Objective： To investigate whether ginsenoside-Rbl （Gs-Rb1） inhibits the apoptosis of hypoxia cardiomyocytes by up-regulating apelin-APJ system and whether the system is affected by hypoxia-induced factor 1α （Hif-...Objective： To investigate whether ginsenoside-Rbl （Gs-Rb1） inhibits the apoptosis of hypoxia cardiomyocytes by up-regulating apelin-APJ system and whether the system is affected by hypoxia-induced factor 1α （Hif-1α）. Methods： Neonatal rat cardiomyocytes were randomly divided into 6 groups： a control group, a simple COCl2 group, a simple Gs-Rbl group, a CoCl2 and Gs-Rbl hypoxia group, a CoCl2 and 3-（5＇-hydroxymethyl-2＇-furyl）-1-benzylindazole （YC-1） group, a CoCl2 and YC-1 group and a Gs-Rbl group, in which YC-1 inhibits the synthesis and accelerates the degradation of Hif-la. The concentration of COCI2, Gs-Rbl and YC-1 was 500 μmol/L, 200 μ mol/L and 5 μmol/L, respectively; the apoptosis ratio was analyzed with a flow cytometer; and apelin, APJ and Hif-1 c= were assayed with immunocytochemistry, Western blot assays and reverse transcription polymerase chain reaction （RT-PCR）. Results： （1） The anti-apoptosis effect of Gs-Rbl on hypoxia cardiomyocytes was significantly inhibited by YC-1; （2） Hypoxia significantly up-graded the expression of mRNA and protein of apelin; this effect was further reinforced by Gs-Rbl and significantly inhibited by YC-1; （3） Gs-Rb1 further strengthened the expression of APJ mRNA and APJ proteins once hypoxia occurred, which was significantly inhibited by YC-1; （4） Gs-Rb1 significantly increased the expression of Hif-1α, which was completely abolished by YC-1; （5） There was a negative relationship between AR and apelin （or APJ, including mRNA and protein）, a positive correlation between apelin （or APJ） protein and Hif-1a protein, in hypoxia cardiomyocytes. Conclusion： The apelin-APJ system plays an important role in the anti-apoptosis effect of Gs- Rb1 on hypoxia neonatal cardiomyocytes, which was partly adjusted by Hif-1α.展开更多
Hypoxic pulmonary hypertension (HPH) is a common complication in patients with chronic obstructive pulmonary disease (COPD), sleep-disordered breathing, or dwellers in high altitude. The exact mechanisms underlying th...Hypoxic pulmonary hypertension (HPH) is a common complication in patients with chronic obstructive pulmonary disease (COPD), sleep-disordered breathing, or dwellers in high altitude. The exact mechanisms underlying the development of HPH still remain unclear. Reactive oxygen species (ROS),hypoxia inducible factors (HIF), and potassium channels (KV) are believed as the main factors during the development of HPH. We propose that the “ROS/Kv/HIF axis” may play an important initiating role in the development of HPH. Being formed under a hypoxic condition, ROS affects the expression and function of HIFs or KV, and consequently triggers multiple downstream signaling pathways and genes expression that participate in promoting pulmonary vasoconstriction and arterial remodeling. Thus, further study determining the initiating role of “ROS/Kv/HIF axis” in the development of HPH could provide theoretic evidences to better understand the underlying mechanisms of HPH, and help identify new potential targets in the treatment of HPH.展开更多
Background Intermittent hypoxia is the main pathophysiological cause of the obstructive sleep apnea syndrome. Astragalus shows improvement of spatial learning and memory abilities under intermittent hypoxia. Our study...Background Intermittent hypoxia is the main pathophysiological cause of the obstructive sleep apnea syndrome. Astragalus shows improvement of spatial learning and memory abilities under intermittent hypoxia. Our study aimed to investigate the protective effect of astragalus against intermittent hypoxia induced-hippocampal neurons impairment in rats and lay the theoretical foundation for the sleep apnea improvement in cognitive function by astragalus. Methods Male Wistar rats were divided into 4 groups： blank control group, normoxia group, intermittent hypoxia group and astragalus treated intermittent hypoxia group. After 6-week treatment, apoptosis of neurons was evaluated by terminal deoxynucleotidyl-transferase-mediated dUTP nick end-labeling （TUNEL） assay. Furthermore, the expression of HIF-la was detected by real-time reverse transcription polymerase chain reaction （RT-PCR） at the mRNA level as well as by immunohistochemistry （IHC） and Western blotting at the protein level. Results HPLC analysis indicated that astragaloside IV, astragaloside II and astragaloside I were the main compounds in astragals extract. Astragalus extract reduced the apoptosis of hippocampal neurons （P 〈0.05） and decreased the expression of HIF-la at both the mRNA and protein levels in hippocampus compared with non-treated groups （P 〈0.05）. Conclusion Astragalus protects aqainst intermittent hypoxia-induced hippocampal neurons impairment in rats.展开更多
Objective:To detect whether Danlou Tablet(DLT)regulates the hypoxia-induced factor(HIF)-1α-angiopoietin-like 4(Angptl4)mRNA signaling pathway and explore the role of DLT in treating chronic intermittent hypoxia(CIH)-...Objective:To detect whether Danlou Tablet(DLT)regulates the hypoxia-induced factor(HIF)-1α-angiopoietin-like 4(Angptl4)mRNA signaling pathway and explore the role of DLT in treating chronic intermittent hypoxia(CIH)-induced dyslipidemia and arteriosclerosis.Methods:The mature adipocytes were obtained from3 T3-L1 cell culturation and allocated into 8 groups including control groups(Groups 1 and 5,0.1 mL of cell culture grade water);DLT groups(Groups 2 and 6,0.1 mL of 1,000μg/mL DLT submicron powder solution);dimethyloxalylglycine(DMOG)groups(Groups 3 and 7,DMOG and 0.1 mL of cell culture grade water);DMOG plus DLT groups(Groups 4 and 8,DMOG and 0.1 mL of 1,000μg/mL DLT submicron powder solution).Groups1-4 used mature adipocytes and groups 5-8 used HIF-1α-siRNA lentivirus-transfected mature adipocytes.After 24-h treatment,real-time polymerase chain reaction and Western blot were employed to determine the mRNA and protein expression levels of HIF-1αand Angptl4.In animal experiments,the CIH model in ApoE^(-/-)mice was established.Sixteen mice were complete randomly divided into 4 groups including sham group,CIH model group[intermittent hypoxia and normal saline(2 mL/time)gavage once a day],Angptl4 Ab group[intermittent hypoxia and Angptl4 antibody(30 mg/kg)intraperitoneally injected every week],DLT group[intermittent hypoxia and DLT(250 mg/kg)once a day],4 mice in each group.After 4-week treatment,enzyme linked immunosorbent assay was used to detect the levels of serum total cholesterol(TC)and triglyceride(TG).Hematoxylin-eosin and CD68 staining were used to observe the morphological properties of arterial plaques.Results:Angptl4 expression was dependent on HIF-1α,with a reduction in mRNA expression and no response in protein level to DMOG or DLT treatment in relation to siHIF-1α-transfected cells.DLT inhibited HIF-1αand Angptl4 mRNA expression(P<0.05 or P<0.01)and reduced HIF-1αand Angptl4 protein expressions with DMOG in mature adipocytes(all P<0.01),as the effect on HIF-1αprotein also existed in the pres展开更多
Background:In the early metastasis of colon cancer,cancer cells detach,migrate,and infiltrate surrounding tissues,including lymph vessels and blood vessels.Tumor heterogeneity arises from both tumor cells and distinct...Background:In the early metastasis of colon cancer,cancer cells detach,migrate,and infiltrate surrounding tissues,including lymph vessels and blood vessels.Tumor heterogeneity arises from both tumor cells and distinct microenvironments.Maldistribution of blood vessels,creates hypoxic regions within the tumors,fostering cancer stem cell-like properties due to reduced oxygen and nutrient supply.Under hypoxia,tumor cells shift to a glycolytic pathway,producing more lactic acid that acidifies the microenvironment and leads to unstable heart rate variability(HRV)factors,weight disparity,and a higher incidence of aberrant crypt foci(ACF).These hypoxic-induced parameters promote cancer cell invasion,increase radiation resistance,and facilitate cancer cell migration.Methods:In this study,we induced hypoxia-preneoplastic colon damage in albino Wister rats by administrating 1,2-dimethyl hydrazine(DMH).After successfully creating a hypoxic environment in albino Wister rats,resulting in preneoplastic colon damage,we randomly allocated Wistar albino rats into seven groups,each containing 8 animals,and conducted a 6-week study.Group 1-Normal control(administered 1 mM EDTA+saline,2 ml/kg/day,p.o.);group 2-Toxic control(administered DMH,30 mg/kg/week,s.c.);group 3-Standard treatment(DMH,30 mg/kg/week,s.c.for 6 weeks),followed by 5-fluorouracil and Leucovorin(25 mg/kg each on 1^(st),3^(rd),7^(th),and 10^(th) days,i.p.after 6 weeks administration of DMH);group 4-Low dose of P1(DMH,30 mg/kg/week,s.c.+P1,2 mg/kg,i.v.,weekly for 3 weeks);group 5-High dose P1(DMH,30 mg/kg/week,s.c.+P1,4 mg/kg,i.v.,weekly for 3 weeks),group 6-Low dose of P2(DMH,30 mg/kg/week,s.c.,+P2,2 mg/kg,i.v.,weekly for 3 weeks),group 7-High dose of P2(DMH,30 mg/kg/week,s.c.,+P2,4 mg/kg,i.v.weekly for 3 weeks).Results:DMH-treated rats exhibited alterations in HRV factors,weight disparity,elevated gastric pH,increased total acidity,a higher incidence of ACF,and changes in antioxidant markers(TBARs,SOD,catalase,GSH).Brightfield microscopy at 40x magnification reveale展开更多
The effects of nicotinamide adenine dinucleotide phosphate （NADPH） oxidase inhibitor apocynin on the enhanced hypoxia induced factor-let （HIF-lct） and endothelin-1 （ET-1） expression, elevated systolic blood pres...The effects of nicotinamide adenine dinucleotide phosphate （NADPH） oxidase inhibitor apocynin on the enhanced hypoxia induced factor-let （HIF-lct） and endothelin-1 （ET-1） expression, elevated systolic blood pressure under chronic intermittent hypoxia （CIH） condition and its action mechanism were investigated. Thirty healthy 8-week old Sprague-Dawley （SD） male rats were randomly divided into three groups （n=10 each）： sham group, CIH group, and apocynin-treated CIH group. Tail artery systolic blood pressure was measured by tail-cuff method. Real-time fluorescence quantitative polymerase chain reaction （PCR） was used to detect the mRNA expression of HIF-lu and ET-1 in the carotid body, and the HIF-1a protein expression was examined by using Western blotting. The levels of malondialdehyde （MDA） and superoxide dismutase （SOD） were determined by using colorimetric method. In addition, the plasma ET-1 and HIF-1a levels were measured by using enzyme-linked immunosorbent assay. It was found that CIH exposure was associated with increased MDA levels, and apo- cynin-treated CIH animals showed reduction in MDA levels. Apocynin treatment prevented CIH-induced hypertension as well as CIH-induced decrease in SOD. The increases of HIF-1a and ET-1 mRNA along with HIF-la protein expression in the carotid body, and elevated circulating HIF-1a and ET-1 levels were observed in CIH-exposed animals. Treatment with apocynin significantly decreased the ET-1 mRNA, HIF-lct protein expression and circulating HIF-la level in CIH-exposed animals, and there was no statistically significant difference in the HIF-lu mRNA expression between CIH group and apo- cynin-treated group. These results indicated that apocynin alleviated CIH-induced hypertension by inhibiting NADPH oxidase, further leading to the reduced vasoconstrictor ET-1 level and oxidative stress. HIF-1a/ET-1 system signal pathway may interact with CIH-induced NADPH oxidase-dependent oxidative stress. Inhibition of NADPH oxidase activity may hopef展开更多
Background:Pulmonary hypertension(PH)represents a threatening pathophysiologic state that can be induced by chronic hypoxia and is characterized by extensive vascular remodeling.However,the mechanism underlying hypoxi...Background:Pulmonary hypertension(PH)represents a threatening pathophysiologic state that can be induced by chronic hypoxia and is characterized by extensive vascular remodeling.However,the mechanism underlying hypoxia-induced vascular remodeling is not fully elucidated.Methods and Results:By using quantitative polymerase chain reactions,western blotting,and immunohistochemistry,we demon-strate that the expression of N-myc downstream regulated gene-1(NDRG1)is markedly increased in hypoxia-stimulated endothelial cells in a time-dependent manner as well as in human and rat endothelium lesions.To determine the role of NDRG1 in endothelial dysfunction,we performed loss-of-function studies using NDRG1 short hairpin RNAs and NDRG1 over-expression plasmids.In vitro,silencing NDRG1 attenuated proliferation,migration,and tube formation of human pulmonary artery endothelial cells(HPAECs)un-der hypoxia,while NDRG1 over-expression promoted these behaviors of HPAECs.Mechanistically,NDRG1 can directly interact with TATA-box binding protein associated factor 15(TAF15)and promote its nuclear localization.Knockdown of TAF15 abrogated the effect of NDRG1 on the proliferation,migration and tube formation capacity of HPAECs.Bioinformatics studies found that TAF15 was involved in regulating PI3K-Akt,p53,and hypoxia-inducible factor 1(HIF-1)signaling pathways,which have been proved to be PH-related pathways.In addition,vascular remodeling and right ventricular hypertrophy induced by hypoxia were markedly alleviated in NDRG1 knock-down rats compared with their wild-type littermates.Conclusions:Taken together,our results indicate that hypoxia-induced upregulation of NDRG1 contributes to endothelial dysfunction through targeting TAF15,which ultimately contributes to the development of hypoxia-induced PH.展开更多
Background:Tumor hypoxia is considered an important factor in metastasis and disease relapse.Evofosfamide is a hypoxia-activated prodrug that selectively targets the hypoxic regions of solid tumors.As hypoxia-inducibl...Background:Tumor hypoxia is considered an important factor in metastasis and disease relapse.Evofosfamide is a hypoxia-activated prodrug that selectively targets the hypoxic regions of solid tumors.As hypoxia-inducible factor-1α(HIF-1α)is overexpressed in nasopharyngeal carcinoma(NPC)tissues,we performed the present study to evaluate the efficacy profile of evofosfamide in NPC.Methods:We evaluated the efficacy of evofosfamide as a single agent or combined with cisplatin(DDP)in the NPC cell lines CNE-2,HONE-1 and HNE-1,and in nude mouse xenograft tumor models.Results:Evofosfamide exhibited hypoxia-selective cytotoxicity in NPC cell lines,with 50%inhibition concentration(IC50)values of 8.33±0.75,7.62±0.67,and 0.31±0.07μmol/L under hypoxia in CNE-2,HONE-1 and HNE-1 cells,respectively.The sensitization ranged from ninefold to greater than 300-fold under hypoxia compared with normoxia controls.The combination of evofosfamide with DDP had a synergistic effect on cytotoxicity in the NPC cell lines by combination index values assessment.Cell cycle G2 phase was arrested after treated with 0.05μmol/L evofosfamide under hypoxia.Histone H2AX phosphorylation(γH2AX)(a marker of DNA damage)expression increased while HIF-1αexpression suppressed after evofosfamide treatment under hypoxic conditions.In the HNE-1 NPC xenograft models,evofosfamide exhibited antitumor activity both as a single agent and combined with DDP.Hypoxic regions in xeno-graft tissue were reduced after both evofosfamide monotherapy and combined therapy with DDP.Conclusions:Our results present preclinical evidence for targeting the selective hypoxic portion of NPC by evofosfa-mide as a single agent and combined with DDP and provide rationale for the potential clinical application of evofosfa-mide for the treatment of nasopharyngeal carcinoma.展开更多
Objective:To explore the expression and clinical significance of Sema4A in triple-negative breast cancer.Metlods:Eighty patients with invasive ductal carcinoma of the breast and 40 normal tissues adjacent to cancer we...Objective:To explore the expression and clinical significance of Sema4A in triple-negative breast cancer.Metlods:Eighty patients with invasive ductal carcinoma of the breast and 40 normal tissues adjacent to cancer were selected.Immumohistochemical methods were used to detect the expression of Sema4A in breast cancer and normal tissues adjacent to cancer,and its relationship with breast cancer clinicopathological features and prognosis.Results:The expression of Sema4a in the serum of BCA patients was significantly higher than that of healthy controls.In addition,the expression of sema4a in BCA cells and in the cell supernatants was also up-regulated under hypoxia.Conclusion:Exogenous Sema4A can protect BCA cells from hypoxia-induced cytotoxicity,inhibit cell apoptosis and promote cell proliferation.展开更多
Objective: To study the correlation of the change of hypoxia-induced factor-1α (HIF-1α) in oral squamous cell carcinoma lesion with lymph node metastasis and malignant biological molecule expression. Methods: The pa...Objective: To study the correlation of the change of hypoxia-induced factor-1α (HIF-1α) in oral squamous cell carcinoma lesion with lymph node metastasis and malignant biological molecule expression. Methods: The patients with oral squamous cell carcinoma who underwent surgical resection in the First Hospital of Yulin between March 2012 and December 2017 were selected as the research subjects, and right amount of oral squamous cell carcinoma lesion and lesion adjacent to carcinoma were collected after surgical resection to determine the mRNA expression of HIF-1α, proliferation genes and invasion genes as well as the contents of angiogenesis molecules. Results: HIF-1α, PCNA, CDK4, CDK6, Slug, β-catenin and MMP9 mRNA expression as well as VEGF, Ang-2, bFGF and COX-2 contents in oral squamous cell carcinoma lesions were significantly higher than those in adjacent lesions whereas PDCD5, Smac, E-cadherin and RECK mRNA expression were significantly lower than those in adjacent lesions;Pearson correlation analysis showed that HIF-1α mRNA expression in oral squamous cell carcinoma lesions was positively correlated with PCNA, CDK4, CDK6, Slug, β-catenin and MMP9 mRNA expression as well as VEGF, Ang-2, bFGF and COX-2 contents, and negatively correlated with PDCD5, Smac, E-cadherin and RECK mRNA expression. Conclusion: Highly expressed HIF-1α in oral squamous cell carcinoma can promote the proliferation and invasion of cancer cells as well as the angiogenesis in the lesion.展开更多
Objective: To detect the expression changes of proton-sensing receptor G protein-coupled receptor 2A (G2A) and ovarian cancer G protein-coupled receptors 1 (OGR1) in human peripheral blood cells of patients with hypox...Objective: To detect the expression changes of proton-sensing receptor G protein-coupled receptor 2A (G2A) and ovarian cancer G protein-coupled receptors 1 (OGR1) in human peripheral blood cells of patients with hypoxia-induced pulmonary hypertension (HPH). Methods: Thirty-one patients with HPH were enrolled for IPH group, 16 males and 15 females, aged (65.19 ± 5.86) years;and 30 healthy people were enrolled for control group (NC group), 15 males and 15 females, aged (63.47 ± 6.16) years. The peripheral blood samples were collected and the mRNA expressions of G2A and OGR1 were determined by using real-time fluorescent quantitative PCR. The pulmonary arterial pressure (PAP) of HPH group was detected with echocardiography for the analysis of blood gas and pulmonary function testing. Human peripheral blood was collected to detect the mRNA levels of G2A, OGR1 and the serum levels of tumor necrosis factor-α (TNF-α). Results: PaCO2 was increased significantly in HPH group than that in NC group (p < .05). The percentage of forced expiratory volume in 1 s in predicted value (FEV1 pro%) and the ratio of FEV1/forced vital capacity (FVC) in HPH group were significant lower than those in NC group (p < .05). The expressions of peripheral blood G2A mRNA and TNF-α in HPH group were increased dramatically than those in NC group (p < .05). The expressions of OGR1 mRNA in peripheral blood had no difference between HPH group and NC group. The expressions of G2A mRNA and TNF-α in HPH group were positively related to pulmonary artery pressure significantly. Conclusions: The expression of proton-sensing receptor G2A and the level of TNF-α were increased in peripheral blood cells of patients with pulmonary hypertension. The expressions of TNF-α and G2A had positive correlations with pulmonary artery pressure.展开更多
Breast cancer usually grows very quickly,becoming insensitive to blood flow in nearby veins;because of that,inside solid tumors it's possible to find a hypoxic environment,in other words,an environment where oxyge...Breast cancer usually grows very quickly,becoming insensitive to blood flow in nearby veins;because of that,inside solid tumors it's possible to find a hypoxic environment,in other words,an environment where oxygen is less available.Another feature of cancer is its angiogenesis rate,because of the high energy demand,new blood vessels must be produced to take nutrients inside the solid tumor mass.Even with normal blood flow bringing the cancer oxygen and nutrients,its cells favor hypoxia,in an event known as Warburg Effect.According to the Warburg Effect,cells,even with normal oxygen rates,prefer to use fermentation instead of the citric acid cycle to produce ATP.For the cancer to operate normally in hypoxia,a transcription factor family is activated,known as hypoxia-induced factors(HIF),composed of a HIF-1βand a HIF-1αsubunits.As HIF-1αis expressed during hypoxia,it is a great target for treatments and a breast cancer biomarker.Because of the role of HIF-1αin cancer and the high incidence of breast cancer worlwide,this review was performed in order to bring the most recent results concerning the role HIF-1αcan exert in breast cancer development and progression.展开更多
BACKGROUND： Cardiocerebrovascular diseases induced cerebral circulation insufficiency and senile vascular dementia can result in ischemic/hypoxic apoptosis of central neurons, which we should pay more attention to an...BACKGROUND： Cardiocerebrovascular diseases induced cerebral circulation insufficiency and senile vascular dementia can result in ischemic/hypoxic apoptosis of central neurons, which we should pay more attention to and prevent and treat as early as possible. Traditional Chinese medicine possesses the unique advantage in this field. Polygonatum, a Chinese herb for invigorating qi, may play a role against the hypoxic apoptosis of brain neurons. OBJECTIVE ： To observe the protective effect of polygonatum polysaccharide on hypoxia-induced apoptosis and necrosis in cerebral cortical neurons cultured in vitro. DESIGN： A comparative experiment.SETTING： Laboratory of Cell Biology, Institute of Basic Medical Sciences, Jiangxi Provincial Academy of Traditional Chinese Medicine. MATERIALS： The experiment was carried out in the Laboratory of Cell Biology, Institute of Basic Medical Sciences, Jiangxi Provincial Academy of Traditional Chinese Medicine from November 2003 to April 2005. Totally 218 Wistar rats （male or female） of clean degree within 24 hours after birth were purchased from the animal center of Jiangxi Medical College （certification number was 021-97-03）. METHODS：① Preparation of cerebral cortical neurons of rats： The cerebral cortical tissues were isolated from the Wistar rats within 24 hours after birth, and prepared to single cell suspension, and the cerebral cortical neurons of neonatal rats were in vitro cultured in serum free medium with Neurobasal plus B27 Supplement. ② Observation on the non-toxic dosage of polygonatum polysaccharide on neurons： After the neurons were cultured for 4 days, polygonatum polysaccharide of different dosages （1-20 g/L） was added for continuous culture for 48 hours, the toxicity and non-toxic dosage of polygonatum polysaccharide on neurons were observed and detected with trypan blue staining. ③Grouping： After hypoxia/reoxygenation, the cultured neurons were divided into normal control group, positive apoptotic group and polygonatum polysacchari展开更多
基金Supported by Liaoning Province Science and Technique Foundation of China(No.201102107)
文摘Objective： To investigate whether ginsenoside-Rbl （Gs-Rb1） inhibits the apoptosis of hypoxia cardiomyocytes by up-regulating apelin-APJ system and whether the system is affected by hypoxia-induced factor 1α （Hif-1α）. Methods： Neonatal rat cardiomyocytes were randomly divided into 6 groups： a control group, a simple COCl2 group, a simple Gs-Rbl group, a CoCl2 and Gs-Rbl hypoxia group, a CoCl2 and 3-（5＇-hydroxymethyl-2＇-furyl）-1-benzylindazole （YC-1） group, a CoCl2 and YC-1 group and a Gs-Rbl group, in which YC-1 inhibits the synthesis and accelerates the degradation of Hif-la. The concentration of COCI2, Gs-Rbl and YC-1 was 500 μmol/L, 200 μ mol/L and 5 μmol/L, respectively; the apoptosis ratio was analyzed with a flow cytometer; and apelin, APJ and Hif-1 c= were assayed with immunocytochemistry, Western blot assays and reverse transcription polymerase chain reaction （RT-PCR）. Results： （1） The anti-apoptosis effect of Gs-Rbl on hypoxia cardiomyocytes was significantly inhibited by YC-1; （2） Hypoxia significantly up-graded the expression of mRNA and protein of apelin; this effect was further reinforced by Gs-Rbl and significantly inhibited by YC-1; （3） Gs-Rb1 further strengthened the expression of APJ mRNA and APJ proteins once hypoxia occurred, which was significantly inhibited by YC-1; （4） Gs-Rb1 significantly increased the expression of Hif-1α, which was completely abolished by YC-1; （5） There was a negative relationship between AR and apelin （or APJ, including mRNA and protein）, a positive correlation between apelin （or APJ） protein and Hif-1a protein, in hypoxia cardiomyocytes. Conclusion： The apelin-APJ system plays an important role in the anti-apoptosis effect of Gs- Rb1 on hypoxia neonatal cardiomyocytes, which was partly adjusted by Hif-1α.
文摘Hypoxic pulmonary hypertension (HPH) is a common complication in patients with chronic obstructive pulmonary disease (COPD), sleep-disordered breathing, or dwellers in high altitude. The exact mechanisms underlying the development of HPH still remain unclear. Reactive oxygen species (ROS),hypoxia inducible factors (HIF), and potassium channels (KV) are believed as the main factors during the development of HPH. We propose that the “ROS/Kv/HIF axis” may play an important initiating role in the development of HPH. Being formed under a hypoxic condition, ROS affects the expression and function of HIFs or KV, and consequently triggers multiple downstream signaling pathways and genes expression that participate in promoting pulmonary vasoconstriction and arterial remodeling. Thus, further study determining the initiating role of “ROS/Kv/HIF axis” in the development of HPH could provide theoretic evidences to better understand the underlying mechanisms of HPH, and help identify new potential targets in the treatment of HPH.
基金This work was supported by grants from Natural Science Foundation of Tianjin （No.10JCYBJC25800）, Tianjin Higher School Science and Technology Development Fund Project （No. 20100132） and Tianjin Medical University Fund （No. 2009KY17）.
文摘Background Intermittent hypoxia is the main pathophysiological cause of the obstructive sleep apnea syndrome. Astragalus shows improvement of spatial learning and memory abilities under intermittent hypoxia. Our study aimed to investigate the protective effect of astragalus against intermittent hypoxia induced-hippocampal neurons impairment in rats and lay the theoretical foundation for the sleep apnea improvement in cognitive function by astragalus. Methods Male Wistar rats were divided into 4 groups： blank control group, normoxia group, intermittent hypoxia group and astragalus treated intermittent hypoxia group. After 6-week treatment, apoptosis of neurons was evaluated by terminal deoxynucleotidyl-transferase-mediated dUTP nick end-labeling （TUNEL） assay. Furthermore, the expression of HIF-la was detected by real-time reverse transcription polymerase chain reaction （RT-PCR） at the mRNA level as well as by immunohistochemistry （IHC） and Western blotting at the protein level. Results HPLC analysis indicated that astragaloside IV, astragaloside II and astragaloside I were the main compounds in astragals extract. Astragalus extract reduced the apoptosis of hippocampal neurons （P 〈0.05） and decreased the expression of HIF-la at both the mRNA and protein levels in hippocampus compared with non-treated groups （P 〈0.05）. Conclusion Astragalus protects aqainst intermittent hypoxia-induced hippocampal neurons impairment in rats.
基金Supported by National Natural Science Foundation of China(No.81473465)。
文摘Objective:To detect whether Danlou Tablet(DLT)regulates the hypoxia-induced factor(HIF)-1α-angiopoietin-like 4(Angptl4)mRNA signaling pathway and explore the role of DLT in treating chronic intermittent hypoxia(CIH)-induced dyslipidemia and arteriosclerosis.Methods:The mature adipocytes were obtained from3 T3-L1 cell culturation and allocated into 8 groups including control groups(Groups 1 and 5,0.1 mL of cell culture grade water);DLT groups(Groups 2 and 6,0.1 mL of 1,000μg/mL DLT submicron powder solution);dimethyloxalylglycine(DMOG)groups(Groups 3 and 7,DMOG and 0.1 mL of cell culture grade water);DMOG plus DLT groups(Groups 4 and 8,DMOG and 0.1 mL of 1,000μg/mL DLT submicron powder solution).Groups1-4 used mature adipocytes and groups 5-8 used HIF-1α-siRNA lentivirus-transfected mature adipocytes.After 24-h treatment,real-time polymerase chain reaction and Western blot were employed to determine the mRNA and protein expression levels of HIF-1αand Angptl4.In animal experiments,the CIH model in ApoE^(-/-)mice was established.Sixteen mice were complete randomly divided into 4 groups including sham group,CIH model group[intermittent hypoxia and normal saline(2 mL/time)gavage once a day],Angptl4 Ab group[intermittent hypoxia and Angptl4 antibody(30 mg/kg)intraperitoneally injected every week],DLT group[intermittent hypoxia and DLT(250 mg/kg)once a day],4 mice in each group.After 4-week treatment,enzyme linked immunosorbent assay was used to detect the levels of serum total cholesterol(TC)and triglyceride(TG).Hematoxylin-eosin and CD68 staining were used to observe the morphological properties of arterial plaques.Results:Angptl4 expression was dependent on HIF-1α,with a reduction in mRNA expression and no response in protein level to DMOG or DLT treatment in relation to siHIF-1α-transfected cells.DLT inhibited HIF-1αand Angptl4 mRNA expression(P<0.05 or P<0.01)and reduced HIF-1αand Angptl4 protein expressions with DMOG in mature adipocytes(all P<0.01),as the effect on HIF-1αprotein also existed in the pres
基金C.Karthikeyan,Indira Gandhi National Tribal University,Lalpur,Amarkantak,Anuppur,Madhya Pradesh,484887,India,for providing the gift sample of 1,2,4-triazine derivatives used for the study.
文摘Background:In the early metastasis of colon cancer,cancer cells detach,migrate,and infiltrate surrounding tissues,including lymph vessels and blood vessels.Tumor heterogeneity arises from both tumor cells and distinct microenvironments.Maldistribution of blood vessels,creates hypoxic regions within the tumors,fostering cancer stem cell-like properties due to reduced oxygen and nutrient supply.Under hypoxia,tumor cells shift to a glycolytic pathway,producing more lactic acid that acidifies the microenvironment and leads to unstable heart rate variability(HRV)factors,weight disparity,and a higher incidence of aberrant crypt foci(ACF).These hypoxic-induced parameters promote cancer cell invasion,increase radiation resistance,and facilitate cancer cell migration.Methods:In this study,we induced hypoxia-preneoplastic colon damage in albino Wister rats by administrating 1,2-dimethyl hydrazine(DMH).After successfully creating a hypoxic environment in albino Wister rats,resulting in preneoplastic colon damage,we randomly allocated Wistar albino rats into seven groups,each containing 8 animals,and conducted a 6-week study.Group 1-Normal control(administered 1 mM EDTA+saline,2 ml/kg/day,p.o.);group 2-Toxic control(administered DMH,30 mg/kg/week,s.c.);group 3-Standard treatment(DMH,30 mg/kg/week,s.c.for 6 weeks),followed by 5-fluorouracil and Leucovorin(25 mg/kg each on 1^(st),3^(rd),7^(th),and 10^(th) days,i.p.after 6 weeks administration of DMH);group 4-Low dose of P1(DMH,30 mg/kg/week,s.c.+P1,2 mg/kg,i.v.,weekly for 3 weeks);group 5-High dose P1(DMH,30 mg/kg/week,s.c.+P1,4 mg/kg,i.v.,weekly for 3 weeks),group 6-Low dose of P2(DMH,30 mg/kg/week,s.c.,+P2,2 mg/kg,i.v.,weekly for 3 weeks),group 7-High dose of P2(DMH,30 mg/kg/week,s.c.,+P2,4 mg/kg,i.v.weekly for 3 weeks).Results:DMH-treated rats exhibited alterations in HRV factors,weight disparity,elevated gastric pH,increased total acidity,a higher incidence of ACF,and changes in antioxidant markers(TBARs,SOD,catalase,GSH).Brightfield microscopy at 40x magnification reveale
基金supported by the National Natural Science Foundation of China(No.81070067)
文摘The effects of nicotinamide adenine dinucleotide phosphate （NADPH） oxidase inhibitor apocynin on the enhanced hypoxia induced factor-let （HIF-lct） and endothelin-1 （ET-1） expression, elevated systolic blood pressure under chronic intermittent hypoxia （CIH） condition and its action mechanism were investigated. Thirty healthy 8-week old Sprague-Dawley （SD） male rats were randomly divided into three groups （n=10 each）： sham group, CIH group, and apocynin-treated CIH group. Tail artery systolic blood pressure was measured by tail-cuff method. Real-time fluorescence quantitative polymerase chain reaction （PCR） was used to detect the mRNA expression of HIF-lu and ET-1 in the carotid body, and the HIF-1a protein expression was examined by using Western blotting. The levels of malondialdehyde （MDA） and superoxide dismutase （SOD） were determined by using colorimetric method. In addition, the plasma ET-1 and HIF-1a levels were measured by using enzyme-linked immunosorbent assay. It was found that CIH exposure was associated with increased MDA levels, and apo- cynin-treated CIH animals showed reduction in MDA levels. Apocynin treatment prevented CIH-induced hypertension as well as CIH-induced decrease in SOD. The increases of HIF-1a and ET-1 mRNA along with HIF-la protein expression in the carotid body, and elevated circulating HIF-1a and ET-1 levels were observed in CIH-exposed animals. Treatment with apocynin significantly decreased the ET-1 mRNA, HIF-lct protein expression and circulating HIF-la level in CIH-exposed animals, and there was no statistically significant difference in the HIF-lu mRNA expression between CIH group and apo- cynin-treated group. These results indicated that apocynin alleviated CIH-induced hypertension by inhibiting NADPH oxidase, further leading to the reduced vasoconstrictor ET-1 level and oxidative stress. HIF-1a/ET-1 system signal pathway may interact with CIH-induced NADPH oxidase-dependent oxidative stress. Inhibition of NADPH oxidase activity may hopef
基金supported by the National Natural Science Foundation of China(Grants No.81970048,82270058)starting fund for scientific research of Huashan Hospital Fudan University(Grant No.2017QD078).
文摘Background:Pulmonary hypertension(PH)represents a threatening pathophysiologic state that can be induced by chronic hypoxia and is characterized by extensive vascular remodeling.However,the mechanism underlying hypoxia-induced vascular remodeling is not fully elucidated.Methods and Results:By using quantitative polymerase chain reactions,western blotting,and immunohistochemistry,we demon-strate that the expression of N-myc downstream regulated gene-1(NDRG1)is markedly increased in hypoxia-stimulated endothelial cells in a time-dependent manner as well as in human and rat endothelium lesions.To determine the role of NDRG1 in endothelial dysfunction,we performed loss-of-function studies using NDRG1 short hairpin RNAs and NDRG1 over-expression plasmids.In vitro,silencing NDRG1 attenuated proliferation,migration,and tube formation of human pulmonary artery endothelial cells(HPAECs)un-der hypoxia,while NDRG1 over-expression promoted these behaviors of HPAECs.Mechanistically,NDRG1 can directly interact with TATA-box binding protein associated factor 15(TAF15)and promote its nuclear localization.Knockdown of TAF15 abrogated the effect of NDRG1 on the proliferation,migration and tube formation capacity of HPAECs.Bioinformatics studies found that TAF15 was involved in regulating PI3K-Akt,p53,and hypoxia-inducible factor 1(HIF-1)signaling pathways,which have been proved to be PH-related pathways.In addition,vascular remodeling and right ventricular hypertrophy induced by hypoxia were markedly alleviated in NDRG1 knock-down rats compared with their wild-type littermates.Conclusions:Taken together,our results indicate that hypoxia-induced upregulation of NDRG1 contributes to endothelial dysfunction through targeting TAF15,which ultimately contributes to the development of hypoxia-induced PH.
基金supported by National Natural Science Foundation of China(Grant No.81502355,81502352).
文摘Background:Tumor hypoxia is considered an important factor in metastasis and disease relapse.Evofosfamide is a hypoxia-activated prodrug that selectively targets the hypoxic regions of solid tumors.As hypoxia-inducible factor-1α(HIF-1α)is overexpressed in nasopharyngeal carcinoma(NPC)tissues,we performed the present study to evaluate the efficacy profile of evofosfamide in NPC.Methods:We evaluated the efficacy of evofosfamide as a single agent or combined with cisplatin(DDP)in the NPC cell lines CNE-2,HONE-1 and HNE-1,and in nude mouse xenograft tumor models.Results:Evofosfamide exhibited hypoxia-selective cytotoxicity in NPC cell lines,with 50%inhibition concentration(IC50)values of 8.33±0.75,7.62±0.67,and 0.31±0.07μmol/L under hypoxia in CNE-2,HONE-1 and HNE-1 cells,respectively.The sensitization ranged from ninefold to greater than 300-fold under hypoxia compared with normoxia controls.The combination of evofosfamide with DDP had a synergistic effect on cytotoxicity in the NPC cell lines by combination index values assessment.Cell cycle G2 phase was arrested after treated with 0.05μmol/L evofosfamide under hypoxia.Histone H2AX phosphorylation(γH2AX)(a marker of DNA damage)expression increased while HIF-1αexpression suppressed after evofosfamide treatment under hypoxic conditions.In the HNE-1 NPC xenograft models,evofosfamide exhibited antitumor activity both as a single agent and combined with DDP.Hypoxic regions in xeno-graft tissue were reduced after both evofosfamide monotherapy and combined therapy with DDP.Conclusions:Our results present preclinical evidence for targeting the selective hypoxic portion of NPC by evofosfa-mide as a single agent and combined with DDP and provide rationale for the potential clinical application of evofosfa-mide for the treatment of nasopharyngeal carcinoma.
文摘Objective:To explore the expression and clinical significance of Sema4A in triple-negative breast cancer.Metlods:Eighty patients with invasive ductal carcinoma of the breast and 40 normal tissues adjacent to cancer were selected.Immumohistochemical methods were used to detect the expression of Sema4A in breast cancer and normal tissues adjacent to cancer,and its relationship with breast cancer clinicopathological features and prognosis.Results:The expression of Sema4a in the serum of BCA patients was significantly higher than that of healthy controls.In addition,the expression of sema4a in BCA cells and in the cell supernatants was also up-regulated under hypoxia.Conclusion:Exogenous Sema4A can protect BCA cells from hypoxia-induced cytotoxicity,inhibit cell apoptosis and promote cell proliferation.
文摘Objective: To study the correlation of the change of hypoxia-induced factor-1α (HIF-1α) in oral squamous cell carcinoma lesion with lymph node metastasis and malignant biological molecule expression. Methods: The patients with oral squamous cell carcinoma who underwent surgical resection in the First Hospital of Yulin between March 2012 and December 2017 were selected as the research subjects, and right amount of oral squamous cell carcinoma lesion and lesion adjacent to carcinoma were collected after surgical resection to determine the mRNA expression of HIF-1α, proliferation genes and invasion genes as well as the contents of angiogenesis molecules. Results: HIF-1α, PCNA, CDK4, CDK6, Slug, β-catenin and MMP9 mRNA expression as well as VEGF, Ang-2, bFGF and COX-2 contents in oral squamous cell carcinoma lesions were significantly higher than those in adjacent lesions whereas PDCD5, Smac, E-cadherin and RECK mRNA expression were significantly lower than those in adjacent lesions;Pearson correlation analysis showed that HIF-1α mRNA expression in oral squamous cell carcinoma lesions was positively correlated with PCNA, CDK4, CDK6, Slug, β-catenin and MMP9 mRNA expression as well as VEGF, Ang-2, bFGF and COX-2 contents, and negatively correlated with PDCD5, Smac, E-cadherin and RECK mRNA expression. Conclusion: Highly expressed HIF-1α in oral squamous cell carcinoma can promote the proliferation and invasion of cancer cells as well as the angiogenesis in the lesion.
文摘Objective: To detect the expression changes of proton-sensing receptor G protein-coupled receptor 2A (G2A) and ovarian cancer G protein-coupled receptors 1 (OGR1) in human peripheral blood cells of patients with hypoxia-induced pulmonary hypertension (HPH). Methods: Thirty-one patients with HPH were enrolled for IPH group, 16 males and 15 females, aged (65.19 ± 5.86) years;and 30 healthy people were enrolled for control group (NC group), 15 males and 15 females, aged (63.47 ± 6.16) years. The peripheral blood samples were collected and the mRNA expressions of G2A and OGR1 were determined by using real-time fluorescent quantitative PCR. The pulmonary arterial pressure (PAP) of HPH group was detected with echocardiography for the analysis of blood gas and pulmonary function testing. Human peripheral blood was collected to detect the mRNA levels of G2A, OGR1 and the serum levels of tumor necrosis factor-α (TNF-α). Results: PaCO2 was increased significantly in HPH group than that in NC group (p < .05). The percentage of forced expiratory volume in 1 s in predicted value (FEV1 pro%) and the ratio of FEV1/forced vital capacity (FVC) in HPH group were significant lower than those in NC group (p < .05). The expressions of peripheral blood G2A mRNA and TNF-α in HPH group were increased dramatically than those in NC group (p < .05). The expressions of OGR1 mRNA in peripheral blood had no difference between HPH group and NC group. The expressions of G2A mRNA and TNF-α in HPH group were positively related to pulmonary artery pressure significantly. Conclusions: The expression of proton-sensing receptor G2A and the level of TNF-α were increased in peripheral blood cells of patients with pulmonary hypertension. The expressions of TNF-α and G2A had positive correlations with pulmonary artery pressure.
基金FAPESP Grant(2017/03558-3)Fellowship grant CNPq(133505/2018-9)to Carlos HFP.
文摘Breast cancer usually grows very quickly,becoming insensitive to blood flow in nearby veins;because of that,inside solid tumors it's possible to find a hypoxic environment,in other words,an environment where oxygen is less available.Another feature of cancer is its angiogenesis rate,because of the high energy demand,new blood vessels must be produced to take nutrients inside the solid tumor mass.Even with normal blood flow bringing the cancer oxygen and nutrients,its cells favor hypoxia,in an event known as Warburg Effect.According to the Warburg Effect,cells,even with normal oxygen rates,prefer to use fermentation instead of the citric acid cycle to produce ATP.For the cancer to operate normally in hypoxia,a transcription factor family is activated,known as hypoxia-induced factors(HIF),composed of a HIF-1βand a HIF-1αsubunits.As HIF-1αis expressed during hypoxia,it is a great target for treatments and a breast cancer biomarker.Because of the role of HIF-1αin cancer and the high incidence of breast cancer worlwide,this review was performed in order to bring the most recent results concerning the role HIF-1αcan exert in breast cancer development and progression.
文摘BACKGROUND： Cardiocerebrovascular diseases induced cerebral circulation insufficiency and senile vascular dementia can result in ischemic/hypoxic apoptosis of central neurons, which we should pay more attention to and prevent and treat as early as possible. Traditional Chinese medicine possesses the unique advantage in this field. Polygonatum, a Chinese herb for invigorating qi, may play a role against the hypoxic apoptosis of brain neurons. OBJECTIVE ： To observe the protective effect of polygonatum polysaccharide on hypoxia-induced apoptosis and necrosis in cerebral cortical neurons cultured in vitro. DESIGN： A comparative experiment.SETTING： Laboratory of Cell Biology, Institute of Basic Medical Sciences, Jiangxi Provincial Academy of Traditional Chinese Medicine. MATERIALS： The experiment was carried out in the Laboratory of Cell Biology, Institute of Basic Medical Sciences, Jiangxi Provincial Academy of Traditional Chinese Medicine from November 2003 to April 2005. Totally 218 Wistar rats （male or female） of clean degree within 24 hours after birth were purchased from the animal center of Jiangxi Medical College （certification number was 021-97-03）. METHODS：① Preparation of cerebral cortical neurons of rats： The cerebral cortical tissues were isolated from the Wistar rats within 24 hours after birth, and prepared to single cell suspension, and the cerebral cortical neurons of neonatal rats were in vitro cultured in serum free medium with Neurobasal plus B27 Supplement. ② Observation on the non-toxic dosage of polygonatum polysaccharide on neurons： After the neurons were cultured for 4 days, polygonatum polysaccharide of different dosages （1-20 g/L） was added for continuous culture for 48 hours, the toxicity and non-toxic dosage of polygonatum polysaccharide on neurons were observed and detected with trypan blue staining. ③Grouping： After hypoxia/reoxygenation, the cultured neurons were divided into normal control group, positive apoptotic group and polygonatum polysacchari
