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Peroxisome proliferator-activated receptor gamma coactivator-1(PGC-1)family in physiological and pathophysiological process and diseases

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1249-1292页

作者： Lu Qian Yanli Zhu Chao Deng Zhenxing Liang Junmin Chen Ying Chen Xue Wang Yanqing Liu Ye Tian Yang Yang Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases Xi'an No.3 HospitalThe Affiliated Hospital of Northwest UniversityNorthwest UniversityXi'an 710021China Xi'an Key Laboratory of Innovative Drug Research for Heart Failure Faculty of Life Sciences and MedicineNorthwest University229 Taibai North RoadXi'an 710069China department of Cardiovascular Surgery The First Affiliated Hospital of Xi'an Jiaotong University277 Yanta West RoadXi'an 710061China department of Cardiothoracic Surgery The First Affiliated Hospital of Zhengzhou University1 Jianshe EastZhengzhou 450052China department of hematology The First Affiliated Hospital of Xi'an JiaotongUniversity277 Yanta West RoadXi'an 710061China

Peroxisome proliferator-activated receptor gamma coactivator-1(PGC-1)family(PGC-1s),consisting of three members encompassing PGC-1a,PGC-1β,and PGC-1-related coactivator(PRC),was discovered more than a quarter-century ***-1s are essential coordinators of many vital cellular events,including mitochondrial functions,oxidative stress,endoplasmic reticulum homeostasis,and *** evidence has shown that PGC-1s are implicated in many diseases,such as cancers,cardiac diseases and cardiovascular diseases,neurological disorders,kidney diseases,motor system diseases,and metabolic *** the upstream modulators and co-activated partners of PGC-1s and identifying critical biological events modulated by downstream effectors of PGC-1s contribute to the presentation of the elaborate network of ***,discussing the correlation between PGC-1s and diseases as well as summarizing the therapy targeting PGC-1s helps make individualized and precise intervention *** this review,we summarize basic knowledge regarding the PGC-1s family as well as the molecular regulatory network,discuss the physio-pathological roles of PGc-1s in human diseases,review the application of PGC-1s,including the diagnostic and prognostic value of PGC-1s and several therapies in pre-clinical studies,and suggest several directions for future *** review presents the immense potential of targeting PGC-1s in the treatment of diseases and hopefully facilitates the promotion of PGC-1s as new therapeutic targets.

关键词： diseases life precise

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Secondary metabolites of mulberry leaves exert anti-lung cancer activity through regulating the PD-L1/PD-1 signaling pathway

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Journal of Pharmaceutical Analysis 2024年第6期14卷 914-925页

作者： Guiqin Ye Xin Sun Jiuzhou Li Yuanyuan Mai Ruilan Gao Jianbin Zhang Cancer Center Department of Medical OncologyKey Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang ProvinceZhejiang Provincial People's HospitalAffiliated People's HospitalHangzhou Medical CollegeHangzhou310014China Clinical Laboratory Yuhuan City HospitalTaizhouZhejiang317600China Hangzhou Medical College Hangzhou311300China department of Neurosurgery Binzhou People's HospitalBinzhouShandong256600China Institute of hematology Research The First Affiliated Hospital of Zhejiang Chinese Medical UniversityHangzhou310060China

Lung cancer ranks the top of malignancies that cause cancer-related deaths *** leaves of Morus alba L are traditional Chinese medicine widely applied in respiratory *** previous work has demonstrated the anti-lung cancer effect of secondary metabolites of mulberry leaf,but their mechanism of action has still not fully *** synthesized Moracin N(MAN)-Probe conjugated with alkyne to label lung cancer cells and identified protein targets by chemical proteomic *** and its probe exerted similar growth-inhibitory effect on human lung cancer *** proteomic results showed that MAN targeted the programmed death ligand 1(PD-L1)checkpoint pathway and T cell receptor(TCR)signaling pathway,indicating its immune-regulatory ***-free surface plasmon resonance(SPR)results showed the direct interaction of MAN with PD-L1 *** docking analysis demonstrated that MAN bound to E158 residue of PD-L1 *** downregulated the expression levels of PD-L1 in a time-and dose-dependent manner and disrupted the PD-L1/programmed death 1(PD-1)binding,including other secondary metabolites of mulberry leaves Guangsangon E(GSE)and Chalcomoracin(CMR).Human peripheral blood mononuclear cells(PBMCs)co-cultured with MAN-treated A549 cells,resulting in the increase of CD8^(+)GZMB^(+)T cells and the decrease of CD8^(+)PD-1^(+)T *** suggested that MAN exerts anti-cancer effect through blocking the PD-L1/PD-1 *** vivo,MAN combined with anti-PD-1 antibody significantly inhibited lung cancer development and metastasis,indicating their synergistic *** together,secondary metabolites of mulberry leaves target the PD-L1/PD-1 signaling,enhance T cell-mediated immunity and inhibit the tumorigenesis of lung *** modulatory effect on tumor microenvironment makes them able to enhance the therapeutic efficacy of immune checkpoint inhibitors in lung cancer.

关键词： Moracin N Click chemistry PD-L1 T cell Lung cancer

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PRC2 primes bivalent genes for transcription induction independent of histone methyltransferase activity

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Science China Life Sciences 2024年第9期67卷 2033-2035页

作者： Meihan Gong Ye Yuan Zhongye Dai Xuejiao Lv Jiacheng Su Dawei Huo Lin Niu Xu Chen Xudong Wu State Key Laboratory of Experimental hematology The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) Department of Cell Biology School of Basic Medical Sciences Tianjin Medical University Bone Marrow Transplantation Center the First Affiliated Hospital Zhejiang University School of Medicine Liangzhu Laboratory Institute of Hematology Zhejiang University

Dear Editor,Polycomb group proteins, conserved epigenetic transcriptional repressors, are crucial for orchestrating diverse developmental gene expression programs(Schuettengruber et al., 2017). The polycomb repressive complex 2(PRC2) catalyzes H3 lysine-27 trimethylation(H3K27me3) to establish a delicate balance with H3K4me3, forming a bivalent chromatin state at target gene promoters and thereby poising them for subsequent transcription activation(Bernstein et al.,2006).

关键词： REPRESSIVE COMPLEX 2 POLYCOMB PROMOTERS

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Identification of TNFRSF1A as a novel regulator of carfilzomib resistance in multiple myeloma

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Oncology Research 2024年第2期32卷 325-337页

作者： JIE ZHAO XUANTAO YANG HAIXI ZHANG XUEZHONG GU department of hematology The First People’s Hospital of Yunnan ProvinceYunnan Province Clinical Research Center for Hematologic DiseaseYunnan Province Clinical Center for Hematologic DiseaseKunming650032China department of Pathology The First People’s Hospital of Yunnan ProvinceKunming650032China

Multiple myeloma(MM)is a hematological tumor with high mortality and recurrence *** is a new-generation proteasome inhibitor that is used as the first-line therapy for ***,the development of drug resistance is a pervasive obstacle to treating ***,elucidating the drug resistance mechanisms is conducive to the formulation of novel therapeutic *** elucidate the mechanisms of carfilzomib resistance,we retrieved the GSE78069 microarray dataset containing carfilzomib-resistant LP-1 MM cells and parental MM *** gene expression analyses revealed major alterations in the major histocompatibility complex(MHC)and cell adhesion *** upregulation of the tumor necrosis factor(TNF)receptor superfamily member 1A(TNFRSF1A)gene was accompanied by the downregulation of MHC genes and cell adhesion ***,to investigate the roles of these genes,we established a carfilzomib-resistant cell model and observed that carfilzomib resistance induced TNFRSF1A overexpression and TNFRSF1A silencing reversed carfilzomib resistance and reactivated the expression of cell adhesion ***,TNFRSF1A silencing suppressed the tumorigenesis of MM cells in immunocompetent mice,indicating that TNFRSF1A may lead to carfilzomib resistance by dampening antitumor ***,our results indicated that TNFRSF1A overexpression conferred carfilzomib resistance in MM cells and suppressed the expression of MHC genes and cell adhesion *** suppression of MHC genes and cell adhesion molecules may impair the interaction between immune cells and cancer cells to impair antitumor *** studies are warranted to further investigate the signaling pathway underlying the regulatory role of TNFRSF1A in MM cells.

关键词： Multiple myeloma Carfilzomib Drug resistance Major histocompatibility complex TNFRSF1A

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Comparing the efficacy and safety of low,medium,and high dosages of selexipag for treating pulmonary hypertension:A systematic review and meta-analysis

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Animal Models and Experimental Medicine 2024年第1期7卷 56-70页

作者： Shang Wang Yi Yan Jian Zhang Ping Yuan Ci-Jun Luo Hong-Ling Qiu Hui-Ting Li Jian Xu Lan Wang Tian-Lan Li Rong Jiang department of Cardio-Pulmonary Circulation Shanghai Pulmonary HospitalSchool of MedicineTongji UniversityShanghaiChina Heart Center and Shanghai Institute of Pediatric Congenital Heart Disease Shanghai Children's Medical CenterNational Children's Medical CenterShanghai Jiaotong University School of MedicineShanghaiChina department of Respiratory and Critical Care Medicine The 416 Hospital of Nuclear IndustryThe Second Affiliated Hospital of Chengdu Medical CollegeChengduChina department of hematology The Affiliated Hospital of Qingdao UniversityQingdaoChina

Background:The maintenance dosage of selexipag is categorized as low,medium or *** order to assess the efficacy and safety of different dosages of selexipag for the risk stratification of pulmonary arterial hypertension(PAH),we performed a sys-tematic review and ***:Studies assessing PAH risk stratification indices,such as the World Health Organization functional class(WHO-FC),six-minute walk distance(6MWD),N-terminal pro-B-type natriuretic peptide(NT-proBNP)level,right atrial pressure(RAP),cardiac index(CI)and mixed venous oxygen saturation(SvO2),were ***:Thirteen studies were *** led to improvements in the 6MWD(MD:24.20 m,95%CI:10.74-37.67),NT-proBNP(SMD:-0.41,95%CI:-0.79-0.04),CI(MD:0.47 L/min/m^(2),95%CI:0.17-0.77)and WHO-FC(OR:0.564,95%CI:0.457-0.697).Subgroup analysis demonstrated that all three dosages improved the 6MWD.A moderate dosage led to improvements in the CI(MD:0.30 L/min/m^(2),95%CI:0.15-0.46)and WHO-FC(OR:0.589,95%CI:0.376-0.922).Within 6 months of treatment,only the WHO-FC and CI were significantly improved(OR:0.614,95%CI:0.380-0.993;MD:0.30 L/min/m^(2),95%CI:0.16-0.45,respectively).More than 6 months of treatment significantly improved the 6MWD,WHO-FC and NT-proBNP(MD:40.87 m,95%CI:10.97-70.77;OR:0.557,95%CI:0.440-0.705;SMD:-0.61,95%CI:-1.17-0.05,respectively).Conclusions:Low,medium,and high dosages of selexipag all exhibited good *** treatment lasted for more than 6 months,selexipag exerted obvious effects,even in the low-dosage *** finding is important for guiding individualized treatments.

关键词： individualized treatments meta-analysis prostacyclin receptor agonist risk stratification systematic review

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Neoadjuvant nivolumab with or without platinum-doublet chemotherapy based on PD-L1 expression in resectable NSCLC(CTONG1804):a multicenter open-label phase II study

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Signal Transduction and Targeted Therapy 2024年第1期9卷 249-258页

作者： Si-Yang Liu Song Dong Xue-Ning Yang Ri-Qiang Liao Ben-Yuan Jiang Qun Wang Xiao-Song Ben Gui-Bin Qiao Jun-Tao Lin Hong-Hong Yan Li-Xu Yan Qiang Nie Hai-Yan Tu Bin-Chao Wang Jin-Ji Yang Qing Zhou Hong-Rui Li Ke Liu Wendy Wu Si-Yang Maggie Liu Wen-Zhao Zhong Yi-Long Wu Guangdong Lung Cancer Institute Guangdong Provincial Key Laboratory of Translational Medicine in Lung CancerGuangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina department of Thoracic Surgery Zhongshan HospitalFudan UniversityShanghaiChina department of Thoracic Surgery Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina department of Pathology Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouChina Fujian Key Laboratory of Advanced Technology for Cancer Screening and Early Diagnosis FuzhouChina Berry Oncology Corporation FuzhouChina Chinese Thoracic Oncology Group(CTONG) GuangzhouChina department of hematology The First Affiliated HospitalJinan UniversityGuangzhouChina

This prospective multicenter phase II study evaluated the clinical efficacy of neoadjuvant nivolumab-exclusive(N)and nivolumab–chemotherapy(N/C)combinations based on PD-L1 *** patients exhibited resectable clinical stage IIA–IIIB(AJCC 8th edition)NSCLC without EGFR/ALK *** received either mono-nivolumab(N)or nivolumab+nabpaclitaxel+carboplatin(N/C)for three cycles based on PD-L1 *** primary endpoint was the major pathological response(MPR).Key secondary endpoints included the pathologic complete response(pCR),objective response rate(ORR),and event-free survival(EFS).Baseline PD-L1 expression and perioperative circulating tumor DNA(ctDNA)status were correlated with pCR and ***-two patients were enrolled,with 46 undergoing *** MPR was 50.0%(26/52),with 25.0%(13/52)achieving pCR,and 16.7%and 66.7%for patients with PD-L1≥50%in N and N/C groups,***(25.0%)patients experienced grade 3 or higher immune-related adverse events during neoadjuvant *** with post-neoadjuvant ctDNA negativity was more likely to have pCR(39.1%)compared with those remained positive(6.7%,odds ratio=6.14,95%CI 0.84-Inf,p=0.077).With a median follow-up of 25.1 months,the 18-month EFS rate was 64.8%(95%CI 51.9–81.0%).For patients with ctDNA–***+,the 18m-EFS rate was 93.8%vs 47.3%(HR,0.15;95%CI 0.04,0.94;p=0.005).Immunochemotherapy may serve as an optimal neoadjuvant treatment even for patients with PD-L1 expression≥50%.ctDNA negativity following neoadjuvant treatment and surgery could help identify superior pathological and survival benefits,which requires further confirmation in a prospective clinical trial(NCT04015778).

关键词： chemotherapy NSCLC treatment

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Efficacy and Safety of Iron Isomaltoside Compared with an Oral Iron Supplement in the Management of Patients with Iron Deficiency Anemia

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Open Journal of Blood Diseases 2024年第1期14卷 17-30页

作者： Zhimin Wu Chunxiao Zhou Chunyan Wu Qiao Song Shilyu Chen Wen Zhang Shaoling Wu department of Medicine Qingdao University Qingdao China department of hematology The Affiliated Hospital of Qingdao University Qingdao China

Objective: To evaluate the treatment outcome of iron isomaltoside compared with an oral iron supplement in the management of iron deficiency anemia (IDA). Methods: The study included patients with IDA who visited the Outpatient Clinic of the department of hematology, the Affiliated hospital of Qingdao university from October 2021 to August 2022 and met the inclusion and exclusion criteria. According to the actual application of iron supplementation, the patients were divided into two groups: iron isomaltoside treatment group and oral iron treatment group. Baseline measurements were collected before the start of treatment, and measurements were collected subsequently at intervals of 1 week, 1 month, and 3 months. The hematological parameters analyzed included Hemoglobin (Hb), Mean corpuscular hemoglobin (MCH), Mean Hemoglobin content (MCH), Mean corpuscular Hemoglobin concentration (MCHC), and Platelet (Plt). Safety data and adverse event profiles were recorded. Results: Intra-group comparisons: After 1 month of treatment, the Hb significantly improved (P 0.05). Inter-group comparisons: The biochemical parameters were significantly improved (P 0.05) in the iron isomaltoside group compared with those in the oral iron group after 1 month of iron supplementation in patients with mild and moderate anemia. Adverse reactions were tolerable for the patients in both iron isomaltoside group and oral iron group. Only 1 patient in iron isomaltoside group developed anaphylactic shock during medication and recovered after aggressive rescue. Conclusions: Iron isomaltoside which increases Hb more rapidly compared with the oral iron supplementation has few adverse reactions and good acceptance.

关键词： Anemia Iron-Deficiency Drug Therapy Iron Isomaltoside 1000 Treatment Outcome

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Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin

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Genes & Diseases 2024年第1期11卷 397-412页

作者： Zhe Chen Qian Guo Shichen Huang Lei Li Feng Wu Zhilong Liu Zhigang Li Tao Chen Guanbin Song Shuangnian Xu Jieping Chen Yu Hou department of hematology Southwest HospitalThird Military Medical University(Army Medical University)Chongqing 400038China Institute of Life Sciences Chongqing Medical UniversityChongqing 400016China Key Laboratory of Biorheological Science and Technology Ministry of EducationCollege of BioengineeringChongqing UniversityChongqing 400044China Chongqing Foreign Language School Chongqing 400039China

Therapeutic targeting FOxO3A(a forkhead transcription factor)represents a prom-ising strategy to suppress acute myeloid leukemia(AML).However,the effective inhibitors that target FOXO3A are lacking and the adaptive response signaling weakens the cytotoxic effect of FOxO3A depletion on AML ***,we show that FOxO3A deficiency induces a compensa-tory response involved in the reactive activation of mTOR that leads to signaling rebound and adaptive *** metabolism acts downstream of mTOR to provoke activa-tion of JNK/c-JUN via reactive oxygen species(ROS).At the molecular level,FOXO3A directly binds to the promoter of G protein gamma subunit 7(GNG7)and preserves its expression,while GNG7 interacts with mTOR and restricts phosphorylated activation of ***,combinatorial inhibition of FOXO3A and mTOR show a synergistic cytotoxic effect on AML cells and prolongs survival in a mouse model of *** a structure-based virtual screening,we report one potent small-molecule FOxO3A inhibitor(Gardenoside)that exhibits a strong effect of anti-FOXO3A DNA *** synergizes with rapamycin to substantially reduce tumor burden and extend survival in AML patient-derived xenograft *** results demonstrate that mTOR can mediate adaptive resistance to FOxO3A inhibition and validate a combinatorial approach for treating AML.

关键词： AML Combinatorial inhibition FOXO3A GNG7 mTOR

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Hexafluoropropylene oxide trimer acid,a perfluorooctanoic acid alternative,induces cardiovascular toxicity in zebrafish embryos

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Journal of Environmental Sciences 2024年第5期139卷 460-472页

作者： Sujie Sun Li Zhang Xue Li Lu Zang Ling Huang Junquan Zeng Zigang Cao Xinjun Liao Zilin Zhong Huiqiang Lu Jianjun Chen Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases Jiangxi Key Laboratory of Developmental Biology of OrgansCenter for Clinical Research Center of the Affiliated Hospital of Jinggangshan UniversityJi’an 343009China Translational Research Institute of Brain and Brain-like Intelligence Shanghai Key Laboratory of Anesthesiology and Brain Functional ModulationDepartment of PediatricsShanghai Fourth People’s HospitalSchool of MedicineTongji UniversityShanghai 200434China State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants School of Environmental Sciences and EngineeringShanghai Jiao Tong UniversityShanghai 200240China department of Interventional and Vascular Surgery Affiliated Hospital of Jinggangshan UniversityJi’an 343009China department of Internal Medicine and hematology Affiliated Hospital of Jinggangshan UniversityJi’an 343009China

As an increasingly used alternative to perfluorooctanoic acid(PFOA),hexafluoropropylene oxide trimer acid(HFPO-TA)has been widely detected in global water ***,little is known regarding its toxic effects on cardiovascular ***,zebrafish embryos were treated with egg water containing 0,60,120,or 240 mg/L *** showed that HFPO-TA treatment led to a significant reduction in both larval survival percentage and heart ***,HFPO-TA exposure caused severe pericardial edema and elongation of the sinus venous to bulbus arteriosus distance(SV-BA)in Tg(myl7:GFP)transgenic larvae,disrupting the expression of genes involved in heart development and thus causing abnormal heart *** sprouting angiogenesis was observed in the 120 and 240 mg/L exposed Tg(fli:GFP)transgenic ***-TA treatment also impacted the mRNA levels of genes involved in the vascular endothelial growth factor(VEGF)pathway and embryonic vascular ***-TA exposure significantly decreased erythrocyte number in Tg(gata1:DsRed)transgenic embryos and influenced gene expression associated with the heme metabolism ***-TA also induced oxidative stress and altered the transcriptional levels of genes related to cell cycle and apoptosis,inhibiting cell proliferation while promoting ***,HFPO-TA exposure may induce abnormal development of the cardiovascular and hematopoietic systems in zebrafish embryos,suggesting it may not be a suitable or safe alternative for PFOA.

关键词： Hexafluoropropylene oxide trimer acid Heart development Vascular development Hemopoiesis Zebrafish embryos

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Management Practices of Locally Advanced and Metastatic Urothelial Carcinoma: A Questionnaire-Based Survey among Lebanese Oncologists

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Open Journal of Urology 2024年第2期14卷 138-149页

作者： Joseph Kattan Sally Temraz Fadi Nasr Arafat Tfayli Christina Khater Anas Mugharbel Hady Ghanem Hampig Raphael Kourie Georges Hachem Sarah Masri Jamil Debs Ali Shamseddine department of hematology-Oncology H&#244tel-Dieu de France University Hospital Faculty of Medicine Saint-Joseph University of Beirut Beirut Lebanon department of Internal Medicine Hematology-Oncology Division American University of Beirut Medical Center Beirut Lebanon hematology-Oncology Division American University of Beirut Medical Center Beirut Lebanon department of hematology-Oncology Saint Charles Hospital Beirut Lebanon department of Internal Medicine Makassed General Hospital Beirut Lebanon hematology-Oncology Division Lebanese American University Medical Center - Rizk Hospital Beirut Lebanon department of hematology-Oncology Saint George Hospital University Medical Center Beirut Lebanon Pfizer Medical Affairs Beirut Lebanon

Background and Objective: The outcome of locally advanced and metastatic urothelial carcinoma LA/mUC has improved over the past years with a plethora of new treatments and the approval of immune checkpoint inhibitors (ICIs), antibody-drug conjugates, and targeted agents, to identify locally advanced metastatic urothelial carcinoma’s current management practices in Lebanon and the implication of the ongoing economic crisis on the medical practice. Methods: An online questionnaire was used to survey ten Lebanese oncologists from six different hospitals, between July 5 and July 11, 2022, requesting information pertaining to their current clinical practice in the pharmacological treatment of locally advanced metastatic urothelial carcinoma. Key Findings: Cisplatin-based chemotherapy was the most frequently reported initial treatment of locally advanced metastatic urothelial carcinoma. Participants reported using immune checkpoint inhibitors in platinum-ineligible patients and those with PDL1 positive tumors. Also, they would not consider the concomitant use of immunotherapy and chemotherapy in the first-line setting. Participants believed that avelumab maintenance is effective in the absence of progression after first-line platinum-based chemotherapy;they would consider initiating it 2 - 10 weeks after completion of chemotherapy. Conclusions and Clinical Implications: After comparing with current international guidelines, this study shows that Lebanese oncologists follow international guidelines and have deep knowledge of recent clinical trials for the management of locally advanced metastatic urothelial carcinoma, regardless of economic crisis challenges.

关键词： Clinical Practice Chemotherapy Immune Checkpoint Inhibitors PDL1 Urothelial Carcinoma

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