK2 expression in OS tissues was higher than in adjacent tissues. Functional assays have demonstrated that ROCK2 contributes to the growth of OS cells by inducing aerobic glycolysis. The current study revealed that ROCK2 knockdown decreased the levels of mitochondrial hexokinase II (HKII). And also indicated that ROCK2 served as a key enzyme in glycolysis and that it served an important role in tumour growth. A significant positive correlation was identified between the mRNA and protein expressions of ROCK2 and HKII, further demonstrating that ROCK2-induced glycolysis and proliferation was dependent on HKII expression in OS cells. Mechanistically, ROCK2 promotes HKII expression by activating the phospho-PI3K/AKT signalling pathway.Conclusion: Taken together, the results of the current study linked the two drivers of OS growth and aerobic glycolysis and identified a new mechanism of ROCK2 control in OS.Keywords: ROCK2, HKII, osteosarcoma, proliferation, glycolysis

Yu Wang, Hao Zhang, Min Zhou, Xinzeyu Yi, Ping Duan, Aixi Yu, Baiwen Qi Department of Orthopaedic Trauma and Microsurgery, Wuhan University Zhongnan Hospital, Wuhan, Hubei 430071, People’s Republic of ChinaCorrespondence: Aixi Yu; Baiwen QiWuhan University Zhongnan Hospital, 169 East Lake Road, Wuchang District, Wuhan, Hubei 430071, People’s Republic of ChinaTel/Fax +86 67813120Email yuaixi@whu.edu.cn; wb002162@whu.edu.cnBackground: Diabetic skin defect is difficult to manage in surgical clinics, and there is still lack of effective treatments for diabetic skin defects. Currently, autologous fat grafting (AFG) is promising in the field of reconstructive surgery, while macrophage infiltration in autologous adipose tissue is considered vital for tissue regeneration. But AFG is rarely applied to the treatment of diabetic skin defects, and whether macrophage infiltration assists AFG to promote wound healing is still unknown.Methods: Full-thickness skin defect diabetic rats were divided into 3 groups: control group, autologous fat grafting (AFG) group and AFG with macrophage depletion (AFG+MD) group. We examined the amount of macrophages in the wounds bed and the expression level of inflammatory factors IL-10, IL-6, TNF-α, and also growth factors PDGF-β, TGF-β, IGF-1 at the same time. The content of collagen-I and α-smooth muscle actin protein in the wounds were determined by Western blot analysis. Finally, the healing of the wounds was evaluated.Results: The AFG group showing more rapid healing, secreting more growth factors and more obvious vascularization in the healing process, compared with the control group. But, the secretion of growth factors and the construction of extracellular matrix (ECM) in the wounds were limited when macrophages were depleted after AFG.Conclusion: AFG promotes the infiltration of macrophages to improve the healing environment of diabetic wounds by increasing the secretion of growth factors and revascularization, which provides a potential method for the treatment of diabetic skin defects.Keywords: diabetic skin defects, autologous fat grafting, wound healing, macrophage depletion

Xu Chen,1,2 Kai Ma,3 Xu Yi,1 Ziyu Xiao,4 Lijuan Xiong,3 Yu Wang,5 Shijun Li2 1Central Laboratory of the Second Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou 550003, People’s Republic of China; 2Laboratory of Bacterial Infectious Disease of Experimental Centre, Guizhou Provincial Centre for Disease Control and Prevention, Guiyang, Guizhou 550004, People’s Republic of China; 3Clinical Laboratory Centre of the Second Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou 550003, People’s Republic of China; 4School of Public Health, Guizhou Medical University, Guiyang, Guizhou 550025, People’s Republic of China; 5Department of Clinical Laboratory Centre, The First People’s Hospital of Guiyang, Guiyang, Guizhou 550004, People’s Republic of ChinaCorrespondence: Shijun LiExperimental Centre, Guizhou Provincial Centre for Disease Control and Prevention, 115 Bageyan Road, Guiyang, Guizhou 550004, People’s Republic of ChinaTel/Fax +86 851 86824290Email zjumedjun@163.comBackground: Enterococcus faecalis, an opportunistic bacterial pathogen, is one of the most frequently isolated bacterial species and cause of serious nosocomial infections in recent decades. A reliable and rapid assay for E. faecalis detection is significant for the diagnosis and follow-up treatment.Methods: A novel assay method, named multiple cross displacement amplification linked with nanoparticle-based lateral flow biosensor (MCDA-LFB), was applied for detecting E. faecalis strains. A set of special 10 primers was designed according to E. faecalis-specific gene Ef0027. The MCDA amplification conditions, including the target DNA concentration, reaction temperature and time, were optimized. The sensitivity and specificity of MCDA method were tested in the current study, and then, the MCDA-LFB technology was applied to detect the E. faecalis strain from clinical samples.Results: The E. faecalis specific primers were valid for the establishment of MCDA-LFB technology forthe detection of E. faecalis based on the Ef0027 gene. The MCDA amplification condition was optimized at 62°C for 35 min. The MCDA products were directly sensed and displayed with a biosensor. The full process, comprising genomic DNA template preparation (approximately 30 mins), amplification of MCDA (35 mins), and the product identification (approximately 2 mins), could be achieved in 70 mins. The MCDA technique could detect as little as 10 fg per reaction system of pure E. faecalis genomic DNA. The specificity of E. faecalis-MCDA-LFB method is 100%, with no cross-reactions to non-E. faecalis strains.Conclusion: The MCDA-LFB technique established in the present study is a reliable, simple, rapid, sensitive and specific method to assay E. faecalis and can be applied for the detection of clinical samples.Keywords: Enterococcus faecalis, limit of detection, multiple cross displacement amplification, gold nanoparticle, lateral flow biosensor, MCDA-LFB

Ning Xia,1,2 Ke Liu,1 Yingying Zhou,1 Yuanyuan Li,1 Xinyao Yi2 1Key Laboratory of New Optoelectronic Functional Materials, College of Chemistry and Chemical Engineering, Anyang Normal University, Anyang, 2College of Chemistry and Chemical Engineering, Central South University, Changsha, China Abstract: miRNAs have emerged as new biomarkers for the detection of a wide variety of cancers. By employing duplex-specific nuclease for signal amplification and gold nanoparticles (AuNPs) as the carriers of detection probes, a novel electrochemical assay of miRNAs was performed. The method is based on conversion of the well-known colorimetric assay into electrochemical analysis with enhanced sensitivity. DNA capture probes immobilized on the electrode surface and ferrocene (Fc)-labeled DNA detection probes (denoted “Fc-DNA-Fc”) presented in the solution induced the assembly of positively charged AuNPs on the electrode surface through the electrostatic interaction. As a result, a large number of Fc-DNA-Fc molecules were attached on the electrode surface, thus amplifying the electrochemical signal. When duplex-specific nuclease was added to recycle the process of miRNA-initiated digestion of the immobilized DNA probes, Fc-DNA-Fc-induced assembly of AuNPs on the electrode surface could not occur. This resulted in a significant fall in the oxidation current of Fc. The current was found to be inversely proportional to the concentration of miRNAs in the range of 0–25 fM, and a detection limit of 0.1 fM was achieved. Moreover, this work presents a new method for converting colorimetric assays into sensitive electrochemical analyses, and thus would be valuable for design of novel chemical/biosensors. Keywords: microRNA, duplex-specific nuclease, gold nanoparticle, signal amplification, electrochemical biosensor, colorimetric assay

Circular RNAs (CircRNAs) are a type of non-coding RNAs, which contain a covalently closed loop structure without 5′ to 3′ free ends. CircRNAs play essential roles in the regeneration of secondary hair follicle (SHF) and cashmere growth in goats. CircRNA-1926 was previously identified in SHF of cashmere goats, but its potential roles are unclear. In this study, we confirmed the expression of circRNA-1926 in SHF bulge of nine cashmere goats with a significantly higher level at anagen than that of telogen. Through the use of both overexpression and siRNA interference, we showed that circRNA-1926 promoted the differentiation of SHF stem cell into hair follicle lineage in cashmere goats which was evaluated via indictor genes Keratin 7 and Keratin 17. Using RNA pull-down, we found that circRNA-1926 bound with miR-148a/b-3p. Additionally, our data indicated that circRNA-1926 promoted the expression of the CDK19 gene. Using dual-luciferase reporter assays, it was revealed that circRNA-1926 positively regulated the CDK19 expression through miR-148a/b-3p. The results from this study demonstrated that circRNA-1926 contributes the differentiation of SHF stem cells into hair follicle lineages in cashmere goats via sponging miR-148a/b-3p to enhance CDK19 expression.

Seed traits affect seed dispersal by animals. However, the combined role of seeds and dispersers in determining seed dispersal is not well explored. We attempted to test how seed traits and predators determine seed dispersal and predation interaction in a rodent-mediated seed dispersal system. Semi-natural enclosure experiments were conducted to investigate seed dispersal and predation of five sympatric tree species with different seed traits, Juglans mandshurica, Quercus mongolica, Pinus koraiensis, Corylus mandshurica and C. heterophylla by three rodent species, Apodemus peninsulae, Tamias sibiricus and Clethrionomys rufocanus showing different body sizes, hoarding behaviors and activity rhythms. Our results demonstrated that seed species with thick coat were removed more slowly than thin-coated seeds in regardless of rodent species, reflecting a consistent negative effect of seed coat on seed dispersal. Seeds with thick coat were less likely to be eaten both in situ and after removal by small rodents. Seeds with high caloric value were more likely to be larder-hoarded, whereas seed traits showed no influence on scatter-hoarding. Rodent species with large body size tended to eat more seeds in situ, while small-sized rodents preferred to eat seeds after removal. Large-sized rodent species scatter-hoarded more seeds, however, small-sized rodents larder-hoarded more seeds. Seeds with thick coat showed high mutualism but low predation with rodents, while rodents with large size showed low mutualism but high predation with seeds. Our results indicate that both seeds and predators play important roles in determining seed dispersal and predation in the seed-rodent dispersal system.