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Addressing chemoresistance with a lipid gemcitabine nanotherapeutic strategy for effective treatment of pancreatic cancer

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Nano Research 2024年第9期17卷 8377-8388页

作者： Jiawei Hong Shiyun Xian Shusen Zheng Hangxiang Wang Donghai Jiang The First Affiliated Hospital NHC Key Laboratory of Combined Multi-Organ TransplantationCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesState Key Laboratory for Diagnosis and Treatment of Infectious DiseasesSchool of MedicineZhejiang UniversityHangzhou 310003China Jinan Microecological Biomedicine shandong laboratory Jinan 250117China

Resistance to gemcitabine in pancreatic cancer poses a significant clinical *** investigation is warranted to assess whether nano-formulation strategy can be employed to enhance the sensitivity of resistant strains to gemcitabine *** this study,using gemcitabine-resistant pancreatic cancer cell lines,we examined the therapeutic potential of a gemcitabine nanodelivery platform and assessed the ability to overcome drug resistance against resistant *** of human equilibrative nucleoside transporter 1(hENT1)led to reduced cellular uptake of gemcitabine,resulting in chemoresistance in pancreatic *** nanoparticles circumvented the entry blockade caused by hENT1 silencing through *** entry via clathrin-mediated endocytosis increased intracellular gemcitabine accumulation in gemcitabine-resistant pancreatic cancer ***,gemcitabine nanoparticles are preferential in vivo delivery to tumor tissues,likely due to the enhanced permeability and retention *** comparison to free gemcitabine,gemcitabine nanoparticles demonstrate a more pronounced cytotoxic effect on gemcitabine-resistant pancreatic cancer cells,with favorable *** study improved the efficacy of gemcitabine through nanotechnology,providing a novel strategy to address gemcitabine-resistant pancreatic cancer.

关键词： pancreatic cancer gemcitabine resistance gemcitabine nanoparticle human equilibrative nucleoside transporter 1

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High-density lipoprotein regulates angiogenesis by affecting autophagy via miRNA-181a-5p

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Science China(Life Sciences) 2024年第2期67卷 286-300页

作者： Bi-Ang Kang Hua-Ming Li Ya-Ting Chen Meng-Jie Deng Yan Li Yue-Ming Peng Jian-Jun Gao Zhi-Wei Mo Jia-Guo Zhou Zhi-Jun Ou Jing-Song Ou Division of Cardiac Surgery Cardiovascular Diseases InstituteThe First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China National-Guangdong Joint Engineering laboratory for diagnosis and treatment of vascular diseases Guangzhou 510080China NHC key laboratory of Assisted Circulation(Sun Yat-sen University) Guangzhou 510080China Guangdong provincial Engineering and Technology Center for diagnosis and treatment of vascular diseases Guangzhou 510080China Division of vascular Surgery The First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China Department of Pharmacology Cardiac and Cerebral Vascular Research CenterZhongshan School of MedicineSun Yat-sen UniversityGuangzhou 510080China Division of Hypertension and vascular diseases Department of CardiologyCardiovascular Diseases InstituteThe First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China Guangdong provincial key laboratory of Brain Function and Disease Zhongshan School of MedicineSun Yat-sen UniversityGuangzhou 510080China

We previously demonstrated that normal high-density lipoprotein(nHDL)can promote angiogenesis,whereas HDL from patients with coronary artery disease(d HDL)is dysfunctional and impairs *** plays a critical role in angiogenesis,and HDL regulates ***,it is unclear whether n HDL and d HDL regulate angiogenesis by affecting *** cells(ECs)were treated with n HDL and d HDL with or without an autophagy ***,endothelial nitric oxide synthase(e NOS)expression,miRNA expression,nitric oxide(NO)production,superoxide anion(O2^(·-))generation,EC migration,and tube formation were evaluated.n HDL suppressed the expression of miR-181a-5p,which promotes autophagy and the expression of e NOS,resulting in NO production and the inhibition of O2^(·-)generation,and ultimately increasing in EC migration and tube formation.d HDL showed opposite effects compared to n HDL and ultimately inhibited EC migration and tube *** found that autophagy-related protein 5(ATG5)was a direct target of ***5 silencing or miR-181a-5p mimic inhibited n HDL-induced autophagy,e NOS expression,NO production,EC migration,tube formation,and enhanced O2^(·-)generation,whereas overexpression of ATG5 or miR-181a-5p inhibitor reversed the above effects of d ***5 expression and angiogenesis were decreased in the ischemic lower limbs of hypercholesterolemic low-density lipoprotein receptor null(LDLr^(-/-))mice when compared to C57BL/6 ***5 overexpression improved angiogenesis in ischemic hypercholesterolemic LDLr^(-/-)*** together,nHDL was able to stimulate autophagy by suppressing miR-181a-5p,subsequently increasing e NOS expression,which generated NO and promoted *** contrast,d HDL inhibited angiogenesis,at least partially,by increasing miR-181a-5p expression,which decreased autophagy and e NOS expression,resulting in a decrease in NO production and an increase in O2^(·-)*** findings reveal a nov

关键词： high-density lipoprotein angiogenesis autophagy ATG5 miRNA endothelial nitric oxide synthase

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Increase of PCSK9 expression in diabetes promotes VEGFR2ubiquitination to inhibit endothelial function and skin wound healing

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Science China Life Sciences 2024年

作者： Jian-Jun Gao Fang-Yuan Wu Yu-Jia Liu Le Li Yi-Jun Lin Yue-Ting Kang Yue-Ming Peng Yi-Fang Liu Chen Wang Zhen-Sheng Ma Yang Cao Hong-Yu Cao Zhi-Wei Mo Yan Li Jing-Song Ou Zhi-Jun Ou Division of Cardiac Surgery Cardiovascular Diseases Institute The First Affiliated Hospital Sun Yat-sen University National-Guangdong Joint Engineering laboratory for diagnosis and treatment of vascular diseases NHC key Laboratory of Assisted Circulation and Vascular Diseases (Sun Yat-sen University) Key Laboratory of Assisted Circulation and Vascular Diseases Chinese Academy of Medical Sciences Guangdong Provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases Division of Hypertension and vascular diseases Department of Cardiology Heart Center The First Affiliated Hospital Sun Yat-sen University Division of vascular Surgery The First Affiliated Hospital Sun Yat-sen University Guangdong provincial key laboratory of Brain Function and Disease Zhongshan School of Medicine Sun Yat-sen University

Diabetic foot ulcers（DFUs） are a serious vascular disease. Currently, no effective methods are available for treating DFUs. Pro-protein convertase subtilisin/kexin type 9（PCSK9） regulates lipid levels to promote atherosclerosis. However, the role of PCSK9 in DFUs remains unclear. In this study, we found that the expression of PCSK9 in endothelial cells（ECs） increased significantly under high glucose（HG）stimulation and in diabetic plasma and vessels. Specifically, PCSK9 promotes the E3 ubiquitin-protein ligase NEDD4 binding to vascular endothelial growth factor receptor 2（VEGFR2）, which led to the ubiquitination of VEGFR2, resulting in its degradation and downregulation in ECs. Furthermore, PCSK9 suppresses the expression and activation of AKT, endothelial nitric oxide synthase（eNOS）, and ERK1/2, leading to decreased nitric oxide（NO） production and increased superoxide anion(O2·-) generation, which impairs vascular endothelial function and angiogenesis. Importantly, using evolocumab to limit the increase in PCSK9 expression blocked the HG-induced inhibition of NO production and the increase in O2·-production, as well as inhibited the phosphorylation and expression of AKT, eNOS, and ERK1/***, evolocumab improved vascular endothelial function and angiogenesis, and promoted wound healing in diabetes. Our findings suggest that targeting PCSK9 is a novel therapeutic approach for treating DFUs.

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Longitudinal gut fungal alterations and potential fungal biomarkers for the progression of primary liver disease

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Science China(Life Sciences) 2024年第6期67卷 1183-1198页

作者： Shiman Jiang Lvwan Xu Yanfei Chen Zheyue Shu Longxian Lv Yuxi Zhao Kefan Bi Sisi Yang Qiangqiang Wang Lanjuan Li State key laboratory for diagnosis and treatment of Infectious diseases National Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Division of Hepatobiliary and Pancreatic Surgery Department of SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China

Liver disease,a major health concern worldwide,is a serious and progressive ***,we not only established a mouse model of DEN+CCl4-induced primary liver disease but also collected clinical human samples to investigate longitudinal alterations in the gut *** liver disease advanced,gut integrity was disrupted,and the mycobiota was disturbed in the mouse *** metabolites associated with hepatocellular carcinoma(HCC)differed from those associated with the cirrhotic phase as follows:levels of stercobilin and aflatoxin B1 dialcohol were reduced,while levels of triterpenoids,bafilomycin A1,and DHEA were increased in the HCC *** abundance of the phylum Chytridiomycota increased as the chronic liver disease progressed and was then replaced by the phylum Ascomycota in *** on the results from clinical human samples,the genus Candida(Ascomycota)(in humans)and the genus Kazachstania(Ascomycota)(in mice)occupied a dominant position in the HCC group,while other fungi were *** increased abundance of *** and depletion of *** may be hallmarks of the progression of liver cirrhosis to early ***,the administration of *** and *** in the LC-HCC progression could accelerate or retard the progression of ***,gut fungi have the potential to serve as a noninvasive clinical biomarker and even a treatment method.

关键词： gut mycobiome liver disease longitudinal studies hepatocarcinogenesis fungal biomarker

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M2-type macrophage membrane-mediated delivery of Carvedilol nanocomplex for acute liver failure treatment and remodeling inflammatory microenvironment

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Nano Research 2024年第7期17卷 6362-6375页

作者： Mingge Shang Yaohui Zhang Junjie Qian Wenchao Wang Xizhi Yu Jiacheng Huang Lin Zhou Shusen Zheng Division of Hepatobiliary and Pancreatic Surgery Department of SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China NHC key laboratory of Combined Multi-organ Transplantation Key Laboratory of Organ TransplantationHangzhou 310003China key laboratory of the diagnosis and treatment of organ Transplantation Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic CancerChinese Academy of Medical Sciences(2019RU019)Hangzhou 310003China State key laboratory for diagnosis and treatment of Infectious diseases National Clinical Research Center for Infectious DiseasesHangzhou 310003China Department of Thyroid Surgery The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Shulan(Hangzhou)Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College Hangzhou 310000China

Interactions of hepatic macrophages with local inflammatory microenvironment is the key factor promoting the development of acute liver failure(ALF).Hence,reprogramming pro-inflammatory M1 into anti-inflammatory M2 phenotype may offer a promising strategy for treating ALF by targeting *** group found Carvedilol possessed potential anti-inflammatory property previously,which had been scarcely reported in *** present a synergy strategy to induce macrophages into the phenotype M2-type anti-inflammatory macrophages with interleukin-4(IL-4)and IL-10 at *** Carvedilol is loaded on the macrophage membrane-camouflaged biomimetic nano-platform(termed as M2M@CNP)to evade reticuloendothelial system(RES)and afford Carvedilol delivery to the inflammatory environment with overproduced reactive oxygen species(ROS),further prolonging its circulation and *** released Carvedilol produced anti-inflammatory,antioxidant and anti-apoptosis effects,combining local M2-type cell membranes(M2-CM)inhibited pro-inflammatory cytokines and ROS levels,which in turn promoted and amplified M1 to M2 phenotype polarization *** study offers new insights into the rational design of biomimetic nanosystems for safe and effective ALF therapy to accelerate the clinical translation.

关键词： acute liver failure hepatic drug delivery M2 macrophage-camouflaged nanoplatform inflammatory microenvironment macrophage polarization

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Human pluripotent stem cell-derived kidney organoids:Current progress and challenges

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World Journal of Stem Cells 2024年第2期16卷 114-125页

作者： Hong-Yan Long Zu-Ping Qian Qin Lan Yong-Jie Xu Jing-Jing Da Fu-Xun Yu Yan Zha Graduate School Zunyi Medical UniversityZunyi 563000Guizhou ProvinceChina Department of laboratory Medicine Guizhou Provincial People’s HospitalGuiyang 550002Guizhou ProvinceChina Department of Nephrology Guizhou Provincial People’s HospitalGuiyang 550002Guizhou ProvinceChina key laboratory of diagnosis and treatment of Pulmonary Immune diseases National Health CommissionGuizhou Provincial People’s HospitalGuiyang 550002Guizhou ProvinceChina

Human pluripotent stem cell(hPSC)-derived kidney organoids share similarities with the fetal ***,the current hPSC-derived kidney organoids have some limitations,including the inability to perform nephrogenesis and lack of a corticomedullary definition,uniform vascular system,and coordinated exit path-way for urinary ***,further studies are required to produce hPSC-derived kidney organoids that accurately mimic human kidneys to facilitate research on kidney development,regeneration,disease modeling,and drug *** this review,we discussed recent advances in the generation of hPSC-derived kidney organoids,how these organoids contribute to the understanding of human kidney development and research in disease ***,the limitations,future research focus,and applications of hPSC-derived kidney organoids were highlighted.

关键词： Kidney Organoids Human pluripotent stem cell Development vascular system Disease modeling

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Research progress in tumor angiogenesis and drug resistance in breast cancer

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Cancer Biology & Medicine 2024年第7期21卷 571-585页

作者： Jiancheng Mou Chenhong Li Qinghui Zheng Xuli Meng Hongchao Tang The Second Clinical Medical College Zhejiang Chinese Medical University Department of Breast Surgery General Surgery Cancer Center Zhejiang Provincial People's Hospital (Affiliated People's Hospital) Hangzhou Medical College key laboratory for diagnosis and treatment of Upper Limb Edema and Stasis of Breast Cancer

Angiogenesis is considered a hallmark pathophysiological process in tumor development. Aberrant vasculature resulting from tumor angiogenesis plays a critical role in the development of resistance to breast cancer treatments, via exacerbation of tumor hypoxia, decreased effective drug concentrations within tumors, and immune-related mechanisms. Antiangiogenic therapy can counteract these breast cancer resistance factors by promoting tumor vascular normalization. The combination of antiangiogenic therapy with chemotherapy, targeted therapy, or immunotherapy has emerged as a promising approach for overcoming drug resistance in breast cancer. This review examines the mechanisms associated with angiogenesis and the interactions among tumor angiogenesis, the hypoxic tumor microenvironment, drug distribution, and immune mechanisms in breast cancer. Furthermore, this review provides a comprehensive summary of specific antiangiogenic drugs, and relevant studies assessing the reversal of drug resistance in breast cancer. The potential mechanisms underlying these interventions are discussed, and prospects for the clinical application of antiangiogenic therapy to overcome breast cancer treatment resistance are highlighted.

关键词： Angiogenesis breast cancer chemotherapy drug resistance immunologic therapy tumor microenvironment (TME) vascular normalization

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Computer-assisted three-dimensional individualized extreme liver resection for hepatoblastoma in proximity to the major liver vasculature

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World Journal of Gastrointestinal Surgery 2024年第4期16卷 1066-1077页

作者： Wen-Li Xiu Jie Liu Jing-Li Zhang Jing-Miao Wang Xue-Feng Wang Fei-Fei Wang Jie Mi Xi-Wei Hao NanXia Qian Dong Department of Pediatric Surgery The Affiliated Hospital of Qingdao UniversityQingdao 266000Shandong ProvinceChina Department of Pediatric Surgery Yijishan Hospital of Wannan Medical CollegeWuhu 241000Anhui ProvinceChina shandong provincial key laboratory of Digital Medicine and Computer-assisted Surgery Shandong College Collaborative Innovation Center of Digital Medicine Clinical Treatment and Nutrition HealthQingdao UniversityQingdao 266003Shandong ProvinceChina

BACKGROUND The management of hepatoblastoma(HB)becomes challenging when the tumor remains in close proximity to the major liver vasculature(PMV)even after a full course of neoadjuvant chemotherapy(NAC).In such cases,extreme liver resection can be considered a potential *** To explore whether computer-assisted three-dimensional individualized extreme liver resection is safe and feasible for children with HB who still have PMV after a full course of *** We retrospectively collected data from children with HB who underwent surgical resection at our center from June 2013 to June *** then analyzed the detailed clinical and three-dimensional characteristics of children with HB who still had PMV after a full course of *** Sixty-seven children diagnosed with HB underwent surgical *** age at diagnosis was 21.4±18.8 months,and 40 boys and 27 girls were ***-nine(88.1%)patients had a single tumor,39(58.2%)of which was located in the right lobe of the liver.A total of 47 patients(70.1%)had PRE-TEXT III or ***-nine patients(58.2%)underwent delayed *** a full course of NAC,16 patients still had close PMV(within 1 cm in two patients,touching in 11 patients,compressing in four patients,and showing tumor thrombus in three patients).There were 6 patients of tumors in the middle lobe of the liver,and four of those patients exhibited liver anatomy *** 16 children underwent extreme liver resection after comprehensive preoperative *** procedures were performed according to the preoperative plan,and the operations were successfully ***,the 3-year event-free survival of 67 children with HB is 88%.Among the 16 children who underwent extreme liver resection,three experienced recurrence,and one died due to multiple *** Extreme liver resection for HB that is still in close PMV after a full course of NAC is both safe and *** approach not only reduces th

关键词： Children Hepatoblastoma Surgery Three-dimensional Computer-assisted

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Low expression of fatty acid oxidation related gene ACADM indicates poor prognosis of renal clear cell carcinoma and is related to tumor immune infltration

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Oncology Research 2024年第3期32卷 545-561页

作者： JIECHUAN QIU TIANMIN YANG YANNING SUN KAI SUN YINGKUN XU QINGHUA XIA Department of Urology Shandong Provincial Hospital A fliated to Shandong First Medical UniversityJinan250021China Depatment of Urology Shandong Provincial HospitalCheeloo College of MedicineShandong UniversityJinan250021China Depatment of Breast and Thyroid Surgery The First Afiliated Hospital of Chongqing Medical UniversityChongqing400042China

This research aims to identify the key fatty acid beta-oxidation(FAO)genes that are altered in kidney renal clear cell carcinoma(KIRC)and to analyze the role of these genes in KIRC The Gene Expression Omnibus(GEO)and FAO datasets were used to identify these key *** rank sum test was used to assess the levels of acyl-CoA dehydrogenase medium chain(ACADM)between KIRC and non cancer *** logistic regression and Wilcoxon rank sum test were used to explore the association between ACADM and clinical *** diagnostic performance of ACADM for KIRC was asessed using a diagnostic receiver operating ch aracteristic(ROC)*** co-expressed genes of ACADM were identifed in LinkedOmics database,and their function and pathway enrichment were *** correlation between ACADM expression level and immune infitration was analyzed by Gene Set Variation Analysis(GSVA)method Additionally,the proliferation,migration,and invasion abilities of KIRC cells were assessed after overexpressing *** differential analysis and intersection,we identifed six hub genes,induding *** found that the expression level of ACADM was decreased in KIRC tissues and had a better diagnostic efect(AUC=0.916).Survival analysis suggested that patients with decreased ACADM expression had a worse *** to correlation analysis,a variety of dinical features were associated with the expression level of ACADML By analyzing the infiltration level of immune cells,we found that ACADM may be related to the enrichment of immune ***,ACADM overexpression inhibited proliferation,migration,and invasion of KIRC *** conclusion,our findings suggest that reduced ACADM expression in KIRC patients is indicative of poor *** results imply that ACADM may be a diagnostic and prognostic marker for individuals with KIRC,offering a reference for dinicians in diagnosis and treatment.

关键词： Kidney renal clear cell carcinoma Acyl CoA dehydrogenase medium chain Immune infiltration Fatty acid oxidation Prognosis

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Subretinal fibrosis secondary to neovascular age-related macular degeneration:mechanisms and potential therapeutic targets

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Neural Regeneration Research 2025年第2期20卷 378-393页

作者： Jingxiang Zhang Xia Sheng Quanju Ding Yujun Wang Jiwei Zhao Jingfa Zhang Department of Ophthalmology People’s Hospital of Huangdao DistrictQingdaoShandong ProvinceChina Department of Urology People’s Hospital of Huangdao DistrictQingdaoShandong ProvinceChina Department of Ophthalmology Shanghai General Hospital(Shanghai First People’s Hospital)Shanghai Jiao Tong University School of MedicineShanghaiChina National Clinical Research Center for Eye diseases Shanghai Key Laboratory of Ocular Fundus DiseasesShanghai Engineering Center for Visual Science and PhotomedicineShanghai Engineering Center for Precise Diagnosis and Treatment of Eye DiseasesShanghaiChina

Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular *** causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular *** pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely ***,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential *** current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/*** review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.

关键词： choroidal neovascularization epithelial-mesenchymal transition mesenchymal transition myofibroblast neovascular age-related macular degeneration submacular fibrosis subretinal fibrosis therapeutic targets transforming growth factor-β vascular endothelial growth factor

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