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Antigen-specific mRNA lipid nanoparticle platforms for the prevention and treatment of allergy and autoimmune diseases

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BMEMat(BioMedical Engineering Materials) 2024年第2期2卷 61-68页

作者： Emma Y.Yim Amanda C.Zhou Yvonne C.Yim Xiang Wang Tian Xia department of molecular Cell and Developmental BiologyUniversity of CaliforniaLos AngelesUSA department of Bioengineering University of CaliforniaLos AngelesUSA department of Chemistry and Biochemistry University of CaliforniaLos AngelesUSA Division of NanoMedicine Department of MedicineCenter for Environmental Implications of Nanotechnology(UC CEIN)California NanoSystems InstituteUniversity of CaliforniaLos AngelesUSA

While most nanomedicines primarily aim to stimulate the immune system against infections or tumors,there is a growing demand for inducing immune tolerance under certain conditions,such as allergic and autoimmune *** have explored nanotechnology-based strategies to induce immune tolerance in a targeted and specific *** approach involves the use of nanoparticles(NPs)to encapsulate immunosuppressive drugs and/or antigens to educate naïve T cells and promote the generation of antigen-specific regulatory T cells that inhibit immune ***,this approach has certain *** hydrophobicity of proteins or peptides restricts the degree to which they can be encapsulated in NPs,which in turn,affects their loading efficiency and treatment *** the emergence of mRNA lipid nanoparticle(LNP)platforms,there is the possibility of overcoming the limitations of protein and peptide *** date,mRNA LNP systems have been shown to provide organ,cellular,and subcellular targeting for the induction of immune *** method of drug delivery is flexible and scalable that can be customized for a specific patient,resulting in an effective means of administering relevant proteins or epitopes to induce antigen-specific immune *** continued research and development,this technology could offer a safer and more effective alternative to current therapies,ultimately improving the quality of life of patients worldwide.

关键词： allergy autoimmune diseases immune tolerance mRNA lipid nanoparticle nanomedicine

Identification of galectin-3 as a novel potential prognostic/predictive biomarker and therapeutic target for cerebral cavernous malformation disease

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Genes & Diseases 2024年第1期11卷 67-71页

作者： Souvik Kar Andrea Perrelli Kiran Kumar Bali Raffaella Mastrocola Arpita Kar Bushra Khan Luis Gand Arnab Nayak Christian Hartmann Wolfram SKunz Amir Samii Helmut Bertalanffy Saverio Francesco Retta International Neuroscience Institute Rudolf-PichlmayrStrasse 4Hannover 30625Germany department of Clinical and Biological Sciences University of TorinoOrbassano(TO)10043Italy CCM Italia Research Network National Coordination Center at the Department of Clinical and Biological SciencesUniversity of TorinoOrbassano(TO)10043Italy department of Experimental Pain Research Mannheim Center for Translational Neuroscience(MCTN)Medical Faculty MannheimHeidelberg UniversityMannheim 68167Germany department of Kidney Liver and Metabolic DiseasesChildren’s HospitalHannover Medical SchoolHannover 30625Germany Ricarda-Huch-Street-10B Hannover 30880Germany Institute of molecular and Cell Physiology Hannover Medical SchoolHannover 30625Germany department of Neuropathology Institute of PathologyHannover Medical SchoolHannover 30625Germany Institute of Experimental Epileptology and Cognition Research and department of Epileptology University Hospital BonnVenusberg-Campus 1Bonn 53127Germany epartment of pharmacology and Physiology University of Rochester Medical CenterRochesterNY 14642USA

cerebrovascular disease of genetic origin characterized by abnormally dilated capillaries and a wide spectrum of symptoms,including headaches,seizures,neurological deficits,and intracerebral *** unpredictable clinical course and the current lack of therapies make the identification of prognostic and predictive biomarkers an imperative research challenge.1 Herein,we provide evidence that galectin-3(Gal-3),a major tissue and circulating biomarker of oxidative stress and inflammation,is significantly up-regulated both in CCM patients and ***,wholetranscriptome sequencing,qRT-PCR,and Western blotting studies demonstrated a significant up-regulation of Gal-3 expression levels both in surgical CCM specimens and in blood samples of CCM patients.

关键词： inflammation cerebral dilated

Id2 epigenetically controls CD8^(+)T-cell exhaustion by disrupting the assembly of the Tcf3-LSD1 complex

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cellular & molecular Immunology 2024年第3期21卷 292-308页

作者： Yiming Li Mingwei Han Haolin Wei Wan Huang Zhinan Chen Tianjiao Zhang Meirui Qian Lin Jing Gang Nan Xiuxuan Sun Shuhui Dai Kun Wang Jianli Jiang Ping Zhu Liang Chen department of Cell Biology of National Translational Science Center for molecular Medicine and department of Clinical Immunology of Xijing Hospital Fourth Military Medical UniversityXi’anShaanxi 710032China State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases GanzhouJiangxi341000Xi’anShaanxi 710032China School of Medicine Shanghai UniversityShanghai 200444China

CD8^(+)T-cell exhaustion is a state of dysfunction that promotes tumor progression and is marked by the generation of Slamf6^(+)progenitor exhausted(Tex^(prog))and Tim-^(3+)terminally exhausted(Tex^(term))*** of DNA binding protein 2(Id2)has been shown to play important roles in T-cell development and CD8^(+)T-cell ***,the role of Id2 in CD8^(+)T-cell exhaustion is ***,we found that Id2 transcriptionally and epigenetically regulates the generation of Texprog cells and their conversion to Texterm *** deletion of Id2 dampens CD8^(+)T-cell-mediated immune responses and the maintenance of stem-like CD8^(+)T-cell subpopulations,suppresses PD-1 blockade and increases tumor ***,through its HLH domain,Id2 binds and disrupts the assembly of the Tcf3-Tal1 transcriptional regulatory complex,and thus modulates chromatin accessibility at the Slamf6 promoter by preventing the interaction of Tcf3 with the histone lysine demethylase ***,Id2 increases the abundance of the permissive H3K4me2 mark on the Tcf3-occupied E-boxes in the Slamf6 promoter,modulates chromatin accessibility at the Slamf6 promoter and epigenetically regulates the generation of Slamf6+Texprog *** LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing *** of LSD1 increases the abundance of Slamf6^(+)Tim-3^(−)Tex^(prog) cells in tumors and the expression level of Tcf1 in Id2-deleted CD8+T *** study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8^(+)T-cell exhaustion,and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion.

关键词： Id2 T-cell exhaustion Epigenetic modification Immune evasion

A comparative in vitro study on the effect of SGLT2 inhibitors on chemosensitivity to doxorubicin in MCF-7 breast cancer cells

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Oncology Research 2024年第5期32卷 817-830页

作者： SHAHID KARIM ALANOUD NAHER ALGHANMI MAHA JAMAL HUDA ALKREATHY ALAM JAMAL HIND A.ALKHATABI MOHAMMED BAZUHAIR AFTAB AHMAD department of Clinical pharmacology Faculty of MedicineKing Abdulaziz UniversityJeddahSaudi Arabia department of Biochemistry Faculty of ScienceKing Abdulaziz UniversityJeddahSaudi Arabia department of Biochemistry College of ScienceUniversity of JeddahJeddah21959Saudi Arabia Health Information Technology department The Applied CollegeKing Abdulaziz UniversityJeddahSaudi Arabia Pharmacovigilance and Medication Safety Unit Center of Research Excellence for Drug Research and Pharmaceutical IndustriesKing Abdulaziz UniversityJeddahSaudi Arabia

Cancer frequently develops resistance to the majority of chemotherapy *** study aimed to examine the synergistic cytotoxic and antitumor effects of SGLT2 inhibitors,specifically Canagliflozin(CAN),Dapagliflozin(DAP),Empagliflozin(EMP),and Doxorubicin(DOX),using in vitro *** precise combination of CAN+DOX has been found to greatly enhance the cytotoxic effects of doxorubicin(DOX)in MCF-7 ***,it was shown that cancer cells exhibit an increased demand for glucose and ATP in order to support their ***,when these medications were combined with DOX,there was a considerable inhibition of glucose consumption,as well as reductions in intracellular ATP and lactate ***,this effect was found to be dependent on the dosages of the *** addition to effectively inhibiting the cell cycle,the combination of CAN+DOX induces substantial modifications in both cell cycle and apoptotic gene *** work represents the initial report on the beneficial impact of SGLT2 inhibitor medications,namely CAN,DAP,and EMP,on the responsiveness to the anticancer properties of *** underlying molecular mechanisms potentially involve the suppression of the function of SGLT2.

关键词： SGLT2 Cancer Cytotoxicity ATP Cell cycle

Correlative factors of poor prognosis and abnormal cellular immune function in patients with Alzheimer’s disease

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World Journal of Clinical Cases 2024年第6期12卷 1063-1075页

作者： Hua Bai Hong-Mei Zeng Qi-Fang Zhang Yue-Zhi Hu Fei-Fei Deng department of Neurology The Third Affiliated Hospital of Guizhou Medical University in ChinaDuyun 558099Guizhou ProvinceChina department of Neurology Guizhou Medical UniversityDuyun 558099Guizhou ProvinceChina Key Laboratory of Medical molecular Biology Guizhou Medical UniversityGuiyang 550004Guizhou ProvinceChina

BACKGROUND Alzheimer’s disease(AD)is a serious disease causing human dementia and social *** quality of life and prognosis of AD patients have attracted much *** role of chronic immune inflammation in the pathogenesis of AD is becoming more and more *** To study the relationship among cognitive dysfunction,abnormal cellular immune function,neuroimaging results and poor prognostic factors in *** A retrospective analysis of 62 hospitalized patients clinical diagnosed with AD who were admitted to our hospital from November 2015 to November *** cognitive dysfunction performance characteristics,laboratory test data and neuroimaging data from medical records within 24 h of admission,including Mini Mental State Examination Scale score,drawing clock test,blood T lymphocyte subsets,and neutrophils and lymphocyte ratio(NLR),disturbance of consciousness,extrapyramidal symptoms,electroencephalogram(EEG)and head nucleus magnetic spectroscopy(MRS)and other *** logistic regression analysis was used to determine independent prog-nostic *** modified Rankin scale(mRS)was used to determine whether the prognosis was *** correlation between drug treatment and prognostic mRS score was tested by the rank sum *** Univariate analysis showed that abnormal cellular immune function,extrapyramidal symptoms,obvious disturbance of consciousness,abnormal EEG,increased NLR,abnormal MRS,and complicated pneumonia were related to the poor prognosis of AD *** logistic regression analysis showed that the decrease in the proportion of T lym-phocytes in the blood after abnormal cellular immune function(odd ratio:2.078,95%confidence interval:1.156-3.986,P<0.05)was an independent risk factor for predicting the poor prognosis of *** number of days of donepezil treatment to improve cognitive function was negatively correlated with mRS score(r=0.578,P<0.05).CONCLUSION The decrease in the proportion of T

关键词： Alzheimer’s disease cellular immunity Prognosis T lymphocytes Magnetic resonance spectroscopy

PEG400-mediated nanocarriers improve the delivery and therapeutic efficiency of mRNA tumor vaccines

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Chinese Chemical Letters 2024年第5期35卷 314-319页

作者： Wen Xiao Fazhan Wang Yangzhuo Gu Xi He Na Fan Qian Zheng Shugang Qin Zhongshan He Yuquan Wei Xiangrong Song department of Critical Care Medicine Frontiers Science Center for Disease-related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China Medical Research Center The First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhou 450000China

Dendritic cell(DC)-targeted delivery of mRNA is a prominent method to boost the efficacy of mRNA tumor *** targeting ligands are often modified on nanocarriers by polyethylene glycol(PEG)linker in mRNA delivery *** the PEG linker length influences the targeting delivery efficiency of mRNA nanocarrier in vivo remains ***,we designed and constructed DC-targeted mRNA delivery systems modified by mannose via different PEG linker lengths(100/400/1000/2000)(MPn-LPX).The top candidate MP_(400)-LPX(the linker was PEG400)showed the optimal mRNA expression and antigen presentation owing to the highly efficient uptake by ***,MP_(400)-LPX could better inhibited tumor growth and extended survival in the E.G7-OVA lymphoma and TC-1 cervical tumor mouse ***,these results demonstrated that PEG400 was the optimal linker for the PEGylated DC-targeted mRNA *** findings provided a new platform for the rational design of targeted mRNA nanovaccines with shorter-length PEG.

关键词： Cancer immunotherapy mRNA vaccines DC-targeted delivery PEGylated liposomes cellular uptake

Integrated proteomic profiling identifies amino acids selectively cytotoxic to pancreatic cancer cells

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The Innovation 2024年第3期5卷 138-145页

作者： Alfred Akinlalu Zachariah Flaten Komila Rasuleva Md Saimon Mia Aaron Bauer Santhalingam Elamurugan Nega Ejjigu Sudipa Maity Amara Arshad Min Wu Wenjie Xia Jia Fan Ang Guo Sijo Mathew Dali Sun department of Electrical and Computer Engineering University of Denver2155 E Wesley AvenueDenverCO 80210USA Biomedical Engineering Program North Dakota State University1401 Centennial BoulevardEngineering AdministrationRoom 203FargoND 58102USA department of Pharmaceutical Sciences School of PharmacyNorth Dakota State University1001 S.1401 Albrecht Boulevard Sudro HallFargoND 58102USA Materials and Nanotechnology Program North Dakota State University1410 North 14th AvenueCIE 201FargoND 58102USA Wenzhou Institute University of Chinese Academy of SciencesWenzhouZhejiang 325000China department of Aerospace Engineering Iowa State UniversityAmesIA 50011USA Center for cellular and molecular Diagnostics Tulane University School of Medicine1430 Tulane AvenueNew OrleansLA 70112USA department of Biochemistry and molecular Biology Tulane University School of Medicine1430 Tulane AvenueNew OrleansLA 70112USA Knoebel Institute for Healthy Aging University of Denver2155 E Wesley AvenueDenverCO 80210USA

Pancreatic adenocarcinoma(PDAC)is one of the most deadly cancers,characterized by extremely limited therapeutic options and a poor prognosis,as it is often diagnosed during late disease *** and selective treatments are urgently needed,since current therapies have limited efficacy and significant side *** proteomics analysis of extracellular vesicles,we discovered an imbalanced distribution of amino acids secreted by PDAC tumor *** findings revealed that PDAC cells preferentially excrete proteins with certain preferential amino acids,including isoleucine and histidine,via extracellular *** amino acids are associated with disease progression and can be targeted to elicit selective toxicity to PDAC tumor *** in vitro and in vivo experiments demonstrated that supplementation with these specific amino acids effectively eradicated PDAC ***,we also identified XRN1 as a potential target for these amino *** high selectivity of this treatment method allows for specific targeting of tumor metabolism with very low toxicity to normal ***,we found this treatment approach is easy-to-administer and with sustained tumor-killing ***,our findings reveal that exocytosed amino acids may serve as therapeutic targets for designing treatments of intractable PDAC and potentially offer alternative treatments for other types of cancers.

关键词： finding identif selectivity

Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer

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Genes & Diseases 2024年第3期11卷 338-350页

作者： Xin Xu Yuan Fang Somaira Nowsheen Ye-Xiong Li Zhenkun Lou Min Deng State Key Laboratory of molecular Oncology and department of Radiation Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China department of General Surgery Shanghai General HospitalShanghai Jiaotong University School of MedicineShanghai 200080China department of General Surgery Zhongshan HospitalFudan UniversityShanghai 200032China department of Dermatology University of California San DiegoSan DiegoCA 92093USA department of Oncology Mayo ClinicRochesterMN 55905USA

The adenosine monophosphate(AMP)-activated protein kinase(AMPK)sits at a cen-tral node in the regulation of energy metabolism and tumor *** is best known to sense high cellular ADP or AMP levels,which indicate the depletion of energy *** studies have shown that the low expression of phosphorylated AMPK is associated with a poor prognosis of pancreatic *** this study,we report that AMPK is also highly sensitive to extracellular matrix(ECM)*** found that AMPK is activated in cells when cultured under low ECM stiffness conditions and is functionally required for the metabolic switch induced by ECM *** regulation of AMPK requires the Hippo kinases but not LKB1/*** kinases directly phosphorylate AMPKa at Thr172 to activate AMPK at low ECM ***,we found AMPK activity is inhibited in patients with pancreatic ductal adenocarcinoma(PDAC)with high ECM stiffness and is associated with a poor survival *** activation of Hippo kinases by ROCK inhibitor Y-27632 in combination with the mitochondrial inhibitor metformin synergistically activates AMPK and dramatically inhibits PDAC ***,these findings establish a novel model for AMPK regulation by the mechanical properties of ECMs and provide a rationale for simultaneously targeting the ECM stiffness-Hippo kinases-AMPK signaling and low glucose-LKB1-AMPK signaling pathways as an effective therapeutic strategy against PDAC.

关键词： AMPKactivity cellularmetabolic switch ECM stiffness Hippokinase signaling Pancreaticductal adenocarcinoma

Metabolic shift in liver: Correlation between perfusion temperature and hypoxia inducible factor-1α

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World Journal of Gastroenterology 2015年第4期21卷 1108-1116页

作者： Andrea Ferrigno Laura Giuseppina Di Pasqua Alberto Bianchi Plinio Richelmi Mariapia VairettiAndrea Ferrigno Unit of cellular and molecular pharmacology and Toxicology Department of Interna Medicine and TherapeuticsUniversity of PaviaPavia 27100 Italy

AIM: To study at what temperature the oxygen carried by the perfusate meets liver requirements in a model of organ perfusion. METHODS: in this study, we correlated hypoxia induciblefactor(Hi F)-1α expression to the perfusion temperature and the hepatic oxygen uptake in a model of isolated perfused rat liver. Livers from Wistar rats were perfused for 6 h with an oxygenated medium at 10, 20, 30 and 37 ℃. Oxygen uptake was measured by an oxygen probe; lactate dehydrogenase activity, lactate release and glycogen were measured spectrophotometrically; bile flow was gravitationally determined; p H of the perfusate was also evaluated; Hi F-1α m RNA and protein expression were analyzed by real time-polymerase chain reaction and ELi SA, respectively. RESULTS: Livers perfused at 10 and 20 ℃ showed no difference in lactate dehydrogenase release after 6 h of perfusion(0.96 ± 0.23 vs 0.93 ± 0.09 m U/min per g) and had lower hepatic damage as compared to 30 and 37 ℃(5.63 ± 0.76 vs 527.69 ± 45.27 m U/min per g, respectively, P s < 0.01). After 6 h, tissue ATP was significantly higher in livers perfused at 10 and 20 ℃than in livers perfused at 30 and 37 ℃(0.89 ± 0.06 and 1.16 ± 0.05 vs 0.57 ± 0.09 and 0.33 ± 0.08 nmol/mg, respectively, P s < 0.01). No sign of hypoxia was observed at 10 and 20 ℃, as highlighted by low lactate release respect to livers perfused at 30 and 37 ℃(121.4 ± 12.6 and 146.3 ± 7.3 vs 281.8 ± 45.3 and 1094.5 ± 71.7 nmol/m L, respectively, P s < 0.02), and low relative Hi F-1α m RNA(0.40 ± 0.08 and 0.20 ± 0.03 vs 0.60 ± 0.20 and 1.47 ± 0.30, respectively, P s < 0.05) and protein(3.72 ± 0.16 and 3.65 ± 0.06 vs 4.43 ± 0.41 and 6.44 ± 0.82, respectively, P s < 0.05) ***: Livers perfused at 10 and 20 ℃ show no sign of liver injury or anaerobiosis, in contrast to livers perfused at 30 and 37 ℃.

关键词： Anaerobiosis Hypoxia inducible factor-1 α ischemia