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A combined nanotherapeutic approach targeting farnesoid X receptor,ferroptosis,and fibrosis for nonalcoholic steatohepatitis treatment

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2228-2246页

作者： Jiangtao Fu Pingping Zhang Zhiguo Sun Guodong Lu Qi Cao Yiting Chen Wenbin Wu Jiabao Zhang Chunlin Zhuang Chunquan Sheng Jiajun Xu Ying Lu Pei Wang the center for Basic research and innovation of Medicine and Pharmacy(MOE) School of PharmacyNaval Medical UniversityShanghai 200433China National Demonstration center for Experimental Pharmaceutical Education Naval Medical University/Second Military Medical UniversityShanghai 200433China department of Diving and Hyperbaric Medicine Naval Special Medical CenterNaval Medical UniversityShanghai 200433China

Obeticholic acid(OCA),a farnesoid X receptor(FXR)agonist with favorable effects on fatty and glucose metabolism,has been considered the leading candidate drug for nonalcoholic steatohepatitis(NASH)***,its limited effectiveness in resolving liver fibrosis and lipotoxicity-induced cell death remains a major ***,a newly recognized form of cell death characterized by uncontrolled lipid peroxidation,is involved in the progression of *** oxide(NO)is a versatile biological molecule that can degrade extracellular *** this study,we developed a PEGylated thiolated hollow mesoporous silica nanoparticles(MSN)loaded with OCA,as well as a ferroptosis inhibitor liproxsatin-1 and a NO donor S-nitrosothiol(ONL@MSN).Biochemical analyses,histology,multiplexed flow cytometry,bulk-tissue RNA sequencing,and fecal 16S ribosomal RNA sequencing were utilized to evaluate the effects of the combined nanoparticle(ONL@MSN)in a mouse NASH *** with the OCA-loaded nanoparticles(O@MSN),ONL@MSN not only protected against hepatic steatosis but also greatly ameliorated fibrosis and ***@MSN also displayed enhanced therapeutic actions on the maintenance of intrahepatic macrophages/monocytes homeostasis,inhibition of immune response/lipid peroxidation,and correction of microbiota *** findings present a promising synergistic nanotherapeutic strategy for the treatment of NASH by simultaneously targeting FXR,ferroptosis,and fibrosis.

关键词： Nonalcoholic steatohepatitis Nanotherapy Farnesoid X receptor Ferroptosis Fibrosis Obeticholic acid S-Nitrosothiol Liproxstatin-1

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Exploration of pathogenic microorganism within the small intestine of necrotizing enterocolitis

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World Journal of Pediatrics 2024年第2期20卷 165-172页

作者： Yan Wang Kun Jiang Qiao Xia Xia Kang Shan Wang Ji-Hong Yu Wen-Feng Ni Xiao-Qin Qi Ying-Na Zhang Jin-Bao Han Gang Liu Lei Hou Zhi-Chun Feng Liu-Ming Huang Clinical Biobank center Medical Innovation Research Division of ChinesePLA General HospitalBeijingChina Institute of Basic medical Sciences Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina Senior department of Pediatrics The Seventh Medical Center of PLA General HospitalBeijing 100700China department of Neurology The First Medical CenterChinese PLA General HospitalBeijing 100853China department of Emergency center National Center for Children's HealthBeijing Children's HospitalCapital Medical UniversityBeijing 100045China

Background Necrotizing enterocolitis(NEC)is the most common severe gastrointestinal emergency in *** designed this study to identify the pathogenic microorganisms of NEC in the microbiota of the small intestine of *** Using the 16S ribosomal DNA(rDNA)sequencing method,we compared and analyzed the structure and diversity of microbiotas in the intestinal feces of different groups of neonates:patients undergoing jejunostomy to treat NEC(NP group),neonates undergoing jejunostomy to treat other conditions(NN group),and neonates with NEC undergoing conservative treatment(NC group).We took intestinal feces and saliva samples from patients at different time *** the beta diversities of the NP,NN,and NC groups were all *** comparing the beta diversities between different time points in the NP group,we found similar beta diversities at time points El to E3 but significant differences between the E2-E3 and E4 time points:the abundances of Klebsiella and Enterococcus(Proteobacteria)were higher at the E1-E3 time points;the abundance of Escherichia-Shigella(Proteobacteria)increased at the E2 time point,and the abundance of Klebsiella decreased significantly,whereas that of Streptococcus increased significantly at the E4 time *** Our results suggest that the pathological changes of intestinal necrosis in the small intestine of infants with NEC are not directly caused by excessive proliferation of pathogenic bacteria in the small *** sources of microbiota in the small intestine of neonates,especially in premature infants,may be affected by multiple factors.

关键词： Microbiota Necrotizing enterocolitis-Small intestine 16S rDNA

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Single-cell RNA-seq reveals the transcriptional program underlying tumor progression and metastasis in neuroblastoma

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Frontiers of Medicine 2024年第4期18卷 690-707页

作者： Zhe Nian Dan Wang Hao Wang Wenxu Liu Zhenyi Ma Jie Yan Yanna Cao Jie Li Qiang Zhao Zhe Liu department of Immunology School of Basic Medical SciencesTianjin Medical UniversityTianjin300070China Zhejiang Key Laboratory of medical Epigenetics Department of Cell BiologySchool of Basic Medical SciencesHangzhou Normal UniversityHangzhou311121China department of Pediatric Oncology Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin’s Clinical Research Center for CancerTianjin300060China Collaborative innovation center for Cancer Personalized Medicine Nanjing Medical UniversityNanjing211166China

Neuroblastoma(NB)is one of the most common childhood *** percent of patients present with widely disseminated clinical signs at diagnosis and exhibit poor ***,the molecular mechanisms triggering NB metastasis remain largely *** this study,we generated a transcriptomic atlas of 15447 NB cells from eight NB samples,including paired samples of primary tumors and bone marrow *** used time-resolved analysis to chart the evolutionary trajectory of NB cells from the primary tumor to the metastases in the same patient and identified a common‘starter’subpopulation that initiates tumor development and ***‘starter’population exhibited high expression levels of multiple cell cycle-related genes,indicating the important role of cell cycle upregulation in NB tumor *** addition,our evolutionary trajectory analysis demonstrated the involvement of partial epithelial-to-mesenchymal transition(p-EMT)along the metastatic route from the primary site to the bone *** study provides insights into the program driving NB metastasis and presents a signature of metastasis-initiating cells as an independent prognostic indicator and potential therapeutic target to inhibit the initiation of NB metastasis.

关键词： single-cell RNA sequencing metastasis neuroblastoma epithelial-to-mesenchymal transition

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METTL14 downregulation drives S100A4^(+)monocyte-derived macrophages via MyD88/NF-κB pathway to promote MAFLD progression

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Signal Transduction and Targeted therapy 2024年第5期9卷 2176-2192页

作者： Yue-fan Wang Wen-li Zhang Zhi-xuan Li Yue Liu Jian Tan Hao-zan Yin Zhi-chao Zhang Xian-jie Piao Min-hao Ruan Zhi-hui Dai Si-jie Wang Chen-yang Mu Ji-hang Yuan Shu-han Sun Hui Liu Fu Yang the third department of Hepatic Surgery Eastern Hepatobiliary Surgery Hospital Affiliated to Naval Medical University200438 ShanghaiChina the department of medical Genetics Naval Medical University200433 ShanghaiChina Translational Medicine research center Medical Innovation Research Division and Fourth Medical Center of the Chinese PLA General Hospital100048 BeijingChina the department of Pharmaceutical Analysis School of PharmacyNaval Medical University200433 ShanghaiChina Key Laboratory of Biosafety Defense Ministry of Education200433 ShanghaiChina Shanghai Key Laboratory of medical Biodefense 200433 ShanghaiChina

Without intervention,a considerable proportion of patients with metabolism‐associated fatty liver disease(MAFLD)will progress from simple steatosis to metabolism‐associated steatohepatitis(MASH),liver fibrosis,and even hepatocellular ***,the molecular mechanisms that control progressive MAFLD have yet to be fully ***,we unraveled that the expression of the N6-methyladenosine(m6A)methyltransferase METTL14 is remarkably downregulated in the livers of both patients and several murine models of MAFLD,whereas hepatocyte-specific depletion of this methyltransferase aggravated lipid accumulation,liver injury,and ***,hepatic Mettl14 overexpression alleviated the above pathophysiological changes in mice fed on a high-fat diet(HFD).Notably,in vivo and in vitro mechanistic studies indicated that METTL14 downregulation decreased the level of GLS2 by affecting the translation efficiency mediated by YthDF1 in an m6A-depedent manner,which might help to form an oxidative stress microenvironment and accordingly recruit Cx3cr1^(+)Ccr2^(+)monocyte-derived macrophages(Mo-macs).In detail,Cx3cr1^(+)Ccr2^(+)Mo-macs can be categorized into M1-like macrophages and S100A4-positive macrophages and then further activate hepatic stellate cells(HSCs)to promote liver *** experiments revealed that CX3CR1 can activate the transcription of S100A4 via CX3CR1/MyD88/NF-κB signaling pathway in Cx3cr1^(+)Ccr2^(+)*** of METTL14 or GLS2,or interfering with this signal transduction pathway such as inhibiting MyD88 could ameliorate liver injuries and *** together,these findings indicate potential therapies for the treatment of MAFLD progression.

关键词： S100A4 MyD88 metabolism

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Targeting carnitine palmitoyl transferase 1A(CPT1A)induces ferroptosis and synergizes with immunotherapy in lung cancer

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Signal Transduction and Targeted therapy 2024年第4期9卷 1675-1689页

作者： Lei Ma Chong Chen Chunxing Zhao Tong Li Lingyu Ma Jiayu Jiang Zhaojun Duan Qin Si Tsung-Hsien Chuang Rong Xiang Yunping Luo department of Immunology Institute of Basic Medical SciencesChinese Academy of Medical SciencesSchool of Basic MedicinePeking Union Medical CollegeBeijing 100005China Collaborative innovation center for Biotherapy Institute of Basic Medical SciencesChinese Academy of Medical SciencesSchool of Basic MedicinePeking Union Medical CollegeBeijing 100005China department of Lung Cancer Surgery Tianjin Medical University General HospitalTianjin 300052China Immunology research center National Health Research InstitutesZhunanMiaoliTaiwanROC department of Immunology Nankai UniversityTianjin 300071China

Despite the successful application of immune checkpoint therapy,no response or recurrence is typical in lung *** stem cells(CSCs)have been identified as a crucial player in immunotherapy-related ***,a form of cell death driven by iron-dependent lipid peroxidation,is highly regulated by cellular metabolism remolding and has been shown to have synergistic effects when combined with *** adaption of CsCs drives tumor resistance,yet the mechanisms of their ferroptosis defense in tumor immune evasion remain ***,through metabolomics,transcriptomics,a lung epithelialspecific Cptla-knockout mouse model,and clinical analysis,we demonstrate that CPT1A,a key rate-limiting enzyme of fatty acid oxidation,acts with L-carnitine,derived from tumor-associated macrophages to drive ferroptosis-resistance and CD8^(+)T cells inactivation in lung ***,CPT1A restrains ubiquitination and degradation of c-Myc,while c-Myc transcriptionally activates CPT1A *** CPT1A/c-Myc positive feedback loop further enhances the cellular antioxidant capacity by activating the NRF2/GPX4 system and reduces the amount of phospholipid polyunsaturated fatty acids through ACSL4 downregulating,thereby suppressing ferroptosis in ***,targeting CPT1A enhances immune checkpoint blockadeinduced anti-tumor immunity and tumoral ferroptosis in tumor-bearing *** results illustrate the potential of a mechanismguided therapeutic strategy by targeting a metabolic vulnerability in the ferroptosis of CsCs to improve the efficacy of lung cancer immunotherapy.

关键词： immunotherapy metabolism peroxidation

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In patients who had a stroke or TIA, enlarged perivascular spaces in basal ganglia may cause future haemorrhagic strokes

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Stroke & Vascular Neurology 2024年第1期9卷 8-17,I0001-I0033页

作者： Yu Tian Mengxing Wang Yuesong Pan Xia Meng Xingquan Zhao Liping Liu Yongjun Wang Yilong Wang department of Neurology Beijing Tiantan HospitalCapital Medical UniversityBeijingChina Chinese Institute for Brain research BeijingChina National center for Neurological Diseases BeijingChina Advanced innovation center for Human Brain Protection Capital Medical UniversityBeijingChina China National Clinical research center for Neurological Diseases BeijingChina

Introduction It remains unclear whether enlarged perivascular spaces(EPVS)predict poor clinical outcomes in patients with acute ischaemic stroke(AIS)or transient ischaemic attack(TIA).Method Data were obtained from the third China National Stroke Registry *** estimated EPVS in basal ganglia(BG)and centrum semiovale(CSO)using a semiquantified scale(Grade from 0 to 4).Using Cox and logistic regression analyses,the associations of EPVS with 3-month and 1-year adverse outcomes(including recurrent stroke,ischaemic stroke,haemorrhagic stroke,combined vascular event,disability and mortality)were *** analyses of any association of cerebral small vessel disease at baseline and development of a small arterial occlusion(SAO)were *** Among 12603 patients with AIS/TIA,median age was 61.7±11.6 years,and 68.2%were *** adjusting for all potential confounders,frequent-to-severe BG-EPVS was associated with a decreased risk of recurrent ischaemic stroke(HR 0.71,95%CI 0.55 to 0.92,p=0.01)but an increased risk of haemorrhagic stroke(HR 1.99,95%CI 1.11 to 3.58,p=0.02)at 1 year after AIS/TIA,compared with none-to-mild *** with frequent-to-severe CSO-EPVS had a decreased risk of disability(OR 0.76,95%CI 0.62 to 0.92,p=0.004)and all-cause death(HR 0.55,95%CI 0.31 to 0.98,p=0.04)within 3-month but not 1-year follow-ups,compared with those with none-to-mild *** analyses showed that both BG-EPVS(HR 0.43,95%CI 0.21 to 0.87,p=0.02)and CSO-EPVS(HR 0.58,95%CI 0.35 to 0.95,p=0.03)were associated with a decreased risk of subsequent ischaemic stroke in patients with SAO during 1-year *** BG-EPVS increased the risk of haemorrhagic stroke in patients already with AIS/TIA within 1 ***,caution is recommended when selecting antithrombotic agents for secondary stroke prevention in patients with AIS/TIA and more severe BG-EPVS.

关键词： patients haemorrhagic prevention

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Tirofiban combined with Aspirin in the Treatment of Acute Penetrating Artery Territory Infarction (STRATEGY): protocol for a multicentre, randomised controlled trial

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Stroke & Vascular Neurology 2024年第1期9卷 75-81,I0047-I0052页

作者： Xiaoling Liao Shuo Feng Yicong Wang Yuesong Pan Weiqi Chen Hui Qu Xingquan Zhao Liping Liu Yongjun Wang Yilong Wang department of Neurology Beijing Tiantan HospitalCapital Medical UniversityBeijingChina China National Clinical research center for Neurological Diseases Beijing TiantanHospitalCapital Medical UniversityBeijingChina Chinese Institute for Brain research BeijingChina National center for Neurological Diseases BeijingChina Advanced innovation center for Human Brain Protection Capital Medical UniversityBeijingChina Beijing Laboratory of Oral Health Capital Medical UniversityBeijingChina

Background Perforating artery territorial infarction(PAI)caused by branch atheromatous disease(BAD)is prone to recurrence and early progression without an effective and well-documented antiplatelet treatment ***,an adjunctive antiplatelet agent,has shown great potential to treat acute ischaemic ***,whether the combination of tirofiban and aspirin can improve the prognosis of PAI remains *** To explore an effective and safe antiplatelet regimen for reducing the risk of recurrence and early neurological deterioration(END)in PAI caused by BAD by comparing the tirofiban and aspirin combination with placebo and aspirin *** Tirofiban combined with Aspirin in the Treatment of Acute Penetrating Artery Territory Infarction(STRATEGY)trial is an ongoing multicentre,randomised,placebo-controlled trial in *** patients shall be randomly assigned to receive standard aspirin with tirofiban or placebo on the first day and standard aspirin from days 2 to *** primary endpoint is a new stroke or END within 90 *** primary safety endpoint is severe or moderate bleeding within 90 *** the STRATEGY trial will assess whether tirofiban combined with aspirin is effective and safe in preventing recurrence and END in patients with *** registration number NCT05310968.

关键词： Aspirin regimen centre

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Mapping multiple phases in curcumin binary solid dispersions by fluorescence contrasting

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Chinese Chemical Letters 2024年第9期35卷 266-272页

作者： Ying Xu Chengying Shen Hailong Yuan Wei Wu Key Laboratory of Smart Drug Delivery of MOE School of PharmacyFudan UniversityShanghai 201203China center for medical research and innovation Shanghai Pudong HospitalFudan University Pudong Medical CenterShanghai 201399China department of Pharmacy Air Force Medical CenterPLABeijing 100142China Jiangxi Provincial People’s Hospital The First Affiliated Hospital of Nanchang Medical CollegeNanchang 330006China

the microphases and miscibility in binary curcumin(Cur)solid dispersions(SDs)with amorphous polyvinylpyrrolidone K30(PVP K30)and semi-crystalline poloxamer(P407)and poly(ethylene glycol)6000(PEG6000)as carriers were investigated by fluorescence contrasting utilizing confocal laser scanning microscopy.A super sensitive fluorophore P4 with typical aggregation-caused quenching properties was employed to stain the continuous polymer phases and contrasted with the autofluorescence of the model drug *** addition,differential scanning calorimetry(DSC)and powder X-ray diffraction(PXRD)were utilized to assist in explanation of the fluorescence *** all three SD systems,there is always a homogenous polymer phase stained by P4 and it is difficult to adulterate Cur crystals by ***-enriched rather than polymer-enriched domains could be *** the Cur-PVP K30 system,Cur exists in an amorphous form at a Cur loading level of 50%and below,while Cur crystallines phase out and continuously grow with the increase of Cur loading from 60%to 90%.the phase behaviors in the Cur-P407 and Cur-PEG 6000 systems are similar but with minor *** both systems,Cur phases out as clusters of drug-enriched domains at a loading level of 20%and below,which however cannot be correlated with crystallization,as evidenced by both DSC and *** is a transition from an amorphous to a crystalline state from 20%to 30%Cur loading,above which Cur crystallines can be *** is interesting that a co-mix phase of both Cur-and PEG 6000-enriched domains can be identified at Cur loading levels of 10%and *** together,it is concluded that contrasting Cur autofluorescence with the signals of P4 proves to be a functional strategy to reveal multiple phases in the binary SD systems investigated.

关键词： Solid dispersion Curcumin PEG PVP Poloxamer Fluorescence Environment-responsive Confocal laser scanning microscopy

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In situ forming injectable MSC-loaded GelMA hydrogels combined with PD for vascularized sweat gland regeneration

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Military medical research 2024年第1期11卷 152-155页

作者： Enhe Jirigala Bin Yao Zhao Li Yi-Jie Zhang Chao Zhang Li-Ting Liang Fan-Liang Zhang Xing-Yu Yuan Xian-Lan Duan Wei Song Meng-De Zhang Yi Kong Xiao-Bing Fu Sha Huang research center for Tissue Repair and Regeneration Medical Innovation Research DepartmentChinese PLA General Hospital and PLA Medical CollegeBeijing 100048China Institute of Basic medical research Inner Mongolia Medical UniversityHohhot 010110China Academy of medical Engineering and Translational Medicine Tianjin UniversityTianjin 300072China School of Medicine Nankai UniversityTianjin 300071China

Dear Editor,three dimensional(3D)bioprinted extracellular matrix(ECM)can be used to provide both biochemical and biophysical cues to direct mesenchymal stem cells(MSCs)differentiation,and then differentiated cells were isolated for implantation in vivo using surgical ***,the reduced cell activity after cell isolation from 3D constructs and low cell retention in injured sites limit its application[1].Methacrylated gelatin(GelMA)hydrogel has the advantage of fast crosslinking,which could resemble complex architectures of tissue construct in vivo[2].Here,we adopted a noninvasive bioprinting procedure to imitate the regenerative microenvironment that could simultaneously direct the sweat gland(SG)and vascular differentiation from MSCs and ultimately promote the replacement of glandular tissue in situ(Fig.1a).

关键词： Sweat gland GelMA In situ niche Cell differentiation Tissue incorporation Vascularization

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RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer

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Military medical research 2024年第1期11卷 34-49页

作者： Yi-Qun Li Fang-Zhou Sun Chun-Xiao Li Hong-Nan Mo Yan-Tong Zhou Dan Lv Jing-Tong Zhai Hai-Li Qian Fei Ma department of medical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China State Key Laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

Background Triple negative breast cancer(TNBC),the most aggressive subtype of breast cancer,is characterized by a high incidence of brain metastasis(BrM)and a poor *** the most lethal form of breast cancer,BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment *** evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis(BCBrM),but the underlying mechanisms are far from being fully *** through analysis of BCBrM transcriptome data from mice and patients,and immunohistochemical validation on patient tissues,we identified and verified the specific down-regulation of retinoic acid receptor responder 2(RARRES2),a multifunctional adipokine and chemokine,in BrM of *** investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo *** signaling pathway components were evaluated using multi-omics *** were performed to elucidate the regulation of lipid metabolic reprogramming of *** We found that downregulation of RARRES2 is specifically associated with BCBrM,and that RARRES2 deficiency promoted BCBrM through lipid metabolic ***,reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue(PTEN)-mammalian target of rapamycin(mTOR)-sterol regulatory element-binding protein 1(SREBP1)signaling pathway to facilitate the survival of breast cancer cells in the unique brain *** Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of ***2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.

关键词： RARRES2 Lipid metabolic reprogramming Brain metastasis(BrM) Breast cancer

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