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MiR-4465-modified mesenchymal stem cell-derived small extracellular vesicles inhibit liver fibrosis development via targeting LOXL2 expression

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第7期25卷 594-604页

作者： Yanjin WANG Yifei CHEN Fuji YANG Xiaolong YU Ying CHU Jing ZHOU Yongmin YAN Jianbo XI Department of laboratory medicine Wujin Hospital Affiliated with Jiangsu UniversityJiangsu UniversityChangzhou 213017China Department of laboratory medicine School of MedicineJiangsu UniversityZhenjiang 212013China Changzhou key laboratory of Molecular Diagnostics and precision Cancer medicine Wujin Clinical College of Xuzhou Medical UniversityChangzhou 213017China

Liver fibrosis is a significant health burden,marked by the consistent deposition of ***,the currently available treatment approaches for this condition are far from *** oxidase-like protein 2(LOXL2)secreted by hepatic stellate cells(HSCs)is a crucial player in the cross-linking of matrix collagen and is a significant target for treating liver *** stem cell-derived small extracellular vesicles(MSC-sEVs)have been proposed as a potential treatment option for chronic liver *** studies have found that MSC-sEV can be used for microRNA delivery into target cells or *** is currently unclear whether microRNA-4465(miR-4465)can target LOXL2 and inhibit HSC ***,it is uncertain whether MSC-sEV can be utilized as a gene therapy vector to carry miR-4465 and effectively inhibit the progression of liver *** study explored the effect of miR-4465-modified MSC-sEV(MSC-sEVmiR-4465)on LOXL2 expression and liver fibrosis *** results showed that miR-4465 can bind specifically to the promoter of the LOXL2 gene in ***,MSC-sEVmiR-4465 inhibited HSC activation and collagen expression by downregulating LOXL2 expression in ***-sEVmiR-4465 injection could reduce HSC activation and collagen deposition in the CCl4-induced mouse ***-sEVmiR-4465 mediating via LOXL2 also hindered the migration and invasion of HepG2 *** conclusion,we found that MSC-sEV can deliver miR-4465 into HSC to alleviate liver fibrosis via altering LOXL2,which might provide a promising therapeutic strategy for liver diseases.

关键词： Mesenchymal stem cell(MSC) Small extracellular vesicle(sEV) MicroRNA-4465(miR-4465) Hepatic stellate cell(HSC) Liver fibrosis

Suppressing Wnt signaling of the blood-tumor barrier to intensify drug delivery and inhibit lipogenesis of brain metastases

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2716-2731页

作者： Yang Tong Pei An Puxian Tang Rui Mu Yuteng Zeng Hang Sun Mei Zhao Ziyan Lv Pan Wang Wanjun Han Chunshan Gui Xuechu Zhen Liang Han Jiangsu key laboratory of Neuropsychiatric diseases and College of Pharmaceutical Sciences Soochow UniversitySuzhou 215123China Jiangsu Province Engineering Research Center of precision Diagnostics and Therapeutics Development Soochow UniversitySuzhou 215123China

Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid *** inhibitors hold therapeutic potential but their intra-tumoral distribution is often blocked by the blood-tumor barrier(BTB).BTB activates its Wnt signaling to maintain barrier properties,e.g.,Mfsd2a-mediated BTB low ***,we reported VCAM-1-targeting nano-wogonin(W@V-NPs)as an adjuvant of nano-orlistat(O@V-NPs)to intensify drug delivery and inhibit lipogenesis of brain metastases.W@V-NPs were proven to be able to inactivate BTB Wnt signaling,downregulate BTB Mfsd2a,accelerate BTB vesicular transport,and enhance tumor accumulation of O@*** the ability to specifically kill cancer cells in a lipid-deprived environment with IC_(50) at 48 ng/mL,W@V-NPs plus O@V-NPs inhibited the progression of brain metastases with prolonged survival of model *** combination did not induce brain edema,cognitive impairment,and systemic toxicity in healthy *** Wnt signaling could safely modulate the BTB to improve drug delivery and metabolic therapy against brain metastases.

关键词： Lipogenesis Brain metastases Blood-tumor barrier Wnt signaling Drug delivery Fatty acid synthase Nanoparticles Combination therapy

Gingipain from Porphyromonas gingivalis causes insulin resistance by degrading insulin receptors through direct proteolytic effects

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International Journal of Oral Science 2024年第3期16卷 539-552页

作者： Fen Liu Bofeng Zhu Ying An Zhifei Zhou Peiying Xiong Xuan Li Yang Mi Tongqiang He Faming Chen Buling Wu Shenzhen Stomatology Hospital(Pingshan) Southern Medical UniversityShenzhenChina key laboratory of Shaanxi Province for Craniofacial precision medicine Research Laboratory Center of StomatologyDepartment of Paediatric DentistryCollege of StomatologyXi’an Jiaotong UniversityXi’anChina State key laboratory of Oral&Maxillofacial Reconstruction and Regeneration National Clinical Research Center for Oral DiseasesShaanxi International Joint Research Center for Oral DiseasesDepartment of PeriodontologySchool of StomatologyThe Fourth Military Medical UniversityXi’anChina Guangzhou key laboratory of Forensic Multi-Omics for precision Identification School of Forensic MedicineSouthern Medical UniversityGuangzhouChina Microbiome medicine Center Department of Laboratory MedicineZhujiang HospitalSouthern Medical UniversityGuangzhouChina Department of Stomatology General Hospital of Tibetan Military CommandLhasaChina Department of Stomatology Center Shenzhen HospitalSouthern Medical UniversityShenzhenChina Department of Obstetrics Northwest Women’s and Children’s HospitalXi’anChina

Periodontitis is a critical risk factor for the occurrence and development of *** gingivalis may participate in insulin resistance(IR)caused by periodontal inflammation,but the functional role and specific mechanisms of *** in IR remain *** the present study,clinical samples were analysed to determine the statistical correlation between *** and IR *** culturing of hepatocytes,myocytes,and adipocytes,and feeding mice *** orally,the functional correlation between *** and IR occurrence was further studied both in vitro and in *** data suggested that the amount of *** isolated was correlated with the Homeostatic Model Assessment for IR *** vitro studies suggested that coculture with *** decreased glucose uptake and insulin receptor(INSR)protein expression in hepatocytes,myocytes,and *** fed *** tended to undergo *** was detectable in the liver,skeletal muscle,and adipose tissue of experimental *** distribution sites of gingipain coincided with the downregulation of *** proteolysed the functional insulin-binding region of *** with *** significantly decreased the INSR–insulin binding *** out gingipain from *** alleviated the negative effects of *** on IR in *** together,these findings indicate that distantly migrated *** may directly proteolytically degrade INSR through gingipain,thereby leading to *** results provide a new strategy for preventing diabetes by targeting periodontal pathogens and provide new ideas for exploring novel mechanisms by which periodontal inflammation affects the systemic metabolic state.

关键词： gingivalis inflammation resistance

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Both gain-and loss-of-function variants of KCNA1 are associated with paroxysmal kinesigenic dyskinesia

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Journal of Genetics and Genomics 2024年第8期51卷 801-810页

作者： Wan-Bing Sun Jing-Xin Fu Yu-Lan Chen Hong-Fu Li Zhi-Ying Wu Dian-Fu Chen Department of Medical Genetics and Center for Rare diseases and Department of Neurologyand Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation in Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China Nanhu Brain-computer Interface Institute HangzhouZhejiang 314050China MOE Frontier Science Center for Brain Science and Brain-machine Integration School of Brain Science and Brain MedicineZhejiang UniversityHangzhouZhejiang 310012China

KCNA1 is the coding gene for Kv1.1 voltage-gated potassium-channelα*** variants of KCNA1 have been reported to manifest as paroxysmal kinesigenic dyskinesia(PKD),but the correlation between them remains unclear due to the phenotypic complexity of KCNA1 variants as well as the rarity of PKD *** the whole exome sequencing followed by Sanger sequencing,we screen for potential pathogenic KCNA1 variants in patients clinically diagnosed with paroxysmal movement disorders and identify three previously unreported missense variants of KCNA1 in three unrelated Chinese *** proband of one family(c.496G>A,p.A166T)manifests as episodic ataxia type 1,and the other two(c.877G>A,p.V293I and c.1112C>A,p.T371A)manifest as *** pathogenicity of these variants is confirmed by functional studies,suggesting that p.A166T and p.T371A cause a loss-of-function of the channel,while p.V293I leads to a gain-of-function with the property of voltage-dependent gating and activation kinetic *** reviewing the locations of PKD-manifested KCNA1 variants in Kv1.1 protein,we find that these variants tend to cluster around the pore domain,which is similar to ***,our study strengthens the correlation between KCNA1 variants and PKD and provides more information on genotype–phenotype correlations of KCNA1 channelopathy.

关键词： Paroxysmal kinesigenic dyskinesia KCNA1 Loss-of-function Gain-of-function Channelopathy Episodicataxiatype1

MSC-derived exosomes attenuate hepatic fibrosis in primary sclerosing cholangitis through inhibition of Th17 differentiation

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Asian Journal of Pharmaceutical Sciences 2024年第1期19卷 119-134页

作者： Wenyi Chen Feiyan Lin Xudong Feng Qigu Yao Yingduo Yu Feiqiong Gao Jiahang Zhou Qiaoling Pan Jian Wu Jinfeng Yang Jiong Yu Hongcui Cao Lanjuan Li State key laboratory for the Diagnosis and Treatment of Infectious diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesNational Medical Center for Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Jinan Microecological Biomedicine Shandong laboratory Jinan 250117China key laboratory of Diagnosis and Treatment of Aging and Physic-chemical Injury diseases of Zhejiang Province Hangzhou 310003China

Primary sclerosing cholangitis(PSC)is an autoimmune cholangiopathy characterized by chronic inflammation of the biliary epithelium and periductal fibrosis,with no curative treatment available,and liver transplantation is inevitable for end-stage *** placentalmesenchymal stem cell(hpMSC)-derived exosomes have demonstrated the ability to prevent fibrosis,inhibit collagen production and possess immunomodulatory properties in autoimmune liver ***,we prepared hpMSC-derived exosomes(Exo^(MSC))and further investigated the anti-fibrotic effects and detailed mechanism on PSC based on Mdr2^(−/−)mice and multicellular organoids established from PSC *** results showed that Exo^(MSC) ameliorated liver fibrosis in Mdr2^(−/−)mice with significant collagen reduction in the preductal area where Th17 differentiation was inhibited as demonstrated by RNAseq analysis,and the percentage of CD4+IL-17A+T cells was reduced both in Exo^(MSC)-treated Mdr2^(−/−)mice(Mdr2^(−/−)-Exo)in vivo and Exo^(MSC)-treated Th17 differentiation progressed in ***,Exo^(MSC) improved the hypersecretory phenotype and intercellular interactions in the hepatic Th17 microenvironment by regulating PERK/CHOP signaling as supported by multicellular ***,our data demonstrate the antifibrosis effect of Exo^(MSC) in PSC disease by inhibiting Th17 differentiation,and ameliorating the Th17-induced microenvironment,indicating the promising potential therapeutic role of Exo^(MSC) in liver fibrosis of PSC or Th17-related diseases.

关键词： Mesenchymal stem cell Exosomes Primary sclerosing cholangitis Fibrosis Organoids Th17

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Advances in the Treatment of autoimmune Hepatitis

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Journal of Clinical and Translational Hepatology 2024年第10期12卷 878-885页

作者： Zelu Meng Yida Yang State key laboratory for Diagnosis and Treatment of Infectious diseases National Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesDepartment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina

autoimmune hepatitis(AIH)is a chronic,progressive inflammatory liver disease caused by autoimmune reactions,with an unknown *** left untreated,it can progress to cirrhosis,liver failure,or even *** most patients respond well to first-line treatments,a significant number experience poor responses or intolerance,requiring the use of second-or third-line *** research into the pathogenesis of AIH is leading to the development of novel therapeutic *** review summarized recent advancements in the treatment of AIH both domestically and internationally.

关键词： Hepatitis,autoimmune Immunosuppression Treatment Management Update Remission Induction Long-term Prognosis

Gut microbiota-mediated modulation of lipid metabolism by punicic acid in diet-induced hepatic steatosis

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Food Science and Human Wellness 2024年

作者： Liping Chen Yifan Lei Hengqian Lu Yongzhong Wang School of Life Sciences， Anhui University Anhui key laboratory of Modern Biomanufacturing key laboratory of Human Microenvironment and precision medicine of Anhui Higher Education Institutes， Anhui University

Pomegranate seed oil (PSO) mainly consisted of punicic acid (PunA)， has gained attention due to rich conjugated linolenic acids and potential application in the improvement of various diseases. The aim of this study was to explore the ability of PunA to modulate lipid metabolism associated with non-alcoholic fatty liver disease (NAFLD) and explore the emerging role of the gut microbiota in modulating hepatic lipid metabolism. In this regard， PunA’s capacity was evaluated through C57BL/6J fed with a choline and L-amino acid defined， high fat diet (CDAHFD). Mice were randomly divided into four groups: NC group， MC group， PSO group and Cur group. Collected results indicated that supplement of PunA improved hepatic lipid profile. PunA administration also ameliorated hepatic steatosis and lipid accumulation. mRNA analysis showed that PunA exerted ameliorative e?ect on hepatic lipid accumulation by downregulating the mRNA expression of Dgat1， Scd-1， Srebp-1c， but increasing expression level of Cpt-1α. Metagenomic analysis discovered that PunA increased species diversity and richness of intestinal microbiota， promoted proliferation of beneficial commensals and restraining the endotoxin-producing microorganisms in cecum of CDAHFD-administrated mice. Furthermore， PunA suppressed lipid accumulation and lipid droplet formation in a cell NAFLD model in vitro. Overall， PunA exhibited anti-lipogenic and lipid-lowering effects， improvement of intestinal flora. In summary， PunA could be a candidate for the exploitation of functional foods or nutraceuticals aiming NAFLD.

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Ptip safeguards the epigenetic control of skeletal stem cell quiescence and potency in skeletogenesis

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Science Bulletin 2024年第13期69卷 2099-2113页

作者： Jianfei Liang Jing Wang Bingdong Sui Yibo Tong Jihua Chai Qin Zhou Chenxi Zheng Hao Wang Liang Kong Haojian Zhang Yi Bai State key laboratory of Oral&Maxillofacial Reconstruction and Regeneration Key Laboratory of Oral Biomedicine Ministry of EducationHubei Key Laboratory of StomatologySchool&Hospital of StomatologyTaikang Center for Life and Medical SciencesWuhan UniversityWuhan 430079China key laboratory of Shaanxi Province for Craniofacial precision medicine Research College of StomatologyXi’an Jiaotong UniversityXi’an 710004China Department of Implant Dentistry College of StomatologyXi’an Jiaotong UniversityXi’an 710004China State key laboratory of Oral&Maxillofacial Reconstruction and Regeneration National Clinical Research Center for Oral DiseasesShaanxi Key Laboratory of StomatologyShaanxi International Joint Research Center for Oral DiseasesCenter for Tissue EngineeringSchool of StomatologyThe Fourth Military Medical UniversityXi’an 710032China State key laboratory of Genetic Resources and Evolution Kunming Institute of ZoologyChinese Academy of SciencesKunming 650223China State key laboratory of Oral&Maxillofacial Reconstruction and Regeneration National Clinical Research Center for Oral DiseasesShaanxi Key Laboratory of StomatologyDepartment of Oral and Maxillofacial SurgerySchool of StomatologyThe Fourth Military Medical UniversityXi’an 710032China Department of Hematology Zhongnan HospitalWuhan UniversityWuhan 430079China Frontier Science Center for Immunology and Metabolism Medical Research InstituteWuhan UniversityWuhan 430079China Taikang Center for Life and Medical Sciences Wuhan UniversityWuhan 430079China

Stem cells remain in a quiescent state for long-term maintenance and preservation of potency;this process requires fine-tuning regulatory *** this study,we identified the epigenetic landscape along the developmental trajectory of skeletal stem cells(SSCs)in skeletogenesis governed by a key regulator,Ptip(also known as Paxip1,Pax interaction with transcription-activation domain protein-1).Our results showed that Ptip is required for maintaining the quiescence and potency of SSCs,and loss of Ptip in type II collagen(Col2)^(+)progenitors causes abnormal activation and differentiation of SSCs,impaired growth plate morphogenesis,and long bone *** also found that Ptip suppressed the glycolysis of SSCs through downregulation of phosphoglycerate kinase 1(Pgk1)by repressing histone H3 lysine 27 acetylation(H3K27ac)at the promoter ***,inhibition of glycolysis improved the function of SSCs despite Ptip *** the best of our knowledge,this is the first study to establish an epigenetic framework based on Ptip,which safeguards skeletal stem cell quiescence and potency through metabolic *** framework is expected to improve SSC-based treatments of bone developmental disorders.

关键词： Skeletal stem cells Bone development Epigenetics Ptip Glycolysis

HIF-1αpromotes virus replication and cytokine storm in H1N1 virus-induced severe pneumonia through cellular metabolic reprogramming

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Virologica Sinica 2024年第1期39卷 81-96页

作者： Xiaoxiao Meng Yong Zhu Wenyu Yang Jiaxiang Zhang Wei Jin Rui Tian Zhengfeng Yang Ruilan Wang Department of Critical Care medicine Shanghai General HospitalShanghai Jiaotong UniversitySchool of MedicineShanghai201620China precision Research Center for Refractory diseases Shanghai General HospitalShanghai Jiaotong UniversitySchool of MedicineShanghai201620China

The mortality of patients with severe pneumonia caused by H1N1 infection is closely related to viral replication and cytokine ***,the specific mechanisms triggering virus replication and cytokine storm are still not fully ***,we identified hypoxia inducible factor-1α(HIF-1α)as one of the major host molecules that facilitates H1N1 virus replication followed by cytokine storm in alveolar epithelial ***,HIF-1αprotein expression is upregulated after H1N1 *** of HIF-1αattenuates pulmonary injury,viral replication and cytokine storm in *** addition,viral replication and cytokine storm were inhibited after HIF-1αknockdown in ***,the invasion of H1N1 virus into alveolar epithelial cells leads to a shift in glucose metabolism to glycolysis,with rapid production of ATP and *** of glycolysis significantly suppresses viral replication and inflammatory *** analysis revealed that H1N1-induced HIF-1αcan promote the expression of hexokinase 2(HK2),the key enzyme of glycolysis,and then not only provide energy for the rapid replication of H1N1 virus but also produce lactate,which reduces the accumulation of the MAVS/RIG-I complex and inhibits IFN-α/β*** conclusion,this study demonstrated that the upregulation of HIF-1αby H1N1 infection augments viral replication and cytokine storm by cellular metabolic reprogramming toward glycolysis mainly through upregulation of HK2,providing a theoretical basis for finding potential targets for the treatment of severe pneumonia caused by H1N1 infection.

关键词： H1N1 Severe pneumonia Virus replication Hypoxia inducible factor-1α Glycolysis