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Jinhong Zuo,* Xiayang Zeng,* Hongyi Ma, Peng Chen, Xinlei Cai, Zhenyu Fan, Jianpeng Qu Massage Department, Zhejiang Hospital, Hangzhou City, People’s Republic of China*These authors contributed equally to this work and co-first authorsCorrespondence: Jianpeng Qu, Massage Department, Zhejiang Hospital, No. 12 Lingyin Road, Xihu District, Hangzhou City, 310000, People’s Republic of China, Email qjp0007@126.comBackground: Neck-type cervical spondylopathy (NTCS), a common degenerative disorder affecting the spine, poses challenges for patients and society. Research has demonstrated the effectiveness of traditional tuina techniques in treating NTCS, although some limitations still exist. Our study aimed to evaluate the effectiveness of combining regular massage techniques with three methods of neck movement (TCM) therapy for managing NTCS, utilizing musculoskeletal ultrasound measurements.Patients and Methods: In this study, 70 eligible patients with non-traumatic cervical spondylosis will be randomly assigned in a 1:1 ratio to either the experimental group, which will receive Tuina combined with a three-method neck movement treatment, or the control group, which will receive standard Tui Na manipulation. All participants will receive treatment for four weeks. Assessments will be conducted using musculoskeletal ultrasound, the McGill Pain Scale, and the Neck Disability Index (NDI) at three-time points: before treatment, at the end of treatment, and after 12 and 16 weeks of treatment.Conclusion: This paper investigates the utility of musculoskeletal ultrasound as a tool for evaluating the therapeutic efficacy of an integrated Traditional Chinese Medicine (TCM) strategy in alleviating pain and enhancing functional outcomes for patients with NTCS. The objective is to present a clinically viable and long-term treatment option.Trial Registration: Chinese Clinical Trial Registry, ChiCTR2300072648. Registered on June 20, 2023.Keywords: neck-type cervical spondylopathy, randomized controlled trial, therapeutic neck movement techniques, musculoskeletal ultrasonography

Dan-Dan Wang,1,2,* Meng-Ke Song,1,3,* Qin Yin,1,2 Wen-Gang Chen,2 Opeyemi Joshua Olatunji,4 Kui Yang,3 Jian Zuo1,3,5 1Xin’an Medicine Research Center, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China; 2Department of Pharmacy, the Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China; 3Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, People’s Republic of China; 4African Genome Center, Mohammed VI Polytechnic University, Ben Guerir, 43150, Morocco; 5Anhui Province Key Laboratory of Non-Coding RNA Basic and Clinical Transformation, Wannan Medical College, Wuhu, 241000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kui Yang; Jian Zuo, Email ykui15556689670@163.com; zuojian8178@163.comBackground: Nicotinamide adenine dinucleotide (NAD)-dependent deacetylase SIRT1 regulates both metabolism and immune functions. This study investigated if SIRT1 inhibitory property of herbal formula Qing-Luo-Yin (QLY) contributed to its anti-rheumatic effects.Methods: Adjuvant-induced arthritis (AIA) rats were treated by QLY and nicotinamide mononucleotide (NMN, a biosynthesis precursor of NAD) for 38 days. After sacrifice, blood, paws, liver and white adipose tissues (WAT) were collected. Pre-adipocytes were cultured by the rats’ serum. The medium was used for monocytes culture. Some pre-adipocytes were treated by QLY-derived SIRT1 inhibitors. SIRT1 was silenced or overexpressed beforehand. The samples were subjected to kits-based quantification, polymerase-chain reaction, western-blot, immunofluorescence, and histology experiments.Results: AIA rats experienced significant fat loss in liver and WAT. Expression of many SIRT1-related signals like PPARγ, PGC-1α, HSL, ATGL and CPT-1A were altered. QLY attenuated all these abnormalities and joint injuries. By pan-acetylation up-regulation, visfatin was obviously reduced in QLY-treated AIA rats’ blood (from 191.8 to 127.0 pg/mL). NMN sustained SIRT1 activation by replenishing NAD, and weakened these effects. QLY-containing serum and the related compounds showed similar impacts on pre-adipocytes, resembling the changes in QLY-treated AIA rats’ WAT. These treatments suppressed AIA serum-induced visfatin secretion (from 49.3 to 36.1 and 30.7 pg/mL). This effect was impaired by SIRT1 overexpression. The medium from the compounds-treated pre-adipocytes impaired NF-κB activation in AIA serum-cultured monocytes.Conclusion: Besides fat depletion, SIRT1 up-regulation in rheumatic subjects’ WAT promotes visfatin production, and exacerbates inflammation. SIRT1 inhibition in WAT is an anti-rheumatic way of QLY independent of immune regulation.Keywords: visfatin, PPARγ, rheumatoid arthritis, Traditional Chinese Medicine, adipocyte

Yongjun Huang,1,* Yong Chen,2,* Guoyun Cheng,1,* Wenqiang Li,3 Hongan Zhang,1,4 Chaoqun Yu,1 Jia Fang,1 Jieyi Zuo,1 Ying Li,1 Lei Xu,1 Dawei Sun1 1Department of Orthopedics, Guangdong Second Provincial General Hospital, Guangzhou, 510317, People’s Republic of China; 2Department of Orthopedics, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, People’s Hospital, Qingyuan, 511518, People’s Republic of China; 3Engineering Technology Research Center for Sports Assistive Devices of Guangdong, Guangzhou Sport University, Guangzhou, 510500, People’s Republic of China; 4The Second Clinical School of Medicine, Southern Medical University, Guangzhou, 510260, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lei Xu; Dawei Sun, Department of Orthopedics, Guangdong Second Provincial General Hospital, 11th Floor, Building 3, No. 466, Xingang Middle Road, Guangzhou, Guangdong Province, 510317, People’s Republic of China, Email orthoxl@163.com; sundw@gd2h.org.cnBackground: As the first line of immune defense and the largest organ of body, skin is vulnerable to damage caused by surgery, burns, collisions and other factors. Wound healing in the skin is a long and complex physiological process that is influenced by a number of different factors. Proper wound care can greatly improve the speed of wound healing and reduce the generation of scars. However, traditional wound dressings (bandages, gauze, etc.) often used in clinical practice have a single function, lack of active ingredients and are limited in use. Hydrogels with three-dimensional network structure are a potential biomedical material because of their physical and chemical environment similar to extracellular matrix. In particular, hydrogel dressings with low price, good biocompatibility, degradability, antibacterial and angiogenic activity are favored by the public.Methods: Here, a carboxymethyl chitosan-based hydrogel dressing (CMCS-TA/Cu2+) reinforced by copper ion crosslinked tannic acid (TA/Cu2+) nanoparticles was developed. This study investigated the physical and chemical characteristics, cytotoxicity, and angiogenesis of TA/Cu2+ nanoparticles and CMCS-TA/Cu2+ hydrogels. Furthermore, a full-thickness skin defect wound model was employed to assess the in vivo wound healing capacity of hydrogel dressings.Results: The introduction of TA/Cu2+ nanoparticles not only could increase the mechanical properties of the hydrogel but also continuously releases copper ions to promote cell migration (the cell migration could reach 92% at 48 h) and tubule formation, remove free radicals and promote wound healing (repair rate could reach 90% at 9 days).Conclusion: Experiments have proved that CMCS-TA/Cu2+ hydrogel has good cytocompatibility, antioxidant and wound healing ability, providing an advantageous solution for skin repair. Keywords: TA/Cu2+ nanoparticles, carboxymethyl chitosan, wound dressing, antioxidant activity

MinChao Feng,1,* Fang Luo,1,* HuiMin Wu,1 Yushan Chen,1 Jinjin Zuo,1 Xueying Weng,1 Guozhong Chen,2 Jian Zhong3 1The First Clinical Medical College, Guangxi University of Traditional Chinese Medicine, Nannig, People’s Republic of China; 2Department of Gastroenterology, the First Affiliated Hospital of Guangxi University of Traditional Chinese Medicine, Nanning, People’s Republic of China; 3Department of Nephrology, the First Affiliated Hospital of Guangxi University of Traditional Chinese Medicine, Nanning, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jian Zhong, Department of Nephrology, the First Affiliated Hospital of Guangxi University of traditional Chinese Medicine, No. 89-9, Dong Ge Lu, Xixiangtang District, Nanning, 530023, People’s Republic of China, Tel +86-18677920877, Email 18922005825@163.comPurpose: YiShen HuoXue decoction (YSHXD) is a formulation that has been used clinically for the treatment of renal fibrosis (RF) for many years. We aimed to clarify therapeutic effects of YSHXD against RF and potential pharmacological mechanisms.Materials and Methods: We used network pharmacology analysis and machine-learning to screen the core components and core targets of YSHXD against RF, followed by molecular docking and molecular dynamics simulations to confirm the reliability of the results. Finally, we validated the network pharmacology analysis experimentally in HK-2 cells and a rat model of RF established by unilateral ureteral ligation (UUO).Results: Quercetin, kaempferol, luteolin, beta-sitosterol, wogonin, stigmasterol, isorhamnetin, baicalein, and dihydrotanshinlactone progesterone were identified as the main active components of YSHXD in the treatment of unilateral ureteral ligation-induced RF, with IL-6, IL1β, TNF, AR, and PTGS2 as core target proteins. Molecular docking and molecular dynamics simulations further confirmed the relationship between compounds and target proteins. The potential molecular mechanism of YSHXD predicted by network pharmacology analysis was confirmed in HK-2 cells and UUO rats. YSHXD downregulated NLRP3, ASC, NF-κBp65, Caspase-1, GSDMD, PTGS2, IL-1β, IL-6, IL-18, TNF-α, α-SMA and upregulated HGF, effectively alleviating the RF process.Conclusion: YSHXD exerts important anti-inflammatory and anti-cellular inflammatory necrosis effects by inhibiting the NLRP3/caspase-1/GSDMD-mediated pyroptosis pathway, indicating that YSHXD represents a new strategy and complementary approach to RF therapy.Graphical Abstract: Keywords: pyroptosis, YiShen HuoXue decoction, renal fibrosis, molecular docking simulation, machine-learning

Xiu-Ping Cheng,1,2,* Xiao-Wan Wang,3,* Han-Fei Sun,4,* Liang Xu,3 Opeyemi Joshua Olatunji,5 Yan Li,1,2,6 Jia-Ting Lin,2,7 Jian Zuo1,2,6 1Xin’an Medicine Research Center, the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China; 2Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, People’s Republic of China; 3Department of Rheumatology, the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China; 4Department of Pharmacy, the Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China; 5African Genome Center, Mohammed VI Polytechnic University, Ben Guerir, 43150, Morocco; 6Center for Xin’an Medicine and Modernization of Traditional Chinese Medicine, Institution of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, 230000, People’s Republic of China; 7Department of Stomatology, the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jia-Ting Lin; Jian Zuo, Email 20141247@wnmc.edu.cn; zuojian8178@163.comBackground: Rheumatoid arthritis (RA) patients are prone to developing different metabolic complications. Traditional Chinese Medicine attributes this uncertainty to varied syndrome types.Methods and Results: We retrospectively analyzed some serological indicators of active RA patients and healthy individuals. Randomly selected RA patients were divided into three groups according to NAMPT and SIRT1 expression levels in white blood cells (WBCs). Their disease severity and metabolic status were compared. Representative blood samples were subjected to a UPLC-MS/MS-based metabolomics analysis. Different human WBCs were treated with oleic acid and palmitic acid in vitro. The results indicated that blood glucose and lipid levels were decreased in RA patients, but their decrease was not in accordance with disease severity. Nutrients in the patients highly expressing SIRT1 were well preserved, with the lowest levels of RF and β-CTX and the highest levels of adiponectin and resistin. Most of them exhibited cold symptoms. When SIRT1 deficiency was obvious, lipid depletion became evident, irrespective of expression levels of NAMPT. Simultaneous high-expression of SIRT1 and NAMPT coincided with the increase in production of lactic acid and the prevalence of hot symptoms. Despite the low levels of IL-6, joint injuries were severe. The corresponding WBCs were especially sensitive to fatty acids anti-inflammatory treatments. The levels of CCL27, CCL11, CCL5, AKP, CRP and ESR were similar among all the groups.Conclusion: NAMPT overexpression is a risk factor for joint injuries and nutrient depletion in RA. Supplementation with lipids would exert beneficial effects on these RA patients. Its aftermath would cause even severe inflammation. Contrarily, SIRT1 up-regulation restrains inflammation and lipid depletion.Keywords: rheumatoid arthritis, inflammation, energy metabolism, blood glucose, lipids, joint damage

Zhiyong Tan,1– 3,* Xiaorong Chen,4,* Jieming Zuo,1– 3,* Shi Fu,1– 3,* Jiansong Wang,1– 3 Haifeng Wang1– 3 1Department of Urology, the Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 2Urological Disease Clinical Medical Center of Yunnan Province, the Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 3Scientific and Technological Innovation Team of Basic and Clinical Research of Bladder Cancer in Yunnan Universities, the Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 4Department of Kidney Transplantation, the Third Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiansong Wang; Haifeng Wang, Department of Urology, the Second Affiliated Hospital of Kunming Medical University, Yunnan Institute of Urology, Kunming, 650101, People’s Republic of China, Email wangjiansong@kmmu.edu.cn; t13085348360@163.comBackground: As known abnormal sialylation exerts crucial roles in the growth, metastasis, and immune evasion of cancers, but the molecular characteristics and roles in bladder cancer (BLCA) remain unclear. This study intends to establish BLCA risk stratification based on sialylation-related genes and elucidate its role in prognosis, tumor microenvironment, and immunotherapy of BLCA.Methods: Bulk RNA-seq and scRNA-seq data were downloaded from open-access databases. The scRNA-seq data were processed using the R package “Seurat” to identify the core cell types. The tumor sub-typing of BLCA samples was performed by the R package “ConsensusClusterPlus” in the bulk RNA-seq data. Signature genes were identified by the R package “limma” and univariate regression analysis to calculate risk scores using the R package “GSVA” and establish risk stratification of BLCA patients. Finally, the differences in clinicopathological characteristics, tumor microenvironment, and immunotherapy efficacy between the different groups were investigated.Results: 5 core cell types were identified in the scRNA-seq dataset, with monocytes and macrophages presenting the greatest percentage, sialylation-related gene expression, and sialylation scores. The bulk RNA-seq samples were classified into 3 tumor subtypes based on 19 prognosis-related sialylation genes. The 10 differential expressed genes (DEGs) with the smallest p-values were collected as signature genes, and the risk score was calculated, with the samples divided into high and low-risk score groups. The results showed that patients in the high-risk score group exhibited worse survival outcomes, higher tumor grade, more advanced stage, more frequency of gene mutations, higher expression levels of immune checkpoints, and lower immunotherapy response.Conclusion: We established a novel risk stratification of BLCA from a glycomics perspective, which demonstrated good accuracy in determining the prognostic outcome, clinicopathological characteristics, immune microenvironment, and immunotherapy efficacy of patients, and we are proposing to apply it to direct the choice of clinical treatment options for patients.Keywords: bladder cancer, bulk RNA-seq, scRNA-seq, sialylation, tumor microenvironment, immunotherapy

Xiaodan Wang,1,* Weiping Deng,1,* Jiehui Zhao,2,* Yongchao Guo,3 Haifang Lai,4 Yueliang Hu,5 Wenyan Kang,1 Yong Li,6– 8 Junli Zuo5 1Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China; 2Department of General Practice, Daning Community Health Service Center, Shanghai, 200072, People’s Republic of China; 3Department of Nutrition, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China; 4Department of Rehabilitation Medicine Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China; 5Department of Geriatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China; 6Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China; 7Institute of Respiratory Disease, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 8Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Disease, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Junli Zuo; Yong Li, Email zjl12616@rjh.com.cn; bangliyong@163.comBackground: Nutrition is an important prevention in old patients with COVID-19. However, in China, there are few studies on the correlation between nutrition and COVID-19.Methods: A total of 148 hospitalized COVID-19 (65.7 ± 16.0 [range: from 21 to 101] years old) patients were enrolled in this study. The information of demographic, biochemical results, vaccination doses, types of COVID-19, PCR test negative conversion time, and scores of Mini Nutritional Assessment Short Form (MNA-SF) for evaluating nutritional status were recorded. We first explored the relationships between MNA-SF performance and the severities of COVID-19 in the groups with non-vaccinated, vaccinated, and all the patients using multivariable ordinal logistic regression. Further, we explored the relationships between performance of MNA-SF and the time of negative conversion of PCR in the groups with non-vaccinated, vaccinated, and all the patients using COX proportional hazards survival regression.Results: Group of patients with malnutrition or at risk of malnutrition group was associated with older of the age, those who had not been vaccinated, in fewer people who were asymptomatic type and in more people who showed longer of the negative conversion time of PCR, lower of the BMI, and the lower of the hemoglobin level. Each additional increase of one point of MNA-SF was associated with a 17% decrease in the odds of a worse type of COVID-19 in all patients, and the significant result exists in non-vaccinated patients. One point increase of MNA-SF was associated with increased 11% of hazard ratios of turning negative of PCR and well-nourished group was associated with increased 46% of hazard ratio of turning negative of PCR.Conclusion: Higher nutrition is associated with less severity of COVID-19, especially in the non-vaccinated group. Higher nutrition is also associated with shorter time of turning negative of PCR in non-ICU COVID-19 patients.Keywords: COVID-19, nutrition, MNA-SF, vaccination

Ting-Ting Luo,1,2,* Yi-Jin Wu,1,2,* Qin Yin,1 Wen-Gang Chen,1 Jian Zuo2,3 1Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China; 2Xin’an Medical Research Center, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China; 3Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jian Zuo, Email zuojian8178@163.comAbstract: Obviously, immune cells like T cells and macrophages play a major role in rheumatoid arthritis (RA). On one hand, the breakdown of immune homeostasis directly induces systemic inflammation; on the other hand, these cells initiate and perpetuate synovitis and tissue damages through the interaction with fibroblast-like synoviocytes (FLS). In recent years, the pathological link between metabolic disorders and immune imbalance has received increasing attention. High energy demand of immune cells leads to the accumulation of metabolic byproducts and inflammatory mediators. They act on various metabolism-sensitive signal pathways as well as relevant transcription factors, such as HIF-1α, and STATs. These molecular events will impact RA-related effectors like circulating immune cells and joint-resident cells in return, allowing the continuous progression of systemic inflammation, arthritic manifestations, and life-threatening complications. In other words, metabolic complications are secondary pathological factors for the progression of RA. Therefore, the status of energy metabolism may be an important indicator to evaluate RA severity, and in-depth explorations of the mechanisms underlying the mystery of how RA-related metabolic disorders develop will provide useful clues to further clarify the etiology of RA, and inspire the discovery of new anti-rheumatic targets. This article reviews the latest research progress on the interactions between immune and metabolism systems in the context of RA. Great importance is attached to the changes in certain pathways controlling both immune and metabolism functions during RA progression.Keywords: rheumatoid arthritis, metabolism, inflammation, immune cells

Dan Li, Jiayin Liu, Xue Zhang, Jing Han, Hui Jin, Long Wang, Li Feng, Zhisong Fan, Jing Zuo, Yudong Wang Department of Medical Oncology, The Fourth Hospital of Hebei Medical University and Hebei Provincial Tumor Hospital, Shijiazhuang, People’s Republic of ChinaCorrespondence: Yudong Wang, Department of Medical Oncology, The Fourth Hospital of Hebei Medical University and Hebei Provincial Tumor Hospital, 12 Jiankang Road, Shijiazhuang, People’s Republic of China, Tel +86 15931166600, Email 15931166600@126.comBackground: Lorlatinib has been suggested as the therapeutic option for patients with ROS1-rearranged non-small-cell lung cancer (NSCLC) after ROS1 tyrosine kinase inhibitor (TKI) failure. However, the mechanism mediating lorlatinib resistance has not been well elucidated in ROS1-rearranged NSCLC. Post- lorlatinib therapeutic options remain scarce.Case Presentation: Herein, we describe a 31-year-old female patient with stage IVB ROS1-rearranged NSCLC. She received 2nd line treatment with crizotinib after chemotherapy failure and achieved a partial response lasting for 15 months. An NF1 p.G127Ter mutation emerged as a potential crizotinib resistance mechanism. She subsequently received lorlatinib treatment and achieved a progression-free survival (PFS) of seven months. Based on the emergence of a resistant BRAF V600E, the patient was switched to a combinatorial targeted therapy with lorlatinib, dabrafenib, and trametinib and attained stable disease. She continued the treatment with a time-to-treatment failure of 5.5 months. The acquisition of NRAS p.Q61R and NTRK amplification may confer resistance to the combinatorial targeted therapy.Conclusion: To the best of our knowledge, we reported the first case demonstrating that BRAF p.V600E can mediate the lorlatinib resistance in ROS1-rearranged NSCLC and the combinational targeted therapy of ROS1 TKI with dabrafenib and trametinib may serve as an efficient therapeutic option for subsequent treatment.Keywords: NSCLC, ROS1 rearrangement, BRAF V600E, lorlatinib combined with dabrafenib and trametinib, case report

Dan-Dan Wang,1,2,* Chi-Yi He,3,* Yi-Jin Wu,1,2 Liang Xu,4 Chao Shi,1 Opeyemi Joshua Olatunji,5 Jian Zuo,1,6,7 Cong-Lan Ji8 1Xin’an Medicine Research Center, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China; 2The Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, People’s Republic of China; 3Department of Gastroenterology, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China; 4Department of Rheumatology, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China; 5Traditional Thai Medical Research and Innovation Center, Faculty of Traditional Thai Medicine, Prince of Songkla University, Hat Yai, 90110, Thailand; 6Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241000, People’s Republic of China; 7Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Wuhu, 241000, People’s Republic of China; 8School of Pharmacy, Anhui College of Traditional Chinese Medicine, Wuhu, 241000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Cong-Lan Ji; Jian Zuo, Email 37709103@qq.com; zuojian8178@163.comBackground: Exact roles of many metabolic regulators in rheumatoid arthritis (RA) are to be clarified. This study aimed to further characterize the impacts of silent information regulator 1 (SIRT1) status changes on this disease.Methods: Fluctuation pattern of SIRT1 expression in adjuvant-induced arthritis (AIA) rats was monitored using periodically collected white blood cells. Another bath of AIA rats were treated by SIRT1 agonist resveratrol. Blood from these rats was used to separate monocytes and plasma, which were subjected to polymerase chain reaction (PCR), enzyme linked immunosorbent assay (ELISA), and biochemical analyses. Clinical implication of SIRT1 activation was verified by treating AIA rat monocytes with SIRT1 agonist and overexpression vector in vitro.Results: SIRT1 deficiency occurred in AIA rats, which was accompanied with down-regulation of interleukin 10 (IL-10) and arginase-1 (ARG-1). Resveratrol eased oxidative stress and increased IL-10 production in vivo. Results of ELISA analysis demonstrated that resveratrol attenuated AIA severity in rats. Furthermore, it restored the altered levels of triglyceride, lactate and pyruvate in blood. Resveratrol promoted IL-10 production, and suppressed glycolysis of AIA monocytes cultured in vitro. SIRT1 overexpression similarly reshaped differentiation profile of AIA monocytes, evidenced by changes in metabolism indicators, IL-10 production and AMP-activated protein kinase (AMPK) pathway status. Although overexpressing SIRT1 in normal cells did not affect glycolysis significantly, it attenuated AMPK antagonist-caused abnormality.Conclusion: SIRT1 deficiency is implicated in AIA-related immune abnormality and metabolism alteration. Activating this signaling with resveratrol would impair the inflammatory polarization of monocytes, and consequently ease the severity of RA.Keywords: inflammation, metabolic reprogramming, monocytes, resveratrol, rheumatoid arthritis

Wei Wei,1,2,* Yongli Pan,2,3,* Xinyu Yang,4 Zhonglun Chen,1 Yue Heng,1 Bufan Yang,1 Mingjun Pu,1 Jiacai Zuo,1 Zhuhong Lai,5 Yufeng Tang,1 Wenqiang Xin2,4 1Department of Neurology, Mianyang Central Hospital, Mianyang, Sichuan, People’s Republic of China; 2Department of Neurology, University Medical Center of Göttingen, Georg-August-University of Göttingen, Göttingen, Lower Saxony, Germany; 3Department of Neurology, Weifang Medical University, Weifang, Shandong, People’s Republic of China; 4Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 5Department of Cardiology, Mianyang Central Hospital, Mianyang, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenqiang Xin, Department of Neurosurgery, Tianjin Medical University General Hospital, Anshan Road No. 154, Tianjin, 300052, People’s Republic of China, Tel +86– 18526201182, Fax +86– 2260362062, Email xinwenqiangdr@126.com Wei Wei, Department of Neurology, Mianyang Central Hospital, Changjia Lane No. 12, Mianyang, 621000, People’s Republic of China, Tel +86– 15983634286, Fax +86-8162222566, Email weiwei1990sci@163.comAbstract: Eukaryotic cells release different types of extracellular vesicles (EVs), including exosomes, apoptotic bodies and microvesicles. EVs carry proteins, lipids and nucleic acids specific to cells and cell states. Autophagy is an intracellular degradation process, which, along with EVs, can significantly affect the development and progression of neurological diseases and, therefore, has been the hotspot. Generally, EVs and autophagy are closely associated. EVs and autophagy can interact with each other. On the one hand, the level of autophagy in target cells is closely related to the secretion and transport of EVs. In another, the application of EVs provides a great opportunity for adjuvant treatment of neurological disorders, for which autophagy is an excellent target. EVs can release their cargos into target cells, which, in turn, regulate the autophagic level of target cells through autophagy-related proteins directly and the non-coding RNA, signal transducer and activator of transcription 3 (STAT3), phosphodiesterase enzyme (PDE) 1-B, etc. signaling pathways indirectly, thus regulating the development of related neurological disorders.Keywords: extracellular vesicle, autophagy, neurological disorders, non-coding RNA, STAT3, PDE1-B

Yanfei Miao,1 Shihua Zhao,1 Jian Zuo,1 Jiqin Sun,1 Jingnan Wang2 1College of Chemistry and Chemical Engineering, Taishan University, Tai’an, People’s Republic of China; 2School of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, People’s Republic of ChinaCorrespondence: Yanfei Miao, College of Chemistry and Chemical Engineering, Taishan University, Tai’an 271000, People’s Republic of China, Tel/Fax +86-0538-6713958, Email ouyang_miaoyanfei@126.comPurpose: The purpose of this work was to develop an ivacaftor self-nanoemulsion drug delivery system (IVA-SNEDDS) using the newly developed double headed miscellaneous lipid (DHML) as oil phase to reduce the food effect and inter-individual absorption variability of IVA.Methods: The lipids with the greatest solubility to IVA were selected as the oil phase of IVA-SNEDDS by saturation solubility method. Then, among different surfactants and co-surfactants, those with good emulsifying ability for the selected oil phase were selected, and the proportion of surfactant and co-surfactant was further selected by pseudo-ternary phase diagram. The prepared IVA-SNEDDS were screened and evaluated in vitro and in beagle dogs.Results: The optimized IVA-SNEDDS formulation consisting of DHML, Tween 80, and Transcutol HP with the weight ratio of 2:2:1 was physically stable and it was easy to disperse in water, pH 1.2 hydrochloric acid and pH 6.8 phosphate buffer solution, and generated a fine homogeneous nanoemulsion, with mean globule size less than 75 nm regardless of dilution ratio. In vitro drug release studies showed that the drug in IVA-SNEDDS could be completely released in a short time, while the drug release in IVA-suspension was less than 1% at 60 min. In vivo, using IVA-suspension (Fed) as a reference, the relative oral bioavailability of IVA-suspension (Fasted), IVA-SNEDDS (Fasted), and IVA-SNEDDS (Fed) were 23.35%, 153.63%, and 149.89%, respectively. This showed that IVA-SNEDDS could eliminate the positive food effect, improve the oral bioavailability, and reduce the IVA absorption difference between individuals.Conclusion: As the oil phase of SNEDDS, DHML can significantly improve the drug solubility and drug loading of IVA-SNEDDS. Moreover, DHML was easily emulsified and can effectively form a nanoemulsion in vivo and in vitro. The prepared IVA-SNEDDS can reduce the inter-individual absorption variability of IVA, eliminate its food effect and improve its oral bioavailability.Keywords: ivacaftor, food effect, self-nanoemulsion drug delivery system (SNEDDS), oral bioavailability, oil phase

Min Wang,1,2,&ast; Dongyue Wang,1,&ast; Jingzhi Zuo,3 Tianyu Liu,4 Zheng Niu,5 Juan Xie,1 Dunyi Qi2 1Department of Anesthesiology, Jinshan Hospital of Fudan University, Shanghai, People’s Republic of China; 2Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China; 3Emergency Department, Yichang Central People’s Hospital, Yichang, Hubei, People’s Republic of China; 4Department of Anesthesiology, Peking University People’s Hospital, Beijing, People’s Republic of China; 5Department of Anesthesiology, Zhangjiagang First People’s Hospital, Zhangjiagang, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dunyi Qi, Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China, Email qdy6808@163.comPurpose: Prophylactic intravenous nalbuphine was administered to observe its median effective dose (ED50) in reducing pain after undergoing laparoscopic total hysterectomy. To investigate the effect of different doses of nalbuphine on postoperative analgesia and adverse reactions in patients.Patients and Methods: The 120 patients undergoing laparoscopic total hysterectomy were divided into 6 groups: group C (control) and group P (5 different doses of nalbuphine) with 20 patients per group. The doses of nalbuphine in group P were in an equally proportional series (groups P1, P2, P3, P4, and P5 received doses of 0.280, 0.200, 0.140, 0.100, and 0.070 mg/kg, respectively), diluted to 20 mL with saline and administered 5 min before the induction of anesthesia. A similar volume (20 mL) of saline was administered to group C 5 min before the induction of anesthesia. The numeric rating scale (NRS) of patients during awakening and after surgery, the number of postoperative salvage analgesia, and the occurrence of postoperative adverse effects were recorded.Results: The ED50 (95% confidence interval (CI)) of nalbuphine in preventing pain during the awakening period in patients calculated using the point-slope method was 0.125 (0.108, 0.145) mg/kg. NRS scores differed among the 6 groups at 30 min and 1 h after extubation (P < 0.001; P < 0.001). Pairwise comparisons between groups revealed that, at 30 min after extubation, compared with group P1, the NRS scores of groups P4, P5, and C were higher (P = 0.001, P < 0.001, P < 0.001); compared with group P2, groups P5 and C had higher NRS scores (P = 0.011, P = 0.001). At 1 h after extubation, the NRS scores of groups P1 and P2 were lower than that of group P4 (P = 0.046, P = 0.036). Compared with the control, only the group P1 had a lower cough score (P = 0.009) and there were no differences in the other groups. There were no differences in sedation score at 10 min after extubation, the incidence of adverse events at 24 h postoperatively, or the number of remedial analgesics at 24 h postoperatively (P > 0.05).Conclusion: The ED50 (95% CI) of nalbuphine as a prophylactic in reducing pain during recovery was 0.125 (0.108, 0.145) mg/kg. Compared with the control, nalbuphine at doses of 0.140, 0.200, and 0.280 mg/kg prevented pain during the awakening period. Among these doses, 0.280 mg/kg was determined to be the best, the occurrence of cough was less during extubation and the postoperative analgesic effect was good. However, it is necessary to pay attention to the occurrence of adverse reactions.Keywords: gynecology, laparoscopy, preventive analgesia, nalbuphine, ED50

Dan-Dan Wang,1,2,&ast; Xin-Yue Wu,3,&ast; Ji-Yang Dong,3 Xiu-Ping Cheng,1,2 Shao-Fei Gu,1,2 Opeyemi Joshua Olatunji,4 Yan Li,1,2 Jian Zuo1,5,6 1Xin’an Medicine Research Center, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China; 2Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, People’s Republic of China; 3Department of Electronic Science, Xiamen University, Xiamen, 361005, People’s Republic of China; 4Faculty of Traditional Thai Medicine, Prince of Songkla University, Hat Yai, 90110, Thailand; 5Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241000, People’s Republic of China; 6Anhui Provincial Engineering Laboratory for Screening and Re-Evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Wuhu, 241000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Li; Jian Zuo Email liyan.0301@163.com; zuojian8178@163.comBackground: Qing-Luo-Yin (QLY) is an anti-rheumatic herbal formula. Despite the well-investigated therapeutic efficacy of QLY, its immune regulatory properties are largely unknown. CD4+ T cells and monocytes are two key parameters in rheumatoid arthritis (RA). This study investigated the changes in these cells in QLY-treated RA animal models.Materials and Methods: RA models were induced in male SD rats and were orally treated with QLY. Dynamic metabolic changes in collagen-induced arthritis (CIA) rats were monitored by 1H NMR approach. The immunity profiles of CIA and adjuvant-induced arthritis (AIA) rats were evaluated using immunohistochemical, PCR, ELISA, cytokine chip, flow cytometry, and immunofluorescence experiments. The bioactive components in QLY were identified by bioinformatic-guided LC-MS analyses. The compounds with high abundance in QLY decoction and easily absorbed were taken as key anti-rheumatic components and used to treat blood-derived immune cells using in vitro experiments.Results: The results indicated that QLY decreased Th17 cells frequency and T cells-released IL-6, IL-17 and GM-CSF in CIA rats, which was attributed to the impaired lymphocyte maturation and altered differentiation. QLY inhibited lactic acid production and inflammatory polarization in the monocytes during the peak period of AIA and CIA. AIA monocytes elicited significant increase in Th17 cells counts, IL-6 and IL-1β secretion in co-cultured splenocytes, which was abrogated by QLY. QLY-containing serum suppressed the phosphorylation of JNK and p65 in AIA lymphocyte-stimulated normal monocytes and consequently inhibited iNOS and IL-1β expression as well as IL-6 and IL-1β production. Matrine, sinomenine and sophocarpine were identified as major bioactive compounds in QLY. These identified compounds effectively inhibited the development of inflammatory T cells using concentrations detected in QLY-treated rats. At higher concentrations (20-fold increase), the chemical stimuli significantly suppressed the production of IL-1β in AIA monocytes by inhibiting JNK and p65 pathways.Conclusion: By targeting inflammatory T cells and monocytes as well as disrupting their interplay, QLY improved immune environment in RA models especially during the active stages of disease.Keywords: traditional Chinese medicine, rheumatoid arthritis, innate immunity, T cells, chronic inflammation, metabolomics

Titilope John Jayeoye,1 Fredrick Nwude Eze,2,3 Oladipupo Odunayo Olatunde,4,5 Sudarshan Singh,6 Jian Zuo,7– 9 Opeyemi Joshua Olatunji10 1Department of Chemistry, Faculty of Physical Science, Alex-Ekwueme Federal University Ndufu-Alike, Abakalilki, Ebonyi State, Nigeria; 2Faculty of Pharmaceutical Science, Prince of Songkla University, Hat Yai, Songkhla, 90112, Thailand; 3Drug Delivery System Excellence of Center, Prince of Songkla University, Hat Yai, Songkhla, 90112, Thailand; 4Department of Food and Human Nutritional Sciences, Faculty of Agricultural and Food Sciences, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada; 5Richardson Centre for Functional Foods and Nutraceuticals, University of Manitoba, Winnipeg, MB, R3T 6C5, Canada; 6Food Technology and Innovation Research Center of Excellence, Institute of Research and Innovation, Walailak University, Nakhon Si Thammarat, 80160, Thailand; 7Department of Traditional Chinese Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241001, People’s Republic of China; 8Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241001, People’s Republic of China; 9Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241001, People’s Republic of China; 10Faculty of Thai Traditional Medicine, Prince of Songkla University, Hat Yai, 90110, ThailandCorrespondence: Opeyemi Joshua OlatunjiFaculty of Thai Traditional Medicine, Prince of Songkla University, Hat Yai, 90110, ThailandEmail opeyemi.j@psu.ac.thTitilope John JayeoyeDepartment of Chemistry, Faculty of Physical Science, Alex-Ekwueme Federal University, Ndufu-Alike (AE-FUNAI), P.M.B. 1010, Abakaliki, Ebonyi State, NigeriaEmail titilope12@gmail.comIntroduction: The use of environmentally benign resources for nanoparticles synthesis is consistently pushed to the front burner in a bid to ensure and enhance environmental protection and beneficiation. In this light, application of different plant parts for the reduction and stabilization of nanoparticles is gaining popularity.Materials and Methods: In this contribution, we have exploited Securidaca inappendiculata stem extract (SISE), as the reducing and stabilizing agent for room temperature synthesis of highly stable and dispersed AgNPs. The major bioactive compounds in SISE were profiled using an ultra-high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UHPLC-MS-QTOF-MS).Results and Discussion: SISE could reduce silver salts to its nanoparticles almost instantaneously with a maximum absorption spectrum at 423 nm, under the optimal conditions. The fabricated SISE AgNPs was extensively characterized using FTIR, TEM, SEM, XRD, EDS, Zeta analysis/DLS and TGA/DTG analysis. SISE AgNPs with average particles size between 10– 15 nm and a zeta potential value of − 19.5 ± 1.8 mV was obtained. It was investigated for in-vitro biological applications by carrying out, antimicrobial, antioxidant, hemolytic, cytotoxicity and antidiabetic assays. It was found that SISE AgNPs exhibited potent antimicrobial capacity against some food borne microbes, good antioxidant property, while also demonstrating high biocompatibility. Moreover, with a view to extending further the applications SISE AgNPs, it was tested as a colorimetric nanoprobe for Hg2+ detection in aqueous environment, where good linearity between 0.10 and 10.0 μM, with a detection limit of 26.5 nM, were obtained. The practicality of the probe was investigated by carrying out Hg2+ detection in water sample, with good accuracy and precision.Discussion: Overall, this work introduced a new stabilizer for biocompatible AgNPs with far-reaching applications.Keywords: silver nanoparticles, Securidaca inappendiculata, biological applications, mercury (II) ion, colorimetric probe

Rui Wang,1,2,&ast; Dan-Feng Li,1,2,&ast; Yi-Fang Hu,1,2 Qiang Liao,1,2 Tian-Tian Jiang,1,2 Opeyemi Joshua Olatunji,3 Kui Yang,2,4 Jian Zuo1,2,5 1Department of Traditional Chinese Medicine, the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China; 2Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, People’s Republic of China; 3Faculty of Traditional Thai Medicine, Prince of Songkla University, Hat Yai, 90112, Thailand; 4Department of Pharmacy, the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China; 5Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian ZuoDepartment of Traditional Chinese Medicine, the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of ChinaEmail zuojian8178@163.comBackground: The Chinese herbal formula Qing-Luo-Yin (QLY) has been successfully used in rheumatoid arthritis treatment for decades. It exhibits notable immune and metabolism regulatory properties. Thereby, we investigated its effects on the interplay between (pre)-adipocytes and monocytes/macrophages under adjuvant-induced arthritis (AIA) circumstances.Methods: Fat reservoir and histological characteristics of white fat tissues (WAT) in AIA rats receiving QLY treatment were examined upon sacrifice. Metabolic parameters, clinical indicators, and oxidative stress levels were determined using corresponding kits, while mRNA/protein expression was investigated by PCR and immunoblotting methods. M1 macrophage distribution in WAT was assessed by flow cytometry. The effects of QLY on (pre)-adipocytes were further validated by experiments in vitro.Results: Compared with normal healthy controls, body weight and circulating triglyceride were declined in AIA rats, but serological levels of free fatty acids and low-density lipoprotein cholesterol were increased. mRNA IL-1β and iNOS expression in white blood cells and rheumatoid factor, C-reactive protein, anti-cyclic citrullinated peptide antibody, MCP-1 and IL-1β production in serum/WAT were up-regulated. Obvious CD86+CD11b+ macrophages were enriched in WAT. Meanwhile, expression of PPAR-γ and SIRT1 and secretion of adiponectin and leptin in these AIA rats were impaired. QLY restored all these pathological changes. Of note, it significantly stimulated PPAR-γ expression in the treated AIA rats. Accordingly, QLY-containing serum promoted SCD-1, PPAR-γ, and SIRT1 expression in pre-adipocytes cultured in vitro. AIA rats-derived peripheral blood mononuclear cells suppressed PPAR-γ and SCD-1 expression in co-cultured pre-adipocytes, but serum from AIA rats receiving QLY treatment did not exhibit this potential. The changes on PPAR-γ expression eventually resulted in varied adipocyte differentiation statuses. PPAR-γ selective inhibitor T0070907 abrogated QLY-induced MCP-1 production decline in LPS-primed pre-adipocytes and reduced adiponectin secretion.Conclusion: QLY was potent in promoting PPAR-γ expression and consequently disrupted inflammatory feedback in WAT by altering monocytes/macrophages polarization and adipocytes differentiation.Keywords: fat metabolism, Qing-Luo-Yin, rheumatoid arthritis, macrophages polarization, adipokine, (pre)-adipocytes

Long Wang,1,* Tiantian Shi,1,* Li Feng,1 Zhisong Fan,1 Xiaoli Xu,2 Xinliang Zhou,1 Xue Zhang,1 Jing Han,1 Li Jing,1 Jiayin Liu,1 Yujie Shan,1 Fengling Liu,1 Jing Zuo,1 Yudong Wang1 1Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, People’s Republic of China; 2Department of Medical Records, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yudong Wang Email 15931166600@126.comPurpose: Several studies have revealed the prognostic value distant metastasis in non-small-cell lung cancer (NSCLC) patients receiving first-line epidermal growth factor receptor (EGFR) inhibitors. However, the question of whether the specific metastatic site could predict survival outcomes remain elusive. This study evaluated the prognostic value of specific metastatic site at diagnosis in first-line icotinib-treated patients with EGFR-mutated advanced NSCLC.Methods: A total of 216 patients with EGFR-mutated stage IV NSCLC who received first-line icotinib treatment were retrospectively enrolled. The associations between the presence of distant metastasis to certain organs at diagnosis and survival outcomes were analyzed.Patients and methods: The presence of distant metastases was not associated with progression-free survival. Patients with liver metastasis showed a significantly shorter OS than those without liver metastasis (14.6m vs 33.0m, p=0.024). Patients with brain metastasis showed a marginally shorter OS than those without brain metastasis (26.5m vs 33.8m, p=0.051). Patients with lung metastasis showed a significantly longer OS than those without lung metastasis (36.0m vs 28.6m, p=0.038). Multivariable Cox regression analysis showed the presence of liver metastasis (HR [hazard ratio]: 2.265, 95% CI [confidence interval]: 1.239– 4.139, p=0.008) and brain metastasis (HR: 1.493, 95% CI: 1.012– 2.202, p=0.043) were independent predictors for unfavorable OS, while lung metastasis (HR: 0.669, 95% CI: 0.460– 0.971, p=0.034) was an independent predictor for favorable OS.Conclusion: The presence of liver and brain metastasis predicted unfavorable OS, while the presence of lung metastasis predicted favorable OS in first-line icotinib-treated patients with EGFR-mutated stage IV NSCLC.Keywords: metastasis, non-small cell lung cancer, EGFR mutations, icotinib, prognostic value

Duan L, Zuo J, Zhang F, et al. Int J Nanomedicine. 2020;15:3605–3620. The authors have advised Figure 9 on page 3618 is incorrect. An error was made during the preparation of images for part 9C. The correct Figure 9 is shown in Download Article. The authors apologise for this error. Read the original article

Jian Zuo,1– 3,* Meng-Qing Tao,1,3,* Xin-Yue Wu,4 Tian-Tian Jiang,1 Opeyemi Joshua Olatunji,5 Jiyang Dong,4 Jun Han,6 Cong-Lan Ji7 1Department of Traditional Chinese Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, People’s Republic of China; 2Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241000, People’s Republic of China; 3Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, People’s Republic of China; 4Department of Electronic Science, Xiamen University, Xiamen, 361005, People’s Republic of China; 5Faculty of Traditional Thai Medicine, Prince of Songkla University, Hat Yai, 90112, Thailand; 6Drug Research and Development Center, School of Pharmacy, Wannan Medical College, Wuhu, 241000, Anhui, People’s Republic of China; 7School of Pharmacy, Anhui College of Traditional Chinese Medicine, Wuhu, 241000, Anhui, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun HanDrug Research and Development Center, School of Pharmacy, Wannan Medical College, Wuhu, 241000, Anhui, People’s Republic of ChinaEmail hanjun@wnmc.edu.cnCong-Lan JiSchool of Pharmacy, Anhui College of Traditional Chinese Medicine, Wuhu, 241000, Anhui, People’s Republic of ChinaEmail 37709103@qq.comBackground: The bark of Securidaca inappendiculata Hassk. is traditionally used for treating inflammatory diseases and bone fractures in China. We have previously validated the xanthone-enriched fraction (XRF) of S. inappendiculata with anti-rheumatic potentials, but mechanism underlying the joints protective effects is still largely unknown.Materials and Methods: The male rats with collagen-induced arthritis (CIA) were treated with XRF. The therapeutic efficacy of XRF was evaluated by arthritis score changes, morphological observation of paws, histological examinations and serological analyses. Protein expression in tissues and cells was investigated by either immunohistochemical or immunoblotting methods, while levels of mRNA expression were investigated by RT-qPCR. Metabolites in serum were detected by LC-MS approach. The joints homogenates were used for analyzing possible targeted genes by genome microarray analyses.Results: Treatment with XRF and methotrexate (MTX) led to significant decrease in arthritis scores, and alleviated deformation of paws in CIA rats. In addition, XRF and MTX reduced circulating TNF-α, IL-1β and IL-17α in the serum and down-regulated TLR4/NF-κB and JNK pathways in joints of CIA rats. Compared to MTX, XRF-loading microemulsion significantly protected joints, which was accompanied by dramatic decrease in MMP3. Differential genes-based KEGG enrichment and metabolomics analysis suggested that XRF reduced fatty acids biosynthesis by regulating PPAR-γ signaling. S inappendiculata-derived 1,7-dihydroxy-3,4-dimethoxyxanthone (XAN) up-regulated PPAR-γ expression in macrophages, but suppressed it in pre-adipocytes in vitro, which was synchronized with SIRT1 changes. Adiponectin production and SCD-1 expression in pre-adipocytes were also decreased. Aside the direct inhibition on MMP3 expression in synovioblast, the presence of XAN in macrophages-pre-adipocytes co-culture system further reinforced this effect.Conclusion: This study revealed the joint protective advantages of the bioactive fraction from S. inappendiculata in CIA rats over MTX, and demonstrated that S. inappendiculata-derived xanthones suppressed the erosive nature of synovioblast acquired under inflammatory circumstances by regulating PPAR-γ signaling-controlled metabolism-immunity feedback.Keywords: peroxisome proliferators-activated receptor gamma, PPAR-γ, energy metabolism, rheumatoid arthritis, metabolomics, macrophage, inflammation

Jun Zuo,1,2 Ruisong Gong,1,2 Xiaowen Liu,2 Jing Zhao1,2 1Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, People’s Republic of China; 2Department of Anesthesiology, China-Japan Friendship Hospital, Beijing 100029, People’s Republic of ChinaCorrespondence: Jing ZhaoDepartment of Anesthesiology, China-Japan Friendship Hospital, No. 2 Yinghua East Road, Beijing 100029, People’s Republic of ChinaEmail zhaojing1009@aliyun.comBackground: Local anesthetics (LAs) have been widely used throughout the healthcare settings, especially in local anesthesia and pain management. The incidence of allergic reactions to LAs remains uncertain. The danger of allergic reactions to the use of LAs in every day of clinical practice is a matter of great concern. Therefore, it is necessary to investigate the risk of true allergy to LAs.Methods: This study retrospectively evaluated the medical records of patients who were referred to an anesthesia allergy clinic in China and underwent allergy tests with LAs over a 10-year period from 2009 to 2019. The following information was collected from medical records: demographics of the patients, reasons for referral, clinical features of drug hypersensitivity reaction (DHR), and test results with LAs. Skin tests combined with an in vitro method, basophil activation test (BAT), were used to investigate allergic reactions to LAs.Results: A group of 109 patients were included in the analysis. The main reason for referral was the presence of a suspected DHR after procedures with LAs (n=68, 62%), the second most common reason for referral was a history of DHR to other drugs and the need to use LAs for upcoming procedures (n=41, 38%). Of the 68 patients with a suspected DHR to LAs, only six cases presented true allergy and showed positive results in skin tests and/or BAT. And all 41 patients who had a history of DHR to other drugs presented negative in all tests.Conclusion: Risk of true allergy to LAs may be very low. However, patients with a suspected history of DHR to LAs should be considered for allergy tests. Skin tests and BAT may be useful in the investigation and diagnosis of true allergy to LAs in clinical practice.Keywords: adverse drug reactions, local anesthetics, allergy, skin tests, BAT

Lian Duan,1 Jianlin Zuo,2 Fuqiang Zhang,1 Binxi Li,3 Zhonghang Xu,4 Hao Zhang,3 Bai Yang,3 Wenzhi Song,5 Jinlan Jiang1 1Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 2Department of Orthopaedics, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 3State Key Laboratory of Supramolecular Structure and Material, College of Chemistry, Jilin University, Changchun, Jilin, People’s Republic of China; 4Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital, Jilin University, Changchun, Jilin, People’s Republic of China; 5Department of Stomatology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of ChinaCorrespondence: Jinlan Jiang; Wenzhi SongChina-Japan Union Hospital of Jilin University, No. 126 Xian Tai Street, Changchun, Jilin, People’s Republic of ChinaTel|Fax +86 431-84995432Email jiangjinlan@jlu.edu.cn; songwz@jlu.edu.cnPurpose: Osteonecrosis of the femoral head (ONFH) is a chronic and irreversible disease that eventually develops into a joint collapse and results in joint dysfunction. Early intervention and treatment are essential for preserving the joints and avoiding hip replacement. In this study, a system of human umbilical mesenchymal stem cells-supermagnetic iron oxide nanoparticles (NPs) @polydopamine (SCIOPs) was constructed. The magnetic targeting system gathers in the lesion area, inhibits the apoptosis of bone cells, enhances osteogenic effect, and effectively treats ONFH under external magnetic field.Materials and Methods: The supermagnetic iron oxide NPs @polydopamine (SPION@PDA NPs) were characterized by transmission electron microscopy and zeta potential, respectively. The effects of SPION@PDA NPs on the viability, proliferation, and differentiation of stem cells were detected by the CCK8 method, flow cytometry, and staining, respectively. The serum inflammatory indicators were detected by Luminex method. The bone mass of the femoral head was analyzed by micro computed tomography. The expression of apoptosis and osteoblast-related cytokines was detected by Western blotting. The osteogenesis of the femoral head was detected by histological and immunohistochemical sections.Results: The SCIOPs decreased the pro-inflammatory factors, and the micro CT showed that the bone repair of the femoral head was enhanced after treatment. The hematoxylin and eosin sections also showed an increase in the osteogenesis in the femoral head. Western blotting results showed and increased expression of anti-apoptotic proteins Akt and Bcl-2, decreased expression of apoptotic proteins caspase-3 and Bad, and increased expression of osteogenic proteins Runx-2 and Osterix in the femoral head.Conclusion: Under the effect of magnetic field and homing ability of stem cells, SCIOPs inhibited the apoptosis of osteoblasts, improved the proliferation ability of osteoblasts, and promoted bone repair in the femoral head through the Akt/Bcl-2/Bad/caspase-3 signaling pathway, thereby optimizing the tissue repair ability.Keywords: SPION@PDA NPs, HU-MSCs, GC-ONFH, apoptosis

Qin Yin,1,* Yi-jin Wu,1,* Shu Pan,1 Dan-dan Wang,2,3 Meng-qing Tao,2,3 Wei-ya Pei,2 Jian Zuo2– 4 1Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College, Wuhu 241000, People’s Republic of China; 2Department of Traditional Chinese Medicine, Yijishan Hospital of Wannan Medical College, Wuhu 241000, People’s Republic of China; 3Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu 241000, People’s Republic of China; 4Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu 241000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jian Zuo Tel +86 15056477665Email zuojian8178@163.comBackground: Studies have shown that α-mangostin (MG) could exert anti-rheumatic effects in vivo by restoring immunity homeostasis, and have indicated that activation of the choline anti-inflammatory pathway (CAP) may contribute to this immunomodulatory property. The current study was designed to further investigate the effects of MG on the CAP in peripheral immune cells and clarify its relevance to the potential anti-rheumatic actions.Methods: The catalytic activity of acetylcholinesterase (AChE) and expression of α 7-nicotinic cholinergic receptor (α 7nAChR) in peripheral blood mononuclear cells (PBMCs) from rats with collagen-induced arthritis (CIA) or human volunteers were evaluated after MG treatment. Consequent influences on the immune environment were assessed by flow cytometry and ELISA analyses. Indirect effects on joints resulting from these immune changes were studied in a co-culture system comprised of fibroblast-like synoviocytes (FLSs) and PBMCs.Results: MG promoted α 7nAChR expression in PBMCs both in vivo and in vitro, and inhibited the enzymatic activity of AChE simultaneously. Activation of the CAP was accompanied by a significant decrease in Th17 cells (CD4+IL-17A+), while no obvious changes concerning the distribution of other T-cell subsets were noticed upon MG treatment. Meanwhile, MG decreased the secretion of TNF-α and IL-1β under inflammatory conditions. PBMCs from MG-treated CIA rats lost the potential to stimulate NF-κB activation and pro-inflammatory cytokine production of FLSs in the co-culture system.Conclusion: Overall, the evidence suggested that MG can improve the peripheral immune milieu in CIA rats by suppressing Th17-cell differentiation through CAP activation, and achieve remission of inflammation mediated by FLSs.Keywords: rheumatoid arthritis, α-mangostin, choline anti-inflammatory pathway, α 7-nicotinic cholinergic receptor, Th17/Treg

Jianghui Liu,1,* Yingxiong Huang,1,* Quanyong Cheng,1,* Jifei Wang,1 Jidong Zuo,1 Ying Liang,2 Gang Yuan11Department of Emergency and Internal Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, People’s Republic of China; 2Department of Nephrology, The Eighth People’s Hospital of Guangzhou, Guangdong 510060, People’s Republic of China*These authors contributed equally to this work Purpose: Renal cell cancer (RCC) is one of the primary causes of malignancy deaths all over the world. The most important cause of RCC-related mortality is metastasis. Epithelial-mesenchymal transition (EMT) plays an important role in metastasis of malignant tumors including RCC. miR-1-3p is confirmed to be decreased in many types of cancer. Nevertheless, the function of miR-1-3p in RCC metastasis and EMT process was still unclear.Materials and methods: In this study, information from clinical investigation, in vitro study, and in vivo study discovered miR-1-3p expression character and its status in RCC. The character of miR-1-3p in invasive and metastatic properties in vitro and in vivo was also inspected in RCC cells and xenograft tumor model, and expression levels of EMT markers were evaluated in RCC cells and tissues.Results: miR-1-3p was proved to be decreased in RCC cell lines and tissues compared with normal renal cells and tissues. miR-1-3p expression level in RCC tissues was closely related with capsulation, lymph node metastasis, and vascular invasion. miR-1-3p was found to be able to block the EMT process in A498 and CAKI-1 RCC cells and tumors. Luciferase reporter assay and expression level rescue assays were employed to reveal that miR-1-3p inhibited the invasion and migration property of RCC cells by directly targeting Fibronectin 1. Upregulation of Fibronectin 1 partially reversed the suppressive effect of miR-1-3p on EMT process.Conclusion: In brief, this study has verified that miR-1-3p blocked the EMT process of RCC cells by reducing Fibronectin 1 expression. miR-1-3p/Fibronectin 1 axis may be considered as a new target for drug development of RCC.Keywords: renal cell carcinoma, microRNA-1-3p, Fibronectin 1, epithelial-to-mesenchymal transition, migration, invasion

Summary: Chemotherapy pre-conditioning is an essential component of chimeric antigen receptor transduced cell therapy. Acute lymphopenia-induced proliferation (LIP) is known to be driven primarily by homeostatic cytokines, but little is known on the underlying mechanisms in humans. We undertook phenotypic and transcriptional analysis of T cells undergoing LIP two weeks post-myeloablative autograft stem cell transplantation. Strong IL-7 signaling was reflected in downregulated IL-7R expression on all T cells, including naive cells, along with parallel increased IL-2Rα expression. Notably, activated residual naive cells expressed Fas indicating recent TCR engagement. Moreover, proportion of Ki67 + FoxP3+ Tregs was almost doubled. Transcriptional analysis revealed increased fatty acid metabolism and interferon signaling responses. In contrast, TGF-β signaling was strongly suppressed. Thus, human LIP response is characterized by cytokine and TCR-driven proliferation which drives global T cell activation but also preferentially triggers regulatory cell expansion which may limit tumor-specific immunity. These features indicate potential therapeutic opportunities to manipulate immunotherapy regimens incorporating LIP conditioning protocols.

The energy crisis and environmental pollution pose great challenges to human development. Traditional vapor-compression cooling consumes abundant energy and leads to a series of environmental problems. Radiative cooling without energy consumption and environmental pollution holds great promise as the next generation cooling technology, applied in buildings mostly in indirect way. In this work, a temperature-regulating module was introduced for direct summer cooling and winter heating. Firstly, the summer experiments were conduct to investigate the radiative cooling performance of the module. And the results indicated that the maximum indoor temperature reached only 27.5 °C with the ambient temperature of 34 °C in low latitude areas and the air conditioning system was on for only about a quarter of the day. Subsequently, the winter experiments were performed to explore the performance of the module in cooling and heating modes. The results indicated that indoor temperature can reach 25 °C in the daytime without additional heat supply and about a quarter of the day didn't require heating in winter. Additionally, the transient model of the module and the building revealed that the electricity saving of 42.4% (963.5 kWh) can be achieved in cooling season with the module, and that was 63.7% (1449.1 kWh) when coupling with energy storage system. Lastly, further discussion about the challenges and feasible solutions for radiative cooling to directly combine with the buildings were provided to advance the application of radiative cooling. Furthermore, with an acceptable payback period of 8 years, the maximum acceptable incremental cost reached 26.2 $/m2. The work opens up a new avenue for the application mode of the daytime radiative cooling technology.

Radiative cooling (RC) dissipates terrestrial heat to outer space through the atmospheric window, without external energy input and production of environmental pollutants. More and more efforts have been devoted to this clean promising cooling technology; thus diverse radiative coolers have emerged. However, the performance, cost, and effectiveness of various radiative coolers are not exactly the same. In addition, the large-scale application of RC technology is impeded by the low energy density, uncontrollable cooling power, and limited sky-facing area. Here, we critically review the recent progress of RC technology, evaluate the cooling performance of various radiative coolers, and discuss the challenges and feasible solutions to commercialize RC technology. Furthermore, valuable insights are provided to make new breakthroughs in this field.