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Piperazine-derived ionizable lipids for enhanced mRNA delivery and cancer immunotherapy

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Nano Research 2024年第8期17卷 7357-7364页

作者： Kai Xu Yujia Xu Jin Sun Xinwei Cheng Chenxi Lu Wenzhong Chen Bingfang He Tianyue Jiang School of pharmaceutical Sciences Nanjing Tech UniversityNanjing 211816China department of Nano Formulation Nanjing GeneLeap BiotechnologyNanjing 210061China

Messenger ribonucleic acid(mRNA)-based therapeutics hold great prospects in disease treatment and lipid nanoparticles(LNPs)are the most extensively applied non-viral platform for RNA delivery in *** the clinical success of LNPs as vehicles have been achieved,developing LNPs with enhanced mRNA transmembrane delivery and transfection efficiency in a non-toxic manner is highly desirable and *** this study,we designed a series of new ionizable amino lipids with piperazinederived headgroups and constructed a group of LNPs to promote the transfection activity of mRNA *** them,LNP formulated with lipid 10(L10-LNP)can efficiently package mRNA and perform superior transfection efficiency both in vitro and in vivo,which is mainly attributed to the improved intracellular uptake and effective endosomal *** verified that a single administration of L10-LNP packaging interleukin(IL)-12 mRNA induced tumor shrink and even regression by robust activation of immune effector CD8^(+)T cells and stimulating the generation of IFN-γwithout causing systemic toxicity,which provides a promising platform for clinical cancer immunotherapy.

关键词： ionizable lipid lipid nanoparticle piperazine-derived lipid mRNA therapeutics cancer immunotherapy

Targeted anti-tumor synergistic effects of Myc decoy oligodeoxynucleotides-loaded selenium nanostructure combined with chemoradiotherapy on LNCaP prostate cancer cells

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Oncology Research 2024年第1期32卷 101-125页

作者： ROGHAYEH GHORBANI MAHMOUD GHARBAVI ALI SHARAFI ELHAM RISMANI HAMED REZAEEJAM YOUSEF MORTAZAVI BEHROOZ JOHARI department of Medical biotechnology School of MedicineZanjan University of Medical SciencesZanjanIran Nanotechnology Research Center Ahvaz Jundishapur University of Medical SciencesAhvazIran Zanjan pharmaceutical biotechnology Research Center Zanjan University of Medical SciencesZanjanIran department of pharmaceutical biotechnology School of PharmacyZanjan University of Medical SciencesZanjanIran molecular Medicine department Biotechnology Research CenterPasteur Institute of IranPasteur AvenueTehranIran department of Radiology Technology School of Allied Medical SciencesZanjan University of Medical SciencesZanjanIran

In the present study,we investigated the synergistic effects of targeted methotrexate-selenium nanostructure containing Myc decoy oligodeoxynucleotides along with X-irradiation exposure as a combination therapy on LNCaP prostate cancer *** decoy ODNs were designed based on the promoter of Bcl-2 gene and analyzed by molecular docking and molecular dynamics *** were loaded on the synthesized Se@BSA@Chi-MTX *** physicochemical characteristics of nanostructures were determined by FTIR,DLS,UV-vis,TEM,EDX,in vitro release,and hemolysis ***,the cytotoxicity properties of them with and without X-irradiation were investigated by uptake,MTT,cell cycle,apoptosis,and scratch assays on the LNCaP cell *** results of DLS and TEM showed negative charge(−9 mV)and nanometer size(40 nm)for Se@BSA@Chi-DEC-MTX NPs,*** results of FTIR,UV-vis,and EDX showed the proper interaction of different parts and the correct synthesis of *** results of hemolysis showed the hemocompatibility of this nanoparticle in concentrations less than 6 mg/*** ODNs release from the nanostructures showed a pH-dependent manner,and the release rate was 15%higher in acidic *** targeted Se@BSA@Chi-labeled ODN-MTX NPs were efficiently taken up by LNCaP cells by targeting the prostate-specific membrane antigen(PSMA).The significant synergistic effects of nanostructure(containing MTX drug)treatment along with X-irradiation showed cell growth inhibition,apoptosis induction(~57%),cell cycle arrest(G2/M phase),and migration inhibition(up to 90%)compared to the *** results suggested that the Se@BSA@Chi-DEC-MTX NPs can potentially suppress the cell growth of LNCaP *** nanostructure system can be a promising approach for targeted drug delivery and chemoradiotherapy in prostate cancer treatment.

关键词： Chemoradiotherapy Combination therapy Decoy oligodeoxynucleotides Myc transcription factor Selenium nanoparticle Prostate cancer

Enhanced axonal regeneration and functional recovery of the injured sciatic nerve in a rat model by lithium-loaded electrospun nanofibrous scaffolds

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Bio-Design and Manufacturing 2024年第5期7卷 701-720页

作者： Banafsheh Dolatyar Bahman Zeynali Iman Shabani Azita Parvaneh Tafreshi Reza Karimi-Soflou Developmental Biology Laboratory School of BiologyCollege of ScienceUniversity of TehranTehran ***Iran department of Biomedical Engineering Amirkabir University of Technology(Tehran Polytechnic)Tehran ***Iran department of molecular Medicine Faculty of Medical BiotechnologyNational Institute of Genetic Engineering and BiotechnologyTehran ***Iran 123

Increasing evidence indicates that engineered nerve grafts have great potential for the regeneration of peripheral nerve injuries(PNIs).While most studies have focused only on the topographical features of the grafts,we have considered both the biophysical and biochemical manipulations in our applied *** achieve this,we fabricated an electrospun nanofibrous scaffold(ENS)containing polylactide nanofibers loaded with lithium(Li)ions,a Wnt/β-catenin signaling *** addition,we seeded human adipose-derived mesenchymal stem cells(hADMSCs)onto this engineered scaffold to examine if their differentiation toward Schwann-like cells was *** further examined the efficacy of the scaffolds for nerve regeneration in vivo via grafting in a PNI rat *** results showed that Li-loaded ENSs gradually released Li within 11 d,at concentrations ranging from 0.02 to(3.64±0.10)mmol/L,and upregulated the expression of Wnt/β-catenin target genes(cyclinD1 and c-Myc)as well as those of Schwann cell markers(growth-associated protein 43(GAP43),S100 calcium binding protein B(S100B),glial fibrillary acidic protein(GFAP),and SRY-box transcription factor 10(SOX10))in differentiated *** the PNI rat model,implantation of Li-loaded ENSs with/without cells improved behavioral features such as sensory and motor functions as well as the electrophysiological characteristics of the injured *** improved function was further validated by histological analysis of sciatic nerves grafted with Li-loaded ENSs,which showed no fibrous connective tissue but enhanced organized myelinated *** potential of Li-loaded ENSs in promoting Schwann cell differentiation of hADMSCs and axonal regeneration of injured sciatic nerves suggests their potential for application in peripheral nerve tissue engineering.

关键词： Stem cell Schwann cell differentiation Electrospun nanofibrous scaffold Lithium ion Nerve regeneration

Amphipathicity mediated endocytosis of mesoporous silica nanoparticles with tunable frameworks

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Nano Research 2024年第9期17卷 8350-8359页

作者： Runfeng Lin Tiancong Zhao Liang Chen Minchao Liu Hongyue Yu Ruicong Wang Minjia Yuan Xiaomin Li Dongyuan Zhao department of Chemistry State Key Laboratory of Molecular Engineering of PolymersiChemShanghai Key Laboratory of Molecular Catalysis and Innovative MaterialsFudan UniversityShanghai 200433China Shanghai Qiran biotechnology Co. Ltd.Shanghai 201702China

Due to the amphiphilic nature of phospholipids in the cell membrane,the amphipathicity of the nanomedicine plays a crucial role in the ***,limited biological characterization methods restrict the study of the state of nanoparticles with different amphiphilicities on cell *** understanding of interaction of amphiphilic particle with cell membrane is still ***,by combining the dissipative particle dynamics(DPD)with the framework construction of mesoporous silica nanoparticles(MSNs),we demonstrate the enhanced endocytosis induced by the *** results confirm that the presence of hydrophobic groups on the surface of nanoparticles can disturb the integrity of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine(POPC)membrane and induce activation of phospholipids to a higher energy level,thereby facilitating the wrapping of *** validate the simulation findings,uniform MSNs with hydrophilic pure silica framework and two types of amphiphilic MSNs with varying hydrophilic organic groups in the framework are rationally synthesized by using different silane *** obtained three kinds of MSNs show similar diameter(~100 nm)and mesopores(~2 nm),but distinct hydrophobicity/hydrophilicity *** phenyl-bridged MSN with a carbon content of 27.1%exhibits enhanced cellular uptake,consistent with the theoretical simulation *** work sheds light on how the surface amphipathicity influences endocytosis through the interaction with cell membrane.

关键词： mesoporous silica nanoparticles mesoporous organosilica endocytosis cell membrane amphipathicity

Sinensetin protects against periodontitis through binding to Bach1 enhancing its ubiquitination degradation and improving oxidative stress

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International Journal of Oral Science 2024年第3期16卷 553-562页

作者： Zhiyao Yuan Junjie Li Fuyu Xiao Yu Wu Zhiting Zhang Jiahong Shi Jun Qian Xudong Wu Fuhua Yan department of Periodontology Nanjing Stomatological HospitalAffiliated Hospital of Medical SchoolInstitute of StomatologyState Key Laboratory of Pharmaceutical BiotechnologySchool of Life SciencesNanjing UniversityNanjingChina

Periodontitis is a chronic inflammatory and immune reactive disease induced by the subgingival *** therapeutic effect for susceptible patients is often unsatisfactory due to excessive inflammatory response and oxidative ***(Sin)is a nature polymethoxylated flavonoid with anti-inflammatory and antioxidant *** study aimed to explore the beneficial effect of Sin on periodontitis and the specific molecular *** found that Sin attenuated oxidative stress and inflammatory levels of periodontal ligament cells(PDLCs)under inflammatory *** Sin to rats with ligation-induced periodontitis models exhibited a protective effect against periodontitis in *** molecular docking,we identified Bach1 as a strong binding target of Sin,and this binding was further verified by cellular thermal displacement assay and immunofluorescence *** immunoprecipitation-quantitative polymerase chain reaction results also revealed that Sin obstructed the binding of Bach1 to the HMOX1 promoter,subsequently upregulating the expression of the key antioxidant factor *** functional experiments with Bach1 knocked down and overexpressed verified Bach1 as a key target for Sin to exert its antioxidant ***,we demonstrated that Sin prompted the reduction of Bach1 by potentiating the ubiquitination degradation of Bach1,thereby inducing HO-1 expression and inhibiting oxidative ***,Sin could be a promising drug candidate for the treatment of periodontitis by targeting binding to Bach1.

关键词： Bach1 period prompt

Fatty acids derived from oviposition systems guide female black soldier flies(Hermetia illucens)toward egg deposition sites

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Insect Science 2024年第4期31卷 1231-1248页

作者： Patrick Klüber Emna Arous Jeanny Jerschow Marco Fraatz Daniel Bakonyi Martin Rühl Holger Zorn department Bioresources Fraunhofer Institute for Molecular Biology and Applied EcologyGiessenGermany Institute of Food Chemistry and Food biotechnology Justus Liebig University GiessenGiessenGermany

The black soldier fly,Hermetia illucens,comes with big promises for industrial purposes since its larvae feed polyphagously on a broad spectrum of organic ***,research focusing on adult flies is scarce,which is inconsistent with their reproductive relevance within the rearing *** particular,directed oviposition is a challenge in artificial ***,decomposing organic matter is commonly used as oviposition substrate,which has extensive potential for improvement in view of the lack of standardization and the risk of microbial ***,we identified three fatty acids and one fatty acid methyl ester derived from the surface of old oviposition sites and targeted to elucidate their effect on preference behavior and oviposition site selection using Y-olfactometry and prepared oviposition sites,*** to tetradecanoic acid attracted gravid females and stimulated oviposition most strongly,while decanoic acid demonstrated a repulsive *** kept in mixed-sex populations were attracted by tetradecanoic acid,resulting in a higher egg mass found in the compound box(3.0–11.4 fold),a≥2.3 fold reduction of nonspecifically deposited eggs,and the highest total egg ***,decanoic and dodecanoic acid caused females to lay a greater proportion of eggs nonspecifically outside both *** data suggest that fatty acids,especially tetradecanoic acid,are important cues for oviposition site selection in black soldier *** order to achieve a directed oviposition behavior,the role of further short-and long-chain fatty acids as attractants should be examined.

关键词： black soldier fly Hermetia illucens fatty acids insects as food and feed oviposition oviposition site selection tetradecanoic acid

Dysregulation of RNA modification systems in clinical populations with neurocognitive disorders

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Neural Regeneration Research 2024年第6期19卷 1256-1261页

作者： Helen M.Knight Merve DemirbugenÖz Adriana PerezGrovas-Saltijeral Division of Cells Organisms and Molecular GeneticsSchool of Life SciencesUniversity of NottinghamNottinghamUK department of pharmaceutical Toxicology Faculty of PharmacyAnkara UniversityAnkaraTurkey

The study of modified RNA known as epitranscriptomics has become increasingly relevant in our understanding of disease-modifying *** of N6 adenosine(m^(6)A)and C5 cytosine(m^(5)C)bases occur on mRNAs,tRNA,mt-tRNA,and rRNA species as well as non-coding *** emerging knowledge of RNA binding proteins that act as writer,reader,and eraser effector proteins,comes a new understanding of physiological processes controlled by these *** processes when spatiotemporally disrupted within cellular nanodomains in highly specialized tissues such as the brain,give rise to different forms of *** this review,we discuss accumulating evidence that changes in the m^(6)A and m^(5)C methylation systems contribute to neurocognitive *** studies first identified mutations within FMR1 to cause intellectual disability Fragile X syndromes several years before FMR1 was identified as an m^(6)A RNA reader ***,familial mutations within the m^(6)A writer gene METTL5,m^(5)C writer genes NSUN2,NSUN3,NSUN5,and NSUN6,as well as THOC2 and THOC6 that form a protein complex with the m^(5)C reader protein ALYREF,were recognized to cause intellectual development ***,differences in expression of the m^(5)C writer and reader effector proteins,NSUN6,NSUN7,and ALYREF in brain tissue are indicated in individuals with Alzheimer's disease,individuals with a high neuropathological load or have suffered traumatic brain ***,an abundance of m^(6)A reader and anti-reader proteins are reported to change across brain regions in Lewy bodies diseases,Alzheimer's disease,and individuals with high cognitive reserve.m^(6)A-modified RNAs are also reported significantly more abundant in dementia with Lewy bodies brain tissue but significantly reduced in Parkinson's disease tissue,whilst modified RNAs are misplaced within diseased cells,particularly where synapses are *** parahippocampal brain tissue,m^(6)A modification is enri

关键词： 5-methylcytosine methylation Alzheimer's disease cognitive diseases epitranscriptomics intellectual disability Lewy body diseases N6 adenosine RNA modification

Development of an active-site titrant for SARS-CoV-2 main protease as an indispensable tool for evaluating enzyme kinetics

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2349-2357页

作者： Rabea Voget Julian Breidenbach Tobias Claff Alexandra Hingst Katharina Sylvester Christian Steinebach Lan Phuong Vu Renato H.Weiße Ulrike Bartz Norbert Sträter Christa E.Müller Michael Gütschow pharmaceutical Institute Pharmaceutical&Medicinal ChemistryUniversity of BonnBonn 53121Germany Institute of Bioanalytical Chemistry Center for Biotechnology and BiomedicineLeipzig UniversityLeipzig 04103Germany department of Natural Sciences University of Applied Sciences Bonn-Rhein-SiegRheinbach 53359Germany

A titrant for the SARS-CoV-2 main protease(M^(pro))was developed that enables,for the first time,the exact determination of the concentration of the enzymatically active M^(pro) by active-site *** covalent binding mode of the tetrapeptidic titrant was elucidated by the determination of the crystal structure of the enzyme–titrant *** fluorogenic substrates of M^(pro),including a prototypical,internally quenched Dabcyl-EDANS peptide,were compared in terms of solubility under typical assay *** exploiting the new titrant,key kinetic parameters for the M^(pro)-catalyzed cleavage of these substrates were determined.

关键词： COVID-19 SARS-CoV-2 Main protease Peptide nitriles Fluorogenic substrates Active-site titration X-ray crystallography Inner filter effect

G protein-mediated signal transduction: a molecular choreography of G protein activation after GTP binding

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Signal Transduction and Targeted Therapy 2024年第8期9卷 3155-3157页

作者： Evi Kostenis Lars Jurgenliemke Judith Alenfelder department of molecular- Cellular-and PharmacobiologyInstitute of Pharmaceutical BiologyUniversity of BonnBonnGermany Graduate Training Group RTG2873 University of BonnBonnGermany

A recent report from the Skiniotis group,'published in Nature,provides fascinating insight into the molecular choreography underlying a quintessential cellular signaling mechanism:G protein-mediated signal *** time-resolved cryo-EM,the authors pieced together many sequential structural snapshots to visualize how a trimeric aβy G protein-after being convinced by its activated G protein-coupled receptor(GPCR)to release GDP-picks up GTP,to set in motion finely tuned conformational transitions that lead to the conversion into the active state and,finally,subunit dissociation as well as disengagement from the receptor.

关键词： Skin activation finally