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Transferrin receptor-targeted immunostimulant for photodynamic immunotherapy against metastatic tumors through b-catenin/CREB interruption

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4118-4133页

作者： Mengyi Yan Xiayun Chen Xiaotong Li Qianqian Liu Baixue Yu Yi Cen Wei Zhang Yibin Liu Xinxuan Li Ying Chen Tao Wang Shiying Li The Fifth Affiliated Hospital Guangdong Provincial Key Laboratory of Molecular Target&Clinical Pharmacologythe NMPA and State Key Laboratory of Respiratory Diseasethe School of Pharmaceutical SciencesGuangzhou Medical UniversityGuangzhou 511436China Department of Anesthesiology the Second Clinical School of Guangzhou Medical UniversityGuangzhou 511436China State key laboratory of Respiratory Diseases Guangdong Key Laboratory of Vascular DiseasesGuangzhou Institute of Respiratory Healththe first Affiliated HospitalGuangzhou Medical UniversityGuangzhou 510120China Department of Pulmonary and Critical Care Medicine Zhujiang HospitalSouthern Medical UniversityGuangzhou 510280China

The immunosuppressive phenotype of tumor cells extensively attenuates the immune activation effects of traditional *** this work,a transferrin receptor(TfR)targeted immunostimulant(PTI)is fabricated for photodynamic immunotherapy against metastatic tumors by interrupting b-catenin signal *** synthesize PTI,the photosensitizer conjugated TfR targeting peptide moiety(Palmitic-K(PpIX)-HAIYPRH)is unitized to encapsulate the transcription interrupter of *** the one hand,the recognition of PTI and TfR can promote drug delivery into tumor cells to destruct primary tumors through photodynamic therapy and initiate an immunogenic cell death with the release of tumorassociated *** the other hand,PTI will interrupt the binding between b-catenin andcAMP response element-binding protein(CREB),regulating the gene transcription to downregulate programmed death ligand 1(PD-L1)while upregulating CeC motif chemokine ligand 4(CCL4).Furthermore,the elevated CCL4 can recruit the dendritic cells to present tumor-specific antigens and promote T cells activation and infiltration,and the downregulated PD-L1 can avoid the immune evasion of tumor cells and activate systemic anti-tumor immunity to eradicate lung *** work may inspire the development of antibody antibody-free strategy to activate systemic immune response in consideration of immunosuppressive conditions.

关键词： Transferrin receptor b-Catenin signal pathway Tumor targeting Photodynamic therapy Immunotherapy Immunogenic cell death Programmed death ligand 1

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Ganoderma Lucidum Spore Oil enhances the effect of cyclophosphamide via inhibiting programmed death-1 and prolongs the survival of H22 tumor-bearing mice

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Journal of Traditional Chinese Medicine 2024年第4期44卷 652-659页

作者： JIANG Zhaojian CAI Hongfei YUAN Cheng CAO Lin XU Wendong HAN Yaming ZHANG Qin LI Jing WANG Qin LIU Juyan Guangzhou HanFang Pharmaceutical Company Limited National Engineering Research Center of Pharmaceutical Processing Technology of Traditional Chinese Medicine and Drug InnovationGuangdong Provincial Key Laboratory of Medicinal LipidsGuangzhou 510240China Zhongshan Medical College Sun Yat-sen UniversityGuangzhou 510080China Guangzhou Pharmaceutical Holdings Limited Guangzhou 510130China National Engineering research Center of Pharmaceutical Processing Technology of Traditional Chinese Medicine and drug Innovation Guangzhou 510240China

OBJECTIVE:To investigate the effect of Ganoderma Lucidum Spore Oil(GLSO)on the tumor growth and survival of H22 tumor-bearing mice treated with cyclophosphamide(CTX),and explore the underlying ***:Allograft H22 hepatocellular carcinoma mouse model was applied to investigate the effect of GLSO on the tumor growth and survival of animals,and Kaplan-Meier survival analysis was used to analyze the life *** biochemical examination was used to determine the levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),urea(UREA)and creatinine(CRE).Western blot analysis was performed to detect Programmed Death-1(PD-1),Programmed Death Ligand 1(PD-L1),Janus Kinase 2(JAK2),phosphorylated Signal Transducer and Activator of Transcription 3(p-STAT3),and Signal Transducer and Activator of Transcription 3(STAT3)***:GLSO increased the anti-tumor effect of CTX and prolonged the survival of H22 tumor-bearing mice treated with ***,GLSO increased the thymus index and showed no obvious toxicity to liver functions of *** also decreased the level of UREA in H22 tumor-bearing mice treated with ***,GLSO could inhibit the expression of PD-1 in spleen,which was independent of JAK2 expression and STAT3 ***,GLSO did not affect the expression of PD-L1,JAK2,and p-STAT3 in tumor ***:GLSO could strengthen the anti-tumor effect of CTX and prolong the life span of H22 tumorbearing mice,while the underlying mechanism might be relevant to the amelioration effect of thymus function and inhibition of PD-1 expression in ***,these findings implied the promising role of GLSO in combination with CTX to extend the survival of patients in clinical chemotherapy of hepatocellular carcinoma.

关键词： carcinoma,hepatocellular cyclophosphamide survival programmed cell death 1 receptor Ganoderma Lucidum SporeOil

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clinical characteristics and outcomes of hospitalized kidney transplant recipients with COVID-19 infection in China during the Omicron wave:a single-center cohort study

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第6期25卷 529-540页

作者： Duo LV Xishao XIE Qinyun YANG Zhimin CHEN Guangjun LIU Wenhan PENG Rending WANG Hongfeng HUANG Jianghua CHEN Jianyong WU Department of clinical Pharmacy the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Zhejiang provincial key laboratory for drug evaluation and clinical research Hangzhou 310003China Kidney Disease Center the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China key laboratory of Kidney Disease Prevention and Control Technology Zhejiang ProvinceHangzhou 310003China Institute of Nephrology Zhejiang UniversityHangzhou 310003China Zhejiang clinical research Center of Kidney and Urinary System Disease Hangzhou 310003China The Third Grade laboratory under the National State Administration of Traditional Chinese MedicineHangzhou 310003China Information Center the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China

Background:Following the short-term outbreak of coronavirus disease 2019(COVID-19)in December 2022 in China,clinical data on kidney transplant recipients(KTRs)with COVID-19 are ***:We conducted a single-center retrospective study to describe the clinical features,complications,and mortality rates of hospitalized KTRs infected with COVID-19 between Dec.16,2022 and Jan.31,*** patients were followed up until Mar.31,***:A total of 324 KTRs with COVID-19 were *** median age was 49 *** median time between the onset of symptoms and admission was 13 ***,azvudine,and nirmatrelvir/ritonavir were administered to 67(20.7%),11(3.4%),and 148(45.7%)patients,***-nine(9.0%)patients were treated with more than one antiviral ***-eight(14.8%)patients were treated with tocilizumab and 53(16.4%)patients received baricitinib *** acute kidney injury(AKI)occurred in 81(25.0%)patients and 39(12.0%)patients were admitted to intensive care *** infections were observed in 55(17.0%)***(15.4%)patients lost their *** 28-d mortality rate of patients was 9.0%and 42(13.0%)patients died by the end of *** Cox regression analysis identified that cerebrovascular disease,AKI incidence,interleukin(IL)-6 level of>6.8 pg/mL,daily dose of corticosteroids of>50 mg,and fungal infection were all associated with an increased risk of death for hospitalized ***:Our findings demonstrate that hospitalized KTRs with COVID-19 are at high risk of *** administration of immunomodulators or the late application of antiviral drugs does not improve patient survival,while higher doses of corticosteroids may increase the death risk.

关键词： Coronavirus disease 2019(COVID-19) Kidney transplant Hospitalization Mortality

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A lateral-immobilization zebrafish microfluidic chip-based system for in vivo real-time evaluation of antithrombotic agents

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Chinese Chemical Letters 2024年第3期35卷 312-315页

作者： Lijuan He Hongxia Du Yi Yang Zhihua Guan Jinjin Li Honglin Li Xudong Lin Lili Zhu Shanghai key laboratory of New drug Design School of PharmacyEast China University of Science&TechnologyShanghai 200237China guangdong provincial key laboratory of Sensor Technology and Biomedical Instrument School of Biomedical EngineeringShenzhen Campus of Sun Yat-sen UniversityShenzhen 518000China Innovation Center for AI and drug Discovery East China Normal UniversityShanghai 200062China

Thrombosis remains a major global health concern mainly characterized by high rates of morbidity and *** models serve as an indispensable tool to understand the underlying pathogenesis of thrombosis and assess the efficacy of novel antithrombotic ***,zebrafish has emerged as a valuable model organism for thrombosis ***,the traditional method of studying zebrafish thrombosis requires a laborious and time-consuming procedure,including anesthesia and manual immobilization of *** this study,based on hydrodynamic force,a lateral-immobilization zebrafish microfluidic chip(LIZMC)was designed to evaluate the cardiovascular system of multiple larvae within a single microscope field of ***,coupling with microscope imaging,real-time monitoring of the peripheral blood circulation in the tail of phenylhydrazine(PHZ)-induced zebrafish thrombosis was ***,the reliability of LIZMC for in vivo evaluation of antithrombotic agents in zebrafish was verified using ***,this novel LIZMC-based system can be used for in vivo zebrafish thrombosis studies and rapid screening of antithrombotic agents.

关键词： Microfluidic chip Zebrafish Thrombosis In vivo evaluation Real-time monitor

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A multifunctional nanoaggregate-based system for detection of rheumatoid arthritis via Optoacoustic/NIR-Ⅱ fluorescent imaging and therapy via inhibiting JAK-STAT/NF-κB/NLRP3 pathways

Aggregate

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Aggregate 2024年第1期5卷 353-366页

作者： Junjie Chen Longqi Chen Zunpan She Fang Zeng Shuizhu Wu Biomedical Division State Key Laboratory of Luminescent Materials and DevicesGuangdong Provincial Key Laboratory of Luminescence from Molecular AggregatesCollege of Materials Science and EngineeringSouth China University of TechnologyGuangzhouChina

Rheumatoid arthritis(RA)is a debilitating autoimmune disease that causes chronic pain and serious complications,presenting a significant challenge to *** approaches for treating RA involve signaling pathways modulation and targeted *** this end,a multifunctional nanosystem,TPC-U@HAT,has been designed for RA therapy,featuring multitargeting,dual-stimuli response,and on-demand drug release ***-U@HAT is composed of a probe/prodrug TPC,a JAK1 kinase inhibitor upadacitinib,and the drug carrier *** is composed of an aggregation-induced emission(AIE)-active NIR-II chromophore TPY and an NF-κB/NLRP3 inhibitor caffeic acid phenethyl ester(CAPE),connected via boronic ester bond which serves as the reactive-oxygen-species-responsive *** carrier,HAT,is created by grafting bone-targeting alendronate and hydrophobic tocopheryl succinate onto hyaluronic acid chains,which can encapsulate TPC and upadacitinib to form TPC-U@*** intravenous injection into mice,TPC-U@HAT accumulates at inflamed lesions of RA through both active and passive targeting,and the overexpressed hyaluronidase and H_(2)O_(2) therein cleave the hyaluronic acid polymer chains and boronate bonds,*** generates an AIE-active chromophore for detection and therapeutic evaluation of RA via both optoacoustic imaging and NIR-II fluorescent imaging and concomitantly releases CAPE and upadacitinib to exert efficacious therapy by inhibiting NF-κB/NLRP3 and JAK-STAT pathways.

关键词： aggregation-induced emission dual-stimuli response multispectral optoacoustic tomography imaging multitargeting NIR-II fluorescence imaging rheumatoid arthritis

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Cinnamaldehyde targets SarA to enhance β-lactam antibiotic activity against methicillin-resistant Staphylococcus aureus

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mLife 2024年第2期3卷 291-306页

作者： Jianguo Li Tingyin Lu Yuefei Chu Yuejun Zhang Jing Zhang Wenzhen Fu Jian Sun Yahong Liu Xiao-Ping Liao Yu-Feng Zhou State key laboratory for Animal Disease Control and Prevention South China Agricultural UniversityGuangzhouChina guangdong provincial key laboratory of Veterinary Pharmaceutics Development and Safety evaluation South China Agricultural UniversityGuangzhouChina Yantai Fushan Center for Animal Disease Control and Prevention YantaiChina

Methicillin-resistant Staphylococcus aureus(MRSA)is a current global public health problem due to its increasing resistance to the most recent antibiotic *** critical approach is to develop ways to revitalize existing ***,we show that the phytogenic compound cinnamaldehyde(CIN)and β-lactam antibiotic combinations can functionally synergize and resensitize clinical MRSA isolates to β-lactam therapy and inhibit MRSA biofilm *** studies indicated that the CIN potentiation effect on β-lactams was primarily the result of inhibition of the mecA expression by targeting the staphylococcal accessory regulator *** alone or in combination with β-lactams decreased sarA gene expression and increased SarA protein phosphorylation that impaired SarA binding to the mecA promoter element and downregulated virulence genes such as those encoding biofilm,α-hemolysin,and *** of SarA-mecA binding thus interfered with PBP2a biosynthesis and this decreased MRSA resistance to β-***,CIN fully restored the anti-MRSA activities of β-lactam antibiotics in vivo in murine models of bacteremia and biofilm ***,our results indicated that CIN acts as a β-lactam adjuvant and can be applied as an alternative therapy to combat multidrug-resistant MRSA infections.

关键词： cinnamaldehyde MRSA SarA β-lactamresistance

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Mechanism of action of the bile acid receptor TGR5 in obesity

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Acta Pharmaceutica Sinica B 2024年第2期14卷 468-491页

作者： Weijun Lun Qihao Yan Xinghua Guo Minchuan Zhou Yan Bai Jincan He Hua Cao Qishi Che Jiao Guo Zhengquan Su guangdong Engineering research Center of Natural Products and New drugs Guangdong Provincial University Engineering Technology Research Center of Natural Products and DrugsGuangdong Pharmaceutical UniversityGuangzhou 510006China guangdong Metabolic Disease research Center of Integrated Chinese and Western Medicine Key Laboratory of Glucolipid Metabolic DisorderMinistry of Education of ChinaGuangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhou 510006China School of Public Health Guangdong Pharmaceutical UniversityGuangzhou 510310China School of Chemistry and Chemical Engineering Guangdong Pharmaceutical UniversityZhongshan 528458China Guangzhou Rainhome Pharm&Tech Co. Ltd.Science CityGuangzhou 510663China

G protein-coupled receptors(GPCRs)are a large family of membrane protein receptors,and Takeda G protein-coupled receptor 5(TGR5)is a member of this *** a membrane receptor,TGR5 is widely distributed in different parts of the human body and plays a vital role in regulating metabolism,including the processes of energy consumption,weight loss and blood glucose *** studies have shown that TGR5 plays an important role in glucose and lipid metabolism disorders such as fatty liver,obesity and *** the global obesity situation becoming more and more serious,a comprehensive explanation of the mechanism of TGR5 and filling the gaps in knowledge concerning clinical ligand drugs are urgently *** this review,we mainly explain the anti-obesity mechanism of TGR5 to promote the further study of this target,and show the electron microscope structure of TGR5 and review recent studies on TGR5 ligands to illustrate the specific binding between TGR5 receptor binding sites and ligands,which can effectively provide new ideas for ligand research and promote drug research.

关键词： Obesity TGR5 Bile acids Ligand Appetite Metabolism GLP-1 Inflammation

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Overexpression of wild-type HRAS drives non-alcoholic steatohepatitis to hepatocellular carcinoma in mice

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Zoological research 2024年第3期45卷 551-566页

作者： Chen Ling Su-Su Liu Yu-Ya Wang Gui-Tao Huo Yan-Wei Yang Nan Xu Hong Wang Yong Wu Yu-Fa Miao Rui Fu Yu-Wei Zhao Chang-Fa Fan College of Life Sciences Northwest UniversityProvincial Key Laboratory of Biotechnology of Shaanxi ProvinceXi’anShaanxi 710069China Division of Animal Model research Institute for Laboratory Animal ResourcesNational Institutes for Food and Drug Control(NIFDC)Beijing 102629China National Center for Safety evaluation of drugs National Institutes for Food and Drug Control(NIFDC)Beijing 100176China Division of HIV/AIDS and Sexually Transmitted Virus Vaccines Institute for Biological Products ControlNational Institutes for Food and Drug Control(NIFDC)Beijing 102629China Division of laboratory Animal Monitoring Institute for Laboratory Animal ResourcesNational Institutes for Food and Drug Control(NIFDC)Beijing 102629China

Hepatocellular carcinoma(HCC),a prevalent solid carcinoma of significant concern,is an aggressive and often fatal disease with increasing global incidence rates and poor therapeutic *** etiology and pathological progression of non-alcoholic steatohepatitis(NASH)-related HCC is multifactorial and ***,no single animal model can accurately mimic the full NASH-related HCC pathological progression,posing considerable challenges to transition and mechanistic ***,a novel conditional inducible wild-type human HRAS overexpressed mouse model(HRAS-HCC)was established,demonstrating 100%morbidity and mortality within approximately one month under normal dietary and lifestyle *** symptoms of HCC such as ascites,thrombus,internal hemorrhage,jaundice,and lung metastasis were successfully replicated in ***-depth pathological features of NASH-related HCC were demonstrated by pathological staining,biochemical analyses,and typical marker gene *** murine anti-PD-1 and sorafenib treatment effectively prolonged mouse survival,further confirming the accuracy and reliability of the *** on protein-protein interaction(PPI)network and RNA sequencing analyses,we speculated that overexpression of HRAS may initiate the THBS1-COL4A3 axis to induce NASH with severe fibrosis,with subsequent progression to ***,our study successfully duplicated natural sequential progression in a single murine model over a very short period,providing an accurate and reliable preclinical tool for therapeutic evaluations targeting the NASH to HCC continuum.

关键词： HRAS THBS1 HCC driver factor NASH Fibrosis Cirrhosis HCC Treatment evaluation

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Saikosaponin D improves nonalcoholic fatty liver disease via gut microbiota-bile acid metabolism pathway

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Food Science and Human Wellness 2024年第5期13卷 2703-2717页

作者： Lan Li Shengye Yang Xinyu Liang Yameng Liu Hualing Xu Xiaozhen Guo Cen Xie Xiaojun Xu State key laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210029China guangdong provincial People's Hospital Guangdong Academy of Medical SciencesGuangzhou 510080China School of Chinese Materia Medica Nanjing University of Chinese MedicineNanjing 210029China State key laboratory of drug research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China

non-alcoholic fatty liver disease(NAFLD)is the main cause of chronic liver disease *** is widely used in the treatment of non-alcoholic fatty liver,and saikosaponin D(SSD)is one of the main active components of *** purpose of this study was to investigate the efficacy of SSD in the treatment of NAFLD and to explore the mechanism of SSD in the improvement of NAFLD based on“gut-liver axis”.Our results showed that SSD dose-dependently alleviated high fat diet-induced weight gain in mice,improved insulin sensitivity,and also reduced liver lipid accumulation and injury-related biomarkers aspartate aminotransferase(AST)and alanine aminotransferase(ALT).Further exploration found that SSD inhibited the mRNA expression levels of farnesoid X receptor(Fxr),small heterodimer partner(Shp),recombinant fibroblast growth factor 15(Fgf15)and apical sodium dependent bile acid transporter(Asbt)in the intestine,suggesting that SSD improved liver lipid metabolism by inhibiting intestinal FXR *** can significantly reduce the gut microbiota associated with bile salt hydrolase(BSH)expression,such as *** BSH expression reduced the ratio of unconjugated to conjugated bile acids,thereby inhibiting the intestinal *** data demonstrated that SSD ameliorated NAFLD potentially through the gut microbiota-bile acidintestinal FXR pathway and suggested that SSD is a promising therapeutic agent for the treatment of NAFLD.

关键词： Saikosaponin D(SSD) non-alcoholic fatty liver disease Bile acids Gut microbiota Farnesoid X receptor

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Functional dissection of parabrachial substrates in processing nociceptive information

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Zoological research 2024年第3期45卷 633-647页

作者： Jin Ke Wei-Cheng Lu Hai-Yang Jing Shen Qian Sun-Wook Moon Guang-Fu Cui Wei-Xin Qian Xiao-Jing Che Qian Zhang Shi-Shi Lai Ling Zhang Ying-Jie Zhu Jing-Dun Xie Tian-Wen Huang Shenzhen key laboratory of drug Addiction Shenzhen-Hong Kong Institute of Brain ScienceBrain Cognition and Brain Disease InstituteShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenGuangdong 518055China CAS key laboratory of Brain Connectome and Manipulation Brain Cognition and Brain Disease InstituteShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhenGuangdong 518055China University of Chinese Academy of Sciences Beijing 100049China Department of Anesthesiology State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer CenterGuangzhouGuangdong 510060China University of Science and Technology of China HefeiAnhui 230027China Department of Anesthesiology Shenzhen University General Hospital and Shenzhen University Academy of Clinical Medical SciencesShenzhen UniversityShenzhenGuangdong 518055China School of Medicine Yunnan UniversityKunmingYunnan 650091China

Painful stimuli elicit first-line reflexive defensive reactions and,in many cases,also evoke second-line recuperative behaviors,the latter of which reflects the sensing of tissue damage and the alleviation of *** lateral parabrachial nucleus(lPBN),composed of external-(elPBN),dorsal-(dlPBN),and central/superior-subnuclei(jointly referred to as slPBN),receives sensory inputs from spinal projection neurons and plays important roles in processing affective information from external threats and body integrity ***,the organizational rules of lPBN neurons that provoke diverse behaviors in response to different painful stimuli from cutaneous and deep tissues remain *** this study,we used region-specific neuronal depletion or silencing approaches combined with a battery of behavioral assays to show that slPBN neurons expressing substance P receptor(NK1R)(lPBNNK1R)are crucial for driving pain-associated self-care behaviors evoked by sustained noxious thermal and mechanical stimuli applied to skin or bone/muscle,while elPBN neurons are dispensable for driving such ***,lPBNNK1R neurons are specifically required for forming sustained somatic pain-induced negative teaching signals and aversive memory but are not necessary for fear-learning or escape behaviors elicited by external ***,both lPBNNK1R and elPBN neurons contribute to chemical irritant-induced nocifensive *** results reveal the functional organization of parabrachial substrates that drive distinct behavioral outcomes in response to sustained pain versus external danger under physiological conditions.

关键词： Lateral parabrachial nucleus Substance P receptor Pain affect Defensive reaction Somatosensory

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