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The dual role of striatal interneurons: circuit modulation and trophic support for the basal ganglia

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Neural Regeneration Research 2024年第6期19卷 1277-1283页

作者： Elliot Wegman Marlena Wosiski-Kuhn Yu Luo Department of molecular and Cellular Biosciences University of Cincinnati 2. Department of Emergency Medicine at the School of Medicine University of Cincinnati Neuroscience Graduate Program University of Cincinnati

Striatal interneurons play a key role in modulating striatal-dependent behaviors, including motor activity and reward and emotional processing. Interneurons not only provide modulation to the basal ganglia circuitry under homeostasis but are also involved in changes to plasticity and adaptation during disease conditions such as Parkinson’s or Huntington’s disease. This review aims to summarize recent findings regarding the role of striatal cholinergic and GABAergic interneurons in providing circuit modulation to the basal ganglia in both homeostatic and disease conditions. In addition to direct circuit modulation, striatal interneurons have also been shown to provide trophic support to maintain neuron populations in adulthood. We discuss this interesting and novel role of striatal interneurons, with a focus on the maintenance of adult dopaminergic neurons from interneuronderived sonic-hedgehog.

关键词： cholinergic dopamine GABAergic interneuron levodopa-induced dyskinesia parvalbumin sonic hedgehog striatum trophic factor

EGFR-targeted and gemcitabine-incorporated chemogene for combinatorial pancreatic cancer treatment

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Nano Research 2024年第2期17卷 848-857页

作者： Miao Xie Qiushuang Zhang Yuanyuan Guo Lijuan Zhu Xinyuan Zhu Chuan Zhang school of Chemistry and Chemical Engineering Frontiers Science Center for Transformative MoleculesInstitute of Molecular MedicineSixth people’s HospitalSchool of MedicineShanghai Key Laboratory for Molecular Engineering of Chiral DrugsShanghai Jiao Tong UniversityShanghai 200240China Department of Radiology Shanghai Jiao Tong University Affiliated Sixth People’s HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200233China Institute of molecular medicine Shanghai Jiao Tong University Affiliated Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200127China

Pancreatic cancer stands out as a recognized intractable tumor due to its high malignancy and mortality rates,which are largely attributed to the insensitivity of current clinical chemotherapies or multidrug-resistance.Combinatorial chemo and gene therapy that integrates different therapeutic targets,may increase the chemosensitivity of pancreatic cancer and synergistically enhance the antitumor efficacy.However,conventional co-delivery of gene and chemo drugs is intensively dependent on complex nanoparticle delivery systems,thus would be limited by unstable drug packaging,nonspecific biodistribution,and biosafety problem.Herein,we rationally designed an epidermal growth factor-receptor(EGFR)-targeted and gemcitabine-incorporated oligonucleotide(termed as chemogene)with anti-Bcl-2 sequence,which achieves simple and precise integration of gemcitabine into a gene regulative agent,as well as the EGFR-targeted delivery for pancreatic cancer therapy.Through solid-phase synthesis,gemcitabine,as the first-line chemodrug for pancreatic cancer,is introduced to the antisense oligonucleotide to replace all cytosine nucleosides to obtain the gemcitabine-integrated chemogene(Ge-ASO^(Bcl-2)).Thereafter,Ge-ASO^(Bcl-2)is covalently coupled with EGFR nanobody to construct the final targeted chemogene without any exogenous carriers.Notably,this nanobody-conjugated chemogene exhibits remarkable tumor targeting capability and antitumor effects both in vitro and in vivo,which initiates a first step toward the application of combinatorial chemo and gene therapy for future pancreatic cancer treatment.

关键词： antisense oligonucleotide chemogene nanobody drug delivery system pancreatic cancer

Comparison of biliary protein spectrum in gallstone patients with obesity and those with normal body weight

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Hepatobiliary & Pancreatic Diseases International 2024年第4期23卷 385-392页

作者： Min-Zhi Chen Ping Xie Xiao-Chang Wu Zhen-Hua Tan Hai Qian Zhi-Hong Ma Xing Yao Department of Hepatopancreatobiliary Surgery Huzhou Central HospitalAffiliated Huzhou HospitalZhejiang University School of MedicineHuzhou 313000China Huzhou Key Laboratory of molecular medicine Huzhou Central HospitalAffiliated Huzhou HospitalZhejiang University School of MedicineHuzhou 313000China

Background:Obesity is a common public health issue and is currently deemed a disease.Research has shown that the risk of gallstones in individuals with obesity is elevated.This study aimed to explore the bile proteomics differences between cholelithiasis patients with obesity and normal body weight.Methods:Bile samples from 20 patients(10 with obesity and 10 with normal body weight)who underwent laparoscopic cholecystectomy at our center were subjected to tandem mass tag labeling(TMT)and liquid chromatography-tandem mass spectrometry(LC-MS/MS),followed by further bioinformatic analysis.Results:Among the differentially expressed proteins,23 were upregulated and 67 were downregulated.Bioinformatic analysis indicated that these differentially expressed proteins were mainly involved in cell development,inflammatory responses,glycerolipid metabolic processes,and protein activation cascades.In addition,the activity of the peroxisome proliferator-activated receptor(PPAR,a subfamily of nuclear receptors)signaling pathway was decreased in the Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis.Two downregulated proteins in the PPAR signaling pathway,APO A-I and APO A-II,were confirmed using enzyme-linked immunosorbent assay.Conclusions:The PPAR signaling pathway may play a crucial role in the development of cholelithiasis among patients with obesity.Furthermore,biliary proteomics profiling of gallstones patients with obesity is revealed,providing a reference for future research.

关键词： Proteome profiling Gallstones Obesity-associated gallstones Tandem mass tag labeling PPAR signaling

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molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer:Unravelling challenges and future directions

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World Journal of Gastroenterology 2024年第13期30卷 1815-1835页

作者： Samantha Sharma Naresh Singh Anita Ahmed Turk Isabella Wan Akshay Guttikonda Julia Lily Dong Xinna Zhang Mateusz Opyrchal Department of Medical and molecular Genetics Indiana University School of MedicineIndianapolisIN 46202United States Division of Hematology/Oncology Department of MedicineIndiana University School of MedicineIndianapolisIN 46202United States Melvin and Bren Simon Comprehensive Cancer Center Indiana University School of MedicineIndianapolisIN 46202United States

Colorectal cancer(CRC)is a complex disease with diverse etiologies and clinical outcomes.Despite considerable progress in development of CRC therapeutics,challenges remain regarding the diagnosis and management of advanced stage metastatic CRC(mCRC).In particular,the five-year survival rate is very low since mCRC is currently rarely curable.Over the past decade,cancer treatment has significantly improved with the introduction of cancer immunotherapies,specifically immune checkpoint inhibitors.Therapies aimed at blocking immune checkpoints such as PD-1,PD-L1,and CTLA-4 target inhibitory pathways of the immune system,and thereby enhance anti-tumor immunity.These therapies thus have shown promising results in many clinical trials alone or in combination.The efficacy and safety of immunotherapy,either alone or in combination with CRC,have been investigated in several clinical trials.Clinical trials,including KEYNOTE-164 and CheckMate 142,have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab,respectively,for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC.Unfortunately,these drugs benefit only a small percentage of patients,with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients.To this end,primary and secondary resistance to immunotherapy remains a significant issue,and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response.This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC.The underlying rationale,challenges faced,and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.

关键词： Colorectal cancer Immune checkpoint inhibitors Clinical trials Immunotherapy Microsatellite instability Microsatellite stability DNA mismatch repair

Platycodin D inhibits angiogenic vascular mimicry in NSCLC by regulating the eIF4E-mediated RNA methylome

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Journal of Pharmaceutical Analysis 2024年第1期14卷 152-155页

作者： Shuyu Zheng Yanlin Xin Jiamin Lin Zejuan Xie Keyu Cheng Shanshan Wang Wenli Lu Hao Yang Tianming Lu Jun Li Ruogu Qi Yuanyuan Guo Department of Biochemistry and molecular Biology School of Medicine&Holistic Integrative MedicineNanjing University of Chinese MedicineNanjing210023China Department of Neurosurgery The Second Affiliated HospitalZhejiang UniversityHangzhou310009China

The treatment of non-small cell lung cancer(NSCLC)remains a challenge due to tumor evolution during anti-angiogenesis therapies,in which the mechanism of vascular mimicry(VM)is believed to result in ineffective treatment[1].To conquer this challenge,substantial effort has recently been devoted to seeking out natural compounds on account of their multitarget actions.As a traditional herbal medicine,platycodin D(PD)is the major bioactive monomer derived from Platycodon grandiflorum(P.grandiflorum)and is used as an expectorant for pulmonary disease in Asia[2].

关键词： NSCLC eIF4E treatment

Si-Wu-Tang attenuates liver fibrosis via regulating lncRNA H19-dependent pathways involving cytoskeleton remodeling and ECM deposition

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Chinese Journal of Natural medicines 2024年第1期22卷 31-46页

作者： QU Jiaorong XUE Xiaoyong WANG Zhixing MA Zhi JIA Kexin LI Fanghong ZHANG Yinhao WU Ruiyu ZHOU Fei ZHAO Piwen LI Xiaojiaoyang school of Life Sciences Beijing University of Chinese MedicineBeijing 100029China school of Chinese Materia Medica Beijing University of Chinese MedicineBeijing 100029China State Key Laboratory of Medical molecular Biology Department of Molecular Biology and BiochemistryInstitute of Basic Medical SciencesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100005China

Liver fibrosis is a dynamic wound-healing response characterized by the agglutination of the extracellular matrix(ECM).Si-Wu-Tang(SWT),a traditional Chinese medicine(TCM)formula,is known for treating gynecological diseases and liver fibrosis.Our previous studies demonstrated that long non-coding RNA H19(H19)was markedly upregulated in fibrotic livers while its deficiency markedly reversed fibrogenesis.However,the mechanisms by which SWT influences H19 remain unclear.Thus,we established a bile duct ligation(BDL)-induced liver fibrosis model to evaluate the hepatoprotective effects of SWT on various cells in the liver.Our results showed that SWT markedly improved ECM deposition and bile duct reactions in the liver.Notably,SWT relieved liver fibrosis by regulating the transcription of genes involved in the cytoskeleton remodeling,primarily in hepatic stellate cells(HSCs),and influencing cytoskeleton-related angiogenesis and hepatocellular injury.This modulation collectively led to reduced ECM deposition.Through extensive bioinformatics analyses,we determined that H19 acted as a miRNA sponge and mainly inhibited miR-200,miR-211,and let7b,thereby regulating the above cellular regulatory pathways.Meanwhile,SWT reversed H19-related miRNAs and signaling pathways,diminishing ECM deposition and liver fibrosis.However,these protective effects of SWT were diminished with the overexpression of H19 in vivo.In conclusion,our study elucidates the underlying mechanisms of SWT from the perspective of H19-related signal networks and proposes a potential SWT-based therapeutic strategy for the treatment of liver fibrosis.

关键词： Liver fibrosis LncRNA H19 Si-Wu-Tang miRNAs Cytoskeleton ECM deposition

All types of base conversions allowed by base editors

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Science China(Life Sciences) 2024年第2期67卷 431-433页

作者： Shun-Qing Liang Wen Xue RNA Therapeutics Institute UMass Chan Medical SchoolWorcester 01655USA Department of molecular Cell and Cancer BiologyUMass Chan Medical SchoolWorcester 01655USA Department of molecular medicine UMass Chan Medical SchoolWorcester 01655USA Li Weibo Institute for Rare Diseases Research UMass Chan Medical SchoolWorcester 01655USA

Base editors(BEs) hold great promise as tools for introducing single-base-pair changes in both basic research and therapeutic applications(Rees and Liu,2018).Base editors are composed of a Cas9 nickase fused to a DNA-modifying enzyme,which chemically modifies nucleobases within a specific targeting window near the Cas9-binding site.

关键词： base bases allowed

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Analysis of the combined effect of rs699 and rs5051 on angiotensinogen expression and hypertension

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Chronic Diseases and Translational medicine 2024年第2期10卷 102-117页

作者： Nicholas R.Powell Tyler Shugg Jacob Leighty Matthew Martin Rolf P.Kreutz Michael T.Eadon Dongbing Lai Tao Lu Todd C.Skaar Division of Clinical Pharmacology Department of MedicineSchool of MedicineIndiana UniversityIndianapolisIndianaUSA Department of Pharmacology and Toxicology School of MedicineIndiana UniversityIndianapolisIndianaUSA Department of Cardiology School of MedicineKrannert Institute of CardiologyIndiana UniversityIndianapolisIndianaUSA Division of Nephrology Department of MedicineSchool of MedicineIndiana UniversityIndianapolisIndianaUSA Department of Medical and molecular Genetics School of MedicineIndiana UniversityIndianapolisIndianaUSA

Background Hypertension(HTN)involves genetic variability in the renin-angiotensin system and influences antihypertensive response.We previously reported that angiotensinogen(AGT)messenger RNA(mRNA)is endogenously bound by miR-122-5p and rs699 A>G decreases reporter mRNA in the microRNA functional-assay PASSPORT-seq.The AGT promoter variant rs5051 C>T is in linkage disequilibrium(LD)with rs699 A>G and increases AGT transcription.The independent effect of these variants is understudied due to their LD therefore we aimed to test the hypothesis that increased AGT by rs5051 C>T counterbalances AGT decreased by rs699 A>G,and when these variants occur independently,it translates to HTN-related phenotypes.Methods We used in silico,in vitro,in vivo,and retrospective models to test this hypothesis.Results In silico,rs699 A>G is predicted to increase miR-122-5p binding affinity by 3%.Mir-eCLIP results show rs699 is 40–45 nucleotides from the strongest microRNA-binding site in the AGT mRNA.Unexpectedly,rs699 A>G increases AGT mRNA in an AGT-plasmid-cDNA HepG2 expression model.Genotype-Tissue Expression(GTEx)and UK Biobank analyses demonstrate liver AGT expression and HTN phenotypes are not different when rs699 A>G occurs independently from rs5051 C>T.However,GTEx and the in vitro experiments suggest rs699 A>G confers cell-type-specific effects on AGT mRNA abundance,and suggest paracrine renal renin-angiotensin-system perturbations could mediate the rs699 A>G associations with HTN.Conclusions We found that rs5051 C>T and rs699 A>G significantly associate with systolic blood pressure in Black participants in the UK Biobank,demonstrating a fourfold larger effect than in White participants.Further studies are warranted to determine if altered antihypertensive response in Black individuals might be due to rs5051 C>T or rs699 A>G.Studies like this will help clinicians move beyond the use of race as a surrogate for genotype.

关键词： angiotensinogen genetic and genomic medicine hypertension rs699

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Two distinct subpopulations of marginal zone B cells exhibit differential antibody-producing capacities and radioresistance

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Cellular & molecular Immunology 2024年第4期21卷 393-408页

作者： Sujin Lee Yeunjung Ko Hyun Woo Lee Won Joon Oh Hun Gi Hong Dinuka Ariyaratne Se Jin Im Tae Jin Kim Department of Immunology Graduate School of Basic Medical ScienceSungkyunkwan University School of MedicineSuwon16419Republic of Korea Department of Immunology and molecular medicine Faculty of Medical SciencesUniversity of Sri JayewardenepuraNugegodaSri Lanka Present address:Immunology and Microbiology Graduate Program Baylor College of MedicineHoustonTX77030USA

Marginal zone(MZ)B cells,which are splenic innate-like B cells that rapidly secrete antibodies(Abs)against blood-borne pathogens,are composed of heterogeneous subpopulations.Here,we showed that MZ B cells can be divided into two distinct subpopulations according to their CD80 expression levels.CD80^(high)MZ B cells exhibited greater Ab-producing,proliferative,and IL-10-secreting capacities than did CD80^(low)MZ B cells.Notably,CD80^(high)MZ B cells survived 2-Gy whole-body irradiation,whereas CD80^(low)MZ B cells were depleted by irradiation and then repleted with one month after irradiation.Depletion of CD80^(low)MZ B cells led to accelerated development of type II collagen(CII)-induced arthritis upon immunization with bovine CII.CD80^(high)MZ B cells exhibited higher expression of genes involved in proliferation,plasma cell differentiation,and the antioxidant response.CD80^(high)MZ B cells expressed more autoreactive B cell receptors(BCRs)that recognized double-stranded DNA or CII,expressed more immunoglobulin heavy chain sequences with shorter complementarity-determining region 3 sequences,and included more clonotypes with no N-nucleotides or with B-1a BCR sequences than CD80^(low)MZ B cells.Adoptive transfer experiments showed that CD21^(+)CD23^(+)transitional 2 MZ precursors preferentially generated CD80^(low)MZ B cells and that a proportion of CD80^(low)MZ B cells were converted into CD80^(high)MZ B cells;in contrast,CD80^(high)MZ B cells stably remained CD80^(high)MZ B cells.In summary,MZ B cells can be divided into two subpopulations according to their CD80 expression levels,Ab-producing capacity,radioresistance,and autoreactivity,and these findings may suggest a hierarchical composition of MZ B cells with differential stability and BCR specificity.

关键词： Marginal Zone B Cell CD80 Autoreactivity Radioresistance