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@#Hypoxia is the most common tumor microenvironment caused by rapid proliferation of tumor cells, and hypoxia-inducible factor (HIF) is the main transcription factor for tumor cells to adapt to hypoxia. Current research has found that HIF can interact with a variety of mesenchymal cells such as fibroblasts, endothelial cells and immune cells in the tumor microenvironment, leading to the transcription and expression of target genes in response to hypoxia, which ultimately promotes tumor angiogenesis, and induces physiological changes such as migration, invasion, and immune escape of tumor cells. However, the signaling pathways involved in the HIF regulatory mechanism are complex, and the mechanism of HIF in the tumor microenvironment need to be further investigated, also most HIF inhibitors are still in the preclinical research stage. This paper reviews the research progress on the effects of HIF on tumor mesenchymal stromal cells to provide a theoretical basis for the diagnosis, prevention and treatment of tumors targeting HIF.
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ObjectiveMyelodysplastic syndromes （MDS） is a group of clonal hematopoietic stem cell disorders，and this study aims to investigate the expression of hypoxia-inducible factor-1α（HIF-1α） in the bone marrow cells of patients with MDS and its correlation with the clinical features of MDS，the therapeutic efficacy of arsenic-containing Chineseherbal compound，and the survival prognosis. MethodAccording to the inclusion and exclusion criteria，27 MDS patients treated with arsenic-containing Chinese herbal compound in the Department of Hematology，Xiyuan Hospital，China Academy of Chinese Medical Sciences from January 2022 to September 2022 were included，and their bone marrow samples were collected by myelotomy. HIF-1α expression level in bone marrow cells was detected by real-time polymerase chain reaction （PCR） to analyze its correlation with clinical features，and logistic and Cox regression was used to analyze the risk factors affecting the efficacy and prognostic survival of MDS patients. ResultThe HIF-1α mRNA expression level was lower in bone marrow cells of MDS patients than in healthy subjects. HIF-1α was positively correlated with the degree of myelodysplasia（r=0.384，P<0.05） and bone marrow granulocytic system%（G%）（r=0.560，P<0.01）. Logistic regression showed that HIF-1α was a risk factor for the prognosis in the follow-up of the efficacy of treatment（P<0.05）and Cox regression showed that HIF-1α was an independent factor affecting the survival prognosis of MDS patients ［odds ratio（OR）=398.968，95% confidence interval（CI）（1.281，116 858.743），P<0.05］. ConclusionThe level of HIF-1α expression in bone marrow cells of MDS patients was closely related to the degree of clinical myelodysplasia and G%，and HIF-1α was a risk factor for the efficacy for and survival prognosis of MDS patients.
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ObjectiveThis study aims to investigate the inhibitory effect of Wutoutang on pannus formation in adjuvant-induced arthritis （AIA） rats with wind-cold-dampness Bi syndrome and its potential mechanism. MethodA total of 40 male SD specific pathogen-free （SPF） rats were selected and divided into blank group， wind-cold-dampness Bi syndrome group ［Complete Freund's Adjuvant （CFA）， 200 μg］， Wutoutang group （15 g·kg-1·d-1）， and indometacin group （10 mg·kg-1） according to random number table method. Except for the blank group， the other groups were given wind-cold-dampness stimulation before the CFA injection. After the rats were administered for 30 days， the basic conditions， onset time， arthritis index score， and foot swelling volume of AIA rats with wind-cold-dampness Bi syndrome were observed. Finally， peripheral arterial blood， ankle joint， and synovial tissue were taken. Enzyme-linked immunosorbent assay （ELISA） was used to detect serum hypoxia-inducible factor-1α （HIF-1α）， vascular endothelial growth factor A （VEGFA） protein content， and rheumatism， including anti-O （ASO）， C-reactive protein （CRP）， and rheumatoid factor （RF）. Hematoxylin-eosin （HE） staining revealed the changes in joint histomorphology. Immunohistochemistry was used to detect the expression of HIF-1α and VEGFA， two important proteins in the ankle pathway. Quantitative real-time polymerase chain reaction （Real-time PCR） was used to reveal mRNA levels of HIF-1α， VEGFA， angiopoietin-1 （Ang-1）， and angiopoietin-2 （Ang-2） in rat synovial tissue. ResultThe foot swelling volume and arthritis score of AIA rats with wind-cold-dampness Bi syndrome were substantially higher （P<0.01） compared with the blank group. Serum CRP， RF， and ASO levels were considerably elevated （P<0.01）. HE staining showed obvious hyperplasia of ankle synovium and synovial inflammation， angiogenesis and pannus formation， and aggravated bone destruction， indicating successful modeling. After the intervention of Wutoutang， the onset time was delayed （P<0.01）. Foot swelling volume and arthritis score were decreased （P<0.01）. Serum CRP， RF， and ASO levels were significantly decreased （P<0.01）. The inflammatory hyperplasia of synovial tissue， angiogenesis and pannus formation， and bone destruction were alleviated. The mRNA levels of HIF-1α， VEGFA， Ang-1， and Ang-2 in the synovial membrane were significantly decreased （P<0.05， P<0.01）. The expressions of HIF-1α and VEGFA in serum and ankle joints were decreased （P<0.01）. In the indomethacin group， the onset time of the disease was delayed （P<0.01）. Foot swelling volume and arthritis score were decreased （P<0.01）. Serum CRP， RF， and ASO levels were significantly decreased （P<0.01）. HIF-1α/VEGFA/Ang signaling pathway was activated， and pathological tissue injury was improved. ConclusionWutoutang can delay the onset time of AIA rats with wind-cold-dampness Bi syndrome， reduce foot swelling volume， arthritis score， rheumatic activity， and improve joint histopathology. It can inhibit pannus formation， and its mechanism may be related to down-regulating the expression of the HIF-1α/VEGFA/Ang pathway.
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ObjectiveTo observe the therapeutic effect of Shugan Huazheng prescription on hepatic fibrosis model rats induced by carbon tetrachloride （CCl4） and explore whether it plays its role through hypoxia-induced factor-1α/vascular endothelial growth factor/transforming growth factor-β1 （HIF-1α/VEGF/TGF-β1） pathway. MethodA total of 54 male SPF SD rats were randomly divided into six groups： blank group， model group， colchicine group （0.2 mg·kg-1）， and high-， medium-， and low-dose groups （29.52， 14.76， and 7.38 g·kg-1） of Shugan Huazheng prescription， with nine rats in each group. The molding was conducted three times a week for eight weeks. Administration began the day after the first injection， and the drug intervention was once a day for eight weeks. On the day after the last administration， the rats were deprived of food and water， and they were killed the next day， during which the physiological status of each group of rats was dynamically monitored. The pathological changes in the liver were observed by hematoxylin-eosin （HE） staining， and the content of hydroxyproline （HYP） and angiotensin Ⅱ （AngⅡ） in liver tissue were detected by enzyme-related immunosorbent assay （ELISA）. Real-time fluorescent quantitative PCR （Real-time PCR） was used to determine the mRNA expression levels of HIF-1α， VEGF， and TGF-β1 in liver tissue， and immunohistochemical method （IHC） and Western blot were used to detect the protein expression levels of HIF-1α， VEGF， and TGF-β1 in liver tissue. ResultCompared with the blank group， the overall condition of rats in the model group decreased significantly. The proliferation of connective tissue and the increase in adipose cells between hepatocytes were obvious. The content of HYP and Ang was increased. The mRNA and protein expressions of HIF-1α， VEGF， and TGF-β1 were increased to varying degrees （P<0.05）. Compared with the model group， the proliferation of connective tissue and inflammatory cell infiltration in the liver tissue of colchicine and Shugan Huazheng prescription groups were reduced. The content of HYP and Ang was decreased. The mRNA and protein expression levels of HIF-1α， VEGF， and TGF-β1 were decreased， and the colchicine group and high-dose group of Shugan Huazheng prescription were the most significant （P<0.05）. ConclusionShugan Huazheng prescription has an obvious therapeutic effect on CCl4-induced hepatic fibrosis model rats. Its therapeutic mechanism may be related to the regulation of the HIF-1α/VEGF/TGF-β1 signaling pathway and the improvement of hepatic hypoxia， vascular remodeling， and the syndrome of Qi deficiency and blood stasis in hepatic fibrosis.
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ObjectiveTo reveal the effects of Huanglian Jiedutang （HLJDT） on the learning and memory abilities of APP/PS1 transgenic mice via hypoxia-inducible factor-1α （HIF-1α）/vascular endothelial growth factor （VEGF） signaling pathway. MethodForty 5-month-old β-amyloid precursor protein （APP）/presenilin 1（PS1） mice were randomized into the model， donepezil （0.001 g·kg-1·d-1）， and low-， medium-， and high-dose （1.5， 3， 6 g·kg-1·d-1， respectively） HLJDT groups， and 8 C57BL/6 mice were taken as the normal group. After 45 days of continuous administration， Morris water maze test was conducted， and the organ indexes were calculated. The morphological structure of cerebral vascular endothelial cells in mice was observed under a transmission electron microscope. Western blot was employed to measure the protein levels of APP， HIF-1α， VEGF，VEGFA， and brain-derived neurotrophic factor （BDNF） in the hippocampus. The mRNA levels of APP， HIF-1α， and VEGF were determined by real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. ResultCompared with the normal group， the model group showed prolonged escape latency （P<0.05）， reduced distance and time around the target platform （P<0.05）， decrease brain and spleen indexes （P<0.05）， vascular endothelial cells with karyopyknosis and not abundant cytoplasm， up-regulated protein levels of APP， HIF-1α， VEGF， and VEGFA （P<0.05）， down-regulated protein level of BDNF （P<0.05）， and up-regulated mRNA levels of APP， HIF-1α， and VEGF （P<0.05） in the hippocampus. Compared with the model group， high-dose HLJDT shortened the escape latency （P<0.05）， increased the distance and time around the target platform （P<0.05）， raised the brain and spleen indexes （P<0.05）， repaired the organelles of vascular endothelial cells， down-regulated the protein levels of APP， HIF-1α， VEGF， and VEGFA （P<0.05）， up-regulated the protein level of BDNF （P<0.05）， and down-regulated the mRNA levels of APP， HIF-1α， and VEGF （P<0.05） in the hippocampus. ConclusionHLJDT can improve the learning and memory abilities of mice by reducing the expression of HIF-1α and VEGF， thus protecting the nerves.
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AIM: To investigate the effect of long non-coding RNA-HIF1A-AS1(lncRNA HIF1A-AS1)on the chemotherapy sensitivity of vincristine(VCR)-resistant in retinoblastoma(RB)cells by regulating the expression of hypoxia-inducible factor-1α(HIF-1α).METHODS: The human RB VCR-resistant cell line SO-RB50/VCR was established, expression of lncRNA HIF1A-AS1 in SO-RB50 and SO-RB50/VCR cells were detected by reverse transcription-quantitative real-time PCR(RT-qPCR); inhibition of lncRNA HIF1A-AS1 expression or simultaneous overexpression of HIF-1α in SO-RB50/VCR cells, and then median inhibitory concentration(IC50)of VCR and cell proliferation and apoptosis were detected in SO-RB50/VCR cells; the protein expressions of HIF-1α, multidrug resistance associate protein(MRP)and P-glycoprotein(P-gp)were measured by Western blot.RESULTS: Compared with SO-RB50 cells, the expression levels of lncRNA HIF1A-AS1 and HIF-1α protein in SO-RB50/VCR cells were increased(P<0.05); after inhibiting the expression of lncRNA HIF1A-AS1 in SO-RB50/VCR cells, the apoptosis rate was significantly increased(P<0.05), optical density(OD450), the IC50 value of VCR on cells and the expression levels of HIF-1α, MRP and P-gp proteins were significantly reduced(P<0.05); overexpression of HIF-1α attenuates the inhibitory effect of down-regulated lncRNA HIF1A-AS1 expression on drug resistance in SO-RB50/VCR cells.CONCLUSION: The lncRNA HIF1A-AS1 was highly expressed in SO-RB50/VCR cells, and inhibition of lncRNA HIF1A-AS1 expression reduced VCR resistance in SO-RB50/VCR cells by down-regulating HIF-1α expression.
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As a common clinical disease, fracture is often accompanied by pain, swelling, bleeding as well as other symptoms and has a high disability rate, even threatening life, seriously endangering patients' physical and psychological health and quality of life. Medical practitioners take many strategies for the treatment of fracture healing, including Traditional Chinese Medicine (TCM). In the early stage of fracture healing, the local fracture is often in a state of hypoxia, accompanied by the expression of hypoxia inducible factor-1α (HIF-1α), which is beneficial to wound healing. Through literature mining, we thought that hypoxia, HIF-1α and downstream factors affected the mechanism of fracture healing, as well as dominated this process. Therefore, we reviewed the local characteristics and related signaling pathways involved in the fracture healing process and summarized the intervention of TCM on these mechanisms, in order to inspirit the new strategy for fracture healing, as well as elaborate on the possible principles of TCM in treating fractures based on the HIF molecular mechanism.
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ABSTRACT Objective: This study aimed to compare the levels of HIF1-α, VEGF, TNF-α, and IL-10 in the peri-implant crevicular fluid of patients with and without peri-implantitis. Methods: Forty patients, comprising 16 with and 24 without peri-implantitis were selected. Results: Patients with peri-implantitis exhibited significantly higher HIF-1α levels than those without peri-implantitis (p=0.0005). TNF-α revealed significant positive correlations with IL-10 (p=0.0008) and VEGF (p=0.0246), whereas HIF-1α and IL-10 levels (p=0.0041) demonstrated a negative and significative correlation in the peri-implantitis group. Conclusion: This study, for the first time demonstrates the balance of HIF-1α, TNFα, IL-10, and VEGF in peri-implantitis. It shows an elevated HIF-1α levels in patients with peri-implantitis, which could have stemmed from persistent inflammation- triggered hypoxia. Furthermore, the positive correlation between TNF-α and VEGF suggests intensified proinflammatory activity in peri-implantitis. Nevertheless, further studies are essential to understand these immune dynamics in peri-implantitis.
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El oxígeno y dióxido de carbono son vitales en la respiración, sus variaciones fuera del rango fisiológico son una amenaza para la supervivencia de las células. La hipoxia es una condición común en la mayoría de los tumores malignos, la cual promueve angiogénesis y vascularización disfuncional, mayor proliferación celular y la adquisición de un fenotipo de transición epitelial a mesenquimatoso, que contribuye con la metástasis; asimismo, altera el metabolismo de las células cancerosas y genera resistencia a la terapia, ya que induce a la inactividad celular. Por tanto, la hipoxia es un factor negativo, asociado a resultados adversos en la mayoría de los tratamientos de los distintos tipos de cáncer. El factor inducible por hipoxia (HIF) es el factor de transcripción relacionado con la hipoxia en cáncer, que produce la activación de más de una centena de genes reguladores de la actividad celular, que generan funciones cruciales para el desarrollo del cáncer. El objetivo principal de la presente revisión es puntualizar la importancia de la hipoxia en la génesis del cáncer, conocer las principales moléculas que interactúan en la expresión del HIF, explicar los mecanismos moleculares de las vías involucradas en la inducción del HIF, las consecuencias celulares por su alteración y las potenciales terapias dirigidas contra este factor. Se consultaron PubMed, Scopus y SciELO, del año 1990 hasta el año 2022, y se buscaron las referencias bibliográficas en relación con las palabras clave asociadas al factor inducible por hipoxia y cáncer. En conclusión, la sobreexpresión de HIF-1α en biopsias tumorales se asocia con una mayor mortalidad de pacientes en cánceres humanos. Los posibles genes diana regulados por HIF-1α que pueden desempeñar un papel en la progresión tumoral están empezando a descubrirse. A pesar de que se han estudiado cientos de compuestos en relación con el HIF en cáncer, en la actualidad existen pocos inhibidores del HIF aprobados en el mercado mundial; asimismo, muchos estudios clínicos, en sus distintas fases en desarrollo, no muestran resultados alentadores. Probablemente, en el futuro, cuando se tenga una mejor comprensión de la estructura, funcionamiento molecular y biológico de este factor, se desarrollarán fármacos más específicos para la inhibición del HIF.
Oxygen and carbon dioxide are essential for breathing; variations in these gases outside of the normal range are a threat to cell survival. Hypoxia is a common condition that occurs in most malignant tumors, increases angiogenesis and defective vascularization, promotes cell proliferation and acquires an epithelial-mesenchymal transition phenotype, which causes metastasis. It also affects cancer cell metabolism and makes patients resistant to treatment by causing cell quiescence. As a result, hypoxia is a detrimental component that is linked to unfavorable outcomes in most cancer treatments. Through the activation of more than a hundred genes that control cell activity, which produce key functions for cancer development, the transcription factor known as hypoxia-inducible factor (HIF) is linked to hypoxia in cancer. This review's main goals are to highlight the role of hypoxia in the development of cancer, identify the key molecules that interact to promote HIF expression, explain the molecular mechanisms of the pathways that lead to HIF induction, describe the cellular effects of HIF alteration, and discuss potential HIF-targeted therapies. Articles from 1990 to 2022 were reviewed in PubMed, Scopus and SciELO databases. Keywords related to cancer and HIF were searched in bibliographical references. In conclusion, HIF-1α overexpression in tumor biopsies is associated with increased patient mortality in human cancers. Potential HIF-1α-regulated target genes that may play a role in tumor progression are starting to be identified. Although hundreds of chemicals have been studied in relation to HIF in cancer, there are currently few approved HIF inhibitors available on the global market; moreover, many clinical trials, in their various stages of development, do not show encouraging results. It is likely that in the future, when there is a better understanding of the structure, molecular and biological functioning of this factor, more specific drugs for HIF inhibition will be developed.
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OBJECTIVE To preliminarily investigate the impacts of galangin （Gal） on fracture healing in osteoporosis （OP） model rats by regulating hypoxia-inducible factor-1α （HIF-1α）/vascular endothelial growth factor （VEGF） signaling pathway. METHODS The OP rat model was constructed by using bilateral ovariectomy surgery. The model rats were randomly divided into sham operation group （normal saline）， model group （normal saline）， Gal low-dose， medium-dose and high-dose groups （2.5， 5， 10 mg/kg）， inhibitor group （10 mg/kg Gal+100 mg/kg HIF-1α/VEGF signaling pathway inhibitor PX-478）， with 12 rats in each group. They were given relevant medicine intraperitoneally， once a day， for 90 consecutive days. The microstructure of rat bones was observed， the biomechanical status of rat femurs was evaluated， and the pathological damage and neovascularization of rat callus tissue were observed. The expression of platelet endothelial cell adhesion molecule-1 （PECAM-1） in the femur was detected. The contents of osteocalcin （OCN）， C-terminal telopeptides of type Ⅰ collagen （CTX-Ⅰ） and bone morphogenetic protein 2 （BMP-2） in serum were detected as well as the expressions of alkaline phosphatase （ALP） and HIF-1α/VEGF signaling pathway- related proteins in callus tissue. RESULTS Compared with the sham operation group， the BMD， BV/TV， Tb.N， Tb.Th， maximum load， the number and area of blood vessels， the average fluorescence intensity of PECAM-1， the contents of OCN and BMP-2， and the expression levels of ALP， HIF-1α and VEGF proteins in the model group were reduced significantly （P＜0.05）， while the content of CTX-Ⅰ increased significantly （P＜0.05）. Compared with the model group， the above indexes of rats were reversed significantly in Gal low-dose， medium-dose and high-dose groups （P＜0.05）， in a dose-dependent manner. Compared with the Gal high-dose group， the above indexes of rats were reversed significantly in the inhibitor group （P＜0.05）. CONCLUSIONS Gal can regulate bone metabolism， improve bone density of OP model rats and promote fracture healing， the mechanism of which may be associated with activating the HIF-1α/VEGF signaling pathway and promoting angiogenesis.
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Objective:To observe the expression of angiopoietin-like protein 4 (ANGPTL4) signaling pathway in adenine-induced chronic kidney disease (CKD) rat model, and to explore the role of this pathway in renal fibrosis.Methods:Thirty-six male Sprague-Dawley rats were randomly divided into control group (saline, intragastric administration, n=15) and CKD group (250 mg·kg -1·d -1 2.5% adenine, intragastric administration, n=21). At the end of the 1st, 2nd and 4th week, 5 rats were randomly selected from each group. Renal function and 24-hour urinary protein quantity were measured. HE and Masson staining were used to observe the pathological changes of kidneys. Immunohistochemistry and real-time PCR were used to detect renal protein and mRNA expressions of hypoxia-inducible factor-1α (HIF-1α), ANGPTL4, bone morphogenetic protein 7 (BMP7), Smad1, α-smooth muscle actin (α-SMA) and type Ⅰ collagen (Col-Ⅰ). Pearson correlation analysis was used to analyze the correlation between the different indicators. Results:(1) Compared with the control group, the expression levels of serum creatinine and blood urea nitrogen in CKD group were higher at each time point, and the expression levels of 24-hour urinary protein quantity were higher at the end of the 2nd and 4th week (all P < 0.05). (2) HE and Masson staining showed that there were obvious renal structural disorders and collagen fiber deposition at each time point in CKD group compared with the control group, which got worse with time. (3) The results of immunohistochemistry and real-time PCR showed that compared with the control group, the protein and mRNA expression levels of ANGPTL4, α-SMA and Col-Ⅰ were higher, while the protein and mRNA expression levels of BMP7 and Smad1 were lower at the end of the 1st, 2nd and 4th week, and the protein and mRNA expression levels of HIF-1α were higher at the end of 2nd and 4th week in CKD group (all P < 0.05). (4) Correlation analysis results showed that HIF-1α and ANGPTL4 mRNA expression were positively correlated with α-SMA mRNA ( r=0.919, P < 0.001; r=0.757, P < 0.001), and also positively correlated with Col-Ⅰ mRNA ( r=0.925, P < 0.001; r=0.777, P < 0.001). HIF-1α mRNA expression was positively correlated with ANGPTL4 mRNA ( r=0.766, P < 0.001). There were significant negative correlations between HIF-1α, ANGPTL4 mRNA and BMP7 mRNA ( r=-0.652, P < 0.001; r=-0.741, P < 0.001). Conclusions:ANGPTL4 signaling pathway may be activated in adenine-induced CKD rat model, and involved in the renal fibrosis process of CKD.
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Objective:To investigate the efficacy of Qingruxiao granules combined with tamoxifen in the treatment of breast hyperplasia and its effect on serum hypoxia-inducible factor-alpha (HIF-α), angiopoietin-2 (Ang-2) and prolactin (PRL) levels. Methods:Ninety-eight patients with breast hyperplasia admitted to Xi'an No.3 Hospital from June 2020 to January 2022 were retrospectively included in this study. They were divided into control and observation groups ( n = 49/group) according to different treatments. The control group was treated with tamoxifen alone. The observation group was treated with Qingruxiao granules combined with tamoxifen. Clinical efficacy, symptom score, ultrasound parameters (glandular layer thickness, longest diameter of mass, maximum diameter of hypoechoic area, inner diameter of lactating tube), endocrine hormone levels (estradiol, progesterone, and prolactin), HIF-α, and Ang-2 pre- and post-treatment, as well as the incidence of adverse reactions were compared between the two groups. Results:Total response rate in the observation group was significantly higher than that in the control group [93.88% (4/49) vs. 77.55%, χ2 = 5.33, P < 0.05). After treatment, breast mass score, breast pain, systemic accompanying symptom, and nipple discharge in the observation group were (1.34 ± 0.29) points, (1.02 ± 0.36) points, (0.68 ± 0.17) points, (0.97 ± 0.15) points, respectively, which were significantly lower than (1.57 ± 0.23) points, (1.45 ± 0.41) points, (0.95 ± 0.26) points, and (1.28 ± 0.26) points, respectively, in the control group ( t = 4.35, 5.52, 6.08, 7.23, all P < 0.001). The glandular layer thickness, the longest diameter of mass, the maximum diameter of hypoechoic area, and the inner diameter of lactating duct in the observation group were (9.45 ± 1.67) mm, (11.46 ± 3.68) mm, (14.37 ± 4.22) mm, and (1.23 ± 0.39) mm, respectively, which were significantly lower than (11.26 ± 2.51) mm, (16.33 ± 4.01) mm, (19.87 ± 5.01) mm, (1.54 ± 0.48) mm in the control group ( t = 4.20, 2.26, 5.88, 3.51, all P < 0.001). Serum estradiol and prolactin levels in the observation group were (122.35 ± 29.76) ng/L and (205.64 ± 36.42) IU/L, respectively, which were significantly lower than (139.76 ± 30.48) ng/L and (251.49 ± 41.87) IU/L in the control group ( t = 2.86, 5.78, both P < 0.05). Serum progesterone level in the observation group was (9.22 ± 1.57) μg/L, which was significantly higher than (7.18 ± 1.21) μg/L in the control group ( t = -7.20, P < 0.05). Serum HIF-α and Ang-2 levels in the observation group were (0.15 ± 0.05) ng/L and (0.98 ± 0.11) ng/L, respectively, which were significantly lower than (0.24 ± 0.07) ng/L and (1.49 ± 0.22) ng/L in the control group ( t = 7.32, 14.51, both P < 0.001). There was no significant difference in the incidence of adverse reactions between the two groups ( P > 0.05). Conclusion:Qingruxiao granules combined with tamoxifen can effectively improve clinical symptoms, reduce tumor size, regulate endocrine hormone levels, decrease the expression of angiogenic factors in patients with breast hyperplasia, and is highly safe.
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Objective:To explore the regulatory role of miR-210 in hypoxia-induced epithelial-mesenchymal transition (EMT) of pancreatic cancer PANC1 cells.Methods:PANC1 cells cultured in normoxia and hypoxia were established in normoxia group and hypoxia group. Recombinant plasmid carrrying miR-210 mimics and miR-210 antagomirs were constructed. The recombinant plasmids were transfected with PANC1 cells cultured in normoxia and hypoxia by liposome method to establish cell lines of miR-210 overexpression (miR-210 mimics normoxia group) and miR-210 expression inhibition (miR-210 antagomirs hypoxia group). The blank plasmids were transfected to establish blank plasmid normoxia group and blank plasmid hypoxia group. Relative expression levels of miR-210 for PANC1 cells were determined by qRT-PCR in each group. Western blot was used to measure the expressions of HIF-1α, NF-κB and EMT related protein such as E-cadherin, β-catenin, vimentin and N-cadherin. Cell relative viability under gemcitabine and in vitro cell invasion ability were detected by CCK8 and Transwell chamber experiments, respectively. Results:The relative expressions of miR-210 in hypoxia group and miR-210 mimics normoxia group were significantly higher than those in normoxia group and blank plasmid normoxia group. However, there were significantly lower in miR-210 antagomirs hypoxia group than those in blank plasmid hypoxia group. The expression levels of HIF-1α, NF-κB and mesenchymal cell markers such as vimentin and N-cadherin in hypoxia group were significantly higher than those in normoxia group (0.74±0.06 vs 0.40±0.05, 1.58±0.16 vs 1.09±0.13, 0.46±0.04 vs 0.17±0.02, 1.27±0.07 vs 0.40±0.03) and the epithelial cell markers such as E-cadherin and β-catenin were significantly lower (0.40±0.07 vs 0.77±0.10, 0.35±0.02 vs 0.94±0.08). The expression levels of HIF-1α, NF-κB, vimentin and N-cadherin in miR-210 mimics normoxia group were significantly higher than those in blank plasmid normoxia group (0.91±0.08 vs 0.40±0.06, 1.52±0.17 vs 1.05±0.14, 0.82±0.06 vs 0.66±0.07, 0.76±0.04 vs 0.46±0.03) and E-cadherin and β-catenin were significantly lower (0.38±0.07 vs 0.65±0.09, 0.50±0.03 vs 0.94±0.08). The expression levels of HIF-1α, NF-κB, vimentin and N-cadherin in miR-210 antagomirs hypoxia group were significantly lower than those in blank plasmid hypoxia group (0.31±0.05 vs 0.55±0.06, 0.68±0.05 vs 1.11±0.13, 0.41±0.03 vs 0.74±0.07, 0.69±0.06 vs 0.78±0.05), while E-cadherin and β-catenin were significantly higher (0.72±0.13 vs 0.50±0.07, 0.71±0.04 vs 0.54±0.05). All the differences among the groups were statistically significant (all P value <0.05). Under gemcitabine, the relative viability of PANC1 cells in hypoxia group and miR-210 mimics normoxia group were significantly higher than those in normoxia group and blank plasmid normoxia group at 48 h (1.10±0.10 vs 0.76±0.05, 1.46±0.11 vs 1.12±0.09) and 72 h (1.12±0.13 vs 0.76±0.05, 1.54±0.13 vs 1.12±0.09) accordingly. However, there were significantly lower in miR-210 antagomirs hypoxia group than those in blank plasmid hypoxia group at 48 and 72 h (0.75±0.09 vs 1.10±0.10, 1.19±0.12 vs 1.46±0.11). All the differences among the groups were statistically significant (all P value <0.05). The number of transmembrane cells in hypoxia group and miR-210 mimics normoxia group was significantly higher than those in normoxia group and blank plasmid normoxia group, respectively (417.50±81.22 vs 228.30±47.71, 371.30±72.81 vs 245.00±33.62 per high field), while those in miR-210 antagomirs hypoxia group was significantly lower than those in blank plasmid hypoxia group (228.30±54.01 vs 433.30±65.63 per high field). All the differences among the groups were statistically significant (all P value <0.05). Conclusions:miR-210 could weaken the sensitivity to gemcitabine and promote the invasion of PANC1 cells by regulating the occurrence of the hypoxia-induced epithelial-mesenchymal transition.
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Hypoxia-inducible factor-1 (HIF-1) is an essential transcription factor, which mediates the transcription of multiple target genes to adapt the body for hypoxia.Oxygen-induced retinal neovascularization (RNV) is an important pathological process of retinopathy of prematurity (ROP). By mediating the transcription of vascular endothelial growth factors, angiopoietin and platelet-derived growth factors, HIF-1 can promote RNV and then lead to ROP.Therefore, HIF-1 plays a vital role in the pathological process of ROP.In this paper, the recent research progress on the role of HIF-1 in oxygen-induced RNV was summarized in order to further the understanding of ROP pathogenesis and treatment.
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Objective:To observe the diurnal changes of serum hypoxia inducible factor-1α (HIF-1α) and its relationship with polysomnography (PSG) parameters in obese patients with obstructive sleep apnea (OSA).Methods:In this study, 64 obese subjects with OSA (experimental group) and 24 normal subjects (control group) were included. PSG monitoring was performed in all subjects, and peripheral blood samples were collected at night and next early morning to detect the expression level of HIF-1 α mRNA and protein concentration in serum. The data were analyzed by SPSS25.0 software. The counting data was represented by n(%), and t-tests were used for inter group comparisons. The measurement data of normal distribution adopted mean ± standard deviation ( ± s), and the inter group comparison adopted Chi-square. Serum HIF-1α mRNA levels and protein concentrations in the two groups were compared and analyzed by Two-way ANOVA, and Spearman rank correlation was used to analyze the correlation. Results:The ratio of male to female in the control group was 15: 9 and the average age was (39.25 ±10.58) years old, while that in the experimental group was 41∶24 with an average age of (41.31 ±15.20) years. The body mass index (BMI) of experimental group was higher, while all the relevant parameters recorded by PSG were significantly different between two groups ( P<0.001). The results showed that there was no significant difference in the expression of HIF-1α mRNA between the control group and the experimental group ( P=0.914), or between night and morning ( P=0.167). The concentration of HIF-1α protein in the control group was significantly lower than that in the experimental group ( P<0.001), but there was no significant difference in the concentration of HIF-1α protein in the same group at night and in the morning ( P=0.798). The results of correlation analysis showed that there was a significant correlation between PSG related indexes(AHI, minimum blood oxygen, mean blood oxygen and SIT90), night and morning mRNA expression and protein concentration ( P<0.05). Conclusions:Compared with normal people, the concentration of serum HIF-1 α protein in obese patients with OSA is higher, but there is no difference between night and morning. The process of HIF-1 α induced by CIH may be involved in post-translational regulation rather than transcription, and other compensatory mechanisms may also be involved.
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Hypoxia inducible factor(HIF)is a key factor in the regulation of oxygen homeostasis, and its expression level is mainly influenced by oxygen concentration in the adaptation of the body to chronic hypoxia, with which many pediatric diseases are closely associated.The response to hypoxia can be altered by HIF and its mediated downstream signaling pathways, in addition to epigenetic modifications such as regulation of overall methylation or histone modification levels to adapt to hypoxic environments.Previous studies have shown that the transcriptional activity and stability of HIF are interrelated with various histone modifications including methylation/demethylation, hydroxylation, deacetylation, phosphorylation, and lactylation, which makes the study of epigenetic modification correlation deserves to be explored in depth as an important potential target for regulating HIF expression levels.
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ObjectiveTo investigate the effect of Chaihu Guizhitang on triple-negative breast cancer （TNBC） cells based on hypoxia-inducible factor-1α （HIF-1α）/vascular endothelial growth factor A （VEGFA） signaling pathway. MethodTNBC xenograft model was established and the cells were randomized into model group， capecitabine group （0.2 mg·kg-1）， Chaihu Guizhitang low-dose group， medium-dose group， and high-dose group （10.62， 21.23， 42.46 g·kg-1）， with 10 mice in each group. After 21 days of medication， the content of tumor necrosis factor-α （TNF-α） in serum was detected by enzyme-linked immunosorbent assay （ELISA）. The expression of HIF-1α mRNA was detected by real-time fluorogenic quantitative polymerase chain reaction （real-time PCR）. Immunohistochemistry （IHC） was employed to detect the expression of HIF-1α， TNF-α， and VEGFA in tumor tissues， and CD34 staining to examine the angiogenesis in tumor tissues. Microvessel density （MVD） was calculated， and the protein expression of HIF-1α， VEGFA， and epidermal growth factor receptor （EGFR） in tumor tissues was measured by Western blot. ResultCompared with the model group， the rest four groups showed low levels of TNF-α （P<0.01）， HIF-1α mRNA （P<0.01）， expression of HIF-1α， TNF-α， VEGFA， and CD34 in cells， and MVD （P<0.05， P<0.01）， and low protein levels of HIF-1α， VEGFA， and EGFR （P<0.01）. Compared with capecitabine group， medium-dose and high-dose Chaihu Guizhitang decreased the level of TNF-α （P<0.01）， HIF-1α mRNA （P<0.01）， expression of HIF-1α， TNF-α， and VEGFA in cells （P<0.01）， CD34 expression， MVD， and protein levels of HIF-1α， VEGFA， and EGFR （P<0.01）. ConclusionChaihu Guizhitang may inhibit the angiogenesis in TNBC cells by regulating the expression of HIF-1α/VEGFA signaling pathway， thus exerting anti-tumor effect.
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OBJECTIVE@#To identify and characterize read-through RNAs and read-through circular RNAs (rt-circ-HS) derived from transcriptional read-through hypoxia inducible factor 1α (HIF1α) and small nuclear RNA activating complex polypeptide 1 (SNAPC1) the two adjacent genes located on chromosome 14q23, in renal carcinoma cells and renal carcinoma tissues, and to study the effects of rt-circ-HS on biological behavior of renal carcinoma cells and on regulation of HIF1α.@*METHODS@#Reverse transcription-polymerase chain reaction (RT-PCR) and Sanger sequencing were used to examine expression of read-through RNAs HIF1α-SNAPC1 and rt-circ-HS in different tumor cells. Tissue microarrays of 437 different types of renal cell carcinoma (RCC) were constructed, and chromogenic in situ hybridization (ISH) was used to investigate expression of rt-circ-HS in different RCC types. Small interference RNA (siRNA) and artificial overexpression plasmids were designed to examine the effects of rt-circ-HS on 786-O and A498 renal carcinoma cell proliferation, migration and invasiveness by cell counting kit 8 (CCK8), EdU incorporation and Transwell cell migration and invasion assays. RT-PCR and Western blot were used to exa-mine expression of HIF1α and SNAPC1 RNA and proteins after interference of rt-circ-HS with siRNA, respectively. The binding of rt-circ-HS with microRNA 539 (miR-539), and miR-539 with HIF1α 3' untranslated region (3' UTR), and the effects of these interactions were investigated by dual luciferase reporter gene assays.@*RESULTS@#We discovered a novel 1 144 nt rt-circ-HS, which was derived from read-through RNA HIF1α-SNAPC1 and consisted of HIF1α exon 2-6 and SNAPC1 exon 2-4. Expression of rt-circ-HS was significantly upregulated in 786-O renal carcinoma cells. ISH showed that the overall positive expression rate of rt-circ-HS in RCC tissue samples was 67.5% (295/437), and the expression was different in different types of RCCs. Mechanistically, rt-circ-HS promoted renal carcinoma cell proliferation, migration and invasiveness by functioning as a competitive endogenous inhibitor of miR-539, which we found to be a potent post-transcriptional suppressor of HIF1α, thus promoting expression of HIF1α.@*CONCLUSION@#The novel rt-circ-HS is highly expressed in different types of RCCs and acts as a competitive endogenous inhibitor of miR-539 to promote expression of its parental gene HIF1α and thus the proliferation, migration and invasion of renal cancer cells.
Subject(s)
Humans , Carcinoma, Renal Cell/pathology , Cell Proliferation , Hypoxia , Kidney Neoplasms , MicroRNAs/genetics , Neoplasm Invasiveness/genetics , RNA, Circular/metabolism , RNA, Small Interfering , Hypoxia-Inducible Factor 1, alpha Subunit/geneticsABSTRACT
The growth, differentiation and proliferation of adipose cells run through the whole life process. Dysregulation of lipid metabolism in adipose cells affects adipose tissue immunity and systemic energy metabolism. Increasingly available data suggest that lipid metabolism is involved in regulating the occurrence and development of various diseases, such as hyperlipidemia, nonalcoholic fatty liver disease, diabetes and cancer, which pose a major threat to human and animal health. Hypoxia inducible factor (HIF) is a major transcription factor mediating oxygen receptors in tissues and organs. HIF can induce disease by regulating lipid synthesis, fatty acid metabolism and lipid droplet formation. However, due to the difference of hypoxia degree, time and mode of action, there is no conclusive conclusion whether it has harmful or beneficial effects on the development of adipocytes and lipid metabolism. This article summarizes the regulation of hypoxia stress mediated transcription regulators and regulation of adipocyte development and lipid metabolism, aiming to reveal the potential mechanism of hypoxia induced changes in adipocyte metabolism pathways.
Subject(s)
Animals , Humans , Lipid Metabolism , Adipocytes/metabolism , Adipose Tissue/metabolism , Hypoxia/metabolism , Transcription Factors/metabolismABSTRACT
OBJECTIVE@#To observe the effects of Xingnao Kaiqiao (regaining consciousness and opening orifices) acupuncture therapy on the expression of hypoxia-inducible factor 1α (HIF-1α) and Nod-like receptor protein 3 (NLRP3) in cerebral ischemia-reperfusion rats, and to explore the mechanism of acupuncture against cerebral ischemia-reperfusion injury.@*METHODS@#Seventy-two male SD rats were randomly divided into a sham-operation group, a model group, an acupuncture group and a non-point acupuncture group, with 18 rats in each one. Using modified Longa thread embolization method, the rat model of acute focal cerebral ischemia was prepared; and after 2 h ischemia, the reperfusion was performed to prepared the model of cerebral ischemia-reperfusion. Immediately after reperfusion, Xingnao Kaiqiao acupuncture method was applied to bilateral "Neiguan" (PC 6) and "Shuigou" (GV 26) in the acupuncture group, while in the non-point acupuncture group, acupuncture was delivered at non-points and all of the needles were retained for 30 min in these two groups. The samples were collected 24 h after reperfusion in the rats of each group. Zea-Longa neurological deficit score was used to evaluate the degree of cerebral neurological impairment, TTC staining was adopted to observe the volume percentage of cerebral infarction, HE staining was provided to observe the morphological changes of brain, and Western blot was applied for detecting the expression of HIF-1α and NLRP3 proteins in the cerebral cortex on the right side.@*RESULTS@#Compared with the sham-operation group, neurological deficit score and volume percentage of cerebral infarction were increased in the model group (P<0.01), and HIF-1α and NLRP3 protein expression was elevated (P<0.01). Compared with the model group, neurological deficit score and volume percentage of cerebral infarction were decreased (P<0.01), and HIF-1α and NLRP3 protein expression was lower (P<0.01) in the acupuncture group. There was no significant difference in above indexes in the non-point acupuncture group compared with the model group (P>0.05). Compared with the sham-operation group, the brain tissue of the rats in the model group and the non-point acupuncture group was loose and edema, and the nuclei were shriveled. The brain tissue morphology in the acupuncture group was similar to that of the sham-operation group.@*CONCLUSION@#Acupuncture can alleviate cerebral ischemia-reperfusion injury, and its mechanism may be related to the regulation of HIF-1α/NLRP3 signaling pathway to attenuate inflammatory response.