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Ning Du,1,* Dan You,2,* Dava Tenzing,3 Dongxiang Qu,2 Jun Meng,1,* Yihui Wang,4,* Juan He5,* 1Department of Pharmacy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, Guangdong Province, People’s Republic of China; 2Department of Pharmacy, The First Hospital of Qiqihar, Qiqihar, Heilongjiang Province, People’s Republic of China; 3Department of Emergency, People’s Hospital of Shigatse City, Shigatse, Xizang Autonomous Region, People’s Republic of China; 4Department of Emergency, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 5Department of Pharmacy, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Juan He, Department of Pharmacy, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China, Email hejuanwin@126.com Yihui Wang, Department of Emergency, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China, Email wangyihui581@163.comPurpose: Infection with carbapenem-resistant Acinetobacter baumannii (CRAB) is a tough nut to crack. Carrimycin is a novel recombinant macrolide antibiotic, and has good anti-infection effects in vivo. At present, it is rarely reported for treatment of CRAB infection. We present a case where a patient with COVID-19 complicated by CRAB infection was successfully treated with a combination therapy including carrimycin, offering clinical insights and experience.Patients and Methods: The patient infected with CRAB was cured by carrimycin combined with tigecycline and amikacin ultimately. We analyzed and summarized the therapeutic regimen and disease feature to provide reference for clinical treatment.Results: The patient was admitted to emergency observation wards with fever and was diagnosed with COVID-19 pneumonia. During the treatment, his condition worsened. He had a fever, cough, and expectoration. After 3 days of empirical treatment with meropenem, tested positive for A. baumannii infection by the next-generation sequencing, and CRAB was detected in blood and sputum culture. Then, he was administered with tigecycline and amikacin immediately for 5 days, however the therapeutic effect was not significant. The patient still remained in a high inflammatory response. Ultimately, the treatment regimen was changed to carrimycin combined with tigecycline and amikacin for 7 days, and then carrimycin combined with tigecycline for 10 days, the patient’s clinical condition gradually improved. The patient received carrimycin monotherapy for 7 days, then discharged.Conclusion: Carrimycin may be a bright alternative for CRAB infection as one of the drugs in combination therapy, especially in a patient with hyperinflammatory response.Keywords: Carrimycin, Carbapenem-resistant Acinetobacter baumannii, CRAB, case report

Xinyu Fan,1,2,* Jiachen Shi,1,* Ye Liu,3 Mengqiu Zhang,1 Min Lu,1,2 Ding Qu1,2 1Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 2Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, People’s Republic of China; 3The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Min Lu, Jiangsu Province Academy of Traditional Chinese Medicine, 100 Shizi Street, Hongshan Road Nanjing 210028, People’s Republic of China, Email lmxlsr6666@163.com Ding Qu, Jiangsu Province Academy of Traditional Chinese Medicine, 100 Shizi Street, Hongshan Road, Nanjing, 210028, People’s Republic of China, Email quding1985@hotmail.comBackground: Berberine (BR) shows promise as a candidate for treating irritable bowel syndrome with diarrhea (IBS-D). However, the undesired physicochemical properties and poor oral absorption limit its clinical translation. A ketogenic diet (KD) can induce intestinal overexpression of cannabidiol (CB) receptors, which may offer a potential target for IBS-D-specific delivery of BR.Methods: The microemulsions loaded with BR and decorated with cannabidiol (CBD/BR-MEs) were developed through a one-step emulsion method. The pharmaceutical behaviors of the CBD/BR-MEs were measured using dynamic light scattering and high-performance liquid chromatography. The efficacy of the anti-IBS-D therapy was evaluated by assessing fecal water content, Bristol score, and AWR score. The intestinal permeability were assessed through immunofluorescent staining of CB1 and ZO-1, respectively. The signaling of CREB/BDNF/c-Fos was also studied along with immunofluorescent and immunohistochemical examination of brain sections.Results: The CBD/BR-MEs, which had a particle size of approximately 30 nm and a surface density of 2% (wt%) CBD, achieved greater than 80% (wt%) encapsulation efficiency of BR. The pharmacokinetics performance of CBD/BR-MEs was significantly improved in the KD-fed IBS-D rats than the standard diet-fed ones, which is highly related to intestinal expression of CB1 receptors. The treatment with CBD/BR-MEs and KD exhibited evident comprehensive advantages over the other groups in terms of anti-IBS-D efficacy. CBD/BR-MEs and KD synergistically decreased intestinal permeability. Moreover, the treatment with CBD/BR-MEs and KD not only blocked the CREB/BDNF/c-Fos signaling in the brain but also decreased the levels of neurotrophic factors, neurotransmitters, and inflammatory cytokines in the serum of IBS-D model rats.Conclusion: Such a design represents the first attempt at IBS-D-targeted drug delivery for improved oral absorption and efficacy through KD-induced target exposure, which holds promising potential for the treatment of IBS-D.Keywords: irritable bowel syndrome-diarrhea, berberine, microemulsion, ketogenic diet, CB1 receptors

Wen Zhang,1,* Yong Li,2,* Liyan Xue,3 Dong Qu,4 Zhichao Jiang,1 Zhen Wang,2 Zhaoyang Yang,3 Aiping Zhou1 1Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China; 2Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China; 3Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China; 4Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Aiping Zhou Email zhouap1825@126.comObjective: To evaluate the efficacy and safety of neoadjuvant chemotherapy with albumin-bound paclitaxel plus cisplatin and capecitabine for locally advanced esophageal squamous cell carcinoma (ESCC).Methods: The data of thirty-one patients with locally advanced ESCC (cT1-2N+M0, cT3-4aNanyM0) received preoperative chemotherapy with albumin-bound paclitaxel plus cisplatin and capecitabine (referred as APCC regimen) were retrospectively analysed. The primary endpoint was pathological complete response (pCR) rate.Results: The median number of chemotherapy cycles with APCC regimen every 3 weeks were 4 (range: 1– 6), which was completed by 23 patients. The clinical efficacy of 30 patients was evaluated and all showed reduction of tumours in varying degrees. Five patients received radiotherapy following chemotherapy. Four patients could not receive surgery due to COVID-19 pandemic. Of the 24 patients who underwent surgery, 3 received radiotherapy following chemotherapy, the resection rate of R0 was 95.8%, 9 cases (37.5%) showed pCR and 16 cases (66.7%) showed major pathological response (MPR). Postoperative pathology of 15 cases (62.5%) were stage I (ypT0-2N0M0). Of the 21 patients who underwent surgery after neoadjuvant chemotherapy alone, 8 (38.1%) had pCR and 15 (71.4%) had MPR. The most common grade 3/4 adverse events of chemotherapy included neutropenia (35.5%) and leukopenia (9.7%). Grade 2 postoperative complications occurred in 3 (12.5%) patients.Conclusion: The preliminary results of this study suggest that preoperative chemotherapy with the triplet regimen of albumin-bound paclitaxel, cisplatin and capecitabine for patients with locally advanced ESCC revealed significant tumour downstage and encouraging pCR rate, with well-tolerable toxicities. The role of this regimen warrants further investigation.Keywords: albumin-bound paclitaxel, cisplatin, capecitabine, esophageal squamous cell carcinoma, neoadjuvant chemotherapy, pathological complete response

Daofeng Qu,1,2 Yang Shen,2 Lingfei Hu,1 Xiaoyuan Jiang,1 Zhe Yin,1 Bo Gao,1 Yuee Zhao,1 Wenhui Yang,1 Huiying Yang,1 Jianzhong Han,2 Dongsheng Zhou1 1State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China; 2School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, China Background: IncR, IncFII, IncpA1763-KPC, and IncN1 plasmids have been increasingly found among Enterobacteriaceae species, but plasmids with hybrid structures derived from the above-mentioned incompatibility groups have not yet been described.Methods: Plasmids p721005-KPC, p504051-KPC, and pA3295-KPC were fully sequenced and compared with previously sequenced related plasmids pHN84KPC (IncR), pKPHS2 (IncFIIK), pKOX_NDM1 (IncFIIY), pHN7A8 (IncFIIpHN7A8), and R46 (IncN1).Results: The backbone of p721005-KPC/p504051-KPC was a hybrid of the entire 10-kb IncR-type backbone from pHN84KPC, the entire 64.3-kb IncFIIK-type maintenance, and conjugal transfer regions from pKPHS2, a 15.5-kb IncFIIY-type maintenance region from pKOX_NDM1 and a 5.6-kb IncpA1763-KPC-type backbone region from pA1763-KPC, and it contained a primary IncR replicon and two auxiliary IncpA1763-KPC and IncN1 replicons. The backbone of pA3295-KPC was a hybrid of a 7.2-kb IncFIIpHN7A8-type backbone region from pHN7A8, the almost entire 33.3-kb IncN1-type maintenance and conjugal transfer regions highly similar to R46, a 26.2-kb IncFIIK-type maintenance regions from pKPHS2, the above 15.5-kb IncFIIY-type maintenance region, and the above 5.6-kb IncpA1763-KPC-type backbone region, and it contained a primary IncFIIpHN7A8 replicon and two auxiliary IncpA1763-KPC and IncN1 replicons. Each of p721005-KPC, p504051-KPC, and pA3295-KPC acquired a wealth of accessory modules, carrying a range of intact and residue mobile elements (such as insertion sequences, unit transposons, and integrons) and resistance markers (such as blaKPC, tetA, dfrA, and qnr).Conclusion: In each of p721005-KPC, p504051-KPC, and pA3295-KPC, multiple replicons in coordination with maintenance and conjugation regions of various origins would maintain a broad host range and a stable replication at a steady-state plasmid copy number. Keywords: multi-replicon plasmids, multi-drug resistance, blaKPC-2, mobile elements

Yunyan Chen,1–3 Ding Qu,1,2 Rongping Fu,1,2 Mengfei Guo,1,2 Yue Qin,1,2 Jian Guo,1,2 Yan Chen1,2 1Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China; 2Research Center for Multicomponent of Traditional Chinese Medicine and Microecology, Jiangsu Provincial Academy of Traditional Chinese Medicine, Nanjing 210028, China; 3Wannan Medical College, Wuhu 241002, China Purpose: A transferrin-modified microemulsion carrying coix seed oil and tripterine (Tf-CT-MEs) was developed for improved tumor-specific accumulation and penetration to enhance cervical cancer treatment. Materials and methods: Tripterine-loaded coix seed oil microemulsion (CT-MEs) was prepared through one-step emulsion method. The morphology, size, and zeta potential of CT-MEs and Tf-CT-MEs were examined by transmission electron microscopy and dynamic light scattering. The cellular uptake and mechanisms of HeLa cells were investigated by flow cytometry. Intratumor penetration was investigated using a HeLa three-dimensional (3D) tumor spheroid as the model. The cytotoxicity of the CT-MEs and Tf-CT-MEs against HeLa cells were evaluated by the MTT assay. Additionally, the apoptotic rate of CT-MEs and Tf-CT-MEs inducing apoptosis in HeLa cells was evaluated. Results: In the physicochemical characterization, coix seed oil and CT-MEs exhibited a small size (32.47±0.15 nm) and nearly neutral surface charge (-0.36±0.11 mV). After modification with transferrin, the particle size of Tf-CT-MEs slightly increased to 40.02±0.21 nm, but the zeta potential decreased remarkably to -13.63±1.31 mV. The IC50 of Tf-CT-MEs against HeLa cells was 0.7260 µM, which was 2.58-fold lower than that of CT-MEs. In cellular studies, the intracellular fluorescence intensity of fluorescein isothiocyanate (FITC)-labeled Tf-CT-MEs (FITC/Tf-CT-MEs) was 2.28-fold higher than that of FITC-labeled CT-MEs (FITC/CT-MEs). The fluorescence signal of Tf-CT-MEs was observed at 350 µm below the surface of the 3D tumor spheroid. The apoptotic rate of cells treated with Tf-CT-MEs was 1.73- and 2.77-fold higher than that of cells treated with CT-MEs and tripterine, respectively, which was associated with mitochondrial-targeted delivery of tripterine. Moreover, Tf-CT-MEs was capable of significantly downregulating the cellular level of antiapoptotic proteins and arrested cell proliferation in the G2/M phase. Conclusion: Taken together, Tf-CT-MEs holds promising potential to be an efficient drug delivery system for combinational therapy of cervical cancer. Keywords: tripterine, coix seed oil, microemulsion, deep penetration, anti-cervical cancer

Ding Qu,1,2 Mingjian Liu,1 Mengmeng Huang,1,2 Lixiang Wang,1 Yan Chen,1,2 Congyan Liu,1,2 Yuping Liu1,2 1Research Center for Multicomponent Traditional Medicine and Microecology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 2Research Center for Multicomponent Traditional Medicine and Microecology, Jiangsu Provincial Academy of Traditional Chinese Medicine, Nanjing, People’s Republic of China Abstract: A nanosized drug delivery platform with a combination of rational components and tumor targeting is significant for enhancement of anticancer therapy and reduction of side effects. In this study, we developed a octanoyl galactose ester-modified microemulsion system self-assembled by coix seed components (Gal(oct)-C-MEs), which improved the tumor accumulation through asialoglycoprotein receptor-mediated endocytosis and promoted the antitumor efficacy through multicomponent-mediated synergistic effect. Octanoyl galactose ester (Gal(oct)) with a yield of 82.3% was synthesized through a green enzymatic reaction and multidimensional characterization. Gal(oct)-C-MEs with a spherical shape had a small and uniform particle size (58.49±1.03 nm), narrow polydispersity index (0.09±0.01) and neutral surface charge (-5.82±0.57 mV). In the cellular uptake studies, the internalized Gal(oct)-C-ME was 2.28-fold higher relative to that of coix seed component-based microemulsions (C-MEs). The half-maximal inhibitory concentration of Gal(oct)-C-MEs against HepG2 cells was 46.5±2.4 µg/mL, which was notably higher than that of C-MEs. Importantly, the intratumor fluorescence of HepG2 xenograft-bearing nude mice treated with Cy5/Gal(oct)-C-MEs was 1.9-fold higher relative to treatment with Cy5/C-MEs. In the study of antitumor efficacy in vivo, HepG2 xenograft-bearing nude mice intragastrically administered Gal(oct)-C-MEs for 14 days exhibited the strongest inhibition of tumor growth and the lowest toxicity against liver and kidney among all the treatments. In summary, Gal(oct)-C-ME, as a highly effective and safe anticancer drug delivery system, showed promising potential for hepatoma therapy. Keywords: coix seed oil, coixan, multicomponent-based microemulsion, hepatic targeting, antihepatoma, oral drug delivery system

Ding Qu,1 Yihua Ma,1 Wenjie Sun,1,2 Yan Chen,1 Jing Zhou,1 Congyan Liu,1 Mengmeng Huang1 1Key Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, 2Department of Pharmaceutics, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China Abstract: A microemulsion-based synergistic dual-drug codelivery system was developed for enhanced cell apoptosis by transporting coix seed oil and etoposide into A549 (human lung carcinoma) cells simultaneously. Results obtained by dynamic light scattering showed that an etoposide (VP16)-loaded coix seed oil microemulsion (EC-ME) delivery system had a small size around 35 nm, a narrow polydispersity index, and a slightly negative surface charge. The encapsulating efficiency and total drug loading rate were 97.01% and 45.48%, respectively, by high-performance liquid chromatography. The release profiles at various pH values showed an obvious pH-responsive difference, with the accumulated amount of VP16 released at pH 4.5 (and pH 5.5) being 2.7-fold higher relative to that at pH 7.4. Morphologic alteration (particle swelling) associated with a mildly acidic pH environment was found on transmission electron microscopy. In the cell study, the EC-ME system showed a significantly greater antiproliferative effect toward A549 cells in comparison with free VP16 and the mixture of VP16 and coix seed oil. The half-maximal inhibitory concentration of the EC-ME system was 3.9-fold and 10.4-fold lower relative to that of free VP16 and a mixture of VP16 and coix seed oil, respectively. Moreover, fluorescein isothiocyanate and VP16 (the green fluorescent probe and entrapped drug, respectively) were efficiently internalized into the cells by means of coix seed oil microemulsion through intuitive observation and quantitative measurement. Importantly, an EC-ME system containing 20 µg/mL of VP16 showed a 3.3-fold and 3.5-fold improvement in induction of cell apoptosis compared with the VP-16-loaded microemulsion and free VP16, respectively. The EC-ME combination strategy holds promise as an efficient drug delivery system for induction of apoptosis and treatment of lung cancer. Keywords: microemulsion, synergistic effect, dual-drug codelivery, coix seed oil, apoptosis induction

Wenjie Sun,1,2,* Ding Qu,1,* Yihua Ma,1 Yan Chen,1,2 Congyan Liu,1 Jing Zhou11Key Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, 2Department of Pharmaceutics, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China*These authors contributed equally to this workAbstract: Silver nanoparticles (AgNPs) are widely used as antibacterial products in various fields. Recent studies have suggested that AgNPs need an appropriate stabilizer to improve their stability. Some antibacterial traditional Chinese medicines (TCMs) contain various reductive components, which can not only stabilize AgNPs but also enhance their antimicrobial activity. In this study, we developed a series of novel AgNPs using a TCM extract as a stabilizer, reducing agent, and antimicrobial agent (TCM-AgNPs). A storage stability investigation of the TCM-AgNPs suggested a significant improvement when compared with bare AgNPs. Further, conjugation of TCMs onto the AgNP surface resulted in stronger antimicrobial potency on antibacterial evaluation using Pseudomonas aeruginosa, Staphylococcus epidermidis, and Staphylococcus aureus with minimum inhibitory concentration 50% (MIC50) ratios (and minimum bactericidal concentration 90% [MBC90] ratios) of AgNPs to respective TCM-AgNPs as assessment indices. Among these, P. cuspidatum Sieb. et-conjugated AgNPs (P.C.-AgNPs) had the advantage of a combination of TCMs and AgNPs and was studied in detail with regard to its synthesis and characterization. The extraction time, reaction temperature, and concentrations of AgNO3 and Polygonum cuspidatum Sieb. et extract were critical factors in the preparation of P.C.-AgNPs. Further, the results of X-ray diffraction and Fourier transform infrared spectroscopy indicated successful preparation of P.C.-AgNPs. In representative studies, P.C.-AgNPs showed a well-defined spherical shape, a homogeneous small particle size (36.78 nm), a narrow polydispersity index (0.105), and a highly negative zeta potential (-23.6 mV) on transmission electron microscopy and dynamic light scattering. These results indicate that TCM-AgNPs have a potential role as antibacterial agents in the clinic setting.Keywords: traditional Chinese medicine, extract, silver nanoparticles, stability, antibacterial, Polygonum cuspidatum Sieb. et

Ding Qu,1,* Wenjie Sun,1,2,* Yan Chen,1,2 Jing Zhou,1 Congyan Liu11Key Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, 2Department of Pharmaceutics, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, People's Republic of China*These authors contributed equally to this workAbstract: A rapid synthesis of silver nanoparticles (AgNPs) using Agrimoniae herba extract as reducing agent and stabilizer (A. herba-conjugated AgNPs [AH-AgNPs]) were designed, characterized, and evaluated for antitumor therapy feasibility. In this study, critical factors in the preparation of silver nanoparticles, including extraction time, reaction temperature, the concentration of AgNO3, and A. herba extract amount, were investigated using ultraviolet-visible spectroscopy. AH-AgNPs with well-defined spherical shape, homogeneous distributional small size (30.34 nm), narrow polydispersity index (0.142), and high negative zeta potential (−36.8 mV) were observed by transmission electron microscopy and dynamic light scattering. Furthermore, the results of X-ray diffraction and Fourier-transform infrared spectroscopy further indicated successful preparation of AH-AgNPs. Acceptable long-term storage stability of AH-AgNPs was also confirmed. More importantly, AH-AgNPs displayed significantly higher antiproliferative effect against a human lung carcinoma cell line (A549 cells) compared with A. herba extract and bare AgNPs prepared by sodium citrate. The half-maximal inhibitory concentrations of AH-AgNPs, bare AgNPs, and A. herba extract were 38.13 µg · mL-1, 184.87 µg · mL-1, and 1.147 × 104 µg · mL-1, respectively. It is suggested that AH-AgNPs exhibit a strong antineoplastic effect on A549 cells, pointing to feasibility of antitumor treatment in the future.Keywords: rapid synthesis, Agrimoniae herba extract, silver nanoparticles, A549 cells, antitumor

Ding Qu, Junjie He, Congyan Liu, Jing Zhou, Yan ChenKey Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Jiangsu, People’s Republic of ChinaAbstract: Ganoderma lucidum triterpene-loaded microemulsions (TMEs) using Coix lacryma-jobi (adlay) seed oil as oil phase were prepared, characterized, and evaluated for enhanced antitumor activity. Ternary phase diagrams for the TMEs were constructed and the optimal preparation was developed. Transmission electron microscopy and dynamic light scattering showed that this formulation had a well defined spherical shape, a homogeneous distribution, a small size, and a narrow polydispersity index. The drug-loading rate was determined to be 9.87% by ultraviolet spectrophotometry, and acceptable stability under various stimulations in vitro was confirmed. Importantly, the TME formulation showed a significantly greater antiproliferative effect towards human lung carcinoma (A549) cells and murine lung tumor (Lewis) cells in comparison with suspension formulations containing triterpene and adlay seed oil as a positive control. The half-maximal inhibitory concentration of the TMEs was about 0.62 mg crude drug per mL, being 2.5-fold improved relative to that of the corresponding suspension formulation, but no significant cytotoxicity was observed for the bare microemulsion in A549 cells and Lewis cells. In vivo, the TME formulation showed markedly enhanced antitumor efficacy in a xenograft model of Lewis lung cancer after intragastric administration. Compared with cyclophosphamide, the TME formulation showed similar antitumor activity but less general toxicity. These results indicate the feasibility of using a microemulsion to increase the solubility of triterpene and adlay. TMEs hold promise as an efficient drug delivery system for the treatment of lung cancer.Keywords: microemulsion, Ganoderma lucidum, triterpene, adlay seed oil, lung cancer

Ling Yuan,1 Congyan Liu,2 Yan Chen,2 Zhenhai Zhang,2 Lei Zhou,1 Ding Qu2 1Department of Pharmaceutics, School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, 2Key Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Provincial Academy of Chinese Medicine, Nanjing, Jiangsu, People's Republic of China Background: The purpose of this study was to evaluate the antitumor effect of cell-penetrating peptide-coated tripterine-loaded nanostructured lipid carriers (CT-NLC) on prostate tumor cells in vitro and in vivo. Methods: CT-NLC were developed to improve the hydrophilicity of tripterine. The antiproliferative effects of CT-NLC, tripterine-loaded nanostructured lipid carriers (T-NLC), and free tripterine in a human prostatic carcinoma cell line (PC-3) and a mouse prostate carcinoma cell line (RM-1) were evaluated using an MTT assay. The advantage of CT-NLC over T-NLC and free tripterine with regard to antitumor activity in vivo was evaluated in a prostate tumor-bearing mouse model. The induced tumor necrosis factor-alpha and interleukin-6 cytokine content was investigated by enzyme-linked immunosorbent assay to determine the effect of CT-NLC, T-NLC, and free tripterine on immune responses. Histologic and TUNEL assays were carried out to investigate the mechanisms of tumor necrosis and apoptosis. Results: CT-NLC, T-NLC, and free tripterine showed high antiproliferative activity in a dose-dependent manner, with an IC50 of 0.60, 0.81, and 1.02 µg/mL in the PC-3 cell line and 0.41, 0.54, and 0.89 µg/mL in the RM-1 cell line after 36 hours. In vivo, the tumor inhibition rates for cyclophosphamide, high-dose (4 mg/kg) and low-dose (2 mg/kg) tripterine, high-dose (4 mg/kg) and low-dose (2 mg/kg) T-NLC, high-dose (4 mg/kg) and low-dose (2 mg/kg) CT-NLC were 76.51%, 37.07%, 29.53%, 63.56%, 48.25%, 72.68%, and 54.50%, respectively, showing a dose-dependent pattern. The induced tumor necrosis factor-alpha and interleukin-6 cytokine content after treatment with CT-NLC and T-NLC was significantly higher than that of high-dose tripterine. Moreover, CT-NLC showed the expected advantage of inducing necrosis and apoptosis in prostate tumor cells. Conclusion: CT-NLC noticeably enhanced antitumor activity in vitro and in vivo and showed dramatically improved cytotoxicity in normal cells in comparison with free tripterine. In summary, CT-NLC could be used as a promising drug delivery system for the treatment of prostate cancer. Keywords: cell-penetrating peptide, nanostructured lipid carriers, tripterine, prostate cancer, antitumor activity

KLF3 is a Krüppel family zinc finger transcription factor with widespread tissue expression and no previously known role in heart development. In a screen for dominant mutations affecting cardiovascular function in N-ethyl-N-nitrosourea (ENU) mutagenized m

【Objective】With the continuous development of satellite technology, the application of satellites to low coverage areas of ground information networks for personnel search and rescue is becoming increasingly popular. As an effective means of indicating the location of personnel and facilities, satellite search and rescue positioning technology is widely used in maritime, aviation, and personal distress rescue operations. Therefore, in the continuous development and research of global satellite search and res-cue systems, achieving high-precision and rapid positioning of search and rescue sources is the main goal.【Methods】In view of the sudden characteristics of satellite search and rescue signals, dual-satellite Time Difference of Arrival (TDOA) and Frequency Difference of Arrival (FDOA) positioning are adopted as the satellite search and rescue positioning methods. The estimation of the required TDOA and FDOA parameters is the key to improve the positioning accuracy. In order to improve the parameter estimation performance and positioning accuracy of dual-satellite TDOA and FDOA positioning technology, this paper proposes a search and rescue positioning technology scheme based on time-frequency difference estimation of windowed Cross Ambiguity Function (CAF). The method of filtering redundant noise by adding windows in time domain is introduced, and the accuracy of time-frequency difference estimation is improved by adding windows in time domain and CAF. The estimated value is substituted into dual-satellite TDOA and FDOA positioning equations to calculate the location of the search and rescue signal source. It means that the purpose of improving the positioning accuracy is to efficiently and accurately find the search/rescue source by improving the estimation accuracy of TDOA/FDOA parameters.【Results】The simulation results show that the method of estimating the TDOA/FDOA parameters of CAF with windows can be applied to search and rescue positioning, and the accurate time-frequency difference estimation value can be obtained through this method. The method proposed in this paper can effectively improve the accuracy of time-frequency difference parameter estimation, and add Fourier transform to reduce the time of parameter estimation, thus optimizing the positioning performance. When the TDOA error is controlled within 4 μs and the FDOA error is controlled within 0.2 Hz, the positioning accuracy can reach the kilometers.【Conclusion】The time-domain windowed time-frequency difference parameter estimation scheme proposed in this paper has improved the positioning performance after being incorporated into the satellite search and rescue positioning technology, which can support the application of the satellite search and rescue positioning technology in the satellite search and rescue system. The algorithm has the advantages of simple structure, low complexity and practical feasibility.

In this study, the joint simulation flow of Adams and AMESim on the kinematics and contact dynamics of the marine high-power hydraulic drive gear clutch is studied, and the joint simulation interactive operation interface is developed. With the given parameters, the visual calculation results can be output. The simulation results show that the dynamic characteristics and impact load of the gear clutch during the axial engagement are affected by the torsional stiffness of the active end and the end face structure of the gear. The maximum opening pressure of the pressure reducing valve is 2.5 MPa, and the maximum thrust under this pressure is 1.884×105 N. When the inner and outer rings collide, the oil pressure will rise rapidly. If the flow of the pressure reducing valve is insufficient, the oil inlet will leak. After multiple joint simulations, it is found that the clutch engagement and disengagement process can be completed around 4 s when the inlet pressure is between 0.008 MPa and 0.01 MPa.