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Chinese Journal of Natural Medicines 2024年第1期22卷 75-88页

作者： SONG Jiangzhou ZOU Guiqing ZHAO Zhou ZHU Ya XUE Jiayu AO Lanjia SUN Huiyong HAO Haiping ZHANG Bo XU Xiaowei State key laboratory of Natural Medicines Key Lab of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityNanjing 210009China State key laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China

NAD(P)H:quinone oxidoreductase 1(NQO1)is a flavin protease highly expressed in various cancer cells.NQO1 catalyzes a futile redox cycle in substrates,leading to substantial reactive oxygen species(ROS)production.This ROS generation results in extensive DNA damage and elevated poly(ADP-ribose)polymerase 1(PARP1)-mediated consumption of nicotinamide adenine dinucleotide(NAD^(+)),ultimately causing cell death.Nicotinamide phosphoribosyltransferase(NAMPT),the rate-limiting enzyme in the NAD^(+)salvage synthesis pathway,emerges as a critical target in cancer therapy.The concurrent inhibition of NQO1 and NAMPT triggers hyperactivation of PARP1 and intensive NAD+depletion.In this study,we designed,synthesized,and assessed a novel series of proqodine A derivatives targeting both NQO1 and NAMPT.Among these,compound T8 demonstrated potent antitumor properties.Specifically,T8 selectively inhibited the proliferation of MCF-7 cells and induced apoptosis through mechanisms dependent on both NQO1 and NAMPT.This discovery offers a promising new molecular entity for advancing anticancer research.

关键词： NQO1 ROS NAMPT NAD^(+) T8

Effects of weaning on intestinal longitudinal muscle-myenteric plexus function in piglets

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Science China(Life Sciences) 2024年第2期67卷 379-390页

作者： Jing Li Fenfen Liu Kaibin Mo Hengjia Ni Yulong Yin key laboratory of Agro-Ecological Processes in Subtropical Region Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic ProcessHunan Research Center of Livestock and Poultry SciencesSouth Central Experimental Station of Animal Nutrition and Feed Science in the Ministry of AgricultureInstitute of Subtropical AgricultureChinese Academy of SciencesChangsha 410125China University of Chinese Academy of Sciences Beijing 100008China Guangdong key laboratory for veterinary Drug development and Safety Evaluation College of Veterinary MedicineSouth China Agricultural UniversityGuangzhou 510642China

Weaning piglets usually suffer from severe diarrhea(commonly known as postweaning diarrhea,PWD)along with intestinal motility disorder.Intestinal peristalsis is mainly regulated by the longitudinal muscle-myenteric plexus(LM-MP).To understand the relationship between intestinal LM-MP function and the development of PWD,we compared the intestinal electrical activity,and the transcriptional profile of the LM-MP between 21-day-old piglets(just weaned,n=7)and 24-day-old piglets(suffered the most severe weaning stress,n=7).The results showed that 24-day-old piglets exhibited different degrees of diarrhea.A significant increase in the slow-wave frequency in the ileum and colon was observed in 24-day-old piglets,while c-kit expression in the intestinal LM-MPs was significantly decreased,indicating that PWD caused by elevated slow-wave frequency may be associated with loss of c-kit.The real-time quantitative PCR(RT-q PCR)and enzyme-linked immunosorbent assay(ELISA)showed that intestinal LM-MPs in 24-day-old piglets may undergo inflammation and oxidative stress.Significant increases in 8-hydroxy-2′-deoxyguanosine and decreases in thioredoxin suggest that weaning may lead to DNA damage in the LM-MP of 24-day-old piglets.In addition,activating transcription factor 3 was significantly upregulated,indicating nerve damage in the LM-MP of 24-day-old piglets.The transcriptomic results showed that most of the differentially expressed genes in the ileal LM-MP after weaning were downregulated and closely related to the cell cycle process.Subsequent RT-q PCR analysis showed that the relative expression of p21 was upregulated,while the expression of cyclin A2,cyclin B1,and proliferating cell nuclear antigen was downregulated in the ileal and colonic LM-MP of 24-day-old piglets,suggesting that weaning may inhibit cell proliferation and cause G1/S cell cycle arrest in ileal and colonic LM-MP.In conclusion,weaning may lead to cell cycle arrest by causing DNA damage in the LM-MP,impairing intestinal motility regulation,and ultimately lea

关键词： weaning piglets diarrhea longitudinal muscle-myenteric plexus

Protective Effects of Danmu Extract Syrup on Acute Lung Injury Induced by Lipopolysaccharide in Mice through Endothelial Barrier Repair

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Chinese Journal of Integrative Medicine 2024年第3期30卷 243-250页

作者： XU Han XU Si-cong LI Li-yan WU Yu-huang TAN Yin-feng CHEN Long LIU Pei LIANG Chang-fu HE Xiao-ning LI Yong-hui Hainan Provincial key lab of Research&development on Tropic Herbs Hainan Medical UniversityHaikou571199China Department of Stomatology the Second Affiliated Hospital of Hainan Medical UniversityHaikou571199China

Objective:To investigate the effects of Danmu Extract Syrup(DMS) on lipopolysaccharide(LPS)-induced acute lung injury(ALI) in mice and explore the mechanism.Methods:Seventy-two male Balb/C mice were randomly divided into 6 groups according to a random number table(n=12),including control(normal saline),LPS(5 mg/kg),LPS+DMS 2.5 mL/kg,LPS+DMS 5 mL/kg,LPS+DMS 10 mL/kg,and LPS+Dexamethasone(DXM,5 mg/kg) groups.After pretreatment with DMS and DXM,the ALI mice model was induced by LPS,and the bronchoalveolar lavage fluid(BALF) were collected to determine protein concentration,cell counts and inflammatory cytokines.The lung tissues of mice were stained with hematoxylin-eosin,and the wet/dry weight ratio(W/D) of lung tissue was calculated.The levels of tumor necrosis factor-α(TNF-α),interleukin(IL)-6 and IL-1βin BALF of mice were detected by enzyme linked immunosorbent assay.The expression levels of Claudin-5,vascular endothelial(VE)-cadherin,vascular endothelial growth factor(VEGF),phospho-protein kinase B(p-Akt) and Akt were detected by Western blot analysis.Results:DMS pre-treatment significantly ameliorated lung histopathological changes.Compared with the LPS group,the W/D ratio and protein contents in BALF were obviously reduced after DMS pretreatment(P<0.05 or P<0.01).The number of cells in BALF and myeloperoxidase(MPO) activity decreased significantly after DMS pretreatment(P<0.05 or P<0.01).DMS pre-treatment decreased the levels of TNF-α,IL-6 and IL-1β(P<0.01).Meanwhile,DMS activated the phosphoinositide 3-kinase/protein kinase B(PI3K/Akt) pathway and reversed the expressions of Claudin-5,VE-cadherin and VEGF(P<0.01).Conclusions:DMS attenuated LPS-induced ALI in mice through repairing endothelial barrier.It might be a potential therapeutic drug for LPS-induced lung injury.

关键词： Danmu Extract Syrup acute lung injury inflammatory factors vascular endothelial growth factor phosphoinositide 3-kinase/protein kinase B Chinese medicine Nauclea officinalis

Core and variable antimicrobial resistance genes in the gut microbiomes of Chinese and European pigs

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Zoological Research 2024年第1期45卷 189-200页

作者： Cui-Hong Tong Zhi-Peng Huo Lu Diao Dan-Yu Xiao Ruo-Nan Zhao Zhen-Ling Zeng Wen-Guang Xiong Guangdong Provincial key laboratory of veterinary Pharmaceutics development and Safety Evaluation South China Agricultural UniversityGuangzhouGuangdong 510642China National Risk Assessment laboratory for Antimicrobial Resistance of Animal Original Bacteria College of Veterinary MedicineSouth China Agricultural UniversityGuangzhouGuangdong 510642China National laboratory of Safety Evaluation(Environmental Assessment)of veterinary Drugs South China Agricultural UniversityGuangzhouGuangdong 510642China National Reference laboratory of veterinary Drug Residues South China Agricultural UniversityGuangzhouGuangdong 510642China

Monitoring the prevalence of antimicrobial resistance genes(ARGs)is vital for addressing the global crisis of antibiotic-resistant bacterial infections.Despite its importance,the characterization of ARGs and microbiome structures,as well as the identification of indicators for routine ARG monitoring in pig farms,are still lacking,particularly concerning variations in antimicrobial exposure in different countries or regions.Here,metagenomics and random forest machine learning were used to elucidate the ARG profiles,microbiome structures,and ARG contamination indicators in pig manure under different antimicrobial pressures between China and Europe.Results showed that Chinese pigs exposed to high-level antimicrobials exhibited higher total and plasmid-mediated ARG abundances compared to those in European pigs(Plaboration in reducing antimicrobial resistance risk and provide validated indicators for evaluating the risk of ARG contamination in pig farms.

关键词： Metagenomic Pig manure Antimicrobial pressure Antimicrobial resistance genes Microbiome

M6PR interacts with the HA2 subunit of influenza A virus to facilitate the fusion of viral and endosomal membranes

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Science China(Life Sciences) 2024年第3期67卷 579-595页

作者： Yuzhen Hu Li Jiang Guangwen Wang Yangming Song Zhibo Shan Xuyuan Wang Guohua Deng Jianzhong Shi Guobin Tian Xianying Zeng Liling Liu Hualan Chen Chengjun Li State key laboratory for Animal Disease Control and Prevention Harbin Veterinary Research InstituteChinese Academy of Agricultural SciencesHarbin 150069China

Influenza A virus(IAV) commandeers numerous host cellular factors for successful replication. However, very few host factors have been revealed to be involved in the fusion of viral envelope and late endosomal membranes. In this study, we identified cation-dependent mannose-6-phosphate receptor(M6PR) as a crucial host factor for the replication of IAV. We found that siRNA knockdown of M6PR expression significantly reduced the growth titers of different subtypes of IAV, and that the inhibitory effect of M6PR siRNA treatment on IAV growth was overcome by the complement of exogenously expressed M6PR. When A549 cells were treated with siRNA targeting M6PR,the nuclear accumulation of viral nucleoprotein(NP) was dramatically inhibited at early timepoints post-infection, indicating that M6PR engages in the early stage of the IAV replication cycle. By investigating the role of M6PR in the individual entry and post-entry steps of IAV replication, we found that the downregulation of M6PR expression had no effect on attachment, internalization, early endosome trafficking,or late endosome acidification. However, we found that M6PR expression was critical for the fusion of viral envelope and late endosomal membranes. Of note, M6PR interacted with the hemagglutinin(HA) protein of IAV, and further studies showed that the lumenal domain of M6PR and the ectodomain of HA2 mediated the interaction and directly promoted the fusion of the viral and late endosomal membranes,thereby facilitating IAV replication. Together, our findings highlight the importance of the M6PR–HA interaction in the fusion of viral and late endosomal membranes during IAV replication.

关键词： influenza A virus M6PR HA membrane fusion late endosome

Effective protective agents against the organ toxicity of T-2 toxin and corresponding detoxification mechanisms: A narrative review

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Animal Nutrition 2024年第1期16卷 251-266页

作者： Pengju Wang Lv-hui Sun Xu Wang Qinghua Wu Aimei Liu Hubei key laboratory of Diabetes and Angiopathy Medicine Research Institute Xianning Medical College Hubei University of Science and Technology Hubei Hongshan laboratory College of Animal Science and Technology Huazhong Agricultural University National Reference laboratory of veterinary Drug Residues (HZAU) and MAO key laboratory for Detection of veterinary Drug Residues Huazhong Agricultural University College of Life Science Yangtze University

T-2 toxin is one of the most widespread and toxic fungal toxins in food and feed. It can cause gastrointestinal toxicity, hepatotoxicity, immunotoxicity, reproductive toxicity, neurotoxicity, and nephrotoxicity in humans and animals. T-2 toxin is physicochemically stable and does not readily degrade during food and feed processing. Therefore, suppressing T-2 toxin-induced organ toxicity through antidotes is an urgent issue. Protective agents against the organ toxicity of T-2 toxin have been recorded widely in the literature, but these protective agents and their molecular mechanisms of detoxification have not been comprehensively summarized. In this review, we provide an overview of the various protective agents to T-2 toxin and the molecular mechanisms underlying the detoxification effects. Targeting appropriate targets to antagonize T-2 toxin toxicity is also an important option. This review will provide essential guidance and strategies for the better application and development of T-2 toxin antidotes specific for organ toxicity in the future.

关键词： T-2 toxin Organ toxicity Protective agent Detoxification mechanism

Essential oils improve nursery pigs' performance and appetite via modulation of intestinal health and microbiota

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Animal Nutrition 2024年第1期16卷 174-188页

作者： Bi-Chen Zhao Tian-Hao Wang Jian Chen Bai-Hao Qiu Ya-Ru Xu Jin-Long Li College of veterinary Medicine Northeast Agricultural University Heilongjiang key laboratory for laboratory Animals and Comparative Medicine Northeast Agricultural University key laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment Northeast Agricultural University

Optimal intestinal health and functionality are essential for animal health and performance,and simultaneously intestinal nutrient transporters and intestinal peptides are also involved in appetite and feed intake control mechanisms.Given the potential of essential oil (EO) in improving animal performance and improving feed palatability,we hypothesized that dietary supplementation of cinnamaldehyde and carvacrol could improve performance and appetite of nursery pigs by modulating intestinal health and microbiota.Cinnamaldehyde (100 mg/kg),carvacrol (100 mg/kg),and their mixtures(including 50 mg/kg cinnamaldehyde and 50 mg/kg carvacrol) were supplemented into the diets of 240 nursery pigs for 42 d,and data related to performance were measured.Thereafter,the influence of EO on intestinal health,appetite and gut microbiota and their correlations were explored.EO supplementation increased (Pdevelopment and the mucus barrier,EO promoted intestinal development and increased (P<0.05) the number of goblet cells.Additionally,we found that piglets in the EO-supplemented group had upregulated (P<0.05) levels of transporters and digestive enzymes in the intestine,which were significantly associated with daily gain and feed utilization.In addition,EO supplementation somewhat improved appetite in nursery pigs,increased the diversity of the gut microbiome and the abundance of beneficial bacteria,and there was a correlation between altered bacterial structure and appetite-related hormones.These findings indicate that EO is effective in promoting growth performance and nutrient absorption as well as in regulating appetite by improving intestinal health and bacterial structure.

关键词： Nursery pig Essential oil Intestinal health Appetite Microbiota

Gene-knockout by iSTOP enables rapid reproductive disease modeling and phenotyping in germ cells of the founder generation

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Science China(Life Sciences) 2024年第5期67卷 1035-1050页

作者： Yaling Wang Jingwen Chen Xueying Huang Bangguo Wu Peng Dai Feng Zhang Jinsong Li Lingbo Wang State key laboratory of Genetic Engineering Shanghai Key Laboratory of Metabolic Remodeling and HealthInstitute of Metabolism and Integrative BiologyFudan UniversityShanghai 200438China Institute of Reproduction and development Obstetrics and Gynecology HospitalFudan UniversityShanghai 200011China NHC key lab of Reproduction Regulation(Shanghai Institute for Biomedical and pharmaceutical Technologies) School of PharmacyFudan UniversityShanghai 200433China Shanghai key laboratoryof Maternal and Fetal Medicine Clinical and Translational Research Center of Shanghai First Maternity and Infant HospitalFrontier Science Center for Stem Cell ResearchSchoolof Life Sciences and TechnologyTongji UniversityShanghai 200092China State key laboratory of Cell Biology CAS Center for Excellence in Molecular Cell ScienceShanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesShanghai 200031China

Cytosine base editing achieves C·G-to-T·A substitutions and can convert four codons(CAA/CAG/CGA/TGG)into STOP-codons(induction of STOP-codons,iSTOP)to knock out genes with reduced mosaicism.iSTOP enables direct phenotyping in founders’somatic cells,but it remains unknown whether this works in founders’germ cells so as to rapidly reveal novel genes for fertility.Here,we initially establish that iSTOP in mouse zygotes enables functional characterization of known genes in founders’germ cells:Cfap43-iSTOP male founders manifest expected sperm features resembling human“multiple morphological abnormalities of the flagella”syndrome(i.e.,MMAF-like features),while oocytes of Zp3-iSTOP female founders have no zona pellucida.We further illustrate iSTOP’s utility for dissecting the functions of unknown genes with Ccdc183,observing MMAF-like features and male infertility in Ccdc183-iSTOP founders,phenotypes concordant with those of Ccdc183-KO offspring.We ultimately establish that CCDC183 is essential for sperm morphogenesis through regulating the assembly of outer dynein arms and participating in the intra-flagellar transport.Our study demonstrates iSTOP as an efficient tool for direct reproductive disease modeling and phenotyping in germ cells of the founder generation,and rapidly reveals the essentiality of Ccdc183 in fertility,thus providing a time-saving approach for validating genetic defects(like nonsense mutations)for human infertility.

关键词： disease modeling infertility multiple morphological abnormalities of the flagella(MMAF) induction of STOP-codons(iSTOP CRISPR-STOP) sperm motility

Preparation of Ephedra houttuynia Granule and Its Therapeutic Mechanism of Anti-Mycoplasma gallisepticum Infection Based on Network Pharmacology

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Journal of Northeast Agricultural University(English Edition) 2024年第2期31卷 76-85页

作者： Zhang Huanqi Han Mingdong Miao Yusong Xu Tianqiao Liang Xin Li Jichang Heilongjiang key laboratory for Animal Disease Control and pharmaceutical development College of Veterinary MedicineNortheast Agricultural UniversityHarbin 150030China Heilongjiang Academy of Agricultural Sciences Harbin 150030China

The use of Chinese herbal medicines can replace antibiotics that cause drug-resistance problems,which are currently necessary for disease control.In this paper,a traditional Chinese medicine compound named Ephedra houttuynia granule for the treatment of Mycoplasma galliscepticum(MG)infection was prepared.Furthermore,its action mechanism was explored through network pharmacology.The optimal extraction and granulation processes of the compound were determined by high performance liquid chromatography(HPLC)method and L9 orthogonal test,and in the treatment experiment,Ephedra houttuynia granule showed a significant therapeutic effect on MG infection.In the study of network pharmacology,the results showed that the core targets of Ephedra houttuynia granule against MG infection were vascular endothelial growth factor(VEGFA),fos proto-oncogene(FOS),prepro-coagulation factor II(F2),etc.,the gene ontology/kyoto encyclopedia of genes and genomes(GO/KEGG)analysis results indicated that the signaling pathways of neuroactive ligand receptor interaction,cAMP,IL-17,T cell receptor,and tumor necrosis factor(TNF)might involve in anti-MG infection.In conclusion,this study would provide a new idea for elucidating the action mechanism of other diseases in veterinary clinic,which had a certain guiding significance.

关键词： Mycoplasma galliscepticum therapeutic mechanism network pharmacology Ephedra houttuynia granule granulating process

Porcine enteric alphacoronavirus infection increases lipid droplet accumulation to facilitate the virus replication

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Journal of Integrative Agriculture 2024年第3期23卷 988-1005页

作者： Qi Gao Yongzhi Feng Ting Gong Dongdong Wu Xiaoyu Zheng Yizhuo Luo Yunlong Yang Zebu Song Lang Gong Guihong Zhang Guangdong Provincial key laboratory of Zoonosis Prevention and Control College of Veterinary MedicineSouth China Agricultural UniversityGuangzhou 510642China Maoming Branch Guangdong Laboratory for Lingnan Modern AgricultureMaoming 525000China key laboratory of Animal Vaccine development Ministry of Agriculture and Rural AffairsGuangzhou 510000China Guangdong laboratory for Lingnan Modern Agriculture Guangzhou 510642China

Coronaviruses are widely transmissible between humans and animals, causing diseases of varying severity. Porcine enteric alphacoronavirus(PEAV) is a newly-discovered pathogenic porcine enteric coronavirus in recent years, which causes watery diarrhea in newborn piglets. The host inflammatory responses to PEAV and its metabolic regulation mechanisms remain unclear, and no antiviral studies have been reported. Therefore, we investigated the pathogenic mechanism and antiviral drugs of PEAV. The transcriptomic analysis of PEAV-infected host cells revealed that PEAV could upregulate lipid metabolism pathways. In lipid metabolism, steady-state energy processes, which can be mediated by lipid droplets(LDs), are the main functions of organelles. LDs are also important in viral infection and inflammation. In infected cells, PEAV increased LD accumulation, upregulated NF-κB signaling, promoted the production of the inflammatory cytokines IL-1β and IL-8, and induced cell death. Inhibiting LD accumulation with a DGAT-1 inhibitor significantly inhibited PEAV replication, downregulated the NF-κB signaling pathway, reduced the production of IL-1β and IL-8, and inhibited cell death. The NF-κB signaling pathway inhibitor BAY11-7082 significantly inhibited LD accumulation and PEAV replication. Metformin hydrochloride also exerted anti-PEAV effects and significantly inhibited LD accumulation, downregulated the NF-κB signaling pathway, reduced the production of IL-1β and IL-8, and inhibited cell death. LD accumulation in the lipid metabolism pathway therefore plays an important role in the replication and pathogenesis of PEAV, and metformin hydrochloride inhibits LD accumulation and the inflammatory response to exert anti-PEAV activity and reducing pathological injury. These findings contribute new targets for developing treatments for PEAV infections.

关键词： porcine enteric alphacoronavirus NF-κB inflammatory pathway lipid droplet metformin hydrochloride