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Size-dependent macrophage-targeting of mannose-modified rosiglitazone liposomes to alleviate inflammatory bowel disease

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Chinese Chemical Letters 2024年第1期35卷 385-391页

作者： Erjin Wang Run Han Mingyue Wu Yuan He Yaxin Cheng Jiahong Lu Ying Zheng State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences(ICMS)University of MacaoMacao 999078China Department of Pharmacy Xuzhou Medical UniversityXuzhou 221004China Faculty of Health Sciences University of MacaoMacao 999078China Guangdong-Hong Kong-Macao Joint Lab on Chinese Medicine and Immune Disease Research University of MacaoMacao 999078China

Inflammatory bowel disease (IBD) is a refractory chronic intestinal inflammatory disease caused by a malfunction of immune system. As the key immune cells in the intestine, macrophages play an important role in maintaining intestinal homeostasis and tissue repair of the IBD. Pharmacological modulation of macrophage function exhibits the promising therapeutic effect for IBD. In this study, mannose-modified liposomes (MAN-LPs) are prepared for macrophage targeting to improve therapeutic efficiency. Rosiglitazone (ROSI) as an agonist of peroxisome proliferators-activated receptor γ (PPAR-γ) is used as the model drug to fabricate different sized liposomes. The impacts of mannose modification and particle size for macrophage targeting are investigated in cells, zebrafish, and mouse models and the therapeutic effects of the MAN-LPs are evaluated on dextran sulfate sodium (DSS)-induced IBD mouse. Compared to unmodified liposome, MAN-LPs display higher uptake by RAW 264.7 cells and better co-localization with macrophage in zebrafish model. Furthermore, MAN-LPs could effectively accumulate in the inflammatory intestinal sites in IBD mouse model. Most importantly, the targeting ability of MAN-LPs is obviously enhanced with the increasing of particle size, whereas the largest MAN-LPs particles achieve the best anti-inflammatory effect in cells, and a higher therapeutic efficiency in IBD mouse model. Therefore, mannose-modified liposome is a promising strategy for macrophage-targeting in IBD treatment. Particle size of MAN-LPs will affect macrophage targeting ability, as well as the therapeutic effect in-vivo.

关键词： Macrophage targeting Liposome mannose Particle size Inflammatory bowel disease

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mannose inhibits the growth of prostate cancer through a mitochondrial mechanism

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Asian Journal of Andrology 2022年第5期24卷 540-548页

作者： Yu-Lin Deng Ren Liu Zhou-Da Cai Zhao-Dong Han Yuan-Fa Feng Shang-Hua Cai Qing-Biao Chen Jian-Guo Zhu Wei-De Zhong Guangdong Provincial Institute of Nephrology Nanfang HospitalSouthern Medical UniversityGuangzhou 510515China Department of Andrology Guangzhou First People’s HospitalSchool of MedicineSouth China University of TechnologyGuangzhou 510180China Department of Urology Guangdong Key Laboratory of Clinical Molecular Medicine and DiagnosticsGuangzhou First People’s HospitalSchool of MedicineSouth China University of TechnologyGuangzhou 510180China Urology Key Laboratory of Guangdong Province The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Medical UniversityGuangzhou 510230China Department of Urology Guizhou Provincial People’s HospitalThe Affiliated Hospital of Guizhou Medical UniversityGuiyang 550002China Department of Urology Surgery Affiliated Foshan Hospital of Southern Medical UniversityFoshan 528000China

The limited treatment options for advanced prostate cancer(PCa)lead to the urgent need to discover new anticancer drugs.mannose,an isomer of glucose,has been reported to have an anticancer effect on various tumors.However,the anticancer effect of mannose in PCa remains unclear.In this study,we demonstrated that mannose inhibits the proliferation and promotes the apoptosis of PCa cells in vitro,and mannose was observed to have an anticancer effect in mice without harming their health.Accumulation of intracellular mannose simultaneously decreased the mitochondrial membrane potential,increased mitochondrial and cellular reactive oxygen species(ROS)levels,and reduced adenosine triphosphate(ATP)production in PCa cells.mannose treatment of PCa cells induced changes in mitochondrial morphology,caused dysregulated expression of the fission protein,such as fission,mitochondrial 1(FIS1),and enhanced the expression of proapoptotic factors,such as BCL2-associated X(Bax)and BCL2-antagonist/killer 1(Bak).Furthermore,lower expression of mannose phosphate isomerase(MPI),the key enzyme in mannose metabolism,indicated poorer prognosis in PCa patients,and downregulation of MPI expression in PCa cells enhanced the anticancer effect of mannose.This study reveals the anticancer effect of mannose in PCa and its clinical significance in PCa patients.

关键词： mannose mannose phosphate isomerase metabolism mitochondria prostate cancer

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mannose metabolism normalizes gut homeostasis by blocking the TNF-α-mediated proinflammatory circuit

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Cellular & Molecular Immunology 2023年第2期20卷 119-130页

作者： Peng Xiao Ziwei Hu Jiaheng Lang Tianyuan Pan Randall Tyler Mertens Huilun Zhang Ke Guo Manlu Shen Hongqiang Cheng Xue Zhang Qian Cao Yuehai Ke Department of Gastroenterology Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina Department of Pathology and Pathophysiology and Department of Gastroenterology at Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina Immunological Disease Research Center Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina Key Laboratory for Immunity and Inflammatory Diseases of Zhejiang Province HangzhouChina Department of Pathology and Pathophysiology Zhejiang University School of MedicineHangzhouChina Department of General Medicine The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina Department of Immunology Harvard Medical SchoolBostonMAUSA Zhejiang Laboratory for Systems and Precision Medicine Zhejiang University Medical CenterHangzhouChina

mannose is a naturally occurring sugar widely consumed in the daily diet;however,mechanistic insights into how mannose metabolism affects intestinal inflammation remain lacking.Herein,we reported that mannose supplementation ameliorated colitis development and promoted colitis recovery.Macrophage-secreted inflammatory cytokines,particularly TNF-α,induced pathological endoplasmic reticulum stress(ERS)in intestinal epithelial cells(IECs),which was prevented by mannose via normalization of protein N-glycosylation.By preserving epithelial integrity,mannose reduced the inflammatory activation of colonic macrophages.On the other hand,mannose directly suppressed macrophage TNF-αproduction translationally by reducing the glyceraldehyde 3-phosphate level,thus promoting GAPDH binding to TNF-αmRNA.Additionally,we found dysregulated mannose metabolism in the colonic mucosa of patients with inflammatory bowel disease.Finally,we revealed that activating PMM2 activity with epalrestat,a clinically approved drug for the treatment of diabetic neuropathy,elicited further sensitization to the therapeutic effect of mannose.Therefore,mannose metabolism prevents TNF-α-mediated pathogenic crosstalk between IECs and intestinal macrophages,thereby normalizing aberrant immunometabolism in the gut.

关键词： Colitis mannose Macrophages Intestinal epithelial cells TNF-alpha Endoplasmic reticulum stress

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Application of mannose-modified fullerene immunomodulator selectively polarizes tumor-associated macrophages potentiating antitumor immunity

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Nano Research 2023年第11期16卷 12855-12863页

作者： Haoyu Wang Lei Li Xinran Cao Mingming Zhen Chunru Wang Chunli Bai Beijing National Laboratory for Molecular Sciences Key Laboratory of Molecular Nanostructure and NanotechnologyCAS Research/Education Center for Excellence in Molecular SciencesInstitution Institute of ChemistryChinese Academy of SciencesBeijing 100190China University of Chinese Academy of Sciences Beijing 100049China

Polarization of tumor associated macrophages(TAMs)has been a promising therapeutic paradigm for tumor.However,how to achieve precise regulation of TAMs and high efficiency of tumor immunotherapy is still a huge challenge.Here,we report dicarboxy fullerene modified with mannose(DCFM)as an immunomodulator to selectively polarize TAMs and prominently boost anti-tumor immunity.The dicarboxy fullerene molecule was synthesized through the Prato reaction and further covalently bonded with mannose,obtaining the DCFM with well-defined structure.Due to the exist of mannose in DCFM,it could accurately recognize mannose receptor in TAMs.Our cellular experiment results showed that mannose modification could notably promote the uptake of DCFM by the immunosuppressive M2-type macrophages that effectively reprogrammed M2-type macrophages into anti-tumor M1-type macrophages,leading to enhance the phagocytosis of tumor cells by macrophages and inhibiting tumor cells migration.Subsequently,we observed that DCFM could significantly distribute into tumor tissues by in vivo fluorescence imaging.Importantly,DCFM exhibited a superior anti-tumor efficiency in the subcutaneous colorectal tumor model.In addition,it showed that DCFM precisely polarized TAMs into M1-type macrophages and actively increased the infiltration of cytotoxic T lymphocytes(CTLs),inducing profound tumor growth inhibition.

关键词： fullerene mannose macrophage targeting tumor-associated macrophage polarization cancer immunotherapy

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mannose metabolism and immune regulation:Insights into its therapeutic potential in immunology-related diseases

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BIOCELL 2023年第11期47卷 2535-2546页

作者： QINGPAN BU PING LI YUNFEI XIA XINPEI WEI KAI SONG School of Life Sciences Changchun Normal UniversityChangchun130032China

mannose,a different isomer of the hydroxyl group at the C-2 position of glucose,shares the same transport carrier protein with glucose to enter cells and participate in the regulation of glucose metabolism.It affects cell growth,differentiation,and function and plays an active role in tumor immunity and inflammatory processes.This paper provides theoretical support for expanding the clinical applications of mannose by exploring its constitution,metabolic pathways,and role in regulating immune cell function and treating immunology-related diseases.

关键词： mannose Metabolism Immune cell Immune regulation

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Changes in fetal mannose and other carbohydrates induced by a maternal insulin infusion in pregnant sheep

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Journal of Animal Science and Biotechnology 2015年第2期6卷 222-229页

作者： Laura D Brown Stephanie R Thorn Alex Cheung Jinny R Lavezzi Frederick C Battaglia Paul J Rozance Perinatal Research Center Division of Neonatology Department of Pediatrics University of Colorado Denver School of Medicine Center for Women’s Health Research University of Colorado Denver School of Medicine

Background： The importance of non-glucose carbohydrates, especially mannose and inositol, for normal development is increasingly recognized. Whether pregnancies complicated by abnormal glucose transfer to the fetus also affect the regulation of non-glucose carbohydrates is unknown. In pregnant sheep, maternal insulin infusions were used to reduce glucose supply to the fetus for both short （2-wk） and long （8-wk） durations to test the hypothesis that a maternal insulin infusion would suppress fetal mannose and inositol concentrations. We also used direct fetal insulin infusions （1-wk hyperinsulinemic-isoglycemic clamp） to determine the relative importance of fetal glucose and insulin for regulating non-glucose carbohydrates. Results： A maternal insulin infusion resulted in lower maternal （50%, P 〈 0.01） and fetal （35-45%, P 〈 0.01） mannose concentrations, which were highly correlated （r^2 = 0.69, P 〈 0.01）. A fetal insulin infusion resulted in a 50% reduction of fetal mannose （P 〈 0.05）. Neither maternal nor fetal plasma inositol changed with exogenous insulin infusions. Additionally, maternal insulin infusion resulted in lower fetal sorbitol and fructose （P 〈 0.01）. Conclusions： Chronically decreased glucose supply to the fetus as well as fetal hyperinsulinemia both reduce fetal non-glucose carbohydrates. Given the role of these carbohydrates in protein glycosylation and lipid production, more research on their metabolism in pregnancies complicated by abnormal glucose metabolism is clearly warranted.

关键词： Fructose Glucose Inositol Insulin mannose Pregnancy

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Soluble mannose receptor as a predictor of prognosis of hepatitis B virus-related acute-on-chronic liver failure

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World Journal of Gastroenterology 2019年第37期25卷 5667-5675页

作者： Tai-Ping Li Shi-He Guan Qin Wang Li-Wen Chen Kai Yang Hao Zhang Department of ClinicalLaboratory The Second Hospital of Anhui Medical University

BACKGROUND Hepatitis B virus-related acute-on-chronic liver failure(HBV-ACLF)is a syndrome with a high short-term mortality rate,and it is crucial to identify those patients at a high mortality risk clinically.AIM To investigate the clinical value of soluble mannose receptor(sMR)in predicting the 90-day mortality of HBV-ACLF patients.METHODS A total of 43 patients were diagnosed with HBV-ACLF between October 2017 and October 2018 at the Second Hospital of Anhui Medical University,and all of them were enrolled in this retrospective study.Their serum sMR levels were determined using an enzyme-linked immunosorbent assay.Demographic and clinical data,including gender,age,albumin level,total bilirubin(TBIL)level,international normalized ratio,HBV-DNA level,HBV serological markers,procalcitonin level,interleukin-6 level,and model for end-stage liver disease(MELD)score were accessed at the time of diagnosis of HBV-ACLF.A multivariate logistic regression analysis was used to analyze the independent risk factors for mortality.RESULTS Serum sMR level was significantly increased in HBV-ACLF patients compared with chronic hepatitis B patients and healthy controls(P<0.01).When compared with surviving patients,it was higher in those patients who succumbed to HBVACLF(P<0.05).Serum sMR level was positively correlated with MELD score(rs=0.533,P=0.001),HBV-DNA level(rs=0.497,P=0.022),and TBIL level(rs=0.894,P<0.001).Serum sMR level(odds ratio=1.007,95%confidence interval:1.004–1.012,P=0.001)was an independent risk factor for the 90-day mortality in the HBV-ACLF cases.The patients with HBV-ACLF were stratified into two groups in accordance with their serum sMR levels at the baseline(low risk:<99.84 pg/mL and high risk:≥99.84 pg/mL).The 90-day mortality rates were 27.3%in the low-risk group and 87.5%in the high-risk group.Furthermore,sMR level apparently improved the performance of MELD score for predicting the prognosis of patients with HBV-ACLF.CONCLUSION Serum sMR level may be a predictor of the prognosis of HBV-ACLF patients.

关键词： Acute-on-chronic liver failure mannose receptor Model for end-stage liver disease Prognosis Risk factor

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Highly Selective Preparation of 3-and 6-Modified mannose/Altrose Derivatives

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Chemical Research in Chinese Universities 2006年第3期22卷 339-342页

作者： LIU Xiao-hong XIE Dang CHENG Chang-mei WANG Xia-yu GUO Xiao-qiang ZHAO Yu-fen Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology of Ministry of Education Department of Chemistry Tsinghua University Beijing 100084 P.R. China Institute of Polymer Science and Engineering Xiangtan University Xiangtan 411105 P.R. China

A highly efficient method to get 3-and 6-modified mannose/ahrose derivatives for oligosaccharide synthesis is described. All the compounds were obtained exclusively with the combinations of 3-and/or 6-hydroxyl protect... 详细信息

关键词： mannose Altrose Selective protection Selective deprotection

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Fluorescence detection of Escherichia coli on mannose modified ZnTe quantum dots

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Chinese Chemical Letters 2020年第6期31卷 1504-1507页

作者： Dudu Wu Dongming Wang Xiaomei Ye Kangrui Yuan Yuling Xie Baohong Li Chaobo Huang Tairong Kuang Zhiqiang Yu Zhi Chen School of Pharmacy Guangdong Medical UniversityDongguan 523808China College of Chemical Engineering Nanjing Forestry University Nanjing 210037China College of Materials Science and Engineering Zhejiang University of TechnologyHangzhou 310014China School of Pharmaceutical Sciences Guangdong Provincial Key Laboratory of New Drug ScreeningSouthern Medical UniversityGuangzhou 510515China State Key Laboratory of Polymer Materials Engineering Sichuan UniversityChengdu 610065China

Rapid detection and identification of Escherichia coli(E.coli)is essential to prevent its quickly spread.In this study,a novel fluorescence probe based on ZnTe quantum dots(QDs)modified by mannose(MAN)had been prepared for the determination of E.coli.The results showed that the obtained QDs showed excellent selectivity toward E.coli,and presented a good linearity in range of 1.0×10~5~1.0×10~8 CFU/mL.The optimum fluorescence intensity for detecting E.coli was found to be at pH 7.0 with a temperature of25℃and incubation time of 20 min.Under these optimum conditions,the detection limit of E.coli was4.6×10~4 CFU/mL.The quenching was discussed to be a static quenching procedure,which was proved by the quenching efficiency of QDs decreased with the temperature increasing.

关键词： ZnTe quantum dots Fluorescence intensity Probe mannose Escherichia coli

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The endo-beta mannase MAN7 contributes to cadmium tolerance by modulating root cell wall binding capacity in Arabidopsis thaliana

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Journal of Integrative Plant Biology 2023年第7期65卷 1670-1686页

作者： Qi Wu Yu Ting Meng Zhi Hang Feng Ren Fang Shen Xiao Fang Zhu State Key Laboratory of Soil and Sustainable Agriculture Institute of Soil ScienceChinese Academy of SciencesNanjing 210008China University of Chinese Academy of Sciences Beijing 100049China College of Environmental and Resource Sciences Zhejiang UniversityHangzhou 310058China

The heavy metal cadmium(Cd) is detrimental to crop growth and threatens human health through the food chain. To cope with Cd toxicity,plants employ multiple strategies to decrease Cd uptake and its root-to-shoot translocation. However, genes that participate in the Cd-induced transcriptional regulatory network, including those encoding transcription factors, remain largely unidentified. In this study, we demonstrate that ENDO-BETA-MANNASE 7(MAN7) is necessary for the response of Arabidopsis thaliana to toxic Cd levels. We show that MAN7 is responsible for mannase activity and modulates mannose content in the cell wall, which plays a role in Cd compartmentalization in the cell wall under Cd toxicity conditions. Additionally,the repression of root growth by Cd was partially reversed via exogenous application of mannose,suggesting that MAN7-mediated cell wall Cd redistribution depends on the mannose pathway.Notably, we identified a basic leucine zipper(bZIP) transcription factor, bZIP44, that acts upstream of MAN7 in response to Cd toxicity.Transient dual-luciferase assays indicated that bZIP44 directly binds to the MAN7 promoter region and activates its transcription. Loss of bZIP44 function was associated with greater sensitivity to Cd treatment and higher accumulation of the heavy metal in roots and shoots.Moreover, MAN7 overexpression relieved the inhibition of root elongation seen in the bzip44mutant under Cd toxicity conditions. This study thus reveals a pathway showing that MAN7-associated Cd tolerance in Arabidopsis is controlled by bZIP44 upon Cd exposure.

关键词： Arabidopsis thaliana bZIP44 cadmium cell wall MAN7 mannose

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