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Virologica Sinica 2022年第6期37卷 942-945页

作者： An-Kai Zhu Sa-Sa Li Shu-Pei Yu Zhao-Yong Zhang Huan Li Jing-Feng Li Shan-Shan Gao Heng Chen Jincun Zhao Run Shi Mingjian Lu Chaoyang Li Affiliated Cancer Hospital and Institute of Guangzhou Medical University State Key Laboratory of Respiratory DiseaseKey Laboratory for Cell Homeostasis and Cancer Research of Guangdong High Education InstituteGuangzhou510095China State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory DiseaseGuangzhou Institute of Respiratory HealthThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou510182China Department of Interventional Radiology Affiliated Cancer Hospital and Institute of Guangzhou Medical UniversityGuangzhou510095China

Dear Editor,Severe Acute Respiratory Syndrome Coronavirus Type 2(SARS-CoV-2) is the pathogen of the coronavirus disease 2019(COVID-19), which has spread worldwide.SARS-CoV-2 is an enveloped virus belongs to the family of β-coronavirus(Xu et al., 2020). Its genome is a linear single-stranded positive-sense RNA about 30,000 nucleotides packed inside a virion with a diameter of 100 nm and a volume of about 10^(6)nm^(3)(Bar-On et al., 2020).

关键词： al. diagnosis specificity

Dl-3-n butylphthalide attenuates brain injury caused by cortical infarction accompanied by cranial venous drainage disturbance

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Stroke & Vascular Neurology 2022年第3期7卷 222-236页

作者： Kangping Song Xiuli Zeng Xiaomei Xie Rongxuan Zhu Jianye Liang Guobing Chen Li’an Huang Department of Neurology Jinan University First Affiliated HospitalGuangzhouChina medical Imaging Center Jinan University First Affiliated HospitalGuangzhouChina institute of Geriatric Immunology Medical college of Jinan UniversityGuangzhouChina

Background Cerebral venous disorder may have a harmful effect on ischaemic stroke;however,the underlying mechanism remains to be elucidated.Although Dl-3-n butylphthalide is a multitarget agent for antiischaemic stroke,its neuroprotective role in brain ischaemia accompanied by brain venous disturbance remains unclear.In this study,we induced cerebral venous disturbance by the occlusion of bilateral external jugular veins(EJVs)to explore the potential mechanism of the adverse effects of cerebrovenous disorders in cerebral infarction and explore the protective effect of Dl-3-n butylphthalide on cerebral infarction accompanied through cerebral venous disturbance.Methods Cerebral venous disturbance was induced in Sprague-Dawley rats through the permanent occlusion of bilateral EJVs,and cerebral ischaemic stroke was induced through the permanent occlusion of the right cortical branches of the middle cerebral artery.2,3,5-triphenyltetrazolium chloride staining,MRI,Evans blue extravasation and behavioural test were performed to evaluate infarction volume,cerebral blood flow(CBF),blood-brain barrier(BBB)integrity and neurological function.Immunofluorescence staining and western blot analysis were performed to detect loss of neuron,endothelial cells,pericytes and tight junctions.Results Bilateral EJVs occlusion did not cause cerebral infarction;however,it increased the infarction volume compared with the simple middle cerebral artery occlusion(MCAO)group,accompanied by severe neuron loss,worse neurological function,lower CBF,increased EJVs pressure,exacerbated Evans blue extravasation and brain oedema,as well as attenuated angiogenesis.Dl-3-n butylphthalide displayed a neuroprotective effect in rats with MCAO accompanied by EJVs occlusion by reducing neuron loss,accelerating CBF restoration,promoting angiogenesis and relieving BBB damage.Conclusion Bilateral EJVs occlusion did not significantly affect normal rats but aggravated brain damage in the case of ischaemic stroke.Dl-3-n butylphthalide treatment plays a neuroprote

关键词： protective infarction disturbance

Berberine enhances the anti-hepatocellular carcinoma effect of NK92-MI cells through inhibiting IFN-gamma-mediated PD-L1 expression

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Liver Research 2022年第3期6卷 167-174页

作者： Kunyuan Wang Chengxin Gu Ganxiang Yu Jiaen Lin Zhilei Wang Qianting Lu Yangzhi Xu Dan Zhao Xiaofeng Jiang Weijian Mai Shiming Liu Hui Yang Department of Gastroenterology The Second Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdongChina Department of Hepatobiliary Surgery The Second Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdongChina guangzhou institute of Cardiovascular Disease The Second Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdongChina

Background and aims:Berberine is one of the most promising clinically tested natural alkaloids,and immunotherapy using natural killer(NK)cells is a potentially effective treatment for hepatocellular carcinoma(HCC).This study aims to elucidate the effect of berberine on the anti-HCC effect of NK92-MI cells.Materials and methods:Human HCC SMMC-7721 and Hep3B cells were co-incubated with NK92-MI cells,berberine(60 or 80 mmol/L),or their combination for 36 h.To evaluate the killing effect of NK92-MI cells on HCC cells,the release of lactate dehydrogenase(LDH)in HCC cells was measured.The anti-tumor effects of berberine,NK92-MI cells,and their combinations were evaluated by MTS,EdU,Tunel,and Western blot assays.A male BALB/c nude mouse subcutaneous tumor model was used to investigate the anti-HCC effect of berberine and NK92-MI cells in vivo.Results:The LDH assay showed that berberine enhanced the cytotoxicity of NK92-MI cells on HCC cells.The combination of berberine and NK92-MI cells demonstrated more obvious anti-HCC effect than did the berberine or NK92-MI single treatment in inhibiting cell proliferation and inducing apoptosis both in vitro and in vivo.Mechanistically,the expression of programmed cell death-ligand 1(PD-L1)in HCC cells was upregulated after co-culture with NK-92MI cells.PD-L1 expression was knocked down,thereby inhibiting the proliferation and promoting apoptosis of HCC cells,and inhibited by berberine that blocked the secretion of interferon gamma(IFN-g),thereby enhancing the anti-tumor effect of NK92-MI cells.Conclusions:Current data show that the immunomodulatory role of berberine is to enhance the cytotoxic effect of NK92-MI cells and inhibit tumor immune escape by reducing the expression of PD-L1.Our study provides a rationale for the clinical application of berberine in combination with NK cells for the treatment of HCC.

关键词： Berberine Hepatocellular carcinoma(HCC) NK92-MI cells Interferon gamma(IFN-g) Programmed cell death-ligand 1(PD-L1)

Bilirubin inhibits lung carcinogenesis by up-regulating cystatin A expression in tumor-infiltrating macrophages

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Genes & Diseases 2023年第6期10卷 2222-2225页

作者： Qingtian Huang Na Zhang Jiangtuan Wang Hua Xu Leyi Yao Qianqian Yang Ding Yan Xi Chen Qian Xue Min Xiao Jiawen Wu Xueheng Wu Qin Liu Daolin Tang Xin Chen Xiaofen Li Jinbao Liu affiliated cancer hospital&institute of guangzhou medical university GuangzhouGuangdong 510095China guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation School of Basic Medical SciencesGuangzhou Medical UniversityGuangzhouGuangdong 511436China institute of Digestive Disease The Sixth Affiliated Hospital of Guangzhou Medical UniversityQingyuan People's HospitalQingyuanGuangdong 511518China Department of Pathology Dongguan People's Hospital Affiliated to Southern Medical UniversityDongguanGuangdong 523059China Department of Surgery UT Southwestern Medical CenterDallasTX 75390USA

As one of the leading causes of cancer deaths worldwide,the pathogenesis of lung cancer is still not completely understood.Bilirubin,a product of heme metabolism,has long been considered a waste product of the body.Increasing evidence suggests that bilirubin has additional antioxidant,anti-inflammatory,and proteasome inhibitory activities.However,the specific role of bilirubin in the formation and development of lung cancer has not been elucidated.

关键词： lung metabolism cancer

A redox-responsive self-assembling COA-4-arm PEG prodrug nanosystem for dual drug delivery suppresses cancer metastasis and drug resistance by downregulating hsp90 expression

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药学学报:英文版 2023年第7期13卷 3153-3167页

作者： Yi Zhou Yingling Miao Qiudi Huang Wenwen Shi Jiacui Xie Jiachang Lin Pei Huang Chengfeng Yue Yuan Qin Xiyong Yu He Wang Linghao Qin Jianhai Chen Nanfang hospital Southern Medical UniversityGuangzhou 510515China Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease and the Fifth affiliated hospital School of Pharmaceutical SciencesGuangzhou Medical UniversityGuangzhou 511436China Center of cancer Research The Second Affiliated HospitalGuangzhou Medical UniversityGuangzhou 510260China School of Pharmacy Guangdong Pharmaceutical UniversityGuangzhou 510006China

Metastasis and resistance are main causes to affect the outcome of the current anticancer therapies.Heat shock protein 90(Hsp90)as an ATP-dependent molecular chaperone takes important role in the tumor metastasis and resistance.Targeting Hsp90 and downregulating its expression show promising in inhibiting tumor metastasis and resistance.In this study,a redox-responsive dual-drug nanocarrier was constructed for the effective delivery of a commonly used chemotherapeutic drug PTX,and a COAmodified 4-arm PEG polymer(4PSC)was synthesized.COA,an active component in oleanolic acid that exerts strong antitumor activity by downregulating Hsp90 expression,was used as a structural and functional element to endow 4PSC with redox responsiveness and Hsp90 inhibitory activity.Our results showed that 4PSC/PTX nanomicelles efficiently delivered PTX and COA to tumor locations without inducing systemic toxicity.By blocking the Hsp90 signaling pathway,4PSC significantly enhanced the antitumor effect of PTX,inhibiting tumor proliferation and invasiveness as well as chemotherapy-induced resistance in vitro.Remarkable results were further confirmed in vivo with two preclinical tumor models.These findings demonstrate that the COA-modified 4PSC drug delivery nanosystem provides a potential platform for enhancing the efficacy of chemotherapies.

关键词： 3-O-(Z)-Coumaroyloleanolic acid cancer metastasis Drug resistance Hsp90 Codelivery Prodrug nanosystem Chemotherapies Redox responsiveness

Chitinase-3 like-protein-1 function and its role in diseases

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Signal Transduction and Targeted Therapy 2020年第1期5卷 820-839页

作者： Ting Zhao Zhongping Su Yingchang Li Xiaoren Zhang Qiang You affiliated cancer hospital&institute Guangzhou Medical UniversityGuangzhouChina Department of Biotherapy Department of GeriatricsSecond Affiliated Hospital of Nanjing Medical UniversityNanjingChina Key Laboratory of Cell Homeostasis and cancer Research of Guangdong Higher Education institutes Guangzhou Medical UniversityGuangzhouChina

Non-enzymatic chitinase-3 like-protein-1(CHI3L1)belongs to glycoside hydrolase family 18.It binds to chitin,heparin,and hyaluronic acid,and is regulated by extracellular matrix changes,cytokines,growth factors,drugs,and stress.CHI3L1 is synthesized and secreted by a multitude of cells including macrophages,neutrophils,synoviocytes,chondrocytes,fibroblast-like cells,smooth muscle cells,and tumor cells.It plays a major role in tissue injury,inflammation,tissue repair,and remodeling responses.CHI3L1 has been strongly associated with diseases including asthma,arthritis,sepsis,diabetes,liver fibrosis,and coronary artery disease.Moreover,following its initial identification in the culture supernatant of the MG63 osteosarcoma cell line,CHI3L1 has been shown to be overexpressed in a wealth of both human cancers and animal tumor models.To date,interleukin-13 receptor subunit alpha-2,transmembrane protein 219,galectin-3,chemo-attractant receptor-homologous 2,and CD44 have been identified as CHI3L1 receptors.CHI3L1 signaling plays a critical role in cancer cell growth,proliferation,invasion,metastasis,angiogenesis,activation of tumor-associated macrophages,and Th2 polarization of CD4+T cells.Interestingly,CHI3L1-based targeted therapy has been increasingly applied to the treatment of tumors including glioma and colon cancer as well as rheumatoid arthritis.This review summarizes the potential roles and mechanisms of CHI3L1 in oncogenesis and disease pathogenesis,then posits investigational strategies for targeted therapies.

关键词： diseases invasion drugs

Strategies for reopening in the forthcoming COVID-19 era in China

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National Science Review 2022年第3期9卷 5-6页

作者： Wei-jie Guan Nan-shan Zhong State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory Disease Guangzhou Institute of Respiratory Health The First Affiliated Hospital of Guangzhou Medical University Guangzhou Medical University Department of Thoracic Surgery Guangzhou Institute for Respiratory Health The First Affiliated Hospital of Guangzhou Medical University Guangzhou Medical University Department of Respiratory and Critical Care Medicine Foshan Second People's HospitalAffiliated Foshan Hospital of Southern Medical University

The transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the culprit pathogen of coronavirus disease 2019 (COVID-19), has resulted in more than 0.43 billion cases and 6 million deaths globally. Compared with other existing variants of concern, the Omicron variant is characterized by significantly greater infectivity (Ro≈6),greater tropism of the upper respiratory tract and lower severity of human infections [1].These characteristics of the Omicron variant are the basis upon which several developed countries are considering reopening.

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Raltitrexed as a synergistic hyperthermia chemotherapy drug screened in patient-derived colorectal cancer organoids

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cancer Biology & Medicine 2021年第3期18卷 750-762页

作者： Lisi Zeng Quanxing Liao Haoran Zhao Shengwei Jiang Xianzi Yang Hongsheng Tang Qingjun He Xiansheng Yang Shuxian Fang Jinfu He Weiwen Cui Laiqiang Huang Shaohua Ma Shuzhong Cui institute of Oncology Affiliated Cancer Hospital and Institute of Guangzhou Medical UniversityGuangzhou 510095China Department of Abdominal Surgery Affiliated Cancer Hospital and Institute of Guangzhou Medical UniversityGuangzhou 510095China institute of Biopharmaceutical and Health Engineering Shenzhen International Graduate SchoolTsinghua UniversityShenzhen 518055China Tsinghua-Berkeley Shenzhen institute(TBSI) Tsinghua UniversityShenzhen 518055China Shenzhen Key Laboratory of Gene and Antibody Therapy Tsinghua UniversityShenzhen 518055China Department of medical Oncology Affiliated Cancer Hospital and Institute of Guangzhou Medical UniversityGuangzhou 510095China Department of Bioengineering University of CaliforniaBerkeley 94720USA

Objective:Organoids have recently been used as in vitro models to screen chemotherapy drugs in combination with hyperthermia treatment in colorectal cancer.Our research aimed to establish a library of patient-derived colorectal cancer organoids to evaluate synergism between chemotherapy drugs and hyperthermia;validate an index of the hyperthermia chemotherapy sensitization enhancement ratio(HCSER)to identify the chemotherapeutics most enhanced by hyperthermia;and recommend chemotherapy drugs for hyperthermic intraperitoneal treatment.Methods:Organoids were grown from cells extracted from colorectal cancer patient samples or colorectal cancer cell lines.Cells from both sources were encapsulated in 3 D Matrigel droplets,which were formulated in microfluidics and phase-transferred into identical cell-laden Matrigel microspheres.The microspheres were seeded in 96-well plates,with each well containing a single microsphere that developed into an organoid after 7 days.The organoids were used to evaluate the efficacy of chemotherapy drugs at both 37℃ as a control and 43℃ for 90 min to examine hyperthermia synergism.Cell viability was counted with 10%CCK8.Results:We successfully established a library of colorectal cancer organoids from 22 patient parental tumors.We examined the hyperthermia synergism of 7 commonly used hyperthermic intraperitoneal chemotherapy drugs.In 11 of the 22 patient organoids,raltitrexed had significant hyperthermia synergism,which was indexed as the highest HCSER score within each patient group.Conclusions:Our results primarily demonstrated the use of patient-derived colorectal cancer organoids as in vitro models to evaluate hyperthermia synergistic chemotherapeutics.We found that hyperthermia enhanced the effect of raltitrexed the most among the common anti-colorectal cancer drugs.

关键词： Colorectal cancer organoids hyperthermia chemotherapy sensitization enhancement ratio raltitrexed

Bilirubin inhibits the anticancer activity of sorafenib by blocking MCL-1 degradation in hepatocellular carcinoma cells

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cancer Biology & Medicine 2022年第7期19卷 1061-1077页

作者： Leyi Yao Qian Zhao Ding Yan Ziying Lei Yali Hao Jinghong Chen Qian Xue Xiaofen Li Qingtian Huang Daolin Tang QPing Dou Xin Chen Jinbao Liu affiliated cancer hospital&institute of guangzhou medical university Guangzhou 510095China guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation State Key Laboratory of Respiratory DiseaseSchool of Basic Medical SciencesGuangzhou Medical UniversityGuangzhou 511436China institute of Digestive Disease of guangzhou medical university The Sixth Affiliated Hospital of Guangzhou Medical UniversityQingyuan People’s HospitalQingyuan 511518China School of Public Health Guangzhou Medical UniversityGuangzhou511436China Department of Surgery UT Southwestern Medical CenterDallasTX 75390USA Barbara Ann Karmanos cancer institute and Departments of Oncology Pharmacology&PathologySchool of MedicineWayne State UniversityDetroitMI 48201USA

Objective:Sorafenib is a first-line drug for advanced hepatocellular carcinoma(HCC).Unfortunately,most patients with HCC do not respond to sorafenib,mainly because of the frequent development of drug resistance.Bilirubin is an end metabolite of heme catabolism and an indicator of liver function,but its direct role in regulating the anticancer activity of sorafenib in HCC cells is unclear.In the current study,we aimed to investigate the mechanism of action of bilirubin in sorafenib-mediated tumor suppression in HCC.Methods:A retrospective observational cohort of 100 patients receiving sorafenib was conducted to evaluate the potential role of bilirubin in predicting the prognosis of patients with HCC.Human HCC cell lines were treated with sorafenib in the absence or presence of bilirubin,and cell proliferation,apoptosis,and signaling pathways were assayed.The antagonistic effect of bilirubin toward sorafenib was assessed in nude mice bearing HCC xenografts.Results:Serum levels of bilirubin(including total,direct,and indirect bilirubin)negatively correlated with the overall survival of patients with HCC treated with sorafenib(Pcancer activity in HCC,and it suggests that bilirubin could be used to predict the efficacy of sorafenib treatment.

关键词： Apoptosis bilirubin hepatocellular carcinoma MCL-1 sorafenib

Added Value of Quantitative Apparent Diffusion Coefficients for Identifying Small Hepatocellular Carcinoma from Benign Nodule Categorized as LI-RADS 3 and 4 in Cirrhosis

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Journal of Clinical and Translational Hepatology 2022年第1期10卷 34-41页

作者： Xi Zhong Hongsheng Tang Tianpei Guan Bingui Lu Chuangjia Zhang Danlei Tang Jiansheng Li Shuzhong Cui Department of medical Imaging Affiliated Cancer Hospital&Institute of Guangzhou Medical UniversityGuangzhouGuangdongChina Department of Abdominal Surgery Affiliated Cancer Hospital&Institute of Guangzhou Medical Univer-sityGuangzhouGuangdongChina

Background and Aims:Correct identification of small hepa-tocellular carcinomas(HCCs)and benign nodules in cirrhosis remains challenging,quantitative apparent diffusion coeffi-cients(ADCs)have shown potential value in characterization of benign and malignant liver lesions.We aimed to explore the added value of ADCs in the identification of small(≤3 cm)HCCs and benign nodules categorized as Liver Imag-ing Reporting and Data System(LI-RADS)3(LR-3)and 4(LR-4)in cirrhosis.Methods:Ninety-seven cirrhosis patients with 109 small nodules(70 HCCs,39 benign nodules)of LR-3 and 4 LR-4 based on major and ancillary magnetic resonance imaging features were included.Multiparametric quantitative ADCs of the lesions,including the mean ADC(ADCmean),min-imum ADC(ADCmin),maximal ADC(ADCmax),ADC standard deviation(ADCstd),and mean ADC value ratio of lesion-to-liv-er parenchyma(ADCratio)were calculated.Regarding the joint diagnosis,a nomogram model was plotted using multivariate logistic regression analysis.The performance was assessed using the area under the receiver operating characteristic curve(AUC).Results:The ADCmean,ADCmin,ADCratio,and ADCstd were significantly associated with the identification of small HCC and benign nodules(p<0.001).For the joint diagnosis,the LI-RADS category(odds ratio[OR]=12.50),ADCmin(OR=0.14),and ADCratio(OR=0.12)were identified as independent factors for distinguishing HCCs from benign nodules.The joint nomogram model showed good calibration and discrimination,with a C-index of 0.947.Compared with the LI-RADS category alone,this nomogram model demon-strated a significant improvement in diagnostic performance,with AUC increasing from 0.820 to 0.967(p=0.001).Con-clusions:The addition of quantitative ADCs could improve the identification of small HCC and benign nodules catego-rized as LR-3 and 4 LR-4 in patients with cirrhosis.

关键词： Hepatocellular carcinoma Liver cirrhosis Liver imaging reporting and data system Magnetic resonance imaging diagnosis