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Food Science and Human Wellness 2024年

作者： Yulong Zhang Han Yang Zhiliang Cheng Hui Ha Fei Liu Yuehua Jiao Key Laboratory of Dairy Science Ministry of Education Food College Northeast Agricultural University Center of drug Safety evaluation Heilongjiang University of Chinese Medicine

Salmonella grows better under aerobic conditions as a facultative anaerobic foodborne pathogenic bacteria. The oxygen-scavenging activity of Lactococcus lactis in the intestinal tract is a promising strategy for preventing Salmonella infection. In this study， the aerobic respiration requirement and preventive mechanism of Lactococcus lactis subsp. lactis (L. lactis) KLDS 4.0325 in murine models infected by Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium) SL1344 were investigated. Results indicate that L. lactis KLDS 4.0325 is capable of aerobic respiratory metabolism in the host intestine when exogenous heme exists， and decrease intestinal oxygen concentration， which in turn trigger autophagy of intestinal cells to reduce S. Typhimurium load， improve gut microbiota composition， alleviate intestinal barrier injury and inflammation response. These results suggest that aerobic respiration L. lactis KLDS 4.0325 can prevent S. Typhimurium infection in a new way in which by restoring intestinal cell hypoxia， maintaining immune balance and regulating intestinal flora.

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Visualization of nasal powder distribution using biomimetic human nasal cavity model

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Acta Pharmaceutica Sinica B 2024年第1期14卷 392-404页

作者： Jiawen Su Yan Liu Hongyu Sun Abid Naeem Huipeng Xu Yue Qu Caifen Wang Zeru Li Jianhua Lu Lulu Wang Xiaofeng Wang Jie Wu Lixin Sun Jiwen Zhang Zhigang Wang Rui Yang Li Wu Key Laboratory of Modern Preparation of TCM Ministry of EducationJiangxi University of Chinese MedicineNanchang 330004China Key Laboratory of Molecular Pharmacology and drug evaluation School of PharmacyMinistry of EducationYantai UniversityYantai 264005China Shanghai Institute of Materia Medica Chinese Academy of SciencesShanghai 201210China Nantong Haimen People’s Hospital Nantong 226199China Yangtze Delta drug Advanced Research Institute Nantong 226126China Shenyang Pharmaceutical University Shenyang 110016China National Institutes for Food and drug Control Beijing 100000China Nanjing University of Chinese Medicine Nanjing 210023China

Nasal drug delivery efficiency is highly dependent on the position in which the drug is deposited in the nasal cavity.However,no reliable method is currently available to assess its impact on delivery performance.In this study,a biomimetic nasal model based on three-dimensional(3D)reconstruction and three-dimensional printing(3DP)technology was developed for visualizing the deposition of drug powders in the nasal cavity.The results showed significant differences in cavity area and volume and powder distribution in the anterior part of the biomimetic nasal model of Chinese males and females.The nasal cavity model was modified with dimethicone and validated to be suitable for the deposition test.The experimental device produced the most satisfactory results with five spray times.Furthermore,particle sizes and spray angles were found to significantly affect the experimental device’s performance and alter drug distribution,respectively.Additionally,mometasone furoate(MF)nasal spray(NS)distribution patterns were investigated in a goat nasal cavity model and three male goat noses,confirming the in vitro and in vivo correlation.In conclusion,the developed human nasal structure biomimetic device has the potential to be a valuable tool for assessing nasal drug delivery system deposition and distribution.

关键词： Nasal drug deposition Nasal drug distribution Nasal drug delivery Biomimetic nasal model Nasal powder Three-dimensional reconstruction Three-dimensional printing Nasal drug distribution

Recombinant adeno-associated virus 8 vector in gene therapy:Opportunities and challenges

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Genes & Diseases 2024年第1期11卷 283-293页

作者： Liyuan Zhao Zixuan Yang Minhui Zheng Lei Shi Mengyun Gu Gang Liu Feng Miao Yan Chang Fanghua Huang Naping Tang Anhui University of Traditional Chinese Medicine HefeiAnhui 230000China Yangtze Delta drug Advanced Research Institute Yangtze Delta Pharmaceutical CollegeNantongJiangsu226133China Shanghai Innostar Bio-Technology Co. LtdChina State Institute of Pharmaceutical IndustryShanghai 201203China Innostar Bio-tech Nantong Co. Ltd.NantongJiangsu 226133China Center for drug evaluation National Medical Products AdministrationBeijing 100022China

In recent years,significant breakthroughs have been made in the field of gene ther-apy.Adeno-associated virus(AAV)is one of the most promising gene therapy vectors and a powerful tool for delivering the gene of interest.Among the AAV vectors,AAV serotype 8(AAv8)has attracted much attention for its efficient and stable gene transfection into specific tissues.Currently,recombinant AAv8 has been widely used in gene therapy research on a va-riety of diseases,including genetic diseases,cancers,autoimmune diseases,and viral diseases.

关键词： AAV8 Adeno-associated virus Gene therapy Primates

Combination of AAV-delivered tumor suppressor PTEN with anti-PD-1 loaded depot gel for enhanced antitumor immunity

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Acta Pharmaceutica Sinica B 2024年第1期14卷 350-364页

作者： Yongshun Zhang Lan Yang Yangsen Ou Rui Hu Guangsheng Du Shuang Luo Fuhua Wu Hairui Wang Zhiqiang Xie Yu Zhang Chunting He Cheng Ma Tao Gong Ling Zhang Zhirong Zhang Xun Sun Key Laboratory of drug-Targeting and drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China Med-X Center for Materials College of Polymer Science and EngineeringSichuan UniversityChengdu 610065China

Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10(PTEN)gene in cancer cells may be associated with immunosuppressive tumor microenvironment(TME)and poor response to immune checkpoint blockade(ICB)therapy.Therefore,efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy.Here,we screened an adeno-associated virus(AAV)capsid for efficient PTEN gene delivery into B16F10 tumor cells.We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death(ICD)and increasing immune cell infiltration.Moreover,we developed an anti-PD-1 loaded phospholipid-based phase separation gel(PPSG),which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo.In order to effectively inhibit the recurrence of melanoma,we further applied a triple therapy based on AAV6-PTEN,PPSG^(@anti-PD-1)and CpG,and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory,which completely rejected tumor recurrence.We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.

关键词： Triple therapy Adeno-associated virus PTEN PPSG@anti-PD-1 CpG Immunogenic cell death Antitumor immune response Immune memory

Kelp Fucoidans Facilitate Vascular Recanalization via Inhibiting Excessive Activation of Platelet in Deep Venous Thrombosis Model of Mouse

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Journal of Ocean University of China 2024年第2期23卷 550-556页

作者： SUN Taohua LIU Jie YAN Taishan CHEN Anjin ZHANG Fang department of Clinical drug Trials Qingdao Municipal HospitalQingdao 266100China department of Pharmacy Qingdao Municipal HospitalQingdao 266100China

This study was carried out explore the mechanism underlying the inhibition of platelet activation by kelp fucoidans in deep venous thrombosis(DVT)mouse.In the control and sham mice,the walls of deep vein were regular and smooth with intact intima,myometrium and adventitia.The blood vessel was wrapped with the tissue and there was no thrombosis in the lumen.In the DVT model,the wall was uneven with thicken intima,myometrium and adventitia.After treated with fucoidans LF1 and LF2,the thrombus was dissolved and the blood vessel was recanalized.Compared with the control group,the ROS content,ET-1 and VWF content and the expression of PKC-βand NF-κB in the model were significantly higher(P<0.05);these levels were significantly reduced following treatments with LF2 and LF1.Compared with H_(2)O_(2)treated-HUVECs,combined LF1 and LF2 treatment resulted in significant decrease in the expression of PKC-β,NF-κB,VWF and TM protein(P<0.05).It is clear that LF1 and LF2 reduces DVT-induced ET-1,VWF and TM expressions and production of ROS,thus inhibiting the activation of PKC-β/NF-κB signal pathway and the activation of coagulation system and ultimately reducing the formation of venous thrombus.

关键词： kelp fucoidans LF1 LF2 deep vein thrombosis platelet

Fine-tuning the activation behaviors of ternary modular cabazitaxel prodrugs for efficient and on-target oral anti-cancer therapy

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Asian Journal of Pharmaceutical Sciences 2024年第2期19卷 188-203页

作者： Mingyang Zhang Yifan Miao Can Zhao Tong Liu Xiyan Wang Zixuan Wang Wenxin Zhong Zhonggui He Chutong Tian Jin Sun department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China Key Laboratory of Advanced drug Delivery Systems of Zhejiang Province Hangzhou 310058China Joint International Research Laboratory of Intelligent drug Delivery Systems Ministry of EducationShenyang 110016China Liaoning Provincial Institute of drug Inspection and Testing Shenyang 110036China

The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.

关键词： Steric disulfide bond Triglyceride-like pr odrugs Cabazitaxel Lymphatic transport Oral chemotherapy

Trametinib boosts palbociclib’s efficacy in breast cancer via autophagy inhibition

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Oncology Research 2024年第7期32卷 1197-1207页

作者： ANGUO WU JIAO YAN TING SU CHI FENG XIN LONG YIRU PAN RUPEI YE TIAN XIA HANAN LONG JIANMING WU XIULI XIAO Sichuan Key Medical Laboratory of new drug Discovery and druggability evaluation Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia MedicaKey Laboratory of Medical Electrophysiology of Ministry of EducationSchool of PharmacySouthwest Medical UniversityLuzhou646000China The department of Pathology The Affiliated Hospital of Southwest Medical UniversityLuzhou646000China The department of Pathology Mianyang Central HospitalSchool of MedicineUniversity of Electronic Science and Technology of ChinaMianyang621000China The department of Pathology Yongchuan Hospital of Chongqing Medical UniversityChongqing402160China School of Basic Medical Sciences Southwest Medical UniversityLuzhou646000China School of Clinical Medical Sciences Southwest Medical UniversityLuzhou646000China

Breast cancer,a predominant global health issue,requires ongoing exploration of new therapeutic strategies.Palbociclib(PAL),a well-known cyclin-dependent kinase(CDK)inhibitor,plays a critical role in breast cancer treatment.While its efﬁcacy is recognized,the interplay between PAL and cellular autophagy,particularly in the context of the RAF/MEK/ERK signaling pathway,remains insufﬁciently explored.This study investigates PAL’s inhibitory effects on breast cancer using both in vitro(MCF7 and MDA-MB-468 cells)and in vivo(tumor-bearing nude mice)models.Aimed at elucidating the impact of PAL on autophagic processes and exploring the potential of combining it with trametinib(TRA),an MEK inhibitor,our research seeks to address the challenge of PAL-induced drug resistance.Ourﬁndings reveal that PAL signiﬁcantly decreases the viability of MCF7 and MDA-MB-468 cells and reduces tumor size in mice while showing minimal cytotoxicity in MCF10A cells.However,PAL also induces protective autophagy,potentially leading to drug resistance via the RAF/MEK/ERK pathway activation.Introducing TRA effectively neutralized this autophagy,enhancing PAL’s anti-tumor efﬁcacy.A combination of PAL and TRA synergistically reduced cell viability and proliferation,and in vivo studies showed notable tumor size reduction.In conclusion,the PAL and TRA combination emerges as a promising strategy for overcoming PAL-induced resistance,offering a new horizon in breast cancer treatment.

关键词： Palbociclib Trametinib Protective autophagy RAF/MEK/ERK MCF7 MDA-MB-468

Protective role of fruits of Rosa odorata var. gigantea against WIRSinduced gastric mucosal injury in rats by modulating pathway related to inflammation, oxidative stress and apoptosis

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Chinese Herbal Medicines 2024年第2期16卷 263-273页

作者： Xinnan Liu Zhen Yuan Lifei Luo Teng Wang Feng Zhao Jingze Zhang Dailin Liu National Key Laboratory of Chinese Medicine Modernization Tianjin University of Traditional Chinese MedicineTianjin 301617China Tianjin Modern Innovation Chinese Medicine Technology Co. Ltd.Tianjin 300380China School of Pharmacy Key Laboratory of Molecular Pharmacology and Drug EvaluationMinistry of EducationCollaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of ShandongYantai UniversityYantai 264005China

Objective: Rosa odorata var. gigantea is a popular medicinal plant. Some studies have demonstrated that ethanolic extract of the fruits of R. odorata var. gigantea(FOE) has gastroprotective properties. The aim of this study was to investigate the gastroprotective activity of FOE on water immersion restrained stress(WIRS)-induced gastric mucosal injury in a rat model and elucidate the possible molecular mechanisms involved.Methods: A rat stress ulcer model was established in this study using WIRS. After rats were treated with FOE orally for 7 d, the effect of FOE treatment was analyzed by hematoxylin and eosin(H&E) staining, and the changes of inflammatory factors, oxidative stress factors, and gastric-specific regulatory factors and pepsin in the blood and gastric tissues of rats were examined by ELISA assay. Molecular mechanism of FOE was investigated by immunohistochemical assay and Western blot.Results: Compared with the WIRS group, FOE could diminish both the macroscopic and microscopic pathological morphology of gastric mucosa. FOE significantly preserved the antioxidants glutathione peroxidase(GSH-PX), superoxide dismutase(SOD) and catalase(CAT) contents;anti-inflammatory cytokines interleukin-10(IL-10) and prostaglandin E2(PGE2) levels as well as regulatory factors tumor necrosis factor-a(TGF-a) and somatostatin(SS) contents, while decreasing malondialdehyde(MDA), nitric oxide synthase(i NOS), tumor necrosis factor(TNF-a), interleukin-1β(IL-1β), interleukin-6(IL-6), gastrin(GAS)and endothelin(ET) levels. Moreover, FOE distinctly upregulated the expression of Nrf2, HO-1, Bcl2 and proliferating cell nuclear antigen(PCNA). In addition, FOE activated the expression of p-EGFR and downregulated the expression of NF-ΚB, Bax, Cleaved-caspase-3, Cyto-C and Cleaved-PARP1, thus promoting gastric mucosal cell survival.Conclusion: The current work demonstrated that FOE exerted a gastroprotective activity against gastric mucosal injury induced by WIRS. The underlying mechanism might be associated with the improvement of

关键词： anti-apoptosis anti-inflammation anti-oxidation gastric mucosal injury Rosa odorata Sweet var.gigantea(Coll.et Hemsl.)Rehd.et Wils water immersion restrained stress

Application of the CatBoost Model for Stirred Reactor State Monitoring Based on Vibration Signals

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Computer Modeling in Engineering & Sciences 2024年第7期140卷 647-663页

作者： Xukai Ren Huanwei Yu Xianfeng Chen Yantong Tang Guobiao Wang Xiyong Du School of Mechanical Engineering Tianjin UniversityTianjin300354China Quality department Shaoxing Key Laboratory of Special Equipment Intelligent Testing and EvaluationShaoxing312071China

Stirred reactors are key equipment in production,and unpredictable failures will result in significant economic losses and safety issues.Therefore,it is necessary to monitor its health state.To achieve this goal,in this study,five states of the stirred reactor were firstly preset:normal,shaft bending,blade eccentricity,bearing wear,and bolt looseness.Vibration signals along x,y and z axes were collected and analyzed in both the time domain and frequency domain.Secondly,93 statistical features were extracted and evaluated by ReliefF,Maximal Information Coefficient(MIC)and XGBoost.The above evaluation results were then fused by D-S evidence theory to extract the final 16 features that are most relevant to the state of the stirred reactor.Finally,the CatBoost algorithm was introduced to establish the stirred reactor health monitoring model.The validation results showed that the model achieves 100%accuracy in detecting the fault/normal state of the stirred reactor and 98%accuracy in diagnosing the type of fault.

关键词： Stirred reactor fault diagnosis vibration signal CatBoost

Macrocyclic peptides:up-and-coming weapons to combat antimicrobial resistance

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1786-1787页

作者： Wen-Jing Wang Xiang-Min Dong Guo-Bo L department of Biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduSichuanChina Key Laboratory of drug Targeting and drug Delivery System of Ministry of Education Department of Medicinal ChemistryWest China School of PharmacySichuan UniversityChengduSichuanChina

Recently,two companion papers published in Nature reported a first-in-class tethered macrocyclic peptide antibiotic targeting carbapenem-resistant A.baumannii(CRAB)and unveiled their unique antibacterial mechanism,whi... 详细信息

关键词： outer macrocyclic Macrocyclic