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Genome editing of PAR2 through targeted delivery of CRISPR-Cas9 system for alleviating acute lung inflammation via ERK/NLRP3/IL-1β and NO/iNOS signalling

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1441-1456页

作者： Xin Zhuo Yue Wu Xiujuan Fu Jianbin Li Yuxin Xiang Xiaoyu Liang Canquan Mao Yuhong Jiang Sichuan engineering research center for Biomimetic Synthesis of natural drugs School of Life Science and EngineeringSouthwest Jiaotong UniversityChengdu 610031China

Excessive and uncontrollable inflammatory responses in alveoli can dramatically exacerbate pulmonary disease progressions through vigorous cytokine releases,immune cell infiltration and protease-driven tissue *** is an urgent need to explore potential drug strategies for mitigating lung ***-activated receptor 2(PAR2)as a vital molecular target principally participates in various inflammatory diseases via intracellular signal ***,it has been rarely reported about the role of PAR2 in lung *** study applied CRISPR-Cas9 system encoding Cas9 and sg RNA(p Cas9-PAR2)for PAR2 knockout and fabricated an anionic human serum albuminbased nanoparticles to deliver p Cas9-PAR2 with superior inflammation-targeting efficiency and stability(TAP/p Cas9-PAR2).TAP/p Cas9-PAR2 robustly facilitated p Cas9-PAR2 to enter and transfect inflammatory cells,eliciting precise gene editing of PAR2 in vitro and in ***,PAR2 deficiency by TAP/p Cas9-PAR2 effectively and safely promoted macrophage polarization,suppressed proinflammatory cytokine releases and alleviated acute lung inflammation,uncovering a novel value of *** also revealed that PAR2-mediated pulmonary inflammation prevented by TAP/p Cas9-PAR2was mainly dependent on ERK-mediated NLRP3/IL-1β and NO/i NOS ***,this work indicated PAR2 as a novel target for lung inflammation and provided a potential nanodrug strategy for PAR2 deficiency in treating inflammatory diseases.

关键词： Protease-activated receptor 2(PAR2) CRISPR-Cas9 Gene editing Inflammation Acute lung inflammation NLRP3 Nanoparticles Drug delivery

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Mannogalactoglucan from mushrooms protects pancreatic islets via restoring UPR and promotes insulin secretion in TIDM mice

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Food Science and Human Wellness 2024年第3期13卷 1390-1401页

作者： Ting Liu Si Chen Yunhe Qu Lujuan Zheng Xiaoxuan Yang Shuhan Men Yuanning Wang Hanrui Ma Yifa Zhou Yuying Fan engineering research center of Glycoconjugates Ministry of EducationJilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural DrugsSchool of Life SciencesNortheast Normal UniversityChangchun 130024China

Type 1 diabetes mellitus(T1DM) lacks insulin secretion due to autoimmune deficiency of pancreaticβ-*** pancreatic islets and enhancing insulin secretion has been therapeutic *** is the main type of polysaccharide from natural mushroom,which has potential medicinal ***,the antidiabetic property of mannogalactoglucan in T1DM has not been fully *** this study,we obtained the neutral fraction of alkali-soluble Armillaria mellea polysaccharide(AAMP-N) with the structure of mannogalactoglucan from the fruiting body of *** and investigated the potential therapeutic value of AAMP-N in *** demonstrated that AAMP-N lowered blood glucose and improved diabetes symptoms in T1DM ***-N activated unfolded protein response(UPR) signaling pathway to maintain ER protein folding homeostasis and promote insulin secretion in *** that,AAMP-N promoted insulin synthesis via upregulating the expression of transcription factors,increased Ca^(2+) signals to stimulate intracellular insulin secretory vesicle transport via activating calcium/calmodulin-dependent kinase Ⅱ(CamkⅡ) and cAMP/PKA signals,and enhanced insulin secretory vesicle fusion with the plasma membrane via vesicle-associated membrane protein 2(VAMP2).Collectively,these studies demonstrated that the therapeutic potential of AAMP-N on pancreatic islets function,indicating that mannogalactoglucan could be natural nutraceutical used for the treatment of T1DM.

关键词： Mannogalactoglucan Mushroom Pancreatic islets Insulin secretion Insulin synthesis Unfolded protein response(UPR) Type 1 diabetes mellitus(T1DM)

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Quantum dot-enabled infrared hyperspectral imaging with single-pixel detection

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Light(Science & Applications) 2024年第6期13卷 1112-1121页

作者： Heyan Meng Yuan Gao Xuhong Wang Xianye Li Lili Wang Xian Zhao Baoqing Sun School of Information Sciences and engineering Shandong UniversityQingdaoChina center for Optics research and engineering(CORE) Key Laboratory of Laser&Infrared System(Shandong University)Ministry of EducationShandong UniversityQingdaoChina School of Mechanical Electrical and Information EngineeringShandong UniversityWeihaiChina

Near-infrared(NIR)hyperspectral imaging is a powerful technique that enables the capture of three-dimensional(3D)spectra-spatial information within the NIR spectral range,offering a wide array of ***,the high cost associated with InGaAs focal plane array(FPA)has impeded the widespread adoption of NIR hyperspectral *** this challenge,in this study,we adopt an alternative approach—single-pixel detection for NIR hyperspectral *** investigation reveals that single-pixel detection outperforms conventional FPA,delivering a superior signal-to-noise ratio(SNR)for both spectral and imaging *** implement this strategy,we leverage self-assembled colloidal quantum dots(CQDs)and a digital micromirror device(DMD)for NIR spectral and spatial information multiplexing,complemented by single-pixel detection for simultaneous spectral and image *** experimental results demonstrate successful NIR hyperspectral imaging with a detection window about 600 nm and an average spectral resolution of 8.6 nm with a pixel resolution of 128×*** resulting spectral and spatial data align well with reference instruments,which validates the effectiveness of our *** circumventing the need for expensive and bulky FPA and wavelength selection components,our solution shows promise in advancing affordable and accessible NIR hyperspectral imaging technologies,thereby expanding the range of potential applications.

关键词： spectral Quantum mirror

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In situ visualization of the cellular uptake and sub-cellular distribution of mussel oligosaccharides

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Journal of Pharmaceutical Analysis 2024年第6期14卷 840-850页

作者： Zhenjie Yu Huarong Shao Xintian Shao Linyan Yu Yanan Gao Youxiao Ren Fei Liu Caicai Meng Peixue Ling Qixin Chen Key Laboratory for Biotechnology drugs of National Health Commission School of Pharmaceutical Sciences&Institute of Materia MedicaMedical Science and Technology Innovation CenterShandong First Medical University&Shandong Academy of Medical SciencesJinan250117China Key Laboratory of Biopharmaceuticals Engineering Laboratory of Polysaccharide DrugsNational-Local Joint Engineering Laboratory of Polysaccharide DrugsShandong Academy of Pharmaceutical ScienceJinan250101China Shenzhen research Institute of Xiamen University ShenzhenGuangdong518057China School of Life Sciences Medical Science and Technology Innovation CenterShandong First Medical University&Shandong Academy of Medical SciencesJinan250117China Departments of Diagnostic Radiology SurgeryChemical and Biomolecular Engineeringand Biomedical EngineeringYong Loo Lin School of Medicine and Faculty of EngineeringNational University of SingaporeSingapore119074Singapore School of Pharmaceutical Sciences Shandong UniversityJinan250101China

Unlike chemosynthetic drugs designed for specific molecular and disease targets,active small-molecule natural products typically have a wide range of bioactivities and multiple targets,necessitating extensive screening and *** address this issue,we propose a strategy for the direct in situ microdynamic examination of potential drug candidates to rapidly identify their effects and mechanisms of *** a proof-of-concept,we investigated the behavior of mussel oligosaccharide(MOS-1)by tracking the subcellular dynamics of fluorescently labeled MOS-1 in cultured *** recorded the entire dynamic process of the localization of fluorescein isothiocyanate(FITC)-MOS-1 to the lysosomes and visualized the distribution of the drug within the ***,lysosomes containing FITC-MOS-1 actively recruited lipid droplets,leading to fusion events and increased cellular lipid *** drug behaviors confirmed MOS-1 is a candidate for the treatment of lipid-related ***,in a high-fat HepG2 cell model and in high-fat diet-fed apolipoprotein E(ApoE)^(-/-)mice,MOS-1 significantly promoted triglyceride degradation,reduced lipid droplet accumulation,lowered serum triglyceride levels,and mitigated liver damage and ***,our work supports the prioritization of in situ visual monitoring of drug location and distribution in subcellular compartments during the drug development phase,as this methodology contributes to the rapid identification of drug ***,this methodology is significant for the screening and development of selective small-molecule drugs,and is expected to expedite the identification of candidate molecules with medicinal effects.

关键词： Cellular imaging Fluorescence labeling Mussel oligosaccharide Lipid metabolism

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Cognitive impairment in cerebral small vessel disease induced by hypertension

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Neural Regeneration research 2024年第7期19卷 1454-1462页

作者： Weipeng Wei Denglei Ma Lin Li Lan Zhang Department of Pharmacy Xuanwu Hospital of Capital Medical UniversityBeijingChina Beijing Geriatric Medical research center Beijing Engineering Research Center for Nervous System DrugsNational Center for Neurological DisordersNational Clinical Research Center for Geriatric DiseasesBeijingChina

Hypertension is a primary risk factor for the progression of cognitive impairment caused by cerebral small vessel disease,the most common cerebrovascular *** r,the causal relationship between hypertension and cerebral small vessel disease remains *** has substantial negative impacts on brain health and is recognized as a risk factor for cerebrovascular *** hypertension and lifestyle factors are associated with risks for stro ke and dementia,and cerebral small vessel disease can cause dementia and *** is the main driver of cerebral small vessel disease,which changes the structure and function of cerebral vessels via various mechanisms and leads to lacunar infarction,leukoaraiosis,white matter lesions,and intracerebral hemorrhage,ultimately res ulting in cognitive decline and demonstrating that the brain is the to rget organ of *** review updates our understanding of the pathogenesis of hypertensioninduced cerebral small vessel disease and the res ulting changes in brain structure and function and declines in cognitive *** also discuss drugs to treat cerebral small vessel disease and cognitive impairment.

关键词： blood-brain barrier cerebral small vessel disease cognitive impairment dementia endothelial dysfunction enlarged perivascular space hypertension lacunar infarction neuroinflammation treatment white matter high signal intensity

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Application of Fusobacterium nucleatum as a biomarker in gastrointestinal malignancies

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World Journal of Gastrointestinal Oncology 2024年第6期16卷 2271-2283页

作者： Long-Chen Yu Ya-Ping Li Yue-Ming Xin Mai Mao Ya-Xin Pan Yi-Xuan Qu Zheng-Dong Luo Yi Zhang Xin Zhang Department of Clinical Laboratory Qilu Hospital of Shandong UniversityShandong Engineering Research Center of Biomarker and Artificial Intelligence ApplicationJinan 250012Shandong ProvinceChina

The morbidity and mortality of gastrointestinal(GI)malignancies are among the highest in the world,posing a serious threat to human *** of the insidious onset of the cancer,it is difficult for patients to be diagnosed at an early stage,and it rapidly progresses to an advanced stage,resulting in poor treatment and *** nucleatum(***)is a gram-negative,sporefree anaerobic bacterium that primarily colonizes the oral cavity and is implicated in the development of colorectal,esophageal,gastric,and pancreatic cancers via various intricate *** development in novel research suggests that *** may function as a biomarker in GI *** the abundance of *** in stool,saliva,and serum samples of patients may aid in the diagnosis,risk assessment,and prognosis monitoring of GI *** editorial systematically describes the biological roles and mechanisms of *** in GI malignancies focusing on the application of *** as a biomarker in the diagnosis and prognosis of GI malignancies to promote the clinical translation of *** and GI tumors-related research.

关键词： Gastrointestinal malignancies Fusobacterium nucleatum Biomarker Diagnosis Prognosis

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Therapeutic strategies of targeting nonapoptotic regulated cell death (RCD) with smallmolecule compounds in cancer

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Acta Pharmaceutica Sinica B 2024年第7期14卷 2815-2853页

作者： Xin Jin Wenke Jin Linlin Tong Jia Zhao Lan Zhang Na Lin Department of Ultrasound Department of Medical Oncology and Department of Hematologythe First Hospital of China Medical UniversityChina Medical UniversityShenyang 110001China Sichuan engineering research center for Biomimetic Synthesis of natural drugs School of Life Science and EngineeringSouthwest Jiaotong UniversityChengdu 610031China

Regulated cell death(RCD)is a controlled form of cell death orchestrated by one or more cascading signaling pathways,making it amenable to pharmacological *** subroutines can be categorized as apoptotic or non-apoptotic and play essential roles in maintaining homeostasis,facilitating development,and modulating *** evidence has recently revealed that RCD evasion is frequently the primary cause of tumor *** non-apoptotic RCD subroutines have garnered attention as promising cancer therapies due to their ability to induce tumor regression and prevent relapse,comparable to ***,they offer potential solutions for overcoming the acquired resistance of tumors toward apoptotic *** an increasing understanding of the underlying mechanisms governing these non-apoptotic RCD subroutines,a growing number of small-molecule compounds targeting single or multiple pathways have been discovered,providing novel strategies for current cancer *** this review,we comprehensively summarized the current regulatory mechanisms of the emerging non-apoptotic RCD subroutines,mainly including autophagy-dependent cell death,ferroptosis,cuproptosis,disulfidptosis,necroptosis,pyroptosis,alkaliptosis,oxeiptosis,parthanatos,mitochondrial permeability transition(MPT)-driven necrosis,entotic cell death,NETotic cell death,lysosome-dependent cell death,and immunogenic cell death(ICD).Furthermore,we focused on discussing the pharmacological regulatory mechanisms of related small-molecule *** brief,these insightful findings may provide valuable guidance for investigating individual or collaborative targeting approaches towards different RCD subroutines,ultimately driving the discovery of novel small-molecule compounds that target RCD and significantly enhance future cancer therapeutics.

关键词： Regulated cell death(RCD) Non-apoptotic RCD subroutine Autophagy Ferroptosis Necroptosis Regulatory mechanism Small-molecule compound Cancer therapy

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Mechanism of action of the bile acid receptor TGR5 in obesity

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Acta Pharmaceutica Sinica B 2024年第2期14卷 468-491页

作者： Weijun Lun Qihao Yan Xinghua Guo Minchuan Zhou Yan Bai Jincan He Hua Cao Qishi Che Jiao Guo Zhengquan Su Guangdong engineering research center of natural Products and New drugs Guangdong Provincial University Engineering Technology Research Center of Natural Products and DrugsGuangdong Pharmaceutical UniversityGuangzhou 510006China Guangdong Metabolic Disease research center of Integrated Chinese and Western Medicine Key Laboratory of Glucolipid Metabolic DisorderMinistry of Education of ChinaGuangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhou 510006China School of Public Health Guangdong Pharmaceutical UniversityGuangzhou 510310China School of Chemistry and Chemical engineering Guangdong Pharmaceutical UniversityZhongshan 528458China Guangzhou Rainhome Pharm&Tech Co. Ltd.Science CityGuangzhou 510663China

G protein-coupled receptors(GPCRs)are a large family of membrane protein receptors,and Takeda G protein-coupled receptor 5(TGR5)is a member of this *** a membrane receptor,TGR5 is widely distributed in different parts of the human body and plays a vital role in regulating metabolism,including the processes of energy consumption,weight loss and blood glucose *** studies have shown that TGR5 plays an important role in glucose and lipid metabolism disorders such as fatty liver,obesity and *** the global obesity situation becoming more and more serious,a comprehensive explanation of the mechanism of TGR5 and filling the gaps in knowledge concerning clinical ligand drugs are urgently *** this review,we mainly explain the anti-obesity mechanism of TGR5 to promote the further study of this target,and show the electron microscope structure of TGR5 and review recent studies on TGR5 ligands to illustrate the specific binding between TGR5 receptor binding sites and ligands,which can effectively provide new ideas for ligand research and promote drug research.

关键词： Obesity TGR5 Bile acids Ligand Appetite Metabolism GLP-1 Inflammation

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An active learning workflow for predicting hydrogen atom adsorption energies on binary oxides based on local electronic transfer features

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Green Energy & Environment 2024年第10期9卷 1489-1496页

作者： Wenhao Jing Zihao Jiao Mengmeng Song Ya Liu Liejin Guo International research center for Renewable Energy State Key Laboratory of Multiphase Flow in Power Engineering Xi'an Jiaotong University Department of Energy and Power engineering Shandong University of Technology

Machine learning combined with density functional theory（DFT） enables rapid exploration of catalyst descriptors space such as adsorption energy, facilitating rapid and effective catalyst screening. However, there is still a lack of models for predicting adsorption energies on oxides,due to the complexity of elemental species and the ambiguous coordination environment. This work proposes an active learning workflow（Le NN） founded on local electronic transfer features（e） and the principle of coordinate rotation invariance. By accurately characterizing the electron transfer to adsorption site atoms and their surrounding geometric structures, Le NN mitigates abrupt feature changes due to different element types and clarifies coordination environments. As a result, it enables the prediction of *H adsorption energy on binary oxide surfaces with a mean absolute error（MAE） below 0.18 e V. Moreover, we incorporate local coverage（θl） and leverage neutral network ensemble to establish an active learning workflow, attaining a prediction MAE below 0.2 e V for 5419 multi-*H adsorption structures. These findings validate the universality and capability of the proposed features in predicting *H adsorption energy on binary oxide surfaces.

关键词： Machine learning Adsorption energy Binary oxide Electron transfer Active learning

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DNA methylation drives a new path in gastric cancer early detection:Current impact and prospects

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Genes & Diseases 2024年第2期11卷 847-860页

作者： Xinhui Wang Yaqi Dong Hong Zhang Yinghui Zhao Tianshu Miao Ghazal Mohseni Lutao Du Chuanxin Wang Department of Clinical Laboratory The Second Hospital of Shandong UniversityJinanShandong 250033China Department of Clinical Laboratory Fuling HospitalChongqing UniversityChongqing 402774China Suzhou research Institute of shandong University SuzhouJiangsu 215123China Department of Biochemistry and Molecular Biology Shandong University School of Basic Medical SciencesJinanShandong 250012China shandong engineering & Technology research center for Tumor Marker Detection JinanShandong 250033China shandong Provincial Clinical Medicine research center for Clinical Laboratory JinanShandong 250033China

Gastric cancer(GC)is one of the most common and deadly cancers *** detection offers the best chance for curative treatment and reducing its ***,the optimal population-based early screening for GC remains *** DNA methylation occurs in the early stage of GC,exhibiting cancer-specific genetic and epigenetic changes,and can be detected in the media such as blood,gastric juice,and feces,constituting a valuable biomarker for cancer early ***,DNA methylation is a stable epigenetic alteration,and many innovative methods have been developed to quantify it rapidly and ***,large-scale clinical validation of DNA methylation serving as tumor biomarkers is still lacking,precluding their implementation in clinical *** conclusion,after a critical analysis of the recent existing literature,we summarized the evolving roles of DNA methylation during GC occurrence,expounded the newly discovered noninvasive DNA methylation biomarkers for early detection of GC,and discussed its challenges and prospects in clinical applications.

关键词： Biomarkers DNA methylation Early detection Gastric cancer Translation

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