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1.
Int J Mol Med ; 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32377717

RESUMO

Bone graft defects may lead to dysfunction of bone regeneration and metabolic disorders of bone mesenchymal stem cells (BMSCs). Puerarin has demonstrated pharmacological activities in the treatment of human metabolic diseases. The purpose of the present study was to investigate the role of puerarin and to explore its possible protective mechanism of action in rats with bone grafts. A bone graft rat model was established using bone grafting surgery and the rats received puerarin or PBS. Reverse transcription­quantitative PCR, western blot, TUNEL, immunofluorescence and immunohistochemistry assays were used to analyze the beneficial effects of puerarin on bone repair. The results demonstrated that puerarin effectively ameliorated pathological graft bone defects, decreased bone loss and apoptosis of BMSCs, promoted BMSC proliferation and differentiation, and increased bone mass and the parameters of bone formation in rats with bone grafts. Puerarin decreased the levels of pro­inflammatory cytokines [tumor necrosis factor (TNF)­α, interleukin (IL)­1ß, IL­17A, IL­6 and transforming growth factor (TGF)­ß1] and increased the levels of anti­inflammatory cytokines (IL­2 and IL­10) in the serum compared with the PBS group. Puerarin treatment was associated with lower serum alanine transaminase, glutamic oxaloacetic transaminase, γ­glutamyl transferase, alkaline phosphatase, direct bilirubin and total bilirubin levels compared with those in the PBS group in experimental rats. The expression of microRNA­155­3p (miR­155­3p) was upregulated, whereas that of p53, TNF­α and signal transducer and activator of transcription (STAT)1 was downregulated in BMSC cultures of puerarin­treated rats. In vitro assay demonstrated that knockdown of miR­155­3p increased p53, TNF­α and STAT1 expression in BMSCs, and blocked puerarin­regulated p53/TNF­α/STAT1 signaling. Most importantly, miR­155­3p knockdown inhibited puerarin­regulated apoptosis, proliferation and differentiation of BMSCs. Moreover, the results demonstrated that puerarin regulated vascular endothelial growth factor expression via the miR­155­3p signaling pathway. In conclusion, the results of the present study demonstrated that the upregulation of miR­155­3p induced by puerarin promoted BMSC differentiation and bone formation and increased bone mass in rats with bone grafts, thereby supporting the potential application of puerarin in the prevention of bone graft defects.

2.
J Control Release ; 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32422211

RESUMO

Indocyanine green (ICG), a safe and clinically approved near-infrared (NIR) dye, was recently explored as a potential photosensitizer due to its excellent photophysical properties. However, ICG tends to form aggregations in physiological solution, causing fluorescence quenching, and fast blood clearance and thereby inefficient tumor accumulation. Herein, we report ICG-based nanodrug delivery systems formed by self-assembly of ICG and chemotherapeutic drugs without any excipients for combined chemo- and phototherapy. Taking advantage of the amphiphilic aromatic structure, ICG readily bounded with hydrophobic aromatic drugs such as SN38 and formed well-dispersible nanoparticles, which reduced its aggregation-induced quenching and thus greatly improved its photodynamic efficiency. The loaded hydrophobic drugs elicited chemotherapy synergizing the photodynamic therapy, giving rise to much enhanced antitumor activity in vitro and in vivo against human glioblastoma cells and breast cancer cells upon NIR irradiation. The work demonstrates the fabrication of readily translational nanoformulations of hydrophobic drugs using amphiphilic drugs.

3.
Toxicol Appl Pharmacol ; 395: 114979, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32234517

RESUMO

Epidemiology suggests that adverse environmental exposure during pregnancy may predispose children to hypercholesterolemia in adulthood. This study aimed to demonstrate hypercholesterolemia induced by prenatal dexamethasone exposure (PDE) in adult male offspring rats and explore the intrauterine programming mechanisms. Pregnant Wistar rats were injected subcutaneously with dexamethasone (0, 0.1, 0.2, and 0.4 mg/kg∙d) from gestational days (GD) 9 to 21, and the serum and liver of the male offsprings were collected at GD21, postnatal week (PW) 12 and 28. Furthermore, the effects of dexamethasone on the expression of low-density lipoprotein receptor (LDLR) and its epigenetic mechanism was confirmed in the bone marrow mesenchymal stem cells (BMSCs) hepatoid differentiated cells and continuous hepatocyte line. PDE could reduce the birth weight of male offsprings, increase the serum total cholesterol (TCH) level in adult rats, and decrease the liver low-density lipoprotein receptor (LDLR) expression. Serum TCH level and liver LDLR expression were decreased in PDE male fetuses in utero (GD21). Moreover, PDE increased the translocation of the glucocorticoid receptor (GR) in the fetal liver, the expression of DiGeorge syndrome critical region 8 gene (DGCR8), the pre- and post-natal expression of miR-148a. The results of PDE offspring in vivo and in vitro exhibited similar changes. These changes could be reversed by overexpressing LDLR, inhibiting miR-148a or GR. PDE caused hypercholesterolemia in male adult offspring rats, which was mediated via dexamethasone activated intrauterine hepatic GR, enhanced the expression of DGCR8 and miR-148a, thereby reducing the expression of LDLR, leading to impaired liver cholesterol reverse transport function, and finally causing hypercholesterolemia in adult rats.

4.
Biomed Pharmacother ; 125: 110032, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32187961

RESUMO

This study was devised to investigate if P-glycoprotein (P-gp) mediated the drug-drug interaction (DDI) between genistein and repaglinide. When genistein was added, the plasma concentrations of repaglinide in rats were increased. The maximum plasma concentration (Cmax) of repaglinide increased from 70.80 ± 7.98 ng/mL to 124.71 ± 9.02 ng/mL and the area under the plasma concentration-time curve (AUC) increased from 134.89 ± 13.65 µg·h/L to 245.95 ± 7.24 µg·h/L. Intestinal absorption of repaglinide was markedly enhanced by genistein or P-gp inhibitor verapamil (Ver), both in situ rat jejunal perfusion studies and in vitro transport assays using everted rat intestinal sac preparations. Furthermore, the accumulation of repaglinide in both Caco-2 cells and IEC-6 cells also increased significantly in the presence of genistein and Ver. The transepithelial transport rate of repaglinide from basolateral-to-apical in MDR1-MDCK cells was 3.6-fold higher than the apical-to-basolateral rate with a net efflux ratio of 1.92 compared with mock-MDCK cells, which was significantly decreased following co-administration with genistein or Ver. In an intracellular accumulation experiment using Rhodamine 123 as a P-gp substrate, genistein significantly increased the intracellular fluorescence of Rhodamine 123. These results indicated that genistein had an inhibitory effect on the efflux function of P-gp. Through molecular docking assays we further found that genistein could bind to the nucleotide-binding domains (NBD) in the cytoplasm of P-gp, thus affecting the functions of P-gp. In conclusion, genistein inhibited the efflux of repaglinide mediated by P-gp in rats and in vitro. The findings suggested that the DDI between genistein and repaglinide is mediated by P-gp, and a dosage adjustment may be needed when they are co-administered in a clinical setting.

5.
J Proteome Res ; 19(5): 1982-1990, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32182071

RESUMO

Pressure cycling technology (PCT)-assisted tissue lysis and digestion have facilitated reproducible and high-throughput proteomic studies of both fresh-frozen (FF) and formalin-fixed paraffin-embedded (FFPE) tissue of biopsy scale for biomarker discovery. Here, we present an improved PCT method accelerating the conventional procedures by about two-fold without sacrificing peptide yield, digestion efficiency, peptide, and protein identification. The time required for processing 16 tissue samples from tissues to peptides is reduced from about 6 to about 3 h. We analyzed peptides prepared from FFPE hepatocellular carcinoma (HCC) tissue samples by the accelerated PCT method using multiple MS acquisition methods, including short-gradient SWATH-MS, PulseDIA-MS, and 10-plex TMT-based shotgun MS. The data showed that up to 8541 protein groups could be reliably quantified from the thus prepared peptide samples. We applied the accelerated sample preparation method to 25 pairs (tumorous and matched benign) of HCC samples followed by a single-shot, 15 min gradient SWATH-MS analysis. An average of 18 453 peptides from 2822 proteins were quantified in at least 20% samples in this cohort, while 1817 proteins were quantified in at least 50% samples. The data not only identified the previously known dysregulated proteins such as MCM7, MAPRE1, and SSRP1 but also discovered promising novel protein markers, including DRAP1 and PRMT5. In summary, we present an accelerated PCT protocol that effectively doubles the throughput of PCT-assisted sample preparation of biopsy-level FF and FFPE samples without compromising protein digestion efficiency, peptide yield, and protein identification.

6.
Int J Biol Macromol ; 152: 295-304, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32112833

RESUMO

In order to obtain the effective antidiabetic polysaccharide derivative, a selenylated polysaccharide (Se-MCPIIa-1), with an average molecular weight (MW) of 4.0038 × 104 Da, was synthesized by reduction of sodium selenite with ascorbic acid in the presence of Momordica polysaccharides (MCPIIa). The selenium (Se) content of Se-MCPIIa-1 was up to 445.0 µg/g, and its average diameter of monodisperse spherical particle size was around 63.78 nm. The morphology and physicochemical properties of Se-MCPIIa-1 were characterized by scanning electron microscope (SEM), atomic force microscope (AFM), Fourier transform infrared spectrometry (FT-IR) and Raman spectroscopy, respectively. The results indicated that Se was conjunct with MCPIIa by esterification. Moreover, the oral administration of Se-MCPIIa-1 showed a gradual normalization in the levels of hypoglyemic test in the STZ-induced diabetic mice. The anti-diabetic effects of Se-MCPIIa-1 in vivo showed that Se-MCPIIa-1 can significantly reduce fasting blood glucose levels and enhance insulin levels as well as antioxidant enzyme activities in diabetic mice with an optimal dosage of 20 mg/kg/body weight. In addition, it was found from histopathological data that Se-MCPIIa-1 could prevent pancreatic islets, liver and kidney damage from diabetes, which suggested that Se-MCPIIa-1 is a promising novel Se supplement and could be applied in the field of food and medicine.

7.
Aging (Albany NY) ; 12(3): 2049-2069, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32023549

RESUMO

Hepatic steatosis and oxidative stress are considered to be the sequential steps in the development of non-alcoholic fatty liver disease (NAFLD). We previously found that catalpol, an iridoid glucoside extracted from the root of Romania glutinosa L, protected against diabetes-induced hepatic oxidative stress. Here, we found that the increased expression of p66shc was observed in NAFLD models and catalpol could inhibit p66shc expression to ameliorate NAFLD effectively. However, the underlying mechanisms remained unknown. The aim of the present study was to investigate the p66shc-targeting miRNAs in regulating oxidative stress and hepatic steatosis, also the mechanisms of catalpol inhibiting NAFLD. We found that the effects of catalpol inhibiting hepatic oxidative stress and steasis are dependent on inhibiting P66Shc expression. In addition, miR-96-5p was able to suppress p66shc/cytochrome C cascade via targeting p66shc mRNA 3'UTR, and catalpol could lead to suppression of NAFLD via upregulating miR-96-5p level. Thus, catalpol was effective in ameliorating NAFLD, and miR-96-5p/p66shc/cytochrome C cascade might be a potential target.

9.
J Agric Food Chem ; 68(7): 2232-2239, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31986031

RESUMO

An antioxidant peptide derived from egg white, Asp-His-Thr-Lys-Glu (DHTKE), possesses specific amino acids related to zinc delivery. This study aimed to demonstrate the molecular basis of interactions between the egg white peptide (DHTKE) and zinc ions and investigate the effect of the DHTKE-Zn complex on zinc delivery through the gastrointestinal system. Approximately one DHTKE molecule can bind one zinc ion (n = 1.048 ± 0.085) through its carboxyl, amino, and imidazole nitrogen groups on Asp, His, and Glu. The formed DHTKE-Zn complex presented uniformly distributed globular particles with a particle size of 100-500 nm and underwent dissociation and re-chelation during gastrointestinal digestion. Moreover, the DHTKE peptide mostly remained stable, with a retention rate of 98.32% under gastrointestinal digestion, although one degradation product (DHTK) was identified by nanoscale liquid chromatography-electrospray ionization-tandem mass spectrometry in the gastrointestinal digests; the effectiveness of DHTKE-Zn digests on enhancing absorption of zinc was comparable to that of the initial complex.


Assuntos
Antioxidantes/química , Portadores de Fármacos/química , Clara de Ovo/química , Trato Gastrointestinal/metabolismo , Peptídeos/química , Zinco/química , Sequência de Aminoácidos , Animais , Galinhas , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Masculino , Ratos , Ratos Wistar , Espectrometria de Massas por Ionização por Electrospray , Zinco/metabolismo
10.
Br J Pharmacol ; 177(9): 1933-1948, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32000294

RESUMO

BACKGROUND AND PURPOSE: Diclofenac is a widely used nonsteroidal anti-inflammatory drug. However, adverse effects in the kidney limit its clinical application. The present study was aimed to evaluate the potential effect of cilastatin on diclofenac-induced acute kidney injury and to clarify the potential roles of renal organic anion transporters (OATs) in the drug-drug interaction between cilastatin and diclofenac. EXPERIMENTAL APPROACH: The effect of cilastatin was evaluated in diclofenac-induced acute kidney injury in mice. Human OAT1/3-transfected HEK293 cells and renal primary proximal tubule cells (RPTCs) were used to investigate OAT1/3-mediated transport and the cytotoxicity of diclofenac. KEY RESULTS: Cilastatin treatment decreased the pathological changes, renal dysfunction and elevated renal levels of oxidation products, cytokine production and apoptosis induced by diclofenac in mice. Moreover, cilastatin increased the plasma concentration and decreased the renal distribution of diclofenac and its glucuronide metabolite, diclofenac acyl glucuronide (DLF-AG). Similarly, cilastatin inhibited cytotoxicity and mitochondrial damage in RPTCs but did not change the intracellular accumulation of diclofenac. DLF-AG but not diclofenac exhibited OAT-dependent cytotoxicity and was identified as an OAT1/3 substrate. Cilastatin inhibited the intracellular accumulation and decreased the cytotoxicity of DLF-AG in RPTCs. CONCLUSION AND IMPLICATIONS: Cilastatin alleviated diclofenac-induced acute kidney injury in mice by restoring the redox balance, suppressing inflammation, and reducing apoptosis. Cilastatin inhibited OATs and decreased the renal distribution of diclofenac and DLF-AG, which further ameliorated the diclofenac-induced nephrotoxicity in mice. Cilastatin can be potentially used in the clinic as a therapeutic agent to alleviate the adverse renal reaction to diclofenac.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31940566

RESUMO

This article addresses the leader-following consensus of a class of multi-agent systems (MASs) subjected to saturation. Unlike previous literature, the followers are with heterogeneous dynamics. To solve this problem, we employ the low-gain feedback technique and the parameterized algebraic Riccati equations to design the controllers. For the fixed and switching network topologies, sufficient conditions are put in place to guarantee the semiglobal stability of the consensus error system. Numerical results are also provided to validate the effectiveness of the control design.

12.
Bioorg Chem ; 95: 103542, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31918398

RESUMO

JAK3 is predominantly expressed in hematopoietic cells and has been a promising therapeutic target for the treatment of B-cell lymphoma. In this study, a new class of thieno[3,2-d]pyrimidines harboring acrylamide pharmacophore were synthesized as potent covalent JAK3 inhibitors (IC50 < 10 nM). Among them, 9a and 9 g displayed the strongest inhibitory potency against JAK3 kinase activity, with IC50 values of 1.9 nM and 1.8 nM, respectively. Furthermore, compared with the reference agents, Spebrutinib and Ibrutinib, 9a not only demonstrated enhanced antiproliferative activity against B lymphoma cells, but also showed very weak proliferative inhibition against normal peripheral blood mononuclear cells (PBMCs) at a concentration of 20 µM. Analysis of the mechanism revealed that 9a could induce the obvious apoptosis in B lymphoma cells and prevent JAK3-STAT3 cascade as well as BTK pathway. Taken together, 9a may be served as a potential new JAK3 inhibitor for the treatment of B-cell lymphoma.

13.
Bioresour Technol ; 301: 122723, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31962245

RESUMO

During the municipal solid waste (MSW) composting, antibiotic resistance genes (ARGs) could be one of the concerns to hinder the application of MSW composting. However, the understanding of enrichment and dissemination of ARGs during the industrial-scale composting is still not clear. Hence, this study aimed to investigate the ARG distributions at different stages in an industrial-scale MSW composting plant. Seven target ARGs and four target mobile genetic elements (MGEs) and bacterial communities were investigated. The abundances of ARGs and MGEs increased during two aerobic thermophilic stages, but they decreased in most ARGs and MGEs after composting. Network analysis showed that potential host bacteria of ARGs were mainly Firmicutes and Actinobacteria. The reduction of potential host bacteria was important to remove ARGs. MGEs were an important factor hindering ARG removal. Water-extractable S and pH were two main physicochemical factors in the changes of microbial community and the abundance of ARGs.


Assuntos
Compostagem , Antibacterianos , Resistência Microbiana a Medicamentos , Genes Bacterianos , Sequências Repetitivas Dispersas , Esterco , Resíduos Sólidos
14.
J Cell Physiol ; 235(4): 3309-3319, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31587272

RESUMO

The aim of this study was to explore whether rhein could enhance the effects of pemetrexed (PTX) on the therapy of non-small-cell lung cancer (NSCLC) and to clarify the associated molecular mechanism. Our study shows that rhein in combination with PTX could obviously increase the systemic exposure of PTX in rats, which would be mediated by the inhibition of organic anion transporters (OATs). Furthermore, the toxicity of PTX was significantly raised by rhein in A549 cells in a concentration-dependent manner. Concomitant administration of rhein and PTX-induced cell apoptosis compared with PTX alone in flow cytometry assays, which was further validated by the protein expressions of the apoptotic markers B-cell lymphoma-2/Bcl-2-associated x (Bcl-2/Bax) and Cleaved-Caspase3 (Cl-Caspase3). Meanwhile, the results of monodansylcadaverine (MDC) dyeing experiments showed that PTX-induced autophagy could be enhanced by combination therapy with rhein in A549 cells. Western blot analysis indicated that the synergistic effect of rhein on PTX-mediated autophagy may be interrelated to PI3K-AKT-mTOR pathway inhibition and to the enhancement of p-AMPK and light chain 3-II (LC3-II) protein levels. From these findings, it could be surmised that rhein enhanced the antitumor activity of PTX through influencing autophagy and apoptosis by modulating the PI3K-AKT-mTOR pathway and Bcl-2 family of proteins in A549 cells. Our findings demonstrated that the potential application of rhein as a candidate drug in combination with PTX is promising for treatment of the human lung cancer.

15.
ChemMedChem ; 15(2): 182-187, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31755225

RESUMO

A new class of pyrimidine derivatives were identified as potent protein tyrosine kinase (PTK) inhibitors for the treatment of idiopathic pulmonary fibrosis (IPF). Most of these small-molecule inhibitors displayed strong enzymatic activity against BTK and JAK3 kinases at concentrations lower than 10 nM. The representative compound N-(3-((5-chloro-2-(4-((1-morpholino)acetylamino)phenylamino)-4-pyrimidinyl)amino)phenyl)acrylamide (6 a) also exhibited high inhibitory potency toward both BTK and JAK kinase families, as well as ErbB4, at a concentration of 10 nM, achieving rates of inhibition higher than 57 %. Additionally, in vivo biological evaluations showed that 6 a can remarkably decrease the severity of IPF disease. All these investigations suggested that the multi-PTK inhibitor 6 a may serve as a promising agent for the treatment of IPF.

16.
Bioorg Chem ; 94: 103408, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31706682

RESUMO

A new class of pyrimidine derivatives were designed and synthesized as potential dual FAK and EGFRT790M inhibitors using a fragment-based drug design strategy. This effort led to the identification of the two most active inhibitors, namely 9a and 9f, against both FAK (IC50 = 1.03 and 3.05 nM, respectively) and EGFRT790M (IC50 = 3.89 and 7.13 nM, respectively) kinase activity. Moreover, most of these compounds also exhibited strong antiproliferative activity against the three evaluated FAK-overexpressing pancreatic cancer (PC) cells (AsPC-1, BxPC-3, Panc-1) and two drug-resistant cancer cell lines (breast cancer MCF-7/adr cells and lung cancer H1975 cells) at concentrations lower than 6.936 µM. In addition, 9a was also effective in the in vivo assessment conducted in a FAK-driven human AsPC-1 cell xenograft mouse model. Overall, this study offers a new insight into the treatment of hard to treat cancers.

17.
Bioorg Med Chem ; 28(2): 115254, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31866272

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a serious and fatal lung disease, with a median survival of only 3-5 years from diagnosis. Janus kinase 3 (JAK3) has a well-established role in the pathogenesis of various autoimmune diseases, including rheumatoid arthritis (RA) and autoimmune-related pulmonary fibrosis. In this study, through the use of a conformationally-constrained design strategy, a series of thieno[3,2-d]pyrimidines were synthesized as potent JAK3 inhibitors for the treatment of IPF. Among them, the most potent JAK3 inhibitor, namely 8e (IC50 = 1.38 nM), significantly reduced the degree of airsacculitis and fibrosis according to hematoxylin-eosin (HE) staining assay for the lung tissue in the bleomycin (BLM)-induced pulmonary fibrosis mouse model. The clear reduction of the lung collagen deposition by the determination of Masson and hydroxyproline (HYP) content also demonstrated its efficacy in the treatment of fibrosis. In addition, 8e also reduced the expression of the inflammatory markers IL-6, IL-17A, TNF-α and malondialdehyde (MDA) in lung tissue, which indicated its higher anti-inflammatory activity compared with that of the reference agents (nintedanib and gefitinib). Furthermore, it possessed low cytotoxicity against normal human bronchial epithelia (HBE) cells (IC50 > 39.0 µM) and C57BL mice. All these evaluated biological properties suggest that 8e may be a potential JAK3 inhibitor for the treatment of IPF.

18.
iScience ; 21: 664-680, 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31733513

RESUMO

Here we describe a proteomic data resource for the NCI-60 cell lines generated by pressure cycling technology and SWATH mass spectrometry. We developed the DIA-expert software to curate and visualize the SWATH data, leading to reproducible detection of over 3,100 SwissProt proteotypic proteins and systematic quantification of pathway activities. Stoichiometric relationships of interacting proteins for DNA replication, repair, the chromatin remodeling NuRD complex, ß-catenin, RNA metabolism, and prefoldins are more evident than that at the mRNA level. The data are available in CellMiner (discover.nci.nih.gov/cellminercdb and discover.nci.nih.gov/cellminer), allowing casual users to test hypotheses and perform integrative, cross-database analyses of multi-omic drug response correlations for over 20,000 drugs. We demonstrate the value of proteome data in predicting drug response for over 240 clinically relevant chemotherapeutic and targeted therapies. In summary, we present a novel proteome resource for the NCI-60, together with relevant software tools, and demonstrate the benefit of proteome analyses.

20.
Cytotechnology ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712922

RESUMO

In the original publication, the AO/EB fluorescent staining result of A549 cells treated with high dose of ZJW for 24 h was repeatedly pasted to those treated with high dose of ZJW for 48 h in Figure 4 due to negligence. In the corrected Fig. 4, we have provided the correct AO/EB result of A549 cells treated with high dose of ZJW for 48 h, which showed no influence to the results.

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