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ELABELA-derived peptide ELA13 attenuates kidney fibrosis by inhibiting the Smad and ERK signaling pathways

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第4期25卷 341-353页

作者： Zhibin YAN Ying SHI Runling YANG Jijun XUE Caiyun FU Zhejiang Provincial key laboratory of Silkworm Bioreactor and Biomedicine College of Life Sciences and MedicineZhejiang Sci-Tech UniversityHangzhou310018China State key laboratory of Applied Organic Chemistry College of Chemistry and Chemical EngineeringLanzhou University Lanzhou 730000China key laboratory of preclinical study for new Drugs of Gansu Province School of Basic Medical Sciences&Research Unit of Peptide ScienceChinese Academy of Medical Sciences2019RU066Lanzhou UniversityLanzhou 730000China

Kidney fibrosis is an inevitable result of various chronic kidney diseases(CKDs)and significantly contributes to end-stage renal ***,there is no specific treatment available for renal ***13(amino acid sequence:RRCMPLHSRVPFP)is a conserved region of ELABELA in all vertebrates;however,its biological activity has been very little *** the present study,we evaluated the therapeutic effect of ELA13 on transforming growth factor-β1(TGF-β1)-treated NRK-52E cells and unilateral ureteral occlusion(UUO)*** results demonstrated that ELA13 could improve renal function by reducing creatinine and urea nitrogen content in serum,and reduce the expression of fibrosis biomarkers confirmed by Masson staining,immunohistochemistry,real-time polymerase chain reaction(RT-PCR),and western *** biomarkers were increased after UUO and decreased by administration of ***,we found that the levels of essential molecules in the mothers against decapentaplegic(Smad)and extracellular signal-regulated kinase(ERK)pathways were reduced by ELA13 treatment in vivo and in *** conclusion,ELA13 protected against kidney fibrosis through inhibiting the Smad and ERK signaling pathways and could thus be a promising candidate for anti-renal fibrosis treatment.

关键词： ELA13 Kidney fibrosis Inflammation Smad Extracllular signal-regulated kinase(ERK)

Tuning the exciton binding energy of covalent organic frameworks for efficient photocatalysis

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Chinese Chemical Letters 2024年第2期35卷 577-583页

作者： Zhangjie Gu Zhen Shan Yulan Wang Jinjian Wang Tongtong Liu Xiaoming Li Zhiyang Yu Jian Su Gen Zhang key laboratory for Soft Chemistry and Functional Materials of Ministry of Education School of Chemistry and Chemical EngineeringNanjing University of Science and TechnologyNanjing 210094China State key laboratory of Photocatalysis on Energy and Environment College of ChemistryFuzhou UniversityFuzhou 350002China MIIT key laboratory of Advanced Display Material and Devices School of Materials Science and EngineeringNanjing University of Science and TechnologyNanjing 210094China key laboratory of preclinical study for new Drugs of Gansu Province School of Basic Medical SciencesLanzhou UniversityLanzhou 730000China

Owing to the large exciton binding energy(>100 meV)of most organic materials,the process of exciton dissociation into free electrons and holes is seriously hindered,which plays a key role in the photocatalytic *** this study,a series of chalcogen(S,Se)-substituted mesoporous covalent organic frameworks(COFs)have been synthesized for enhanced photocatalytic organic *** measurements indicate that the introduction of semi-metallic Se atom and the enlargement of conjugation degree can not only reduce the exciton binding energy accelerating the charge separation,but also reduce the band gap of *** a result,the COF-NUST-36 with the lowest exciton binding energy(39.5 meV)shows the highest photocatalytic performance for selective oxidation of amines(up to 98%*** 97.5%Sel.).This work provides a feasible method for designing COFs with high photocatalytic activity by adjusting exciton binding energy.

关键词： Covalent organic frameworks Exciton binding energy Atom substitution Extended conjugation Photocatalysis

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A kinetic resolution accompanied chirality transformation process for asymmetric synthesis of chiral phenol, oxaziridine, and α-hydroxyl cyclic ketone

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Science China Chemistry 2024年第9期67卷 2989-2997页

作者： Pengxin Wang Xiaoyong Zhang Lingqing Wang Rui Wang Dongxu Yang key laboratory of preclinical study for new Drugs of Gansu Province School of Basic Medical Sciences & Research Unit of Peptide ScienceChinese Academy of Medical Sciences Lanzhou University State key laboratory of Bioactive Substance and Function of Natural medicines Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College School of Sciences Great Bay University Institute of Systems and Physical Biology Shenzhen Bay Laboratory

Chirality transformation is a basic, attractive, and important strategy for obtaining enantioenriched products with desired chiral elements. The reported chirality conversion reaction often involves the process from one type of chirality to another one. To better utilize the chirality transformation strategy for obtaining two or more products with different chiral elements in a single reaction, a new method of kinetic resolution accompanied by a chirality transformation protocol is proposed and successfully realized in this study. This process is used for the asymmetric oxidation of phenol compounds along with the kinetic resolution of oxaziridines. A wide scope of products, including axially chiral phenols, oxaziridines, and α-hydroxyl cyclic ketones were smoothly obtained in high levels of yields and enantioselectivities in the developed method. These products can be readily used for the synthesis of various types of chiral ligands, which are potential choices for other catalytic asymmetric reactions.

关键词： chirality transformation kinetic resolution accompanied axially chiral phenols chiral oxaziridines

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Control of defensive behavior by the nucleus of Darkschewitsch GABAergic neurons

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National Science Review 2024年第4期11卷 70-83页

作者： Huiying Zhao Jinrong Liu Yujin Shao Xiang Feng Binhan Zhao Li Sun Yijun Liu Linghui Zeng Xiao-ming Li Hongbin Yang Shumin Duan Yan-qin Yu Department of Neurology of Second Affiliated Hospital and School of Brain Science and Brain medicine Zhejiang University School of Medicine Nanhu Brain-Computer Interface Institute Liangzhu laboratory MOE Frontier Science Center for Brain Science and Brain-Machine Integration State Key Laboratory of Brain-Machine Intelligence Zhejiang University NHC and CAMS key laboratory of Medical Neurobiology Zhejiang University key laboratory of Novel Targets and Drug study for Neural Repair of Zhejiang Province School of Medicine Hangzhou City University

The nucleus of Darkschewitsch(ND), mainly composed of GABAergic neurons, is widely recognized as a component of the eye-movement controlling system. However, the functional contribution of ND GABAergic neurons(NDGABA) in animal behavior is largely unknown. Here, we show that NDGABA neurons were selectively activated by different types of fear stimuli, such as predator odor and foot *** and chemogenetic manipulations revealed that NDGABA neurons mediate freezing ***, using circuit-based optogenetic and neuroanatomical tracing methods, we identified an excitatory pathway from the lateral periaqueductal gray(l PAG) to the ND that induces freezing by exciting ND inhibitory outputs to the motor-related gigantocellular reticular nucleus, ventral part(Gi V). Together,these findings indicate the NDGABA population as a novel hub for controlling defensive response by relaying fearful information from the l PAG to Gi V, a mechanism critical for understanding how the freezing behavior is encoded in the mammalian brain.

关键词： nucleus of Darkschewitsch GABAergic population defensive behavior freezing neural circuitry

Electroacupuncture ameliorates blood-brain barrier disruption after ischemic stroke through histone acetylation regulation at the matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 2 genes

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Journal of Traditional Chinese medicine 2024年第4期44卷 734-744页

作者： CHEN Yonglin OUYANG Ling MENG Lingling WU Bufan PENG Rou LIU Sitong HOU Dan WANG Yaling JING Xinyue LU Shengfeng FU Shuping key laboratory of Acupuncture and medicine Research of Ministry of Education Nanjing University of Chinese Medicine

OBJECTIVE: To explore whether the regulation of matrix metalloproteinase 9(MMP-9)/tissue inhibitors of MMPs(TIMPs) gene expression through histone acetylation is a possible mechanism by which electroacupuncture(EA)protects blood-brain barrier(BBB) integrity in a middle cerebral artery occlusion(MCAO) rat ***: Male Sprague-Dawley rats were divided into four groups: the sham group, the MCAO group, the MCAO + EA(MEA) group, and the MCAO + EA + HAT inhibitor(HATi) group. The MCAO model was generated by blocking the middle cerebral artery. EA was applied to Baihui(GV20). Samples were collected 1 or 3 d after reperfusion. Neurological function scores and Evans blue extravasation were employed to evaluate the poststroke injury. The effect of EA on MMP-9/TIMPs gene expression was assessed by real-time fluorescence quantitative polymerase chain reaction(RT-qPCR) and chromatin immunoprecipitation(ChIP). RESULTS: Our results showed that EA treatment prominently improved neurological function and ameliorated BBB disruption. The RT-qPCR assay showed that EA reduced the expression of MMP-9 and promoted TIMP-2 mRNA expression, but HATi reversed these effects of EA. In addition, ChIP results revealed that EA decreased the enrichment of H3K9ace/H3K27ace at MMP-9 promoters and notably stimulated the recruitment of H3K9ace/H3K27ace at TIMP-2 promoter. CONCLUSION: EA treatment at Baihui(GV20) regulates the transcription of MMP-9 and TIMP-2 through histone acetylation modification in the acute stage of stroke, which preserves the structural integrity of the BBB in MCAO rats. These findings suggested that the histone acetylation-mediated transcriptional activity of target genes may be a crucial mechanism of EA treatment in stroke.

关键词： blood-brain barrier electroacupuncture histone acetylation matrix metalloproteinase 9 tissue inhibitor of metalloproteinases

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Nuciferine alleviates collagen-induced arthritic in rats by inhibiting the proliferation and invasion of human arthritis-derived fibroblast-like synoviocytes and rectifying Th17/Treg imbalance

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Chinese Journal of Natural medicines 2024年第4期22卷 341-355页

作者： WANG Hao GENG Xiaolong AI Fangbin YU Zhilun ZHANG Yan ZHANG Beibei LV Cheng GAO Ruiyang YUE Bei DOU Wei The MOE key laboratory of Standardization of Chinese medicines Shanghai Key Laboratory of Compound Chinese Medicinesand the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese MedicineInstitute of Chinese Materia MedicaSchool of Traditional Chinese Materia MedicaShanghai University of Traditional Chinese Medicine(SHUTCM)Shanghai 201203China

Rheumatoid arthritis(RA)is a chronic autoimmune disorder marked by persistent synovial inflammation and joint degradation,posing challenges in the development of effective ***,an alkaloid found in lotus leaf,has shown promising anti-inflammatory and anti-tumor effects,yet its efficacy in RA treatment remains *** study investigated the antiproliferative effects of nuciferine on the MH7A cell line,a human RA-derived fibroblast-like synoviocyte,revealing its ability to inhibit cell proliferation,promote apoptosis,induce apoptosis,and cause G1/S phase ***,nuciferine significantly reduced the migration and invasion capabilities of MH7A *** therapeutic potential of nuciferine was further evaluated in a collagen-induced arthritis(CIA)rat model,where it markedly alleviated joint swelling,synovial hyperplasia,cartilage injury,and inflammatory *** also improved collagen-induced bone erosion,decreased pro-inflammatory cytokines and serum immunoglobulins(IgG,IgG1,IgG2a),and restored the balance between T helper(Th)17 and regulatory T cells in the spleen of CIA *** results indicate that nuciferine may offer therapeutic advantages for RA by decreasing the proliferation and invasiveness of FLS cells and correcting the Th17/Treg cell imbalance in CIA rats.

关键词： Rheumatoid arthritis Collagen-induced arthritis Fibroblast-like synoviocyte Immune imbalance Nuciferine

Early Growth Response Gene-1 Deficiency Interrupts TGFβ1 Signaling Activation and Aggravates Neurodegeneration in Experimental Autoimmune Encephalomyelitis Mice

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Neuroscience Bulletin 2024年第3期40卷 283-292页

作者： Yunyi Lan Xinyan Han Fei Huang Hailian Shi Hui Wu Liu Yang Zhibi Hu Xiaojun Wu Shanghai key laboratory of Compound Chinese medicines The Ministry of Education Key Laboratory for Standardization of Chinese MedicinesThe State Administration of TCM Key Laboratory for New Resources and Quality Evaluation of Chinese MedicineInstitute of Chinese Materia MedicaShanghai University of Traditional Chinese MedicineShanghai201203China Central laboratory Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghai200021China

Early growth response protein 1(Egr-1)triggers the transcription of many genes involved in cell growth,differentiation,synaptic plasticity,and ***,its mechanism in neuronal survival and degeneration is still poorly *** study demonstrated that Egr-1 was down-regulated at mRNA and protein levels in the central nervous system(CNS)of experimental autoimmune encephalomyelitis(EAE)***-1 knockout exacerbated EAE progression in mice,as shown by increased disease severity and incidence;it also aggravated neuronal apoptosis,which was associated with weakened activation of the BDNF/TGFβ1/MAPK/Akt signaling pathways in the CNS of EAE ***,Egr-1 siRNA promoted apoptosis but mitigated the activation of BDNF/TGFβ1/MAPK/Akt signaling in SH-SY5Y *** results revealed that Egr-1 is a crucial regulator of neuronal survival in EAE by regulating TGFβ1-mediated signaling activation,implicating the important role of Egr-1 in the pathogenesis of multiple sclerosis as a potential novel therapy target.

关键词： Early growth response protein 1 Transforming growth factor-beta 1 Multiple sclerosis Experimental autoimmune encephalomyelitis Neurodegeneration

Design of pH-responsive antimicrobial peptide melittin analog-camptothecin conjugates for tumor therapy

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Asian Journal of Pharmaceutical Sciences 2024年第1期19卷 135-146页

作者： Sujie Huang Yuxuan Gao Ling Ma Bo Jia Wenhao Zhao Yufan Yao Wenyuan Li Tongyi Lin Rui Wang Jingjing Song Wei Zhang Institute of Pharmacology School of Basic Medical SciencesLanzhou UniversityLanzhou 730000China key laboratory of preclinical study for new Drugs of Gansu Province School of Basic Medical Sciences&Research Unit of Peptide ScienceChinese Academy of Medical SciencesLanzhou UniversityLanzhou 730000China State key laboratory of Veterinary Etiological Biology College of Veterinary MedicineLanzhou UniversityLanzhou 730000China Lanzhou University Second Hospital Lanzhou UniversityLanzhou 730000China

Melittin,a classical antimicrobial peptide,is a highly potent antitumor ***,its significant toxicity seriously hampers its application in tumor *** this study,we developed novel melittin analogs with pH-responsive,cell-penetrating and membranelytic activities by replacing arginine and lysine with *** conjugation with camptothecin(CPT),CPT-AAM-1 and CPT-AAM-2 were capable of killing tumor cells by releasing CPT at low concentrations and disrupting cell membranes at high concentrations under acidic ***,we found that the C-terminus of the melittin analogs was more suitable for drug conjugation than the ***-AAM-1 significantly suppressed melanoma growth in vivo with relatively low ***,the present study demonstrates that the development of antitumor drugs based on pH-responsive antimicrobial peptide-drug conjugates is a promising strategy.

关键词： Antimicrobial peptide Peptide-drug conjugate Cell-penetrating activity Membrane disruption Antitumor activity

Depletion of Gsdma1/2/3 alleviates PMA-induced epidermal hyperplasia by inhibiting the EGFR–Stat3/Akt pathway

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Journal of Molecular Cell Biology 2024年第1期16卷 29-42页

作者： Qiyao Liu Manyun Li Minli Sun Ruyue Xin Yushu Wang Qin Chen Xiang Gao Zhaoyu Lin MOE key laboratory of Model Animals for Disease study State Key Laboratory of Pharmaceutical BiotechnologyJiangsu Key Laboratory of Molecular MedicineModel Animal Research CenterNational Resource Center for Mutant Mice of ChinaNanjing Drum Tower HospitalSchool of MedicineNanjing UniversityNanjing 210061China Department of Oral Surgery Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200240China

Homeostasis of the skin barrier is essential for maintaining normal skin *** A(GSDMA)is highly expressed in the skin and associated with many skin diseases,such as melanoma and *** mice,GSDMA is encoded by three gene homologues,namely Gsdma1,Gsdma2,and *** Gsdma3 gain-of-function mutations cause hair loss and skin inflammation,Gsdma3-deficient mice do not show any visible phenotypes in skin and hair *** explore the physiological function of GSDMA,we generated conventional Gsdma1/2/3 knockout(KO)*** mice showed significantly alleviated epidermal hyperplasia and inflammation induced by phorbol 12-myristate 13-acetate(PMA).Furthermore,the alleviation of epidermal hyperplasia depended on the expression of Gsdma1/2/3 specifically in ***,Gsdma1/2/3 depletion downregulated epidermal growth factor receptor(EGFR)ligands,leading to the decreased EGFR–Stat3/Akt *** results demonstrate that depletion of Gsdma1/2/3 alleviates PMA-induced epidermal hyperplasia partially by inhibiting the EGFR–Stat3/Akt pathway.

关键词： GSDMA epidermal hyperplasia PMA Hb-egf EGFR Stat3 Akt