MiR-31a-5p aggravates apoptosis in myocardial ischemia by targeting HIF-1α / 中国胸心血管外科临床杂志

@#Objective To investigate the expression of miR-31a-5p in myocardial infarction (MI) mice and its potential mechanism. Methods A dataset was downloaded from the gene expression database, and miR-31a-5p and its predicted target gene hypoxia-inducible factor-1α (HIF-1α) were screened using bioinformatics methods. The MI model was established by ligating the left anterior descending branch of the coronary artery in C57BL/6J male mice which were randomly divided into sham and MI groups (n=6 in each group). The in vitro hypoxic cell model was induced by treatment of H9c2 cells with cobalt chloride (CoCl2) and divided into a control group, a model group, a NC group, a miR-31a-5p mimic group and a miR-31a-5p inhibitor group. The degree of myocardial tissue fibrosis was stained by Masson and analyzed. The expression levels of miR-31a-5p and HIF-1α mRNA in mouse myocardial tissues and H9c2 cells were detected by qRT-PCR. Western blotting was used to detect the expression levels of B-cell lymphoma 2 (Bcl-2), cleaved-caspase 3 apoptotic protein in mouse myocardial tissues and HIF-1α and apoptotic protein in H9c2 cells, respectively. The dual luciferase reporter gene assay was used to verify the targeting relationship between miR-31a-5p and HIF-1α. Results Masson staining showed significantly increased fibrosis in MI mice (P<0.000 1); miR-31a-5p, cleaved-caspase 3 were significantly elevated and Bcl-2 was decreased in MI mice and CoCl2 treated H9c2 (P<0.05). The results of dual luciferase reporter assay showed that the relative luciferase activity of miR-31a-5p mimic cotransfected with HIF-1α-3'-UTR WT plasmid was reduced (P<0.000 1); miR-31a-5p mimic decreased HIF-1α expression and increased apoptotic protein levels in CoCl2 induced H9c2 cells (both P<0.05), while miR-31a-5p exerted the opposite effect. Conclusion miR-31a-5p can aggravate apoptosis in myocardial ischemia by targeting HIF-1α.

Effect of Gualou Xiebai Banxiatang on Myocardial Microangiogenesis and HIF-1α/VEGF-related Pathways in Myocardial Ischemia Model Rats / 中国实验方剂学杂志

ObjectiveTo investigate the effect of Gualou Xiebai Banxiatang on cardiac function and myocardial histopathological changes in rats with ischemic myocardial injury， and to observe the effect of myocardial microvascular density （MVD）， phosphatidylinositol 3-kinase （PI3K）， mammalian target of rapamycin （mTOR）， hypoxia-inducible factor-1 alpha （HIF-1α）， and vascular endothelial growth factor （VEGF） signaling pathways on myocardial microangiogenesis. MethodSeventy male SD rats were randomly selected， with six rats in the normal group. The remaining rats were fed a high-fat diet and injected with isoproterenol hydrochloride （ISO，80 mg·kg-1·d-1， 2 d） to induce a hyperlipidemia-based ischemic heart disease model. After successful modeling， the rats were randomly divided into the model group， high， medium， and low dose groups of Gualou Xiebai Banxiatang， and the metoprolol group. The high， medium， and low dose groups of Gualou Xiebai Banxiatang were given Gualou Xiebai Banxiatang at 10.42， 5.21， 2.61 g·kg-1·d-1， respectively， while the metoprolol group was given metoprolol at 2.6 mg·kg-1·d-1. Both the normal and model groups were given an equivalent volume of physiological saline for 28 days. After the intervention， relevant tests were conducted， and serum was collected to measure heart function-related indicators. Hematoxylin-eosin （HE） and Masson staining were performed on ventricular tissue to observe pathological changes under a light microscope. Immunohistochemistry （IHC） was used to detect the positive expression of platelet endothelial cell adhesion molecule （CD31）. Enzyme-linked immunosorbent assay （ELISA） was used to detect the expression of N-terminal pro-brain natriuretic peptide （NT-proBNP） and VEGF. Western blot was used to detect the protein expression levels of PI3K/mTOR/HIF-1α/VEGF. ResultCompared with the normal group， the model group showed significantly increased serum levels of LDH， CK， CK-MB， NT-proBNP， and VEGF （P<0.01）， significantly increased collagen volume fraction （CVF） （P<0.01）， significantly decreased MVD （P<0.01）， and elevated protein expression levels of PI3K， mTOR， HIF-1α， and VEGF （P<0.05， P<0.01）. Compared with the model group， the metoprolol group had significantly lower serum levels of LDH， CK， CK-MB， and NT-proBNP （P<0.01）， significantly higher VEGF levels （P<0.01）， significantly decreased CVF （P<0.01）， significantly increased MVD （P<0.01）， and significantly increased protein expression levels of PI3K， mTOR， and VEGF （P<0.01）， with no statistically significant change in HIF-1α protein expression. Compared with the model group， the high and medium dose groups of Gualou Xiebai Banxiatang had decreased serum levels of LDH， CK， CK-MB， and NT-proBNP （P<0.05， P<0.01）， increased VEGF levels （P<0.05， P<0.01）， significantly reduced CVF （P<0.01）， increased MVD （P<0.05， P<0.01）， and significantly increased protein levels of PI3K， mTOR， HIF-1α， and VEGF （P<0.01）. In the low dose group of Gualou Xiebai Banxiatang， compared with the model group， serum levels of LDH and NT-proBNP were decreased （P<0.05）， VEGF was increased （P<0.05）. Moreover， CVF was decreased （P<0.05）， and the protein expression levels of PI3K， mTOR， HIF-1α， and VEGF were significantly increased （P<0.01）. ConclusionGualou Xiebai Banxiatang can improve cardiac function， reduce myocardial pathological damage， enhance endothelial cell function， promote myocardial microvascular formation， and upregulate the expression of PI3K， mTOR， HIF-1α， and VEGF proteins in myocardial tissue in rats with ischemic myocardial injury.

The effect of apigenin on apoptosis and HIF-1α/NF-κB signaling pathway in renal cancer A498 cells / 中国医师杂志

Objective:To explore the effects of apigenin on apoptosis and hypoxia inducible factor-1α (HIF-1α)/nuclear factor κB (NF-κB) signaling pathway in renal cancer A498 cells.Methods:Human renal cell carcinoma A498 cells were cultured in vitro and divided into different concentrations of apigenin (10, 20, 40 μmol/L) groups, apigenin (40 μmol/L)+ HIF-1α agonist dimethylenediaminoacetic acid (DMOG) group, HIF-1α inhibitor rifiximab (YC-1) group, and control group. Cell proliferation was detected using cell counting kit-8 (CCK-8) assay and plate clone formation assay, apoptosis was detected using Hoechst 33258 staining and flow cytometry, and expression of apoptotic proteins and HIF-1/NF-B pathway proteins was detected using Western blot assay.Results:Celery extract significantly inhibited the proliferation of A498 cells, and the inhibitory effect was concentration dependent ( P<0.001). Compared with the control group, the apoptosis rates of A498 cells in the 10, 20, and 40 μmol/L apigenin groups and YC-1 groups were significantly increased [(4.35±1.04)% vs (10.06±1.13)%, (18.52±2.58)%, (32.17±2.63)%, (26.94±2.41)%], as well as the expression levels of B lymphocyte tumor 2 related protein (Bax) and Cleaved Caspase-3 protein, while the expression levels of B lymphocyte tumor 2 (Bcl-2) were significantly reduced (all P<0.001). Compared with the control group, the HIF-1α protein expression levels (0.85±0.08 vs 0.63±0.06, 0.31±0.03, 0.16±0.02) and p-NF-κB p65/NF-κB p65 ratio (0.82±0.08 vs 0.51±0.05, 0.30±0.03, 0.13±0.01) of A498 cells in the 10, 20, and 40 μmol/L apigenin groups were significantly reduced (all P<0.001). Compared with the apigenin group, the apoptosis rate of A498 cells in the apigenin+ DMOG group was significantly reduced [(32.17±2.63)% vs (14.85±1.62)%], and the expression levels of Bax and Cleared Caspase-3 proteins were significantly reduced, while the expression levels of Bcl-2 proteins were significantly increased (all P<0.001). Conclusions:Apigenin may promote apoptosis in renal cancer A498 cells by inhibiting the activation of the HIF-1α/NF-κB signaling pathway.

Research progress on SENP1/HIF-1α regulation of vascular differentiation of dental pulp stem cells / 中国医师杂志

Dental pulp stem cells (DPSC) are pluripotent stem cells with high differentiation potential isolated from dental pulp. Using DPSC for vascular regeneration may be a good option. Hypoxia inducible factor-1α (HIF-1α) is an upstream gene of vascular endothelial growth factor (VEGF), and the small ubiquitin like protease 1 (SENP1) can reverse the small ubiquitin like (SUMO) modification of HIF-1α. Through the regulation of SENP1/HIF-1α, good vascular regeneration characteristics have been demonstrated in many in vitro and in vivo experiments. The SENP1/HIF-1α signaling axis has varying degrees of promoting and inhibiting effects on many solid tumors. Although there is relatively little literature on the role of the SENP1/HIF-1α signaling axis in dental pulp stem cells, it can be determined that SENP1/HIF-1α plays an important role in the angiogenesis of dental pulp stem cells. This article will elucidate the SENP1/HIF-1α signaling pathway and its mechanism of promoting vascular differentiation of DPSC.

Regulating anaerobic metabolism and promoting myocardial ischemia-hypoxia injury by diesel particulate matter and its key component benzoapyrene via targeting oxygen sensors / 环境与职业医学

Background The exposure to diesel particulate matter (DPM) and its polycyclic aromatic hydrocarbons (PAH) is closely related to the morbidity and mortality of ischemic heart disease (IHD). However, it is unclear what key components and targets of DPM exposure involve in myocardial ischemia-hypoxia injury and associated mechanisms. Objective To identify key PAH components of DPM that act on myocardial hypoxic injury, andclarify the role of oxygen sensors-regulated anaerobic metabolism in DPM and key components-induced hypoxic injury and the targets of the key PAH components. Methods Human cardiomyocyte cell line AC16 cells were exposed to 0, 1, 5, and 10 μg·mL−1 DPM in a high glucose DMEM medium with 10% fetal bovine serum (FBS) (HGM) or low FBS (0.5%) in high glucose DMEM medium (LFM), for 12 h under 2% O2, and expression of hypoxia-inducible factor-1α (HIF-1α), Bax, and Cleaved-caspase3 was determined by Western blotting. Under normal condition, the cell viability was detected after PAH exposure for 12 h. Under the condition of ischemia-hypoxia model, cells were exposed to 0, 0.005, 0.5, and 5 µg·mL−1 PAH for 12 h, and the protein expression of HIF-1α, Bax, and Cleaved-caspase3 was determined. After exposure to DPM or PAH for 12 h, the contents of pyruvate and lactate in cells were detected. Pretreatment with glycolysis inhibitor GSK2837808A was used to explore the role of glycolysis in DPM and benzo[a]pyrene (BaP)-induced hypoxia injury. A molecular docking technique was used to analyze the binding affinity between PAH and oxygen sensors (prolyl hydroxylase domain-containing protein 2, PHD2, and factor-inhibiting hypoxia-inducible factor 1, FIH1), and the protein levels of PHD2, FIH1, and hydroxyl-HIF-1-alpha (OH-HIF-1α) after the DPM or BaP treatment were further determined. Results Under hypoxia, DPM exposure in the LFM induced the expression of HIF-1α, Bax, and Cleaved-caspase3 (P<0.01). Therefore, hypoxia and LFM were selected as the basic ischemia and hypoxia condition. Except for anthracene (Ant) (P>0.05), other PAH decreased cell viability when the concentration was above 1 μg·mL−1 (P<0.05). All concentrations of BaP induced the expression of HIF-1α protein (P<0.05), and the protein levels of Bax and Cleaved-caspase3 were up-regulated after the 0.5 and 5 µg·mL−1 BaP exposure (P<0.01). After exposure to DPM (1, 5 and 10 μg·mL−1) or BaP (0.5 and 5 μg·mL−1), the intracellular pyruvate and lactate contents increased (P<0.05). The glycolysis inhibitor co-treatment decreased the levels of HIF-1α, Bax, and Cleaved-caspase3 proteins compared with the DPM or BaP exposure group for 12 h (P＜0.05). The binding abilities of the five PAHs to the oxygen sensors PHD2 and FIH1 were strong, and BaP was the strongest. Although the DPM or BaP exposure had no effects on the protein levels of PHD2 and FIH1 in AC16 cells (P＜0.05), the protein level of OH-HIF-1α was decreased (P＜0.01). Conclusion BaP exposure can promote hypoxia and injury of myocardial cells and is the key PAH component of DPM that induces myocardial ischemia and hypoxia injury. BaP exposure inhibits the hydroxylation function of PHD2 on HIF-1α by combining with PHD2, decreases the level of OH-HIF-1α and induces HIF-1α accumulation. And then HIF-1α promotes anaerobic metabolism and accelerates ischemia and hypoxia injury of myocardial cells.

Regulation of osteogenic differentiation under hypoxia by EphrinB2/EphB4 in MC3T3-E1 cells / 口腔疾病防治

Objective @# To investigate the effect of erythropoietin producing hepatocyte kinase receptor ligand B2-erythropoietin producing hepatocyte kinase receptor B4 (EphrinB2/EphB4) on the osteogenic differentiation of MC3T3-E1 cells in a hypoxic environment to provide experimental evidence for hypoxia regulation of osteoblast differentiation.@*Methods @# Control groups and cobalt chloride (CoCl2)-induced hypoxia groups were set up first. qRT-PCR was used to detect the mRNA expression of the osteogenic markers alkaline phosphatase (ALP), collogen1 (COL I), runt-related transcription factor 2 (RUNX2) and osteocalcin (OCN). ALP staining was used to detect the activity of cell alkaline phosphatase after osteogenic induction. The mRNA and protein expression levels of hypoxia inducible factor-1α (HIF-1α), EphrinB2 and EphB4 in the two groups were detected via qRT-PCR and Western blot. Then, the CoCl2 + inhibitor group was established. NVP-BHG712, an EphB4 phosphorylation inhibitor, was added to this group to prevent EphrinB2 from binding to EphB4 and producing signals. qRT-PCR and Western blot were used to detect the mRNA and protein expression of osteogenic markers, including ALP, RUNX2, COL I, and OCN. ALP staining and Alizarin red S staining were used to measure osteoblast differentiation and mineralization. @*Results @# Compared with the control group, the mRNA expression of the osteogenic differentiation markers ALP, RUNX2, COL-1, and OCN in MC3T3-E1 cells increased, and ALP activity and mineralization were enhanced under CoCl2-induced hypoxia in vitro (P<0.05). Additionally, the expression of HIF-1α, EphrinB2 and EphB4 was upregulated at the mRNA and protein levels under hypoxia (P<0.05). When NVP-BHG712 was used to block the connection between EphrinB2 and EphB4, the expression of osteogenic markers and ALP activity and mineralization were decreased (P<0.05).@*Conclusion@#EphrinB2/EphB4 can promote osteogenic differentiation of MC3T3-E1 cells and increase the expression of osteogenic markers and tissue mineralization in a hypoxic environment.

Research progress on T cell glycolytic metabolism in oral lichen planus / 口腔疾病防治

@#Oral lichen planus (OLP) is a chronic inflammatory disease of the oral mucosa. The pathogenesis of OLP is still unclear. Immune abnormalities mediated by T cells and related cytokines play a crucial role in the pathogenesis of OLP. In recent years, glycolytic metabolism-related transporters, enzymes and regulators, such as glucose transporter-1 (Glut1), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), lactate dehydrogenase A (LDHA), mammalian target of rapamycin (mTOR) and hypoxia inducible factor-1α (HIF-1a), have attracted an increasing amount of attention in OLP by regulating the proliferation and differentiation of T cells and the secretion of inflammatory factors. It has been shown that 2-deoxy-D-glucose (2-DG) or rapamycin (RAPA) inhibits the glycolytic metabolism of T cells and then inhibits OLP. This article reviews the research progress of glycolytic metabolism-related transporters, enzymes and regulatory factors in OLP in recent years.

Expression Changes of Hypoxia-Inducible Factor-1α in G-CSF Induced Hematopoietic Stem Cell Mobilization / 中国实验血液学杂志

OBJECTIVE@#To investigate the expression and its relative mechanism of hypoxia-inducible factor-1α(HIF-1α) in bone marrow(BM) of mice during G-CSF mobilization of hematopoietic stem cells (HSC) .@*METHODS@#Flow cytometry was used to detect the proportion of Lin-Sca-1+ c-kit+ (LSK) cells in peripheral blood of C57BL/6J mice before and after G-CSF mobilization. And the expression of HIF-1α and osteocalcin (OCN) mRNA and protein were detected by RQ-PCR and immunohistochemistry. The number of osteoblasts in bone marrow specimens of mice was counted under the microscope.@*RESULTS@#The proportion of LSK cells in peripheral blood began to increase at day 4 of G-CSF mobilization, and reached the peak at day 5, which was significantly higher than that of control group (P<0.05). There was no distinct difference in the expression of HIF-1α mRNA between bone marrow nucleated cells and osteoblasts of steady-state mice (P=0.073), while OCN mRNA was mainly expressed in osteoblasts, which was higher than that in bone marrow nucleated cells (P=0.034). After mobilization, the expression level of HIF-1α increased, but OCN decreased, and the number of endosteum osteoblasts decreased. The change of HIF-1α expression was later than that of OCN and was consistent with the proportion of LSK cells in peripheral blood.@*CONCLUSION@#The expression of HIF-1α in bone marrow was increased during the mobilization of HSC mediated by G-CSF, and one of the mechanisms may be related to the peripheral migration of HSC induced by osteoblasts inhibition.

Modulation of hypoxia inducible factor-1 alpha in neurons after cerebral hypoxia by recombinant adenovirus-mediated hypoxia inducible factor-1 alpha / 中华老年医学杂志

Objective:To investigate the regulatory effects and possible mechanisms of recombinant adenovirus-mediated hypoxia inducible factor-1 alpha(HIF-1α)transfection on HIF-1α in post-hypoxic rat cortical neurons.Methods:(1)Preparation of rats' cerebral cortical neurons in primary culture and hypoxia model.Recombinant adenovirus-mediated HIF-1α(AdHIF-1α)transfection and recombinant Ad transduction in normal and hypoxic cells.Then they will be divided into normal control group, hypoxia group, the recombinant adenovirus hypoxia-inducible factor-1α(AdHIF-1α)gene transfection group and recombinant adenovirus empty vector(Ad)transfection group.(2)To observe the transfection of AdHIF-1α/ Ad under fluorescence microscopy.The expression of hypoxia-inducible factor-1 alpha(HIF-1α)were observed by Western blot analysis in each group of neurons at 12 h、24 h、48 h and 72 h.Results:Hypoxic neurons transfected with Ad/AdHIF-lα showed the obvious expression 48 h under fluorescence microscopy.At each time of the AdHIF-1α gene transfection group, the expression of HIF-1α is significantly increased, the positive expression emerges at 12 h, the expression increased at 24 h, and it reaches the peak at 48 h, until 72 h declines, and it has statistical significance compared with the hypoxia group( P<0.01, P<0.05), but the Ad group has no statistically significant differences compared with the hypoxia group. Conclusions:The transfection of recombinant adenovirus-mediated HIF-1α gene can significantly increase the expression levels of HIF-1α in hypoxic neurons, and it may play a protective role in the neurons after hypoxia.

Inhibitory effect of resveratrol on neovascularization in cutaneous squamous cell carcinoma by suppressing the SUMOylation of hypoxia-inducible factor 1α protein / 中华皮肤科杂志

Objective:To explore intrinsic mechanisms underlying the inhibitory effect of resveratrol on neovascularization in cutaneous squamous cell carcinoma from the perspective of ubiquitin/ubiquitin-like protein modification balance.Methods:The human cutaneous squamous cell carcinoma cell line A431 was used as the research object. Cultured A431 cells at exponential growth phase were divided into 3 groups (control group, 50 μmol/L resveratrol group, and 100 μmol/L resveratrol group) to be cultured with mediums containing 0, 50, and 100 μmol/L resveratrol, respectively. Cell proliferation activity was assessed by the 3- (4,5) -dimethylthiazol (-z-y1) -2,5-di-phenytetrazoliumromide (MTT) assay after 48-hour culture; the vasculogenic mimicry formation assay was performed to evaluate the vasculogenic mimicry formation ability of A431 cells after 12-hour treatment with resveratrol; Western blot analysis was conducted to detect the relative protein expression levels of ubiquitin, small ubiquitin-related modifier-1 (SUMO1), hypoxia-inducible factor 1α (HIF-1α), and vascular endothelial growth factor receptor (VEGFR) in different groups after 48-hour treatment with resveratrol. Then, 24 8-week-old BALB/c male thymectomized mice were randomly and equally divided into 3 groups to be subcutaneously inoculated with A431 cells in the inguinal region, followed by intraperitoneal injections of 1 mg/kg or 2 mg/kg resveratrol (1 mg/kg or 2 mg/kg resveratrol group), or the same volume of physiological sodium chloride solutions (control group) ; the intraperitoneal injections were done once every 3 days in all groups; all the above mice were sacrificed on the 21st day, and the tumors were resected and weighed. Immunohistochemistry assay was performed to determine the CD31 expression in tumor tissues. One-way analysis of variance was used for comparisons among multiple groups, and least significant difference (LSD) - t test was used for multiple comparisons. Results:The proliferation rate of A431 cells significantly differed among the control group, 50 μmol/L resveratrol group, and 100 μmol/L resveratrol group ( F = 17.75, P = 0.017), and was significantly lower in the 50 μmol/L resveratrol group (66.53% ± 5.09%) and the 100 μmol/L resveratrol group (35.88% ± 4.28%) than in the control group (100%, LSD- t = 21.17, 29.04, P = 0.011, 0.004, respectively) ; the total length of vessel wall-like structures formed by A431 cells significantly differed among the 3 groups ( F = 21.37, P = 0.004), and was significantly lower in the 50 μmol/L resveratrol group (102.73 ± 11.36 μm) and the 100 μmol/L resveratrol group (37.83 ± 4.19 μm) than in the control group (185.26 ± 8.02 μm, both P < 0.05) ; the relative protein expression levels of ubiquitin, SUMO1, HIF-1α, and VEGFR also significantly differed among the 3 groups, the ubiquitin protein expression was significantly higher in the 50 μmol/L resveratrol group (2.09 ± 0.13) and the 100 μmol/L resveratrol group (3.53 ± 0.16) than in the control group (0.68 ± 0.11, both P < 0.05), while the protein expression of SUMO1, HIF-1α, and VEGFR was significantly lower in the 50 μmol/L resveratrol group (1.87 ± 0.13, 0.81 ± 0.06, 0.73 ± 0.09, respectively) and the 100 μmol/L resveratrol group (1.02 ± 0.11, 0.45 ± 0.06, 0.39 ± 0.05, respectively) than in the control group (3.10 ± 0.11, 0.97 ± 0.08, 0.98 ± 0.07, respectively, all P < 0.05). In the mice experiment, the weight of subcutaneous tumors and the proportion of CD31-positive cells in tumor tissues significantly differed among the control group, 1 mg/kg resveratrol group, and 2 mg/kg resveratrol group (weight: 3.29 ± 0.57 g, 2.91 ± 0.49 g, 2.55 ± 0.52 g; proportion: 76.24% ± 5.51%, 39.45% ± 5.48%, 12.07% ± 3.54%; F = 14.33, 15.34, P = 0.019, 0.021, respectively), and were significantly lower in the 1 mg/kg resveratrol group and 2 mg/kg resveratrol group than in the control group (all P < 0.05) . Conclusion:Resveratrol could inhibit tumor growth and neovascularization in tumor tissues, which were possibly associated with the inhibitory effect of resveratrol on neovascularization in cutaneous squamous cell carcinoma by suppressing the SUMOylation of HIF-1α protein via ubiquitin/ubiquitin-like protein modification pathways.

Expression and role of angiopoietin-like protein 4 signaling pathway in rats with adenine- induced chronic kidney disease / 中华肾脏病杂志

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.

Expression and clinical significance of LncRNA HIF1A-AS1 in proliferative diabetic retinopathy / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To investigate the expression and diagnostic value of long non-coding RNA(LncRNA)hypoxia-inducible factor 1 alpha antisense RNA 1(HIF1A-AS1)in serum of patients with proliferative diabetic retinopathy(PDR).METHODS: A total of 160 patients with diabetic retinopathy(DR)admitted to our hospital from July 2019 to July 2021 were selected as the research objects. According to the degree of disease, they were divided into PDR group(80 cases)and nonproliferative diabetic retinopathy(NPDR)group(80 cases). At the same time, 100 healthy cases in our hospital were selected as the control group. Detect and compare serum triglyceride(TG), total cholesterol(TC), high-density lipoprotein cholesterol(HDL-C), low-density lipoprotein cholesterol(LDL-C), fasting blood glucose(FBG)and the level of glycosylated hemoglobin A1c(HbA1c); The expression level of LncRNA HIF1A-AS1 in serum was detected by real-time fluorescence quantitative PCR(qRT-PCR)method; Logistic regression was used to analyze the risk factors that affected the occurrence of PDR; Receiver operating characteristic curve(ROC)was used to analyze the clinical value of LncRNA HIF1A-AS1 level in the diagnosis of PDR. RESULTS: The expression level of LncRNA HIF1A-AS1 in the serum of the patients in the PDR group was significantly higher than that in the NPDR group and the control group, and the NPDR group was higher than the control group(P&#x003C;0.05); The course of disease, HbA1c, TC, TG, LDL-C, FBG levels in the PDR group and the NPDR group were significantly higher than those of the control group, the HDL-C level in the PDR group was significantly lower than that in the control group(P&#x003C;0.05); The level of LncRNA HIF1A-AS1 was positively correlated with the course of disease, HbA1c, TC, TG, LDL-C and FBG(P&#x003C;0.05), and negatively correlated with HDL-C(P&#x003C;0.05); Logistic regression analysis showed that the LncRNA HIF1A-AS1, course of disease, FBG, HbA1c, TC, TG, LDL-C were all risk factors for PDR(P&#x003C;0.05); ROC results showed that the area under the curve(AUC)of the LncRNA HIF1A-AS1 level predicting PDR was 0.766(95%CI: 0.692～0.829), the corresponding sensitivity was 66.25% and the specificity was 78.75%.CONCLUSION: The level of LncRNA HIF1A-AS1 in the serum of PDR patients is up-regulated, it is a risk factor for the occurrence of PDR and it can be used as a potential serological indicator for predicting the occurrence of PDR.

Role of HIF-1α/BNIP3 signaling pathway in dexmedetomidine-induced reduction of myocardial ischemia-reperfusion-induced brain injury in mice / 中华麻醉学杂志

Objective:To evaluate the role of hypoxia-inducible factor-1α (HIF-1α)/Bcl-2/E1B 19-kDa interacting protein 3 (BNIP3) signaling pathway in dexmedetomidine-induced reduction of myocardial ischemia-reperfusion (I/R)-induced brain injury in mice.Methods:Sixty clean-grade healthy male C57BL/6 mice, aged 8-10 weeks, weighting 20-30 g, were divided into 5 groups ( n=12 each) using a random number table method: sham operation group (S group), myocardial I/R group (IR group), myocardial I/R plus dexmedetomidine group (IRD group), myocardial I/R plus HIF-1α inhibitor 2ME2 group (IR-M group), and myocardial I/R plus dexmedetomidine plus HIF-1α inhibitor 2ME2 group (IRD-M group). The myocardial I/R-induced brain injury was produced by ligating the left anterior descending coronary artery for 30 min followed by 2 h of reperfusion in anesthetized mice.Dexmedetomidine 50 μg/kg was intraperitoneally injected at 5 min before ischemia in IRD group and IRD-M group.In IR-M and IRD-M groups, 2ME2 15 mg/kg was intraperitoneally injected at 5 min before ischemia.Blood samples were collected from the thoracic aorta at 2 h of reperfusion to measure the serum S-100β protein and neuron-specific enolase (NSE) concentrations.The animals were then sacrificed, brains were removed and hippocampi were obtained for determination of the apoptosis index (by TUNEL method) and expression of HIF-1α, BNIP3, Beclin-1, microtubule-associated protein 1 light chain 3 (LC3) and phosphorylated Tau protein (p-Tau) (by Western blot) and for microscopic examination of the pathological changes in hippocampal CA1 region.LC3Ⅱ/Ⅰ ratio was calculated. Results:Compared with group S, the concentrations of serum S-100β protein and NSE and apoptosis index of hippocampal neurons were significantly increased, the expression of HIF-1α, BNIP3, Beclin-1 and p-Tau was up-regulated, LC3Ⅱ/Ⅰ ratio was increased ( P<0.05), and the pathological changes in hippocampal CA1 region were aggravated in group IR.Compared with group IR, the concentrations of serum S-100β protein and NSE and apoptosis index of hippocampal neurons were significantly decreased, the expression of HIF-1α, BNIP3 and Beclin-1 was up-regulated, the expression of p-Tau was down-regulated, and LC3Ⅱ/Ⅰ ratio was increased ( P<0.05), and the pathological changes in hippocampal CA1 region were significantly attenuated in group IRD.Compared with group IRD, the concentrations of serum S-100β protein and NSE and apoptosis index of hippocampal neurons were significantly increased, the expression of p-Tau was up-regulated, the expression of HIF-1α, BNIP3 and Beclin-1 was down-regulated, LC3Ⅱ/Ⅰ ratio was decreased ( P<0.05), and the pathological changes in hippocampal CA1 region were aggravated in IR-M and IRD-M groups. Conclusions:HIF-1α/BNIP3 signaling pathway is involved in dexmedetomidine-induced reduction of myocardial I/R-induced brain injury in mice.

Mechanism study of Curcumin on inhibiting experimental choroidal neovascularization <i>in vitro</i> by AKT/HIF-1α/VEGF pathway / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To investigate the effect and mechanism of curcumin on inhibiting choroidal neovascularization(CNV)<i>in vitro</i>. METHODS: Human retinal pigment epithelial(ARPE-19)cells chemical hypoxia model was established by cobalt chloride(CoCl2). CCK-8 method was used to detect the effect of curcumin on the activity of ARPE-19 cells induced by CoCl2. RT-qPCR and Western blot were used to detect the expression of AKT, HIF-1α, VEGF mRNA and protein in ARPE-19 cells hypoxia model induced by CoCl2. Cell scratch test, transwell chamber migration test, transwell chamber invasion test and matrigel matrix hose lumen formation test were used to observe the effects of conditioned medium of curcumin in ARPE-19 cells on the proliferation, migration, invasion and lumen formation of human umbilical vein endothelial cells(HUVEC)in non-contact condition. RESULTS:Chemical hypoxia model of ARPE-19 cells can successfully establish by CoCl2 at 100μmol/L. CoCl2 at the final concentration of 100μmol/L can promote the expression of AKT, HIF-1α and VEGF mRNA and p-AKT, HIF-1α and VEGF protein in ARPE-19 cells. Curcumin at the final concentration of 100μmol/L can reduce the expression of AKT, HIF-1α and VEGF mRNA in ARPE-19 hypoxia model. Curcumin at the final concentration of 100μmol/L can reduce the expression of AKT, HIF -1α and VEGF proteins in ARPE-19 hypoxia model. The conditioned medium of low(6.25μmol/L), medium(25μmol/L)and high dose(100μmol/L)curcumin in ARPE-19 cells can significantly inhibit the level migration of HUVEC. The conditioned medium in high dose group can significantly inhibit the vertical migration and cell invasion of HUVEC. The conditioned medium of middle and high dose curcumin in ARPE-19 cells can inhibit the lumen formation of HUVEC. CONCLUSION:Curcumin at 100μmol/L can protect ARPE-19 cells from hypoxia induced by CoCl2. Curcumin can inhibit the formation of blood vessels at the cellular level.

Protective effect of astragalus-containing serum on cobalt chloride-induced hypoxia injury in ARPE-19 cells / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM: To study the protective effect of astragalus-containing serum on cobalt chloride(CoCl2)-induced hypoxia injury of human retinal pigment epithelial cells(ARPE-19), so as to explore whether astragalus can improve diabetic retinopathy(DR)by anti-oxidative stress.<p>METHODS: The ARPE-19 hypoxia model induced by CoCl2 was established and divided into the following 5 groups: normal group(cells were cultured normally without any treatment), hypoxia model group(200μmol/L CoCl2), blank serum group(200μmol/L CoCl2+blank serum), low-dose drug-containing serum group(200μmol/L CoCl2+10% medicated serum)and high-dose drug-containing serum group(200μmol/L CoCl2+20% medicated serum); CCK-8 detects cell viability; Detect the levels of reduced glutathione(GSH)and malondialdehyde(MDA)in the cell supernatant with a kit; ELISA was used to detect the content of hypoxia-inducible factor-1α(HIF-1α)and vascular endothelial growth factor(VEGF)in cell culture medium; Real-time quantitative PCR(qPCR)to detect the mRNA levels of VEGF, HIF-1α and Prolyl hydroxylase-2(PHD-2); The expressions of VEGF, HIF-1α and PHD-2 were detected by Western Blot.<p>RESULTS: Hypoxia model of ARPE-19 can successfully establish by CoCl2 at 200μmol/L. Low-dose and high-dose astragalus-containing serum could inhibit hypoxia-induced ARPE-19 proliferation(<i>P</i><0.05), increase the GSH level and reduce the MDA content in ARPE-19 with hypoxic injury(<i>P</i><0.05). Low-dose and high-dose astragalus-containing serum could inhibit the expression of HIF-1α and VEGF in ARPE-19 hypoxic injury supernatant(<i>P</i><0.05), as well as the mRNA and protein expressions of VEGF, HIF-1α and PHD-2 in ARPE-19(<i>P</i><0.05).<p>CONCLUSION: Low-dose and high-dose astragalus-containing serum alleviates the hypoxia injury of ARPE-19 induced by CoCl2 through anti-oxidant effect.

Expression of silent information regulator 1 and 3 and hypoxia-inducible factor 1α in cutaneous squamous cell carcinoma tissues and cells / 中华皮肤科杂志

Objective:To determine the expression of silent information regulator 1 (Sirt1) , Sirt3 and hypoxia-inducible factor 1α (HIF-1α) in cutaneous squamous cell carcinoma (CSCC) tissues and cells, and to explore their role in the occurrence and development of CSCC.Methods:From January 2019 to December 2020, 30 lesional skin tissues were obtained from patients with histopathologically confirmed poorly-, moderately- or well-differentiated CSCC, and 30 normal skin tissues were obtained from patients with non-cancerous diseases in Department of Dermatology, General Hospital of Ningxia Medical University. A CSCC cell line A431 and a human keratinocyte cell line HaCaT were cultured. Immunohistochemical study, Western blot analysis and real-time quantitative PCR (RT-PCR) were performed to determine the protein and mRNA expression of Sirt1, Sirt3 and HIF-1α in CSCC tissues of different grades of differentiation and normal skin tissues, cytochemical and immunofluorescence staining and RT-PCR were conducted to determine the protein and mRNA expression of Sirt1, Sirt3 and HIF-1α in A431 and HaCaT cells, respectively. Comparisons of measurement data among multiple groups were performed by using one-way analysis of variance, and comparisons between two groups by using t test. Results:Immunohistochemical study showed that the expression level of Sirt3 (expressed as the average optical density) was 100 ± 12.12, 117.72 ± 26.23, 127.32 ± 24.45, 132.71 ± 31.61 in the normal skin tissues and well-, moderately- and poorly-differentiated CSCC tissues respectively, and there was a significant difference among these groups ( F = 20.14, P < 0.001) ; the expression of Sirt1 and HIF-1α increased in turn from the normal skin tissues to the well-, moderately- and poorly-differentiated CSCC tissues, and significantly differred in these groups ( F = 174.50, 225.00, respectively, both P < 0.001) . As Western blot analysis revealed, the expression level of Sirt3 significantly differed among the normal skin tissues, well-, moderately- and poorly-differentiated CSCC tissues (expressed as relative gray value: 1.000 ± 0.132, 1.403 ± 0.411, 1.387 ± 0.393, 1.677 ± 0.683, respectively; F = 34.97, P < 0.001) , and so did the expression levels of Sirt1 and HIF-1α ( F = 69.29, 199.90, respectively, both P < 0.00l) , with a gradually increasing trend in their expression levels from the the normal skin tissues to well-, moderately- and poorly-differentiated CSCC tissues. RT-PCR showed that the mRNA expression of Sirt3, Sirt1 and HIF-1α was sequentially increased from the normal skin tissues to well-, moderately- and poorly-differentiated CSCC tissues, and significant differences were observed among these groups ( F = 113.00, 174.50, 50.33, respectively, all P < 0.001) . The protein expression levels of Sirt3, Sirt1 and HIF-1α were significantly higher in the A431 cells than in the HaCaT cells ( t = 16.75, 18.34, 27.76, respectively, all P < 0.001) , and so were their mRNA expression levels ( t= 14.22, 9.62, 16.86, respectively, all P < 0.001) . Conclusion:Increased expression of Sirt3, Sirt1 and HIF-1α was observed in CSCC tissues and cells, which may promote the occurrence and development of CSCC.

Effect of pomegranate peel polyphenols on mTOR/HIF-1α/IL-17 signaling pathway in a rat auriclular model of acne / 中华皮肤科杂志

Objective:To explore the anti-inflammatory effect of pomegranate peel polyphenols on a rat auriclular model of acne and its mechanism of action.Methods:Totally, 36 specific-pathogen-free SD rats were randomly divided into 6 groups: blank group, model group, low-, medium- and high-dose pomegranate peel polyphenol groups and positive control group. In all groups except the blank group, 0.5 ml of 100% oleic acid was applied to the openings of bilateral auricular ducts once a day for 3 consecutive weeks, followed by subcutaneous injections of 50 μl of Propionibacterium acnes suspension at the oleic acid-applied sites once a day for 3 consecutive days, so as to establish a rat auriclular model of acne. After the model was confirmed to be successfully established by naked eyes, the low-, medium-, high-dose pomegranate peel polyphenol groups were topically treated with 0.5 mg of 1.4%, 2.8%, 5.6% (mass fraction) pomegranate peel polyphenol ointment respectively, the positive control group was topically treated with 0.5 mg of clindamycin hydrochloride gel, and the blank group and model group were topically treated with the same amount of distilled water. All the topical treatments were performed twice a day for 2 consecutive weeks. Twenty-four hours after the last topical treatment, abdominal aortic blood samples were collected, and enzyme-linked immunosorbent assay (ELISA) was conducted to detect the serum level of interleukin 17 (IL-17) in rats; rat auricular tissues were resected, hematoxylin-eosin (HE) staining was performed to observe histopathological changes of the skin tissues in each group, and immunohistochemical study to determine the expression of mammalian target of rapamycin (mTOR) , hypoxia-inducible factor-1α (HIF-1α) , and retinoic acid-related orphan receptor-γt (RORγt) in local tissues. Data meeting the assumptions of homogeneity of variances were analyzed by using one-way analysis of variance, and those that did not meet the assumptions of homogeneity of variances were analyzed by using Kruskal-Wallis H test; multiple comparisons were performed by using least significant difference- t test. Results:Compared with the model group, the pomegranate peel polyphenol groups and positive control group showed marked improvement in cysts, desquamation, crusts and epidermal keratinization, and reduced infiltration with inflammatory factors in the dermis at the modeling site. The serum level of IL-17 was significantly lower in the low-, medium- and high-dose pomegranate peel polyphenol groups (61.03 ± 5.99 ng/L, 55.35 ± 2.24 ng/L, 54.35 ± 4.29 ng/L, respectively) , positive control group (48.11 ± 4.07 ng/L) and blank group (42.10 ± 5.62 ng/L) than in the model group (70.24 ± 3.30 ng/L; t = 3.12, 5.34, 5.70, 8.29, 10.54, respectively, all P<0.05) . Immunohistochemical study revealed that the HIF-1α expression level was significantly lower in the low-, medium- and high-dose pomegranate peel polyphenol groups (0.29 ± 0.05, 0.29 ± 0.03, 0.33 ± 0.02, respectively) and positive control group (0.30 ± 0.01) than in the model group (0.41 ± 0.04; t = 4.89, 5.50, 3.62, 5.21, respectively, all P<0.05) ; the RORγt expression level was significantly lower in the low- and high-dose pomegranate peel polyphenol groups (0.28 ± 0.02, 0.31 ± 0.04, respectively) than in the model group (0.35 ± 0.02, t = 3.68, 2.18, respectively, both P<0.05) ; there was no significant difference in the mTOR expression level among these groups ( P = 0.119) . Conclusion:Pomegranate peel polyphenols could improve inflammatory reactions in the rat auriclular model of acne, which may be related to the down-regulation of HIF-1α/RORγt signaling pathway.

Hypoxia-inducible factor 1α affects the migration and invasion of hypoxia-inducible pancreatic cancer cells through regulating miRNA-296-5p / 肿瘤研究与临床

Objective:To investigate the effect of miRNA-296-5p (miR-296-5p) on the migration and invasion of hypoxia-induced pancreatic cancer cells and its related mechanisms.Methods:Human pancreatic cancer cell line PANC-1 was selected. Pancreatic cancer tissues from 55 pancreatic cancer patients who underwent the resection and adjacent carcinoma normal pancreatic tissues from 10 patients at Shanghai Fengxian District Central Hospital and Bengbu Medical College First Affiliated Hospital between January 2010 and December 2014 were collected. The expression levels of hypoxia-inducible factor 1α (HIF-1α) and miR-296-5p in tissue microarray of pancreatic cancer and adjacent carcinoma normal pancreatic tissues were detected by using immunohistochemistry and in situ hybridization. The relationship between miR-296-5p and HIF-1α as well as their correlation with clinicopathological characteristics of patients were analyzed. PANC-1 cells were divided into hypoxic group and normoxic group. Transwell assay was used to detect the cell migration and invasion ability of both groups. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to examine the expressions of HIF-1α and miR-296-5p under hypoxic environment of both groups. The expression of HIF-1α was interfered by transfecting small interfering RNA (siRNA). PANC-1 cells were divided into PANC-1 group (the empty control), PANC-1-NC group (the negative control) and PANC-1-siRNA group. The expression of miR-296-5p was measured. After co-transfecting miR-296-5p agonist and miR-296-5p inhibitor, the cells were divided into Agomir-miR-296-5p group (agonist group), Agomir-miR-296-5p-NC group (agonist negative control group), Antagomir-miR-296-5p group (inhibitor group) and Antagomir-miR-296-5p-NC group (inhibitor negative control group). Transwell assay was used to detect the cell migration and invasion ability of all groups. Luciferase reporter gene system was used to verify whether miR-296-5p promoter region had binding site of HIF-1α.Results:The high expression rate of HIF-1α in pancreatic cancer tissues was higher than that of adjacent carcinoma normal pancreatic tissues [81.8% (45/55) vs. 0 (0/10), P<0.01], and the high expression rate of miR-296-5p in pancreatic cancer tissues was lower than that of adjacent carcinoma normal pancreatic tissues [12.7% (7/55) vs. 90.0% (9/10), χ2 = 27.23, P<0.01]. The expression of HIF-1α was negatively correlated with that of miR-296-5p ( r = -0.53, P<0.01). The low expression of miR-296-5p was closely related with the tumor diameter, TNM staging, lymph node metastasis (all P<0.05). The number of PANC-1 invasion cell was 15.3±2.1 in normoxic group and 24.7±1.5 in hypoxic group, and the difference was statistically significant ( t = 0.26, P = 0.003). The number of PANC-1 migration cell was 20.7±3.8 in hypoxic group and 32.7±1.2 in normoxic group, and the difference was statistically significant ( t = 5.25, P = 0.006). The relative expression level of HIF-1α mRNA in PANC-1 cell of hypoxic group was higher than that of normoxic group [(1.00±0.01) vs. (0.30±0.02)], and the difference was statistically significant ( t = 56.45, P<0.01); the relative expression level of miR-296-5p in PANC-1 cell of hypoxic group was lower than that of normoxic group [(1.14±0.04) vs. (3.05±0.20)], and the difference was statistically significant ( t = 16.05, P<0.01). The number of invasion cells in PANC-1 group, PANC-1-NC group and PANC-1-siRNA group was 24.7±1.5, 25.7±1.5, 12.0±1.7, respectively, and the difference was statistically significant ( F = 68.13, P<0.01).The cell invasion ability in PANC-1-siRNA group was decreased compared with that in PANC-1 group ( t = 9.50, P = 0.001). The number of cell migration was 32.7±1.2, 37±1.0, 17.3±1.2, respectively in PANC-1 group, PANC-1-NC group and PANC-1-siRNA group, and the difference was statistically significant ( F = 262.09, P<0.01). The cell migration ability in PANC-1-siRNA group was decreased compared with that in PANC-1 group ( t = 16.26, P<0.01). The cell invasion and migration ability in Antagomir-miR-296-5p group was increased compared with that in PANC-1 group (all P<0.05); the cell invasion and migration ability in Agomir-miR-296-5p group was decreased compared with that in PANC-1 group (all P<0.05). The results of luciferase activity detected by luciferase reporter gene system showed that miR-296-5p had the target binding to HIF-1α. Conclusions:HIF-1α plays a key role in the invasion and migration of hypoxia-induced pancreatic cancer cells through negatively reducing miR-296-5p.

Expressions and significances of silent information regulator 1, hypoxia-inducible factor-1α and mutant P53 proteins in colorectal adenocarcinoma / 肿瘤研究与临床

Objective:To investigate the expression levels of silent information regulator 1 (SIRT1), hypoxia-inducible factor-1α (HIF-1α) and mutant P53 proteins in colorectal adenocarcinoma tissues and their clinical significances.Methods:The data of 68 cases of colorectal adenocarcinoma confirmed by pathology in Shanxi Traditional Chinese Medical Hospital from March 2015 to October 2021 were collected. The expressions of SIRT1, HIF-1α and mutant P53 proteins in colorectal adenocarcinoma tissues and paracancerous tissues were determined by immunohistochemistry. The correlation among SIRT1, HIF-1α and mutant P53 proteins and their relationship with clinicopathological features of patients were analyzed.Results:Among 68 colorectal adenocarcinoma tissues and paracancerous tissues, SIRT1 protein was positive in 38 cases (55.88%) and 11 cases (16.18%) ( χ2 = 23.25, P < 0.001), HIF-1α protein was positive in 47 cases (69.12%) and 5 cases (7.35%) ( χ2 =54.92, P < 0.001), and mutant P53 protein was positive in 41 cases (60.29%) and 0 cases (0) ( P < 0.001). The positive expression rate of SIRT1 protein was high in patients with high clinical stage and lymph node metastasis (both P < 0.05); the positive expression rate of HIF-1α protein was high in patients with poor differentiation ( P < 0.05); the positive expression rate of mutant P53 protein was high in patients with poor differentiation and lymph node metastasis (both P < 0.05). There was a negative correlation between expressions of SIRT1 and mutant P53 proteins ( rs = -0.38, P = 0.001); there was a positive correlation between expressions of HIF-1α and mutant P53 proteins ( rs = 0.56, P < 0.001); there was a negative correlation between expressions of SIRT1 and HIF-1α proteins ( rs = -0.40, P = 0.001). Conclusions:SIRT1, HIF-1α and mutant P53 proteins are highly expressed in colorectal adenocarcinoma and are correlated with clinicopathological features suggesting poor prognosis. Combined detection of the three proteins may be used for the diagnosis and prognosis of colorectal adenocarcinoma and serve as a new target for treatment.

Mechanism and application of hypoxia affecting immunotherapy drug resistance / 国际肿瘤学杂志

Immunotherapy is a new anti-tumor method. The application of immune checkpoint inhibitor greatly improves the survival benefit for patients, but the drug resistance of immunotherapy affects the efficacy. Therefore, it is very important to explore the mechanism of drug resistance and solve the problem of drug resis-tance in tumor immunotherapy. Hypoxia in tumor microenvironment is the key factor of immune drug resistance. Hypoxia can inhibit the immune cells function and lead to immune escape through various mechanisms. It can be the breakthrough for overcoming the immunotherapy drug resistance that blocking pathway of hypoxia to promote immune resistance. By reviewing the mechanism of immunotherapy drug resistance induced by hypoxia, it is helpful to explore the development prospect of hypoxia-inducible factor-1α (HIF-1α) related targeted drugs in clinical application for immunotherapy.