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Introducing urea into tirapazamine derivatives to enhance anticancer therapy

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National Science Review 2024年第4期11卷 245-253页

作者： Yajun Xu Jianlin Lv Chaoying Kong Ya Liu Kun Wang Zhaohui Tang Xuesi Chen Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied ChemistryChinese Academy of Sciences school of applied Chemistry and Engineering University of Science and Technology of China

Tirapazamine（TPZ） has been approved for multiple clinical trials relying on its excellent anticancer potential.However,as a typical hypoxia-activated prodrug（HAP）,TPZ did not exhibit survival advantages in Phase Ⅲ clinical trials when used in combination therapy due to the insufficient hypoxia levels in patients' tumors.In this study,to improve the therapeutic effects of TPZ,we first introduced urea to synthesize a series of urea-containing derivatives of TPZ.All urea-containing TPZ derivatives showed increased hypoxic cytotoxicity（9.51-30.85-fold） compared with TPZ,while maintaining hypoxic selectivity.TPZP,one of these derivatives,showed 20-fold higher cytotoxicity than TPZ while maintaining a similar hypoxic cytotoxicity ratio.To highly efficiently deliver TPZP to the tumors and reduce its side effects on healthy tissues,we further prepared TPZP into a nanodrug with fibrin-targeting ability:FT11-TPZP-NPs.CA4-NPs,a vascular disrupting agent,was used to increase the fibrin level within tumors and exacerbate tumor hypoxia.By being combined with CA4-NPs,FT11-TPZP-NPs can accumulate in the hypoxia-aggravated tumors and activate sufficiently to kill tumor cells.After a single-dose treatment,FT11-TPZP-NPs+CA4-NPs showed a high inhibition rate of 98.1% against CT26 tumor models with an initial volume of ～480 mm3and four out of six tumors were completely eliminated;it thereby exerted a significant antitumor effect.This study provides a new strategy for improving the therapeutic effect of TPZ and other HAPs in anticancer therapy.

关键词： tirapazamine vascular disrupting agent hypoxia-activated prodrug combretastatin A4 urea

TRAIL and Celastrol Combinational Treatment Suppresses Proliferation, Migration, and Invasion of Human Glioblastoma Cells via Targeting Wnt/β-catenin Signaling Pathway

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Chinese Journal of Integrative Medicine 2024年第4期30卷 322-329页

作者： QIN Jing-jing NIU Meng-da CHA Zhe GENG Qing-hua LI Yu-lin REN Chun-guang David P.Molloy YU Hua-rong Research Center of Neuroscience School of Basic Medical SciencesChongqing Medical UniversityChongqing(400016)China Laboratory of Developmental Biology Department of Cell Biology and GeneticsSchool of Basic Medical SciencesChongqing Medical UniversityChongqing(400016)China Department of Biochemistry and Molecular Biology School of Basic Medical SciencesChongqing Medical UniversityChongqing(400016)China

Objective To investigate the mechanistic basis for the anti-proliferation and anti-invasion effect of tumor necrosis factor-related apoptosis-induced ligand(TRAIL)and celastrol combination treatment(TCCT)in glioblastoma cells.Methods Cell counting kit-8 was used to detect the effects of different concentrations of celastrol(0-16µmol/L)and TRAIL(0-500 ng/mL)on the cell viability of glioblastoma cells.U87 cells were randomly divided into 4 groups,namely control,TRAIL(TRAIL 100 ng/mL),Cel(celastrol 0.5µmol/L)and TCCT(TRAIL 100 ng/mL+celastrol 0.5µmol/L).Cell proliferation,migration,and invasion were detected by colony formation,wound healing,and Transwell assays,respectively.Quantitative reverse transcription polymerase chain reaction and Western blotting were performed to assess the levels of epithelial-mesenchymal transition(EMT)markers(zona occludens,N-cadherin,vimentin,zinc finger E-box-binding homeobox,Slug,and β-catenin).Wnt pathway was activated by lithium chloride(LiCl,20 mol/L)and the mechanism for action of TCCT was explored.Results Celastrol and TRAIL synergistically inhibited the proliferation,migration,invasion,and EMT of U87 cells(P<0.01).TCCT up-regulated the expression of GSK-3β and down-regulated the expression of β-catenin and its associated proteins(P<0.05 or P<0.01),including c-Myc,Cyclin-D1,and matrix metalloproteinase(MMP)-2.In addition,LiCl,an activator of the Wnt signaling pathway,restored the inhibitory effects of TCCT on the expression of β-catenin and its downstream genes,as well as the migration and invasion of glioblastoma cells(P<0.05 or P<0.01).Conclusions Celastrol and TRAIL can synergistically suppress glioblastoma cell migration,invasion,and EMT,potentially through inhibition of Wnt/β-catenin pathway.This underlies a novel mechanism of action for TCCT as an effective therapy for glioblastoma.

关键词： celastrol Chinese medicine tumor necrosis factor-related apoptosis-induced ligand glioblastoma β-catenin Tripterygium wilfordii

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Single-cell RNA sequencing to understand host-virus interactions

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Virologica Sinica 2024年第1期39卷 1-8页

作者： Jia-Tong Chang Li-Bo Liu Pei-Gang Wang Jing An Department of Microbiology School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China

Single-cell RNA sequencing(scRNA-seq)has allowed for the profiling of host and virus transcripts and host-virus interactions at single-cell resolution.This review summarizes the existing scRNA-seq technologies together with their strengths and weaknesses.The applications of scRNA-seq in various virological studies are discussed in depth,which broaden the understanding of the immune atlas,host-virus interactions,and immune repertoire.scRNA-seq can be widely used for virology in the near future to better understand the pathogenic mechanisms and discover more effective therapeutic strategies.

关键词： Single-cell RNA sequencing(scRNA-seq) Host-virus interaction COVID-19 Flavivirus

Combinational therapy with Myc decoy oligodeoxynucleotides encapsulated in nanocarrier and X-irradiation on breast cancer cells

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Oncology Research 2024年第2期32卷 309-323页

作者： BEHROOZ JOHARI MILAD PARVINZAD LEILAN MAHMOUD GHARBAVI YOUSEF MORTAZAVI ALI SHARAFI HAMED REZAEEJAM Department of medical Biotechnology School of MedicineZanjan University of Medical SciencesZanjanIran Zanjan Pharmaceutical Biotechnology Research Center Zanjan University of Medical SciencesZanjanIran Nanotechnology Research Center Ahvaz Jundishapur University of Medical SciencesAhvazIran Department of Radiology Technology School of Allied Medical SciencesZanjan University of Medical SciencesZanjanIran

The Myc gene is the essential oncogene in triple-negative breast cancer(TNBC).This study investigates the synergistic effects of combining Myc decoy oligodeoxynucleotides-encapsulated niosomes-selenium hybrid nanocarriers with X-irradiation exposure on the MDA-MB-468 cell line.Decoy and scramble ODNs for Myc transcription factor were designed and synthesized based on promoter sequences of the Bcl2 gene.The nanocarriers were synthesized by loading Myc ODNs and selenium into chitosan(Chi-Se-DEC),which was then encapsulated in niosome-nanocarriers(NISM@Chi-Se-DEC).FT-IR,DLS,FESEM,and hemolysis tests were applied to confirm its characterization and physicochemical properties.Moreover,cellular uptake,cellular toxicity,apoptosis,cell cycle,and scratch repair assays were performed to evaluate its anticancer effects on cancer cells.All anticancer assessments were repeated under X-ray irradiation conditions(fractionated 2Gy).Physicochemical characteristics of niosomes containing SeNPs and ODNs showed that it is synthesized appropriately.It revealed that the anticancer effect of NISM@Chi-Se-DEC can be significantly improved in combination with X-ray irradiation treatment.It can be concluded that NISM@Chi-Se-DEC nanocarriers have the potential as a therapeutic agent for cancer treatment,particularly in combination with radiation therapy and in-vivo experiments are necessary to confirm the efficacy of this nano-drug.

关键词： Combinational therapy Antisense therapy Myc signaling pathway Niosomes Radiation therapy SeNPs

Antimicrobial,antibiofilm,angiogenesis,anti-inflammatory,and wound healing activities of zinc nanoparticles green synthesized using Ferula macrecolea extract

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Asian Pacific Journal of Tropical Biomedicine 2024年第6期14卷 259-268页

作者： Sultan F.Alnomasy Department of medical Laboratories sciences College of Applied Medical SciencesShaqra UniversityAl-Quwayiyah 19257Saudi Arabia

Objective:To assess the antimicrobial,antibiofilm,anti-inflammatory,angiogenic,and wound healing activities of zinc nanoparticles(ZNPs)green synthesized using Ferula macrecolea extract.Methods:The green synthesis was conducted using the precipitation method.Then,the minimum inhibitory concentration(MIC),minimum bactericidal concentration(MBC),and minimum biofilm inhibition concentration 50%(MBIC50)of ZNPs against Staphylococcus aureus(S.aureus)and Pseudomonas aeruginosa(P.aeruginosa)were evaluated.The effects of ZNPs on the gene expressions of Staphylococcus spp.[intracellular adhesion A(icaA)and D(icaD)]and P.aeruginosa(rhlI and rhlR)were investigated using quantitative real-time PCR.In addition,the effects of ZNPs on wound healing,angiogenesis,and anti-inflammatory markers were assessed.Results:The green-synthesized ZNPs demonstrated significant antimicrobial efficacy against S.aureus and P.aeruginosa.The biofilm formation in S.aureus and P.aeruginosa was also inhibited by ZNPs with MBIC50 values of 3.30μg/mL and 2.08μg/mL,respectively.Additionally,ZNPs downregulated the expression of biofilm-related genes icaA,icaD,rhlI,and rhlR in the tested bacteria.They also demonstrated promising in vitro wound healing effects by promoting fibroblast cell proliferation and wound closure in a dose-dependent manner.A significant increase in the expression of HLA-G5 and VEGF-A genes as well as a marked decrease in the expression of NF-κB,IL-1β,and TNF-αgenes were observed in cells treated with ZNPs compared to the control group(P<0.05).Conclusions:ZNPs display promising antibacterial effects against S.aureus and P.aeruginosa and wound-healing effects by inhibiting biofilm formation,inducing angiogenesis,and reducing inflammation.However,further studies must be conducted to specify the accurate mechanisms of action and toxicity of ZNPs.

关键词： Wound healing Antibacterial Angiogenesis Nanomedicine Ferula macrecolea Inflammation

Assessment of tear film parameters post-treatment with commercial eyelid cleaning wipes:a pilot study

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International Journal of Ophthalmology(English edition) 2024年第4期17卷 659-664页

作者： Amal Aldarwesh Ali Almustanyir Raied Fagehi Khalaf Alruways Abdulaziz Bin Turki Mansour Alghamdi Muteb Khalaf Alanazi Balsam Alabdulkader Wafa Alotaibi Mosaad Alhassan Department of Optometry College of Applied Medical SciencesKing Saud UniversityRiyadh 11433Saudi Arabia

AIM:To investigate the short-term effects of commercially available eyelid-cleaning wipes on film parameters.METHODS:This study enrolled 48 healthy participants aged 20-35y(both males and females).Clinical assessment included the Ocular Surface Disease Index(OSDI)questionnaire,non-invasive tear break-up time(NITBUT),tear meniscus height(TMH),and lipid layer pattern(LLP).Based on these initial results,participants were categorized as either non-dry eye or dry eye.Participants in each group were randomly allocated to either Blephaclean■or Systane■treatments.Changes in NITBUT,TMH,and LLP levels before and after lid wipe treatment were assessed.RESULTS:The dry eye group exhibited significantly higher OSDI scores and lower NITBUT and TMH levels than in the non-dry eye group(P0.05).Similarly,the LLP levels were significantly improved with Systane■(P<0.001)post-treatment compared to individuals in the non-dry eye group.However,the dry eye subjects showed higher posttreatment LLP levels than the untreated group(P<0.02).CONCLUSION:The short-term effects of Systane®eyelid wipes on tear film parameters suggest their effectiveness in dry eye disease.Nonetheless,further exploration of their long-term impact is essential to justify their cost effectiveness and efficacy in treating both aqueous deficiency and evaporative dryness.

关键词： dry eye lid wipes tear break-up time tear meniscus height

Modularized viromimetic polymer nanoparticle vaccines(VPNVaxs) to elicit durable and effective humoral immune responses

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National Science Review 2024年第3期11卷 200-214页

作者： Zichao Huang Xinyu Zhuang Liping Liu Jiayu Zhao Sheng Ma Xinghui Si Zhenyi Zhu Fan Wu Ningyi Jin Mingyao Tian Wantong Song Xuesi Chen Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied ChemistryChinese Academy of Sciences school of applied Chemistry and Engineering University of Science and Technology of China Changchun Veterinary Research Institute Chinese Academy of Agricultural Sciences Jilin Biomedical Polymers Engineering Laboratory State Key Laboratory of Polymer Physics and Chemistry Changchun Institute of Applied Chemistry Chinese Academy of Sciences

Virus-like particle(VLP) vaccines had shown great potential during the COVID-19 pandemic, and was thought to be the next generation of antiviral vaccine technology due to viromimetic structures. However,the time-consuming and complicated processes in establishing a current recombinant-protein–based VLP vaccine has limited its quick launch to the out-bursting pandemic. To simplify and optimize VLP vaccine design, we herein report a kind of viromimetic polymer nanoparticle vaccine(VPNVax), with subunit receptor-binding domain(RBD) proteins conjugated to the surface of polyethylene glycol-b-polylactic acid(PEG-b-PLA) nanoparticles for vaccination against SARS-CoV-2. The preparation of VPNVax based on synthetic polymer particle and chemical post-conjugation makes it possible to rapidly replace the antigens and construct matched vaccines at the emergence of different viruses. Using this modular preparation system, we identified that VPNVax with surface protein coverage of 20%–25% had the best immunostimulatory activity, which could keep high levels of specific antibody titers over 5 months and induce virus neutralizing activity when combined with an aluminum adjuvant. Moreover, the polymer nano-vectors could be armed with more immune-adjuvant functions by loading immunostimulant agents or chemical chirality design. This VPNVax platform provides a novel kind of rapidly producing and efficient vaccine against different variants of SARS-CoV-2 as well as other viral pandemics.

关键词： vaccine polymer nanomaterials SARS-CoV-2

Prevalence of Anemia in Patients with Diabetes Mellitus:A Systematic Review and Meta-Analysis

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Biomedical and Environmental sciences 2024年第1期37卷 96-107页

作者： Monireh Faghir-Ganji Narjes Abdolmohammadi Maryam Nikbina Alireza Amanollahi Alireza Ansari-Moghaddam Rozhan Khezri Hamidreza Baradaran Student Research Committee Iran University of Medical SciencesTehranIran Department of Epidemiology School of Public HealthIran University of Medical SciencesTehranIran Department of Epidemiology School of Public HealthTehran University of Medical SciencesTehranIran Department of Midwifery Shoushtar Faculty of Medical SciencesShoushtarIran Department of Epidemiology School of Public Health and SafetyShahid Beheshti University of Medical SciencesTehranIran Trauma and Injury Research Center Iran University of Medical SciencesTehranIran Health Promotion Research Center Zahedan University of Medical SciencesZahedanIran Endocrine Research Center Institute of Endocrinology and MetabolismIran University of Medical SciencesTehranIran

Objective Anemia is a common public health concern in patients with type 2 diabetes worldwide.This study aimed to identify the prevalence of anemia among patients with diabetes.Methods Electronic databases,including PubMed,Scopus,Web of sciences,and Google Scholar,were searched systematically for studies published between 2010 and 2021.After removing duplicates and inappropriate reports,the remaining manuscripts were reviewed and appraised using theNewcastleOttawa Scale(NOS)tool.A random-effects model was used to calculate the pooled estimates of the extracted data using Stata version 17.Heterogeneity of the studies was assessed using the Q statistic.Results A total of 51 articles containing information on 26,485 patients with diabetes were included in this study.The articles were mainly from Asia(58.82%)and Africa(35.29%).The overall prevalence of anemia was 35.45%(95%CI:30.30–40.76),with no evidence of heterogeneity by sex.Among the two continents with the highest number of studies,the prevalence of anemia in patients with diabetes was significantly higher in Asia[40.02;95%CI:32.72–47.54]compared to Africa[28.46;95%CI:21.90–35.50](P for heterogeneity=0.029).Moreover,there has been an increasing trend in the prevalence of anemia in patients with diabetes over time,from[15.28;95%CI:9.83–22.21]in 2012 to[40.70;95%CI:10.21–75.93]in 2022.Conclusion Globally,approximately 4 in 10 patients with diabetes suffer from anemia.Therefore,routine anemia screening and control programs every 3 months might be useful in improving the quality of life of these patients.

关键词： Prevalence Diabetic foot Anemia Diabetes mellitus

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Oscillatory Dynamics of Heterogeneous Stem Cell Regeneration

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Communications on applied Mathematics and Computation 2024年第1期6卷 431-453页

作者： Xiyin Liang Jinzhi Lei school of Mathematical sciences Center for Applied MathematicsTiangong UniversityTianjin300387China

Stem cell regeneration is an essential biological process in the maintenance of tissue homeostasis;dysregulation of stem cell regeneration may result in dynamic diseases that show oscillations in cell numbers.Cell heterogeneity and plasticity are necessary for the dynamic equilibrium of tissue homeostasis;however,how these features may affect the oscillatory dynamics of the stem cell regeneration process remains poorly understood.Here,based on a mathematical model of heterogeneous stem cell regeneration that includes cell heterogeneity and random transition of epigenetic states,we study the conditions to have oscillation solutions through bifurcation analysis and numerical simulations.Our results show various model system dynamics with changes in different parameters associated with kinetic rates,cellular heterogeneity,and plasticity.We show that introducing heterogeneity and plasticity to cells can result in oscillation dynamics,as we have seen in the homogeneous stem cell regeneration system.However,increasing the cell heterogeneity and plasticity intends to maintain tissue homeostasis under certain conditions.The current study is an initiatory investigation of how cell heterogeneity and plasticity may affect stem cell regeneration dynamics,and many questions remain to be further studied both biologically and mathematically.

关键词： Stem cell regeneration Heterogenous Hopf bifurcation Hematopoietic dynamical disease