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Thymoquinone affects hypoxia-inducible factor-1αexpression in pancreatic cancer cells via HSP90 and PI3K/AKT/mTOR pathways

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World Journal of Gastroenterology 2024年第21期30卷 2793-2816页

作者： Zhan-Xue Zhao Shuai Li Lin-Xun Liu Department of General Surgery Qinghai Provincial People's HospitalXining 810007Qinghai ProvinceChina Department of Clinical Pharmacy The Affiliated Hospital of Qinghai UniversityXining 810001Qinghai ProvinceChina

BACKGROUND Pancreatic cancer(PC)is associated with some of the worst prognoses of all major cancers.Thymoquinone(TQ)has a long history in traditional medical practice and is known for its anti-cancer,anti-inflammatory,anti-fibrosis and antioxidant pharmacological activities.Recent studies on hypoxia-inducible factor-1α(HIF-1α)and PC have shown that HIF-1αaffects the occurrence and development of PC in many aspects.In addition,TQ could inhibit the development of renal cancer by decreasing the expression of HIF-1α.Therefore,we speculate whether TQ affects HIF-1αexpression in PC cells and explore the mechanism.AIM To elucidate the effect of TQ in PC cells and the regulatory mechanism of HIF-1αexpression.METHODS Cell counting kit-8 assay,Transwell assay and flow cytometry were performed to detect the effects of TQ on the proliferative activity,migration and invasion ability and apoptosis of PANC-1 cells and normal pancreatic duct epithelial(hTERTHPNE)cells.Quantitative real-time polymerase chain reaction and western blot assay were performed to detect the expression of HIF-1αmRNA and protein in PC cells.The effects of TQ on the HIF-1αprotein initial expression pathway and ubiquitination degradation in PANC-1 cells were examined by western blot assay and co-immunoprecipitation.RESULTS TQ significantly inhibited proliferative activity,migration,and invasion ability and promoted apoptosis of PANC-1 cells;however,no significant effects on hTERT-HPNE cells were observed.TQ significantly reduced the mRNA and protein expression levels of HIF-1αin PANC-1,AsPC-1,and BxPC-3 cells.TQ significantly inhibited the expression of the HIF-1αinitial expression pathway(PI3K/AKT/mTOR)related proteins,and promoted the ubiquitination degradation of the HIF-1αprotein in PANC-1 cells.TQ had no effect on the hydroxylation and von Hippel Lindau protein mediated ubiquitination degradation of the HIF-1αprotein but affected the stability of the HIF-1αprotein by inhibiting the interaction between HIF-1αand HSP90,thus promoting its ubiquitination

关键词： Thymoquinone Pancreatic cancer hypoxia-inducible factor-1α PI3K/AKT/mTOR HSP90

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Lichong decoction inhibits micro-angiogenesis by reducing the expressions of hypoxia inducible factor-1αand vascular endothelial growth factor in hysteromyoma mouse model

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Journal of Traditional Chinese Medicine 2020年第6期40卷 928-937页

作者： Wang Wenna Zhang Wufang Li Donghua Qian Ruiya Zhu Lijuan Liu Yu Chen Chao School of Traditional Chinese Medicine Capital Medical UniversityBeijing 100069China Gynecology department The fourth ward of Beijing Obstetrics and Gynecology HospitalCapital Medical University Beijing Maternaland ChildBeijing 100006China

OBJECTIVE:To investigate the efficacy of Lichong decoction(LD)from Traditional Chinese Medicine,on micro-angiogenesis in a mouse model of hysteromyoma.METHODS:A mouse model of hysteromyoma was developed by orthotopic intrauterine injection of primary human myoma cells isolated from patients from the Beijing Obstetrics and Gynecology Hospital into CB-17 Scid mice.Mice were administered high-dose LD,low-dose LD,mifepristone or water(control)daily by gavage for 4 weeks.Uterine diameter and coefficient(uterine weight/body weight)were measured.Uterine morphology was assessed by light microscopy(hematoxylin and eosin)and transmission electron microscopy.Serum levels of estradiol,progesterone,follicle-stimulating hormone and luteinizing hormone(LH)were measured by enzyme-linked immunosorbent assay.Uterine protein expression of hypoxia inducible factor(HIF)-1α,CD31 and proliferating cell nuclear antigen(PCNA)was detected by immunohistochemistry.VEGF and HIF-1αm RNAs were quantified by RT-PCR.RESULTS:High-dose LD,low-dose LD and mifepristone reduced uterine diameter and coefficient,and attenuated the morphologic abnormalities associated with hysteromyoma.High-dose LD,low-dose LD and mifepristone inhibited hysteromyoma-induced micro-angiogenesis,as evidenced by a decrease in the number of new microvessels co-immunostaining for CD31 and PCNA(P<0.01).High-dose LD and mifepristone lowered serum levels of estradiol,progesterone and LH(P<0.05).High-dose LD,low-dose LD and mifepristone down-regulated HIF-1αm RNA and protein expressions and VEGF m RNA expression(P<0.01).CONCLUSION:The inhibition of hysteromyoma by LD may involve reductions in HIF-1αand VEGF expression and suppression of micro-angiogenesis.

关键词： Leiomyoma Neovascularization pathologic hypoxia-inducible factor-1α Vascular endothelial growth factors Lichong decoction

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Natural products as potent inhibitors of hypoxia-inducible factor-1α in cancer therapy

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Chinese Journal of Natural Medicines 2020年第9期18卷 696-703页

作者： ZHONG Jin-Cheng LI Xiao-Bo LYU Wen-Yu YE Wen-Cai ZHANG Dong-Mei College of Pharmacy Jinan UniversinyGuangzhou 510632.China Guangdong Province Key Laboratory of Pharmacodynamic Constituents 0f Traditional Chinese Medicine and New Drugs Research Jinan UniversityGuangzhou 510632China

hypoxia is a prominent feature of tumors. hypoxia-inducible factor-1α(HIF-1α), a major subunit of HIF-1, is overexpressed in hypoxic tumor tissues and activates the transcription of many oncogenes. Accumulating evidence has demonstrated that HIF-1α promotes tumor angiogenesis, metastasis, metabolism, and immune evasion. Natural products are an important source of antitumor drugs and numerous studies have highlighted the crucial role of these agents in modulating HIF-1α. The present review describes the role of HIF-1α in tumor progression, summarizes natural products used as HIF-1α inhibitors, and discusses the potential of developing natural products as HIF-1α inhibitors for the treatment of cancer.

关键词： hypoxia-inducible factor-1α hypoxia Cancer Natural products Anticancer treatment

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Effect of environmental factors on chemoresistance of HepG2 cells by regulating hypoxia-inducible factor-1α

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Chinese Medical Journal 2012年第6期125卷 1095-1103页

作者： ZHU Hong LUO Shun-feng WANG Ji LI Xin WANG Hui PU Wang-yang ZHANG Hong ZHUANG Zhi-xiang Department of Oncology Second Affiliated Hospital of Soochow University Suzhou Jiangsu 215006 China Hepatic Surgery Center First Affiliated Hospital of Fujian Medical University Fuzhou Fujian 350005 China

Background Accumu1αting evidence demonstrates that the microenvironment of the host has an important effect on the chemoresistance of tumors. We also found that the formation of intrinsic multidrug resistance is re1αted to environmental factors that are common with tumor growth of hepatocellu1αr carcinoma. The aim of this study was to explore the molecu1αr mechanisms by which multidrug resistance of hepatocellu1αr carcinoma is induced by the microenvironment. In particu1αr, the regu1αtion of nuclear transcription factor （hypoxia-inducible factor-1α, HIF-1α） activation in the process of multidrug resistance formation was investigated. Methods HepG2 cells were exposed to different microenvironmental conditions respectively, such as hypoxia, stimu1αtion of glucose deprivation and transfection of p1αsmid PcDNA3/HBx. In the HepG2 cells, the expression of the re1αted MDR proteins, HIF-1α protein expression and localization, activity of extracellu1αr signal-regu1αted kinase /mitogen-activated protein kinase （ERK/MAPK） were detected. Specific inhibitor U0126 was used to block ERK/MAPK signal pathway, the alteration of HIF-1α and the re1αted MDR proteins were investigated. Multivariate analysis of variance （MANOVA） repeated measures and one-way analysis of variance （ANOVA） followed by Tukey test or t-test were used to determine differences over time and effects of the treatments. Results The above three microenvironment factors increase the expression of the re1αted MDR proteins （including P-gp, LRP, and MRP1） and induce MDR of HepG2 cells. HIF-1α was induced at the protein and mRNA levels and the nuclear translocation was also increased. The activity of ERK/MAPK was also increased in HepG2 cells. But when ERK/MAPK pathway was inhibited, the mRNA and protein decreased. Inhibition of ERK/MAPK significantly reduced HIF-1α, whereas HIF-1α mRNA levels were not affected. expression of MDR1, MRP1, and LRP was to some extent activated HIF-1α protein and the nuclear translocation of Conclusions The microenvironmental factors coul

关键词： HepG2 cells hypoxia-inducible factor-1α chemoresistance

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Hyperbaric oxygen intervention on expression of hypoxia-inducible factor-1 α and vascular endothelial growth factor in spinal cord injury models in rats

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Chinese Medical Journal 2013年第20期126卷 3897-3903页

作者： ZHOU Yi LIU Xue-hua QU Shao-dong YANG Jing WANG Zhi-wei GAO Chun-jin SU Qing-jun Department of Orthopedics Shenzhou Hospital Shenyang Medical College Shenyang Liaoning 110002 China Department of Hyperbaric Oxygen Beijing ChaoYang Hospital Capital Medical University Beijing 100020 China Department of Orthopedics Beijing Mentougou District Hospital Beijing 102300 China Department of Orthopedics Beijing ChaoYang Hospital Capital Medical University Beijing 100020 China

Background Hyperbaric oxygen （HBO） intervention is a main therapeutic method and the curative effect has been certified for spinal cord injury （SCI）, but the mechanisms of the neuroprotective effect of HBO on SCI remain elusive. This study aimed to observe the change in expression of hypoxia-inducible factor-1α （HIF-1α） and vascular endothelial growth factor （VEGF） after SCI at different time points and to investigate the neuroprotective mechanism of HBO on SCI in rats.

关键词： hyperbaric oxygen spinal cord injury hypoxia-inducible factor-1α vascular endothelial growth factor

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A Transcriptomic Analysis of Physiological Significance of hypoxia-inducible factor-1α in Myogenesis and Carbohydrate Metabolism of Genioglossus in Mice

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Chinese Medical Journal 2017年第13期130卷 1570-1577页

作者： Tong Hao Yue-Hua Liu Yuan-Yuan Li Yun Lu Hong-Yi Xu Department of Orthodontics School and Hospital of Stomatology Tongji University Shanghai Engineering Research Center of Tooth Restoration and Regeneration Shanghai 200072 China Department of Orthodontics Shanghai Stomatological Hospital Shanghai 200001 China

Background： Chronic intermittent hypoxia is the most remarkable feature of obstructive sleep apnea/hypopnea syndrome and it can induce the change of hypoxia-inducible factor-1α （H IF-1α） expression and contractile properties in the genioglossus. To clarify the role of HIF-lot in contractile properties of the genioglossus, this study generated and compared high-throughput RNA-sequencing data from genioglossus between HIF-1α conditional knockout （KO） mice and littermate wild-type （WT） mice. Methods： KO mice were generated with cre-loxP strategy. Gene expression profile analysis was performed using gene enrichment analysis. Gene ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway analyses of differently expressed messenger RNAs were performed to identify the related pathways and biological lhnctions. Six differentially expressed genes （DEGs） were validated by qualitative reverse transcription polymerase chain reaction. Results： A total of 142 （77 upregulated and 65 downregulated） transcripts were found to exhibit statistically significant difference between the HIF-la-KO and WT mice. GO and KEGG analyses indicated that DEGs included genes involved in ＂skeletal muscle cell differentiation,＂＂muscle organ development,＂＂glucose metabolic process,＂＂glycogen biosynthetic and metabolic process,＂ etc. Conclusion： This study might provide evidence that H IF-lot affects the expression of multiple genes involved in the myogenesis, muscle developrnent, and carbohydrate metabolism through transcriptome analysis in conditional HIE-1α-KO mice.

关键词： Carbohydrate Metabolism Genioglossus hypoxia-inducible factor-1α Myogenesis Transcriptomic Analysis

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Mitochondrial dysfunction affects hepatic immune and metabolic remodeling in patients with hepatitis B virus-related acute-onchronic liver failure

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World Journal of Gastroenterology 2024年第8期30卷 881-900页

作者： Yu Zhang Xiao-Ling Tian Jie-Qun Li Dong-Sheng Wu Qiang Li Bin Chen Department of Hepatology Institute of HepatologyThe First Affiliated Hospital of Hunan University of Chinese MedicineChangsha 410021Hunan ProvinceChina Department of Liver Transplant Transplant Medical Research CenterThe Second Xiangya Hospital of Central South UniversityChangsha 410011Hunan ProvinceChina Department of Surgery The First Affiliated Hospital of Hunan University of Chinese MedicineChangsha 410021Hunan ProvinceChina

BACKGROUND Immune dysregulation and metabolic derangement have been recognized as key factors that contribute to the progression of hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF).However,the mechanisms underlying immune and metabolic derangement in patients with advanced HBV-ACLF are unclear.AIM To identify the bioenergetic alterations in the liver of patients with HBV-ACLF causing hepatic immune dysregulation and metabolic disorders.METHODS Liver samples were collected from 16 healthy donors(HDs)and 17 advanced HBV-ACLF patients who were eligible for liver transplantation.The mitochondrial ultrastructure,metabolic characteristics,and immune microenvironment of the liver were assessed.More focus was given to organic acid metabolism as well as the function and subpopulations of macrophages in patients with HBV-ACLF.RESULTS Compared with HDs,there was extensive hepatocyte necrosis,immune cell infiltration,and ductular reaction in patients with ACLF.In patients,the liver suffered severe hypoxia,as evidenced by increased expression of hypoxia-inducible factor-1α.Swollen mitochondria and cristae were observed in the liver of patients.The number,length,width,and area of mitochondria were adaptively increased in hepatocytes.Targeted metabolomics analysis revealed that mitochondrial oxidative phosphorylation decreased,while anaerobic glycolysis was enhanced in patients with HBV-ACLF.These findings suggested that,to a greater extent,hepa-tocytes used the extra-mitochondrial glycolytic pathway as an energy source.Patients with HBV-ACLF had elevated levels of chemokine C-C motif ligand 2 in the liver homogenate,which stimulates peripheral monocyte infiltration into the liver.Characterization and functional analysis of macrophage subsets revealed that patients with ACLF had a high abundance of CD68^(+)HLA-DR^(+)macrophages and elevated levels of both interleukin-1βand transforming growth factor-β1 in their livers.The abundance of CD206^(+)CD163^(+)macrophages and expression of interleukin-10 decreased.Th

关键词： Acute-on-chronic liver failure hypoxia-inducible factor-1α Mitochondria Metabolic phenotype Immune cells

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Correlation of hypoxia-inducible factor-1 alpha and erythropoietin protein and mRNA to cerebral ischemic tolerance in a focal ischemia/reperfusion model using the twice suture method

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Neural Regeneration Research 2009年第11期4卷 846-852页

作者： Renliang Zhao Yongjun Wang Department of Neurology Beijing Tiantan Hospital Capital University of Medical Sciences Beijing 100050 China Department of Neurology Affiliated Hospital of Medical College Qingdao University Qingdao 266003 Shandong Province China

BACKGROUND： Numerous studies have shown that transient ischemic preconditioning induces cerebral ischemic tolerance. However, the underlying mechanisms of endogenous protection following ischemic preconditioning remain unclear. OBJECTIVE： To dynamically measure erythropoietin and hypoxia-inducible factor-1α （HIF-1α） mRNA and protein expression at various times following preconditioning, and to investigate effects of erythropoietin and HIF-1α on cerebral ischemic tolerance in a model of focal ischemia/reperfusion established using the twice suture method. DESIGN, TIME AND SETTING： The randomized, controlled study was performed at the Institute of Anatomy, Medical College, Qingdao University, China from March 2006 to March 2007. MATERIALS： Rabbit anti-rat HIF-1α monoclonal antibody and biotinylated goat anti-rabbit IgG （Boster, China）, rabbit anti-rat erythropoietin monoclonal antibody （Santa Cruz Biotechnology, USA）, and one-step RT-PCR kit （Qiagen, Germany） were used in this study. METHODS： A total of 99 healthy, male, Wistar rats were randomly assigned to three groups： sham surgery （n = 9）, non-ischemic preconditioning （n = 45）, and ischemic preconditioning （n = 45）. In the ischemic preconditioning group, rat models of pre-ischemia-reperfusion-ischemia-reperfusion were established by occluding the left middle cerebral artery using the twice suture method. In the non-ischemic preconditioning group, pre-ischemia was replaced by sham surgery. Subsequently, the ischemic preconditioning and non-ischemic preconditioning groups were equally divided into five subgroups according to time of first reperfusion, including 1-, 3-, 7-, 14-, and 21-day subgroups. The sham surgery group received the sham surgery twice. MAIN OUTCOME MEASURES： HIF-la and erythropoietin protein expression was measured in the cerebral cortex, corpus striatum, and hippocampus of the ischemic hemisphere. HIF-1α and erythropoietin mRNA expression were determined in the frontal and parietal cortex of the ischemic hemisphere. RESULTS：（1） Intergroup com

关键词： ischemic tolerance ischemic preconditioning cerebral ischemia rat hypoxia-inducible factor-1α erythropoietin

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Adenovirus-mediated hypoxia-inducible factor-1 alpha gene transfer induces angiogenesis and neurogenesis following cerebral ischemia in rats

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Neural Regeneration Research 2008年第4期3卷 378-383页

作者： Wanfu Wu Xiu Chen Zhen Yu Changlin Hu Wenqin Cai Department of Neurology the SecondAffiliated Hospital Chongqing Medical University Chongqing 400016 China Department of Neurobiology Third Mifitary Medical University of Chinese PLA Chongqing 400038 China

BACKGROUND： hypoxia-inducible factor-1 （HIF-1） accumulates under conditions of hypoxia. HIF-1α target genes have pleiotropic effects on neurogenesis, neuroprotection and angiogenesis in the brain. OBJECTIVE： To investigate whether a recombinant adenovirus carrying HIF-1α can increase the expression of HIF-I a in vivo and thus promote angiogenesis and neurogenesis in a rat model of focal cerebral ischemia. DESIGN, TIME AND SETTING： The randomized, controlled experiment was performed at the Department of Neurobiology, Third Military Medical University of Chinese PLA from September 2006 to October 2007. MATERIALS： 68 healthy adult male Sprague-Dawley （SD） rats, weighing 230-250 g, were used. HIF-I a antibody was purchased from Wuhan Boster Company. Vascular endothelial growth factor （VEGF） antibody was purchased from Santa Cruz Biotech Company. METHODS： All 68 rats were induced with a transient middle cerebral artery occlusion （MCAO）, according to the method of intra-luminal vascular occlusion. 54 rats, in which MCAO was successfully induced, were randomly divided into adenovirus （Ad） group and recombinant adenovirus with HIF-1α gene （Ad-HIF-1α ） group （27 rats for each group）. Rats were injected with 10 μL Ad （Ad group） or Ad-HIF-1α （Ad-HIF-1α group） into the lateral ventricle, 1 day after MCAO induction. MAIN OUTCOME MEASURES： Reverse transcription polymerase chain reaction was used to measure the expression of HIF-1α and of VEGF. Immunohistochemistry was used to detect the localization of HIF-1α, VEGF and factor Ⅷ in ischemic penumbra. Rat newborn nerve cells were labeled with 5-bromodeoxyuridine （BrdU） after ischemia. BrdU/neurofilament 200 （NF200） and BrdU/glial fibrillary acidic protein （GFAP） double labeled immunofluorescent histochemistry was used to identify the differentiation of newborn cells. Neurological function was evaluated using the modified neurological severity score （NSS）. RESULTS： Compared with Ad, Ad-HIF-1α enhanced the expression of HIF-1α and VEGF （P 〈 0.01）. The numbers of factor VIII, BrdU,

关键词： hypoxia-inducible factor-1α rats angiogenesis neurogenesis focal ischemia

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Expression of hypoxia-inducible factor-1 a and vascular endothelial growth factor in the retina of diabetic rats

Expression of hypoxia-inducible factor-1 a and vascular endo...

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中国中西医结合学会眼科专业委员会第十四届学术年会暨海峡...

作者： Xu Jianbin Xu guoxing The first affiliated hospital of Fujian Medical University Fujian institute of ophthalmology

Objective To detect the expression of hypoxia-inducible factor-1 α(HIF-1 α)and vascular endothelial growth factor(VEGF) in the retina of diabetic rats,and to investigate the role of them in the pathogenesis of diabetic retinopathy(DR).Methods 120 SD rats were randomly divided into two groups:control group and DR group.Diabetes was induced by streptozotocin(STZ)intraperitoneal injection in DR group.The techniques of immunohistochemical and reverse transcription polymerase chain reaction(RT-PCR) were used to examine the expression of HIF-1 α,VEGF protein and mRNA in retina respectively at 1,3,6 months after STZ injection.Results The result of immunohistochemical and RT-PCR showed that,the expression of HIF-1α,VEGF protein and mRNA in retina were not found in control group,but were found gradually increased in DR group(P<0.05).There was a positive correlation between the expression of HIF-1 α and that ofVEGF(r=0.630,P<0.05).Conclusions HIF-1α may regulate the expression of VEGF,and both involved in the pathogenesis of DR.

关键词： diabetic retinopathy hypoxia-inducible factor-1α vascular endothelial growth factor

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