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Liyang Dong,1,* Yafang Zhao,1,* Juan Luo,1,2 Xiaopeng Li,1 Shuxian Wang,1 Menghan Li,1 Peng Zou,1 Hui Kong,1 Qingguo Wang,1 Yan Zhao,1 Huihua Qu1 1School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Institute of Precision Medicine, Peking University Shenzhen Hospital, Shenzhen, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qingguo Wang; Yan Zhao, Email wangqg8558@sina.com; zhaoyandr@163.comBackground: Acute myocardial infarction (AMI) is a common cardiovascular disease in clinic. Currently, there is no specific treatment for AMI. Carbon dots (CDs) have been reported to show excellent biological activities, which hold promise for the development of novel nanomedicines for the treatment of cardiovascular diseases.Methods: In this study, we firstly prepared CDs from the natural herb Curcumae Radix Carbonisata (CRC-CDs) by a green, simple calcination method. The aim of this study is to investigate the cardioprotective effect and mechanism of CRC-CDs on isoproterenol (ISO) -induced myocardial infarction (MI) in rats.Results: The results showed that pretreatment with CRC-CDs significantly reduced serum levels of cardiac enzymes (CK-MB, LDH, AST) and lipids (TC, TG, LDL) and reduced st-segment elevation and myocardial infarct size on the ECG in AMI rats. Importantly, cardiac ejection fraction (EF) and shortening fraction (FS) were markedly elevated, as was ATPase activity. In addition, CRC-CDs could significantly increase the levels of superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT), and reduce the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in myocardial tissue, thereby exerting cardioprotective effect by enhancing the antioxidant capacity of myocardial tissue. Moreover, the TUNEL staining image showed that positive apoptotic cells were markedly declined after CRC-CDs treatment, which indicate that CRC-CDs could inhibit cardiomyocyte apoptosis. Importantly, The protective effect of CRC-CDs on H2O2 -pretreated H9c2 cells was also verified in vitro.Conclusion: Taken together, CRC-CDs has the potential for clinical application as an anti-myocardial ischemia drug candidate, which not only provides evidence for further broadening the biological application of cardiovascular diseases, but also offers potential hope for the application of nanomedicine to treat intractable diseases. Keywords: acute myocardial infarction, Curcumae Radix Carbonisata, carbon dots, oxidative stress

Xu M, Fu Y, Fang Y, et al. Infect Drug Resist. 2019;12:641–653. Page 647, Molecular characteristics of the K. pneumoniae isolates, first paragraph, right column, second sentence from the bottom, the text “The PFGE results showed that the homology of 44 isolates was diverse (Figure 3)” should read “The PFGE results showed that the homology of 44 isolates was diverse (Figure 4)”. Page 648, left column, last sentence, the text “In general, ST11 KPC-2-producing hvKP strains harbored more antibioticresistant genes and less virulence factors when compared with the non-ST11 KPC-2-producing hvKP (Figure 5)” should read “In general, ST11 KPC-2-producing hvKP strains harbored more antibioticresistant genes and less virulence factors when compared with the non-ST11 KPC-2-producing hvKP (Figure 6)”. Page 648, right column, first sentence, the text “Among the 15 KPC-2-producing hvKP strains, 4 strains (KP35, KP37, KP43, and KP44) shared >75% similarity and classified into one cluster (Figure 3), while the remaining 11 strains exhibited distinct genetic relationship” should read “Among the 15 KPC-2-producing hvKP strains, 4 strains (KP35, KP37, KP43, and KP44) shared >75% similarity and classified into one cluster (Figure 4), while the remaining 11 strains exhibited distinct genetic relationship”. Page 649, left column, second paragraph, first sentence, the text “Consistent with the epidemiology trend of K. pneumoniae meningitis in some Asian countries especially in Taiwan,3,4” should read “Consistent with the epidemiology trend of K. pneumoniae meningitis in Taiwan,3,4”. The authors apologize for these errors.

Xiujuan Chang,1,* Shumin Yu,2,* Jianzhi Pang,1 Wei Zhang,1 Huifang Kong,1 Jiagan Huang,1 Guojie Zhang,1 Huixin Zhang,1 Yueyue Gu,1,3 Yan Chen,1 Bin Yang,1 Jingping Liu,4 Zhen Zeng1– 3 1Department of Liver Disease Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, People’s Republic of China; 2 302 Clinical Medical School Peking University, Beijing, 100039, People’s Republic of China; 3The Fifth School of Clinical Medicine, Anhui Medical University, Hefei, Anhui Province, 230032, People’s Republic of China; 4Oncology Department, Electric Power Hospital of Beijing, Beijing, 100073, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhen Zeng, Department of Liver Disease Medicine, The Fifth Medical Center of Chinese PLA General Hospital, No. 100 West 4th Ring Middle Road, Beijing, 100039, People’s Republic of China, Tel +86 15010540233, Email zengzhen1970@sina.comBackground: We explore the dose–efficacy relationship of lenvatinib plus anti-PD-1 in patients with unresectable hepatocellular carcinoma (u-HCC) infected with hepatitis B virus (HBV) in real-world practice. Furthermore, we identify the population sensitive to lenvatinib plus anti-PD-1 treatments.Methods: This retrospective study included 70 patients treated with lenvatinib plus at least 3 cycles of anti-PD-1 and 140 with lenvatinib alone. Stabilized inverse probability of treatment weighting (SIPTW) was used to balance clinical features between the two groups. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were analyzed. Subpopulation treatment effect pattern plot (STEPP) estimated treatment-effect differences between the two groups.Results: The median age was 54 years, and 189 (90%) cases were male. A total of 180 (85%) patients were infected with HBV. A slowly increasing 12-month survival rate was with the cycles of anti-PD-1, and 5 cycles and more of anti-PD-1 appeared the most beneficial and stable survival rate. The lenvatinib plus at least 3 cycles anti-PD-1 group had better OS (21.4 vs 14 months, p = 0.041), PFS (8.0 vs 6.3 months, p = 0.015) than the lenvatinib alone group in unadjusted cohorts, and the SIPTW adjusted cohorts had confirmed it. For patients with portal vein trunk invasion (PVTI) or extrahepatic spread (EHS) combined with Child-Pugh class B (CPB), lenvatinib plus anti-PD-1 made the 12-month survival rate increase by 38%, while, in the other population, it did only 18%. The two groups had similar AEs (p ≥ 0.05).Conclusion: The lenvatinib combined with at least 3 cycles of anti-PD-1 was efficacy and safe for u-HCC patients infected with HBV. Especially, patients with PVTI or EHS combined with CPB may benefit most from the combination therapy.Graphical Abstract: Keywords: hepatocellular carcinoma, real-world study, anti-PD-1, lenvatinib

Yumin Chen,1 Wei Xiong,2,3 Ying Zhang,1 Xue Bai,1 Guoliang Cheng,1 Yifan Zhang,1 Rui Chen,1 Yinghui Guo,1 Hui Kong,1 Yue Zhang,4 Huihua Qu,5 Yan Zhao1 1School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3Institutes of Health Research, Mayinglong Pharmaceutical Group Co., Ltd, Wuhan, Hubei, People’s Republic of China; 4School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 5Centre of Scientific Experiment, Beijing University of Chinese Medicine, Beijing, People’s Republic of ChinaHuihua QuCentre of Scientific Experiment, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, People’s Republic of China, Email quhuihuadr@163.comCorrespondence: Yan Zhao, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, People’s Republic of China, Email zhaoyandr@163.comBackground: At present, people are susceptible to developing depression and anxiety disorders in response to stress. However, there is no specific medicine for anxiety. Os Draconis (OD, named “Long gu” in Chinese) are fossilized bones that have been used in traditional Chinese medicine to treat neurological diseases for thousands of years. Thus, we conducted this study to determine the biological basis for the anxiolytic effect of OD.Methods: In this study, novel carbon dots (OD-CDs) from OD decoctions were discovered and separated. OD-CDs were anatomized using nanomaterials characterization methods to characterize the morphological structure, optical properties, and functional group properties. Four behavioural tests were conducted to observe the behavioural activities of mice, including the open field test (OFT), light/dark box test (LDT), elevated plus maze test (EPMT), and novelty-suppressed feeding test (NSFT), to determine its anxiolytic effects. Moreover, we assessed the possible mechanisms of the OD-CDs by detecting hormones associated with the hypothalamic-pituitary-adrenal (HPA) axis.Results: OD-CDs were spherical and monodispersed with a narrow size distribution between 1 and 5 nm and had a yield of 3.67%. OD-CDs increased the activity time of mice in the central zone in the OFT. The mice in the experimental group showed more frequent activity in the light compartment and the open arms, in LDT and EPMT, respectively. In addition, OD-CDs shortened the feeding latency in the NSFT. Furthermore, the results after OD-CDs intervention showed a significant increase in serum serotonin (5-HT) and norepinephrine (NE). In addition, the concentrations of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ATCH), and corticosterone (CORT) were decreased.Conclusion: These results demonstrate a definite anxiolytic effect of OD-CDs and reveal the possible mechanism of action of OD-CDs’ anxiolytic effect, which supports the research of OD for neurological disorders and a promising new trend of therapeutic approach and drug development.Graphical Abstract: Keywords: Os Draconis, carbon dots, anti-anxiety, HPA axis

Qin Zhou,1 Huanjun Luo,2 Xiaowei Wang,2 Peng Li,3 Haibo Kong,1 Baomei He1 1Center for Reproductive Medicine, Department of Pediatrics, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, People’s Republic of China; 2Bengbu Medical College, Bengbu, Anhui Province, People’s Republic of China; 3Department of Gastroenterology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, People’s Republic of ChinaCorrespondence: Baomei He, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), No. 158 Shangtang Road, Hangzhou, Zhejiang Province, 310014, People’s Republic of China, Tel/Fax +86 13588008667, Email heyan916@126.comPurpose: Status epilepticus (SE) is a life-threatening condition causing brain damage, hippocampal necrosis and apoptosis. This study aimed to determine whether microRNA-210 regulates seizure and apoptosis by targeting the TLR4 /NF-κB1 associated signaling pathway.Methods: In a pilocarpine-induced epileptic rat model, the expressions of microRNA-210 (miR-210), TLR4, NF-κB1 and caspase-3 were assessed by a quantitative polymerase chain reaction and Western blotting. Tunel detects hippocampal neuron apoptosis.Results: We found that miR-210, TLR4, NF-κB1 and caspase-3 were upregulated in the hippocampus of the rat model compared with that of control. The knockdown of miR-210 significantly restored the expression levels of TLR4, NF-κB1 and caspase-3 and increased hippocampal apoptosis.Conclusion: These findings showed that the downregulation of miR-210 promoted apoptosis of hippocampal neurons by negatively regulating the TLR4/NF-кB1 signaling pathway.Keywords: apoptosis, microRNA, NF-κB1, status epilepticus, TLR4

Weili Wang,1,2,* Rongrong Wang,3,* Yuntao Zhang,1,2 Lei Zeng,1,2 Haisen Kong,4 Xueli Bai,1,2 Wei Zhang,1,2 Tingbo Liang1,2,5,6 1Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Liver Transplant Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 3Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4Department of Laboratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 5Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 6Key Laboratory of Combined Multi-organ Transplantation of the Ministry of Health, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tingbo Liang, Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China, Email liangtingbo@zju.edu.cnObjective: There are few therapeutic options for infections caused by carbapenem-resistant Enterobacterales (CRE) in children following liver transplantation. Ceftazidime-avibactam (CAZ-AVI), a recently licensed antibacterial in China, was utilized as a salvage therapy against CRE in our center, and its efficacy and safety were therefore assessed.Methods: The retrospective, observational study was conducted at the First Affiliated Hospital of Zhejiang University. Pediatric liver transplantation patients (≤ 12 years) who received CAZ-AVI as a salvage therapy against CRE infections were included from January 2020 to December 2021. Clinical success and all-cause death during hospitalization were the primary outcomes. Recurrence of infection, drug-related adverse events, and changes in inflammatory biomarkers were collected.Results: Six children were enrolled, with a median age of 10.1 (interquartile range (IQR) 5.5– 13.8) months. Primary intraperitoneal infections occurred in all patients, with five patients developing bloodstream infections. KPC carbapenemases were detected in most isolates, and the susceptibility results showed general sensitivity to tigecycline, polymyxin B, and CAZ-AVI. Tigecycline-based therapy was taken as the initial treatment and withdrawn because of clinical failure (5 cases) or cholestasis (1 case). After CRE infection, the median time to convert to CAZ-AVI was 7.5 (IQR 7.0– 8.8) days, and the median CAZ-AVI treatment length was 21.0 (IQR 20.3– 28.5) days. Clinical success was achieved in all patients, with a zero percent all-cause death rate. No CRE infections recurred throughout hospitalization, and no resistance to CAZ-AVI was detected. Patients experienced vomiting (1/6), skin rash (1/6), and a transient increase in cystatin C (2/6), γ-glutamyltransferase (2/6), and alkaline phosphatase (3/6).Conclusion: CAZ-AVI was shown to be a successful salvage treatment for CRE infection in pediatric liver transplant recipients, with minor and temporary drug-related side effects.Keywords: ceftazidime-avibactam, carbapenem-resistant Enterobacterales, pediatric liver transplantation, salvage treatment, effectiveness, safety

Yusheng Zhao,1 Yue Zhang,2 Hui Kong,1 Guoliang Cheng,1 Huihua Qu,3 Yan Zhao1 1School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 2School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 3Centre of Scientific Experiment, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of ChinaCorrespondence: Huihua Qu; Yan Zhao Tel +86 10 6428 6705Fax +86 1 6428 6821Email quhuihuadr@163.com; zhaoyandr@163.comIntroduction: The charcoal processed product of Armeniacae Semen Amarum (ASA), ASA Carbonisata (ASAC), has long been used for its anti-inflammatory effects. However, the material basis and mechanism of action of ASAC remain unclear.Aim: To explore the anti-inflammatory effects of Armeniacae Semen Amarum Carbonisata-derived carbon dots (ASAC-CDs).Methods: The physicochemical properties of ASAC-CDs including morphology, optical properties, functional groups were characterized by a series of methods, mainly including electron microscopy, optical technology and X-ray photoelectron spectroscopy. The anti-inflammatory effect of ASAC-CDs was evaluated and confirmed using acute lung injury (ALI) induced by lipopolysaccharides (LPS) in rats.Results: The ASAC-CDs ranged from 1.5 to 5.5 nm in diameter, with a quantum yield of 3.17%. ASAC-CDs alleviated LPS-induced inflammation, as demonstrated by reducing the levels of IL-6, IL-1β and TNF-α and increasing the contents of IL-10 in rat serum. More interestingly, ASAC-CDs reduce the content of MDA and MPO and increase the activity of SOD and the content of GSH, indicating the antioxidant activity of ASAC-CDs.Conclusion: These results demonstrate the remarkable anti-inflammatory effects of ASAC-CDs against ALI induced by LPS, which provide an important basis for the application of ASAC-CDs in clinical anti-pneumonia, and lay an experimental foundation for the research and development of novel nano-drugs.Keywords: Armeniacae Semen Amarum Carbonisata, carbon dots, lipopolysaccharide, anti-inflammatory

Wen Huang,1,* Ping Liu,1,* Min Zong,2,* Qian-Qian Chen,1 Hong Zhou,1 Hui Kong,1 Wei-Ping Xie1 1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of China; 2Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei-Ping Xie; Hui KongDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Road, Nanjing, 210029, People’s Republic of ChinaEmail wpxie@njmu.edu.cn; konghui@njmu.edu.cnBackground: A growing interest exists in identifying reliable and low-cost biomarkers or factors that could predict the therapeutic response, prognosis, recurrence, and survival in small-cell lung cancer (SCLC). This study aimed to investigate the better predictors of chemotherapy efficacy and prognosis in patients with SCLC receiving first-line chemotherapy and radiotherapy.Materials and Methods: This study retrospectively retrieved the medical records of patients with SCLC treated with first-line platinum-based chemotherapy and radiotherapy from January 2016 to June 2019 in the First Affiliated Hospital of Nanjing Medical University. Plasma biochemical parameters, clinical features, and overall survival (OS) time were collected. The independent effects of plasma parameters on patient survival were assessed by conducting univariate and multivariate Cox regression analyses. The optimal cut-off values of independent risk factors in the ROC curve and Kaplan–Meier survival analysis were determined using MedCalc software.Results: Statistically significant differences in lactate dehydrogenase (LDH) and fibrinogen (Fbg) were found between the complete remission + partial remission group and the non-responders, which consisted of stable-disease and progressive-disease groups, after first-line chemotherapy. Multivariate Cox regression analysis showed that LDH and Fbg were independent risk factors in predicting PFS (LDH HR: 1.013, 95% CI: 1.002– 1.030, P = 0.037; Fbg HR: 1.622, 95% CI: 1.094– 2.526, P = 0.017) and OS (LDH HR: 1.021, 95% CI: 1.008– 1.034, P = 0.001; Fbg HR: 2.168, 95% CI: 1.324– 3.550, P = 0.002). The AUC of LDH and Fbg was 0.77 and 0.745, respectively. The cut-off value of LDH and Fbg in predicting OS was 263 U/L and 4.03 g/L. When these two data were combined, the AUC reached 0.832, better than that of LDH and Fbg alone. The objective response rate (ORR) and OS were significantly different among these three different groups according to the addition of the assigned value (P < 0.05).Conclusion: Combined retreatment serum LDH and Fbg levels may be a better potential biomarker for predicting the clinical efficacy of chemotherapy and the prognosis of individuals with SCLC. Combining these two parameters could improve prediction efficacy.Keywords: lactate dehydrogenase, fibrinogen, overall survival, prognosis, small cell lung cancer

Ping Liu,1,* Wen Huang,1,* Yirui Ding,1 Jianbing Wu,2 Zhuangzhuang Liang,2 Zhangjian Huang,2 Weiping Xie,1 Hui Kong1 1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, People’s Republic of China; 2State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weiping Xie; Hui KongDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People’s Republic of ChinaTel +86-25-68136426Fax +86-25-68136269Email wpxie@njmu.edu.cn; konghui@njmu.edu.cnBackground: Pulmonary arterial hypertension (PAH) is an incurable disease that urgently needs therapeutic approaches. Based on the therapeutic effects of fasudil and dichloroacetate (DCA) on PAH, we aimed to explore the effects and potential mechanism of a new salt, fasudil dichloroacetate (FDCA), in a SU5416 plus hypoxia (SuHx)-induced rat model of PAH.Methods: The rat model of PAH was established by a single subcutaneous injection of SU5416 (20 mg/kg) followed by hypoxia (10% O2) exposure for 3 weeks. FDCA (15, 45, or 135 mg/kg i.g. daily) or the positive control, bosentan (100 mg/kg i.g. daily), were administered from the first day after SU5416 injection. After 3-week hypoxia, hemodynamic parameters, and histological changes of the pulmonary arterial vessels and right ventricle (RV) were assessed. Additionally, in vitro, the effects of FDCA (50 μM), compared with equimolar doses of fasudil, DCA, or fasudil+DCA, on the proliferation, migration, and contraction of human pulmonary arterial smooth muscle cell (PASMC) under hypoxia (1% O2) were evaluated.Results: FDCA dose-dependently attenuated SuHx-induced PAH, with significant reductions in RV systolic pressure, pulmonary artery wall thickness, pulmonary vessel muscularization, perivascular fibrosis, as well as RV hypertrophy and fibrosis. In vitro, FDCA inhibited hypoxia-induced PASMC proliferation, migration, and contraction to a greater degree than fasudil or DCA alone by restoring mitochondrial function, reducing intracellular Ca2+, and inhibiting calcium/calmodulin-dependent kinase (Ca2+/CaMK) activity as well as Rho-kinase activity.Conclusion: FDCA ameliorates hypoxia-induced PASMC dysfunction by inhibiting both Ca2+/CaMK and Rho-kinase signaling pathways, as well as maintaining mitochondrial homeostasis, thus alleviating SuHx-induced PAH.Keywords: pulmonary arterial hypertension, fasudil dichloroacetate, pulmonary arterial smooth muscle cells, hypoxia, calcium

Yan Zhao,1 Fang Lu,2 Yue Zhang,2 Meiling Zhang,1 Yusheng Zhao,3 Juan Luo,1 Hui Kong,1 Huihua Qu4 1School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 2School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 3School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 4Beijing Institute of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of ChinaCorrespondence: Hui Kong; Huihua QuBeijing University of Chinese Medicine, No. 11, Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, People’s Republic of ChinaTel +86 10-62486705Email doris7629@126.com; quhuihuadr@163.comBackground: It is well known that smoking is harmful to health; however, it can also ameliorate anxiety. To date, it is unclear whether any nanoparticles found in cigarette mainstream smoke (CS) contribute to this effect.Aim: The aim of this study was to assess the particle composition of CS to identify novel anti-anxiety components.Methods: Carbon dots (CDs) from CS (CS-CDs) were characterised using high-resolution transmission electron microscopy, Fourier-transform infrared, ultraviolet, fluorescence, X-ray photoelectron spectroscopy, X-ray diffraction and high-performance liquid chromatography. The anti-anxiety effects of CS-CDs in mouse models were evaluated and confirmed with the elevated plus maze and open-field tests.Results: The quantum yield of CS-CDs was 13.74%, with a composition of C, O, and N. In addition, the surface groups contained O-H, C-H, C=O, C-N, N-H, C-O-C, and COO− bonds. Acute toxicity testing revealed that CS-CDs had low in vitro and in vivo toxicity within a certain concentration range. The results of the elevated plus maze and open-field tests showed that CS-CDs had a significant anti-anxiety effect and a certain sedative effect in mice. The mechanism of these effects may be related to the decrease in glutamate levels and promotion of norepinephrine production in the mouse brain, and the decrease in dopamine in mouse serum due to CS-CDs.Conclusion: CS-CDs may have anti-anxiety and certain sedative effects. This study provides a new perspective for a more comprehensive understanding of the components, properties, and functions of CS. Furthermore, it offers a novel target for the development of smoking cessation treatments, such as nicotine replacement therapy.Keywords: carbon dots, cigarette mainstream smoke, anxiety, smoking cessation therapy

Jie Hu,1,* Juan Luo,1,* Meiling Zhang,1 Jiashu Wu,1 Yue Zhang,2 Hui Kong,1 Huihua Qu,3 Guoliang Cheng,4 Yan Zhao1 1School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 2School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 3Center of Scientific Experiment, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 4State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Lunan Pharmaceutical Group Co., Ltd., Linyi, 276000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan ZhaoSchool of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, People’s Republic of ChinaTel +86 010-62486705Email zhaoyandr@bucm.edu.cnGuoliang ChengState Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Lunan Pharmaceutical Group Co., Ltd., No. 209 Hong Qi Lu, Lanshan District, Linyi, 276000, Shandong Province, People’s Republic of ChinaTel +86 18905391156Email 18905391156@163.comAim: To explore the effects of Radix Sophorae Flavescentis carbonisata-based carbon dots (RSFC-CDs) on an ethanol-induced acute gastric ulcer rat model.Methods: The structure, optical properties, functional groups and elemental composition of RSFC-CDs synthesized by one-step pyrolysis were characterized. The gastric protective effects of RSFC-CDs were evaluated and confirmed by applying a rat model of ethanol-induced acute gastric ulcers. The underlying mechanisms were investigated through the nuclear factor-kappa B (NF-κB) signalling pathway and oxidative stress.Results: RSFC-CDs with a diameter ranging from 2– 3 nm mainly showed gastric protective effects by reducing the levels of NF-κB, tumour necrosis factor-α (TNF-α), interleukin (IL)-6, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione (GSH), malondialdehyde (MDA) and inducible nitric oxide synthase (iNOS) to inhibit ethanol-induced inflammation and oxidative stress.Conclusion: RSFC-CDs have anti-inflammatory and anti-oxidative effects, making them promising for application in ethanol-induced gastric injury.Keywords: carbon dots, Radix Sophorae Flavescentis, gastroprotection, anti-inflammatory, antioxidant

Yusheng Zhao,1 Yue Zhang,2 Hui Kong,3 Meiling Zhang,3 Jinjun Cheng,3 Jiashu Wu,3 Huihua Qu,4 Yan Zhao3 1School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, People’s Republic of China; 2School of Life Sciences, Beijing University of Chinese Medicine, Beijing 100029, People’s Republic of China; 3School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, People’s Republic of China; 4Centre of Scientific Experiment, Beijing University of Chinese Medicine, Beijing 100029, People’s Republic of ChinaCorrespondence: Huihua Qu Tel +86 10 6428 6705Fax +86 10 6428 6821Email quhuihuadr@163.comYan Zhao Tel +86 10 6428 6705Fax +86 10 6428 6821Email zhaoyandr@163.comIntroduction: The charcoal processed product of Paeoniae Radix Alba (PRA), PRA Carbonisata (PRAC), has long been used for its hepatoprotective effects. However, the material basis and mechanism of action of PRAC remain unclear.Aim: To explore the hepatoprotective effects of Paeoniae Radix Alba Carbonisata-derived carbon dots (PRAC-CDs).Methods: PRAC-CDs were characterized using transmission electron microscopy, high-resolution transmission electron microscopy, ultraviolet, fluorescence, Fourier transform infrared and X-ray photoelectron spectroscopy, X-ray diffraction, and high-performance liquid chromatography. The hepatoprotective effect of PRAC-CDs was evaluated and confirmed using the classic carbon tetrachloride acute liver injury model.Results: PRAC-CDs averaged 1.0– 2.4 nm in size and exhibited a quantum yield of 5.34% at a maximum excitation wavelength of 320 nm and emission at 411 nm. PRAC-CDs can reduce the ALT and AST levels of mice with carbon tetrachloride-induced acute liver injury and have a mitigating effect on the rise in TBA and TBIL. More interestingly, PRAC-CDs can significantly reduce MDA and increase SOD levels, demonstrating that PRAC-CDs can improve the body’s ability to scavenge oxygen free radicals and inhibit free radical-induced liver cell lipid peroxidation, thereby preventing liver cell damage.Conclusion: These results demonstrate the remarkable hepatoprotective effects of PRAC-CDs against carbon tetrachloride-induced acute liver injury, which provide new insights into potential biomedical and healthcare applications of CDs.Keywords: Paeoniae Radix Alba carbonisata, carbon dots, hepatoprotective

Shouzhong Wang,1 Tao Wang,1 Darui Liu,2 Haiyan Kong3 1Department of Minimally Invasive Intervention Center, Zaozhuang Tumor Hospital, Zaozhuang, Shandong 277500, People’s Republic of China; 2Department of Burn and Plastic Surgery, Tengzhou Central People’s Hospital, Zaozhuang, Shandong 277500, People’s Republic of China; 3Department of Clinical Laboratory, Tengzhou Central People’s Hospital, Tengzhou, Shandong, People’s Republic of ChinaCorrespondence: Haiyan KongDepartment of Clinical Laboratory, Tengzhou Central People’s Hospital, 181 Xingtan Road, Tengzhou 277599, Shandong, People’s Republic of ChinaTel +86-13806329800Email x8dke3@163.comBackground: Non-small cell lung cancer (NSCLC) is a common malignant tumor in humans. Long non-coding RNA (lncRNA) involved in cancer progression has been reported frequently. The objective of this study was to investigate the role of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and explore a novel mechanism in NSCLC development.Materials and Methods: The expression of MALAT1, copper metabolism MURR1 domain-containing 8 (COMMD8) and microRNA-613 (miR-613) was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels of COMMD8, Cyclin D1, Ki67, B cell lymphoma/leukemia-2 (Bcl-2), Bcl-2 associated X protein (Bax), lactate dehydrogenase A (LDHA), CD63 and CD81 were determined by Western blot. Cell proliferation, the number of colonies and cell apoptosis were assessed by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), colony formation and flow cytometry assays, respectively. Glycolysis was distinguished based on glucose consumption, lactate production and LDHA activity. The role of MALAT1 in vivo was verified by animal experiments. The relationship between miR-613 and MALAT1 or COMMD8 was predicted by the bioinformatics tool starbase and verified by dual-luciferase reporter assay. The exosomes were isolated using the corresponding kit and identified by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA).Results: MALAT1 and COMMD8 were aberrantly upregulated in NSCLC tissues and cells. MALAT1 or COMMD8 knockdown blocked cell proliferation, colony formation and glycolysis but accelerated cell apoptosis in vitro. Besides, MALAT1 knockdown reduced tumor growth in vivo. We found that miR-613 was a target of MALAT1, and miR-613 could bind to the 3ʹ untranslated region (3ʹUTR) of COMMD8. MALAT1 regulated the expression of COMMD8 by absorbing miR-613. Moreover, the extracellular MALAT1 was transmitted by wrapping into exosomes.Conclusion: MALAT1 promoted malignant activities of NSCLC cells through targeting miR-613/COMMD8 axis, and exosome-mediated transfer of NSCLC might be a novel approach for NSCLC treatment.Keywords: MALAT1, COMMD8, miR-613, NSCLC, exosome

Jiashu Wu,1 Meiling Zhang,1 Jinjun Cheng,1 Yue Zhang,2 Juan Luo,1 Yuhan Liu,1 Hui Kong,1 Huihua Qu,3 Yan Zhao1 1School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, People’s Republic of China; 2School of Science Life, Beijing University of Chinese Medicine, Beijing 100029, People’s Republic of China; 3Center of Scientific Experiment, Beijing University of Chinese Medicine, Beijing 100029, People’s Republic of ChinaCorrespondence: Yan Zhao Tel +86 010 6428 6705Fax +86 1 6428 6821Email zhaoyandr@163.comIntroduction: A correlation is established between the efficacy of Chinese herbal medicine and its charcoal drugs. Lonicerae japonicae Flos (LJF) is commonly used to treat fever, carbuncle, and tumors, among others. LJF Carbonisatas (LJFC) is preferred for detoxifying and relieving dysentery and its related symptoms. However, the mechanisms underlying the effects of LJFC remain unknown.Aim: The aim of this study was to explore the effects of LJFC-derived carbon dots (LJFC-CDs) on lipopolysaccharide (LPS)-induced fever and hypothermia rat models.Methods: LJFC-CDs were characterized using transmission electron microscopy, high-resolution transmission electron microscopy, Fourier-transform infrared, ultraviolet, fluorescence, X-ray photoelectron spectroscopy, X-ray diffraction and high-performance liquid chromatography. The anti-inflammatory effects of LJFC-CDs were evaluated and confirmed using rat models of LPS-induced fever or hypothermia.Results: The LJFC-CDs ranged from 1.0 to 10.0 nm in diameter, with a yield of 0.5%. LJFC-CDs alleviated LPS-induced inflammation, as demonstrated by the expression of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 and the recovery of normal body temperature.Conclusion: LJFC-CDs may have an anti-inflammatory effect and a potential to alleviate fever and hypothermia caused by inflammation.Keywords: carbon dots, Lonicerae japonicae Flos, anti-inflammatory, lipopolysaccharide

Jian Liu,1 Peng Liu,2 Tiantian Xu,1 Zhiwei Chen,1 Huimin Kong,1 Weihong Chu,1 Yingchao Wang,1 Yufeng Liu1 1Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People’s Republic of China; 2Department of Pediatric Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People’s Republic of ChinaCorrespondence: Jian LiuThe First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou 450052, People’s Republic of ChinaEmail liujian018@qq.comIntroduction: Berberine has been reported to inhibit cancer cell growth by apoptosis induction and exhibits a protective role against cancer progression. The current study aims to investigate the effects of berberine on acute lymphoblastic leukemia (ALL) and the mechanism beyond apoptosis.Methods: Cell viability was determined in ALL cell lines EU-6 and SKW-3 using trypan blue staining. Cell autophagy was determined by immunofluorescence and Western blot. ALL xenograft mice were established to investigate the anti-tumor effects of BBR. The molecular mechanism was explored in ALL cell lines using siRNA and signaling inhibitors.Results: Herein, we show that berberine treatment significantly inhibits ALL cell viability and promotes cell death by inducing autophagy in a dose-dependent manner. Moreover, berberine significantly alleviates the aggressive pathological condition in ALL xenograft mice. Mechanistic studies exhibit that berberine induces autophagic death in ALL cells by inactivating AKT/mTORC1 signaling. Chemically targeting AKT/mTORC1 signaling controls berberine-induced cell autophagy in vitro, and blockade of autophagic process blunts berberine-alleviated pathological condition in vivo.Discussion: In conclusion, our study reveals that berberine could induce ALL cell autophagic death by inactivating AKT/mTORC1 signaling that could be used to develop small molecule drug for ALL treatment.Keywords: acute lymphoblastic leukemia, berberine, AKT/mTORC1, autophagy

Min Yu,1,* Liyao Peng,1,* Ping Liu,1 Mingxia Yang,2 Hong Zhou,1 Yirui Ding,1 Jingjing Wang,3 Wen Huang,1 Qi Tan,1 Yanli Wang,1 Weiping Xie,1 Hui Kong,1 Hong Wang1 1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, Changzhou 213003, People’s Republic of China; 3Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hui Kong; Hong WangDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, People’s Republic of ChinaTel +86-25-68136426Fax +86-25-68136269Email konghui@njmu.edu.cn; hongwang@njmu.edu.cnBackground: Endothelial cells dysfunction is one of the hallmark pathogenic features of pulmonary arterial hypertension (PAH). Paeoniflorin (PF) is a monoterpene glycoside with endothelial protection, vasodilation, antifibrotic, anti–inflammatory and antioxidative properties. However, the effects of PF on PAH remain unknown.Methods: Here, we investigated the efficacy of PF in the SU5416/hypoxia (SuHx) rat model of PAH. Human pulmonary arterial endothelial cells (HPAECs) were exposed to 1% O2 with or without PF treatment.Results: Hemodynamics analysis showed that prophylactic treatment with PF (300 mg/kg i.g. daily for 21 days) significantly inhibited chronic hypoxia/SU5416-induced elevations of right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index in rats. Meanwhile, PF significantly reduced pulmonary vascular remodeling, as well as alleviated collagen deposition in lungs and right ventricles in SuHx rats. Additionally, PF inhibited SuHx–induced down-regulation of endothelial marker (vascular endothelial cadherin) and up-regulation of mesenchymal markers (fibronectin and vimentin) in lung, suggesting that PF could inhibit SuHx–induced endothelial-to-mesenchymal transition (EndMT) in lung. Further in vitro studies confirmed that PF treatment suppressed hypoxia-induced EndMT in HPAECs, which was abolished by the knockdown of bone morphogenetic protein receptor type 2 (BMPR2) in HPAECs.Conclusion: Taken together, our findings suggest that PF ameliorates BMPR2 down-regulation-mediated EndMT and thereafter alleviates SuHx–induced PAH in rats.Keywords: paeoniflorin, pulmonary arterial hypertension, endothelial-to-mesenchymal transition, BMPR2, hypoxia

Min Xu,1,* Yiqi Fu,2,* Yunhui Fang,3 Hao Xu,3 Haishen Kong,3 Yanchao Liu,1 Yu Chen,1,3 Lanjuan Li3 1Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Center of Clinical Laboratory, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; 2Department of Respiratory Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; 3State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China *These authors contributed equally to this work Background: Klebsiella pneumoniae has been the leading causative pathogen for adult bacterial meningitis in several Asian countries. The clinical and microbiological characteristics of K. pneumoniae meningitis in mainland China are still unknown. Materials and methods: The clinical data of patients with K. pneumoniae meningitis from January 2011 to July 2017 in a tertiary hospital were retrospectively evaluated. The isolates were tested for antibiotic-resistance genes, virulence-associated genes, and molecular subtypes. Hypervirulent K. pneumoniae (hvKP) was defined as the presence of pLVPK-like virulence plasmid. Results: During the study period, a total of 48 patients with meningitis caused by K. pneumoniae were identified, accounting for 21.2% (48/226) of Gram-negative bacilli meningitis. Of the 44 available isolates, 65.9% (29/44) were carbapenem resistant, and all except one harbored blaKPC-2. K64 was the most common serotype (n=13), followed by K47 (n=11) and K1 (n=5). The pLVPK-related genetic loci were found in about half of isolates (iutA: 56.8%, iucA: 56.8%, rmpA2:50.0%, rmpA: 43.2%, and iroN: 40.9%). Twenty-two strains carrying pLVPK-derived virulence plasmid were defined as hvKP. Notably, the coexistence of blaKPC-2-encoding plasmid and the pLVPK-derived virulence plasmid was detected in 15 strains (34.1%, 15/44), suggesting K. pneumoniae carbapenemase-2 (KPC-2)-producing hvKP. The proportion of KPC-2-producing hvKP by year increased remarkably from 0% (2011) to 71.4% (2017). Of the 15 KPC-2-producing hvKP strains, 80.0% (12/15) were assigned to sequence type 11 and 2 strains (13.3%) belonged to clonal complex 23. Most of the patients infected with KPC-2-producing hvKP had preceding postneurosurgical state (93.3%, 14/15) and severe pneumonia (73.3%, 11/15). All the cases (100%, 15/15) had fatal outcome. Conclusion: The high prevalence and mortality of K. pneumoniae, especially KPC-2-producing hvKP meningitis, in China should be of concern. The implementation of epidemiological surveillance and identification of an effective clinical treatment are paramount. Keywords: meningitis, hypervirulent K. pneumonia, blaKPC-2, rmpA2, pLVPK-like virulence plasmid

Haishen Kong,1,2 Lingmei Fang,3 Rujin Jiang,4 Jixiang Tong2 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; 2Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Department of Laboratory Medicine, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; 3Clinical Laboratory, Chunan First People’s Hospital, Zhejiang Province People’s Hospital Chunan Branch, Hangzhou, China; 4Clinical Laboratory, Yuhang Hospital of Traditional Chinese Medicine, Hangzhou, China Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen. Various virulence and antiseptic-resistant factors increase the pathogenicity of MRSA strains and allow for increased infection rates.Purpose: The purpose of this study was to investigate the prevalence and distribution of virulence-associated and antiseptic-resistant genes from epidemic MRSA strains isolated from East China.Methods: A newly designed multiplex PCR assay was used to assess whether the virulence-associated genes sasX and pvl and the chlorhexidine tolerance gene qacA/B were present in 189 clinical isolates of MRSA. Multilocus sequence typing (MLST) and Staphylococcal protein A (spa) typing of these isolates were also performed. The frequency of these genes in isolates with epidemic sequence types (STs) was investigated. Results: Twenty STs and 36 spa types with five epidemic clones (ST5-t311, ST59-t437, ST5-t002, ST239-t030, and ST239-t037) were identified. The prevalence of sasX, pvl, and qacA/B in all isolates was 5.8%, 10.1%, and 20.1%, respectively. The prevalences of these genes in isolates with ST5, ST59, ST239, and other ST genetic backgrounds were all significantly different (P

Yan Zhao,1,* Yue Zhang,2,* Gaofeng Qin,1 Jinjun Cheng,1 Wenhao Zeng,2 Shuchen Liu,1 Hui Kong,1 Xueqian Wang,1 Qingguo Wang,1 Huihua Qu3 1School of Basic Medical Sciences, 2School of Chinese Materia Medica, 3Center of Scientific Experiment, Beijing University of Chinese Medicine, Beijing, People’s Republic of China *These authors contributed equally to this work Abstract: The unique features of quantum dots (QDs) make them desirable fluorescent tags for cell and developmental biology applications that require long-term, multitarget, and highly sensitive imaging. In this work, we imaged fluorescent cadmium telluride/zinc sulfide (CdTe/ZnS) QDs in organs, tissues, and cells, and analyzed the mechanism of their lymphatic uptake and cellular distribution. We observed that the fluorescent CdTe/ZnS QDs were internalized by lymph nodes in four cell lines from different tissue sources. We obtained the fluorescence intensity–QD concentrations curve by quantitative analysis. Our results demonstrate that cells containing QDs can complete mitosis normally and that distribution of QDs was uniform across cell types and involved the vesicular transport system, including the endoplasmic reticulum. This capacity for CdTe/ZnS QD targeting provides insights into the applicability and limitations of fluorescent QDs for imaging biological specimens. Keywords: quantum dots, lymph nodes, fluorescence imaging, biodistribution

Xuesong Chen,1,* Kouying Liu,1,* Zhiyue Wang,2 Yinsu Zhu,2 Yang Zhao,3 Hui Kong,1 Weiping Xie,1 Hong Wang1 1Department of Respiratory Medicine, 2Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, 3Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, People’s Republic of China *These authors contributed equally to this work Abstract: Computed tomography (CT) is widely used for evaluation of lung diseases. To evaluate the value of CT measurement of pulmonary artery for diagnosis of chronic obstructive pulmonary disease (COPD) and its comorbidity pulmonary hypertension (PH), we retrospectively reviewed the CT of 221 patients with COPD and 115 control patients without cardiovascular or lung disease. Patients with COPD were divided into PH (COPD-PH) and non-PH according to systolic pulmonary artery pressure. Main pulmonary artery (MPA), right pulmonary artery (RPA) and left pulmonary artery branches, and ascending aorta (AAo) and descending aorta (DAo) diameters were measured. Meanwhile, the ratios of MPA/AAo and MPA/DAo were calculated. MPA, RPA, and left pulmonary artery diameters were significantly larger in COPD than those in the controls, and this augment was more obvious in COPD-PH. AAo and DAo diameters did not vary obviously between groups, while MPA/AAo and MAP/DAo increased significantly in COPD and PH. MPA could be helpful for COPD diagnosis (MPA diameter ≥27.5 mm, sensitivity 54%, and specificity 80%), and RPA could be applied for COPD-PH diagnosis (RPA diameter ≥23.4 mm, sensitivity 67%, and specificity 76%). There was a marked correlation between MPA/DAo and systolic pulmonary artery pressure (r=0.594, P

Huae Xu,1,2 Zhibo Hou,3 Hao Zhang,4 Hui Kong,2 Xiaolin Li,4 Hong Wang,2 Weiping Xie21Department of Pharmacy, 2Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China; 3First Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, People's Republic of China; 4Department of Geriatric Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of ChinaAbstract: Earlier studies have demonstrated the promising antitumor effect of tetrandrine (Tet) against a series of cancers. However, the poor solubility of Tet limits its application, while its hydrophobicity makes Tet a potential model drug for nanodelivery systems. We report on a simple way of preparing drug-loaded nanoparticles formed by amphiphilic poly(N-vinylpyrrolidone)-block-poly(ε-caprolactone) (PVP-b-PCL) copolymers with Tet as a model drug. The mean diameters of Tet-loaded PVP-b-PCL nanoparticles (Tet-NPs) were between 110 nm and 125 nm with a negative zeta potential slightly below 0 mV. Tet was incorporated into PVP-b-PCL nanoparticles with high loading efficiency. Different feeding ratios showed different influences on sizes, zeta potentials, and the drug loading efficiencies of Tet-NPs. An in vitro release study shows the sustained release pattern of Tet-NPs. It is shown that the uptake of Tet-NPs is mainly mediated by the endocytosis of nanoparticles, which is more efficient than the filtration of free Tet. Further experiments including fluorescence activated cell sorting and Western blotting indicated that this Trojan strategy of delivering Tet in PVP-b-PCL nanoparticles via endocytosis leads to enhanced induction of apoptosis in the non-small cell lung cancer cell A549 line; enhanced apoptosis is achieved by inhibiting the expression of anti-apoptotic Bcl-2 and Bcl-xL proteins. Moreover, Tet-NPs more efficiently inhibit the ability of cell migration and invasion than free Tet by down-regulating matrix metalloproteinases (MMP)-2 and MMP-9, as well as up-regulating tissue inhibitor of MMP-3 (TIMP-3). Therefore, data from this study not only confirms the potential of Tet in treating lung cancer but also offers an effective way of improving the anticancer efficiency of Tet by nanodrug delivery systems.Keywords: tetrandrine, poly(N-vinylpyrrolidone), lung cancer, nanoparticles

We present the cosmological implications from final measurements of clustering using galaxies, quasars, and Lyα forests from the completed Sloan Digital Sky Survey (SDSS) lineage of experiments in large-scale structure. These experiments, composed of data from SDSS, SDSS-II, BOSS, and eBOSS, offer independent measurements of baryon acoustic oscillation (BAO) measurements of angular-diameter distances and Hubble distances relative to the sound horizon, rd, from eight different samples and six measurements of the growth rate parameter, fσ8, from redshift-space distortions (RSD). This composite sample is the most constraining of its kind and allows us to perform a comprehensive assessment of the cosmological model after two decades of dedicated spectroscopic observation. We show that the BAO data alone are able to rule out dark-energy-free models at more than eight standard deviations in an extension to the flat, ΛCDM model that allows for curvature. When combined with Planck Cosmic Microwave Background (CMB) measurements of temperature and polarization, under the same model, the BAO data provide nearly an order of magnitude improvement on curvature constraints relative to primary CMB constraints alone. Independent of distance measurements, the SDSS RSD data complement weak lensing measurements from the Dark Energy Survey (DES) in demonstrating a preference for a flat ΛCDM cosmological model when combined with Planck measurements. The combined BAO and RSD measurements indicate σ8=0.85±0.03, implying a growth rate that is consistent with predictions from Planck temperature and polarization data and with General Relativity. When combining the results of SDSS BAO and RSD, Planck, Pantheon Type Ia supernovae (SNe Ia), and DES weak lensing and clustering measurements, all multiple-parameter extensions remain consistent with a ΛCDM model. Regardless of cosmological model, the precision on each of the three parameters, ωΛ, H0, and σ8, remains at roughly 1%, showing changes of less than 0.6% in the central values between models. In a model that allows for free curvature and a time-evolving equation of state for dark energy, the combined samples produce a constraint ωk=-0.0022±0.0022. The dark energy constraints lead to w0=-0.909±0.081 and wa=-0.49-0.30+0.35, corresponding to an equation of state of wp=-1.018±0.032 at a pivot redshift zp=0.29 and a Dark Energy Task Force Figure of Merit of 94. The inverse distance ladder measurement under this model yields H0=68.18±0.79 km s-1 Mpc-1, remaining in tension with several direct determination methods; the BAO data allow Hubble constant estimates that are robust against the assumption of the cosmological model. In addition, the BAO data allow estimates of H0 that are independent of the CMB data, with similar central values and precision under a ΛCDM model. Our most constraining combination of data gives the upper limit on the sum of neutrino masses at mν

In preparation for the Dark Energy Spectroscopic Instrument (DESI), a new top end was installed on the Mayall 4-meter telescope at Kitt Peak National Observatory. The refurbished telescope and the DESI instrument were successfully commissioned on sky between 2019 October and 2020 March. Here we describe the pointing, tracking and imaging performance of the Mayall telescope equipped with its new DESI prime focus corrector, as measured by six guider cameras sampling the outer edge of DESI's focal plane. Analyzing ∼500,000 guider images acquired during commissioning, we find a median delivered image FWHM of 1.1 arcseconds (in the r-band at 650 nm), with the distribution extending to a best-case value of ∼0.6 arcseconds. The point spread function is well characterized by a Moffat profile with a power-law index of β ≈ 3.5 and little dependence of β on FWHM. The shape and size of the PSF delivered by the new corrector at a field angle of 1.57 degrees are very similar to those measured with the old Mayall corrector on axis. We also find that the Mayall achieves excellent pointing accuracy (several arcseconds RMS) and minimal open-loop tracking drift (< 1 milliarcsecond per second), improvements on the telecope's pre-DESI performance. In the future, employing DESI's active focus adjustment capabilities will likely further improve the Mayall/DESI delivered image quality.