JOURNAL OF HAZARDOUS MATERIALS
·
2021
·
IF 10.588
Yuhao Wu,Junke Wang,Tianxin Zhao,Jiadong Chen,Lian Kang,Yuexin Wei,Lindong Han,Lianju Shen,Chunlan Long,Shengde Wu,Guanghui Wei
Di-(2-ethylhexyl) phthalate (DEHP) is an extensively used plasticizer and has been shown to cause reproductive dysfunction in humans and model animals. However, the exact mechanisms of testicular injury induced by DEHP exposure have not been fully clarified. Using gas chromatography-mass spectrometry, we found that mono-2-ethylhexyl ester (MEHP, a major biometabolite of DEHP) and DEHP concentrations were elevated in mouse serum after DEHP exposure. Using RNA-seq, we found that ferroptosis and HIF-1 signaling pathways might be involved in testicular injury due to prepubertal DEHP exposure. Subsequent Western blotting, ferrous iron and MDA measurements, and immunofluorescence of testicular sections verified the RNA-seq findings. Consistently, based on the RNA-seq findings, we found that ferroptosis and HIF-1 signaling pathways might play crucial roles in Leydig and Sertoli cell injury due to MEHP exposure in vitro. Further experiments also confirmed ferroptosis in Leydig and Sertoli cells. Using Western blotting, cellular immunofluorescence and ChIP-qPCR, we found that MEHP exposure caused HIF-1α accumulation and stabilization, resulted in HIF-1α translocation into the nucleus, and induced HIF-1α/ Hmox1 binding in Leydig and Sertoli cells. To clarify whether HIF-1α plays a pivotal role in MEHP-induced ferroptosis, we knocked out Hif-1α using the CRISPR/Cas9 technique. We found that Hif-1α knockout rescued MEHP-induced ferroptosis. In summary, our findings certified that prepubertal DEHP exposure led to ferroptosis in mouse testes via the HIF-1α/HO-1 signaling pathway.
研究领域:
毒理学
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生殖生物学
·
分子生物学
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DOI
PubMed
高影响因子
Frontiers in Physiology
·
2021
·
IF 4.566
Lin Jinyan,Fan Lele,Han Yuming,Guo Juanjuan,Hao Zhiqiang,Cao Lingna,Kang Jiamin,Wang Xiaoqin,He Jianping,Li Jingang
The Gansu zokor (Eospalax cansus) is a subterranean rodent species that is unique to China. These creatures inhabit underground burrows with a hypoxia environment. Metabolic energy patterns in subterranean rodents have become a recent focus of research; however, little is known about brain energy metabolism under conditions of hypoxia in this species. The mammalian (mechanistic) target of rapamycin complex 1 (mTORC1) coordinates eukaryotic cell growth and metabolism, and its downstream targets regulate hypoxia inducible factor-1α (HIF-1α) under conditions of hypoxia to induce glycolysis. In this study, we compared the metabolic characteristics of hypoxia-tolerant subterranean Gansu zokors under hypoxic conditions with those of hypoxia-intolerant Sprague-Dawley rats with a similar-sized surface area. We exposed Gansu zokors and rats to hypoxia I (44 h at 10.5% O2) or hypoxia II (6 h at 6.5% O2) and then measured the transcriptional levels of mTORC1 downstream targets, the transcriptional and translational levels of glycolysis-related genes, glucose and fructose levels in plasma and brain, and the activity of key glycolysis-associated enzymes. Under hypoxia, we found that hif-1α transcription was upregulated via the mTORC1/eIF4E pathway to drive glycolysis. Furthermore, Gansu zokor brain exhibited enhanced fructose-driven glycolysis under hypoxia through increased expression of the GLUT5 fructose transporter and ketohexokinase (KHK), in addition to increased KHK enzymatic activity, and utilization of fructose; these changes did not occur in rat. However, glucose-driven glycolysis was enhanced in both Gansu zokor and rat under hypoxia II of 6.5% O2 for 6 h. Overall, our results indicate that on the basis of glucose as the main metabolic substrate, fructose is used to accelerate the supply of energy in Gansu zokor, which mirrors the metabolic responses to hypoxia in this species.
研究领域:
生理学
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分子生物学
·
代谢学
·
神经科学
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DOI
PubMed
高影响因子
Biomedical Materials
·
2026
·Vol. 21
·期 3
·035012
·
IF 3.9
Xuefei Xiang,Yufang Yang,Heyou Gao,ZhiYun Chen,JingYi Xie,QingChuan Hu,Yu Wang
Composite scaffolds composed of porous polyurethane (PU) block copolymer and nano-hydroxyapatite (n-HA) have demonstrated significant potential in bone defect repair. However, the co-effect of osteogenesis and angiogenesis during the process of large bone defect repair is still not yet fully understood. Recent research has found that erythropoietin (EPO) is essential for both osteogenesis and angiogenesis, offering a new research direction for bone regeneration strategies. In this study, a polydopamine (pDA)-modified, EPO-functionalized HA/PU scaffold was fabricated, and its physicochemical properties, release kinetics, and effects on bone repair were systematically investigated. In vitro, a co-culture system of human umbilical vein endothelial cells and rat bone marrow mesenchymal stem cells was used to evaluate the scaffold’s effects on cell proliferation, osteogenic, angiogenic, and HIF-1α/ vascular endothelial growth factor (VEGF) pathway. In vivo, the modified composite scaffold was implanted onto the cranial bone defects of Sprague-Dawley rats to assess its efficacy in promoting bone repair and HIF-1α/VEGF pathway. In vitro, the EPO/pDA/HA/PU group showed more three-dimensional cell morphology with prominent pseudopodia, facilitating cell adhesion, and significantly increased mRNA expression of ALP, Runx2, CD31, CD34, HIF-1α and VEGF. In vivo, the EPO/pDA/HA/PU group exhibited the most significant bone regeneration, with micro- computed tomography analysis confirming a significantly higher the ratio of bone tissue volume to total tissue volume (BV/TV) compared to the blank and HA/PU control groups. These results indicated that the modified composite scaffold enabled sustained release of EPO, which upregulated the expression of HIF-1α and VEGF, thereby enhancing osteogenic and angiogenic capabilities both in vitro and in vivo. Our research demonstrated that loading of EPO onto the HA/PU composite scaffold could effectively promote osteogenesis and angiogenesis. HIF-1α/VEGF signaling plays a crucial role in this process. This discovery provides novel insights and methods for using HIF-1α/VEGF as a regulatory target to advance the clinical translation of large bone defects repair.
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PubMed
高影响因子
Scientific Reports
·
2026
·
IF 4.9
Niu Jiale,Liu Guangxia,He Guangyao,Zhang Xiaomeng,Bai Huihui,Lu Yamin
To investigate the role of IL-17 in macrophage M1 polarization within a type 2 diabetic (T2DM) milieu and to evaluate the therapeutic potential of its neutralizing antibody. PMA-differentiated THP-1 macrophages were polarized to M1 state. Under high glucose, cells were treated with IL-17 and an IL-17 neutralizing antibody. Inflammatory cytokines (IL-1β, IL-6, TNF-α) were measured; mRNA levels of TNF-α, HIF-1α, and NLRP3 were assessed by qPCR; and protein expression related to the NF-κB, mTOR/HIF-1α axis and pyroptosis (NLRP3, Caspase-1, GSDMD) was analyzed by Western Blot. High glucose and IL-17 synergistically promoted M1 polarization, enhancing proinflammatory cytokine secretion. This was associated with activation of the NF-κB, mTOR/HIF-1α signaling axis and induction of pyroptosis, evidenced by NLRP3 inflammasome assembly, Caspase-1 activation, and GSDMD cleavage. The IL-17 neutralizing antibody effectively suppressed these pathological processes. IL-17 acts as a key immunological amplifier in diabetes, driving M1 polarization, oxidative stress, and pyroptosis via the NF-κB, mTOR/HIF-1α axis and NLRP3 inflammasome. Treatment with an αIL-17 effectively reversed the aberrant activation of the aforementioned cellular phenotypes and signaling pathways, partially restoring macrophage functional balance. This finding provides preliminary experimental support for further exploration of IL-17-targeted immunomodulatory strategies to ameliorate diabetes-associated metabolic inflammation.
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产品关联
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PubMed
高影响因子
Journal of Functional Foods
·
2026
·
IF 3.9
Zexuan Wu,Yonghong Long,Fugang Huang,Ze Yang,Yanzuo Wu,Yihong Gan,Xiufang Chen,Guanqun Xie
Capsaicin (CAP), the pungent compound in chili peppers, is well-known for its anti-inflammatory properties, yet its role in autoimmune immunometabolism remains unexplored. In a murine model of Collagen-Induced Arthritis,CAP markedly attenuated joint swelling, cartilage damage, and bone erosion. Mechanistically, CAP targeted HIF-1α, leading to a coordinated suppression of both BNIP3-mediated mitophagy and the characteristic glycolytic shift in M1 macrophages. This dual metabolic suppression was recapitulated in human THP-1-derived M1-like macrophages, where it inhibited M1 polarization and reduced pro-inflammatory cytokine secretion. Collectively, these data identify CAP as a food-derived immunometabolic modulator that alleviates rheumatoid arthritis (RA) by concurrently disrupting mitophagy and glycolysis in M1 macrophages via HIF-1α.
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高影响因子
Gastroenterology Research and Practice
·
2022
·
IF 1.919
Sheng Chen,Quan-Jin Dong,Zi-Ang Wan,Shan Gao,Shi-Liang Tu,Rui Chai
Objective. BHLHE41 has been shown to be a marker of tumorigenesis. Colon cancer (CC) is a common malignant tumor of colonic mucosa. This study mainly explored the mechanism of BHLHE41 in alleviating malignant behavior of hypoxia-induced CC cells. Methods. The levels of BHLHE41 in CC and normal cell lines were tested by Western blot and qRT-PCR. After, CC cells were subjected to hypoxia treatment and BHLHE41 overexpression transfection, and the BHLHE41 expression, the effect of BHLHE41 on CC cell viability, apoptosis, migration, and invasion and cell cycle were tested by qRT-PCR and relevant cell functional experiments. HIF-1α and epithelial-mesenchymal transition- (EMT-) related proteins were tested by Western blot. Moreover, CC tumor-bearing model was established in nude mice, and the effect of BHLHE41 on the tumor was evaluated by measuring the tumor volume and weight. Then, the expressions of BHLHE41 and EMT-related proteins were detected by immunohistochemistry and Western blot. Results. Western blot and qRT-PCR showed that BHLHE41 was lowly expressed in CC cells. BHLHE41 overexpression could inhibit the hypoxia-induced CC cell viability, migration, and invasion, induce apoptosis, and alter cell cycle. Besides, BHLHE41 overexpression could enhance the levels of E-cadherin but reduce the levels of HIF-1α, N-cadherin, vimentin, and MMP9 in hypoxia-induced CC cells. Moreover, BHLHE41 overexpression reduced tumor volume, weight, and EMT-related proteins levels in tumor tissues. Conclusions. BHLHE41 overexpression could mitigate the malignant behavior of hypoxia-induced CC via modulating the HIF-1α/EMT pathway.
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DOI
PubMed
高影响因子
Journal of Oncology
·
2022
·
IF 4.501
Hongliang You,Dao Wang,Linlin Wei,Jiao Chen,Huanhuan Li,Yufeng Liu
Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer, with a feature of easy to induce multidrug resistance and relapse. Abundant studies have proved that iron overload strengthens the growth and metastasis of tumor cells. Herein, we found that deferoxamine (DFO) effectively decreased the concentration of intracellular iron in ALL cells. DFO inhibited proliferation, induced apoptosis, and obstructed cell cycle of ALL cells, whereas DFO and dextriferron (Dex) used in combination significantly decreased the sensitivity of ALL cells to DFO. Reactive oxygen species (ROS) level was reduced in ALL cells treated with DFO, and the combination of DFO and Dex reversed the effects of DFO. In vivo, DFO inhibited mouse tumor growth. Besides, cyclinD1, β-catenin, c-Myc, hypoxia inducible factor 1 (HIF-1), p-p38MAPK, and p-ERK1/2 protein levels were significantly downregulated, and the levels of prolyl hydroxylase-2 (PHD-2) were upregulated after treated with DFO, whereas Dex treatment reversed those in vivo and in vitro. In conclusion, DFO inhibited the proliferation and ALL xenograft tumor growth, obstructed the cell cycle, and induced apoptosis of ALL cells, probably via inactivating the ROS/HIF-1α, Wnt/β-catenin, and p38MAPK/ERK signaling.
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产品关联
DOI
PubMed
高影响因子
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
·
2015
·Vol. 56
·期 13
·8166-8178
·
IF 3.404
Guoxu Xu,Daohuan Kang,Chaoyang Zhang,Hui Lou,Chen Sun,Qian Yang,Lixia Lu,Guo-Tong Xu,Jingfa Zhang,Fang Wang
Purpose:Zinc transporter 8 (ZnT8) was downregulated in hypoxic retina, which could be rescued by hypoxia-inducible factor-1α (HIF-1α) inhibition. Erythropoietin (EPO) protects retinal cells in diabetic rats through inhibiting HIF-1α as one of its mechanisms. We hence tried to explore the effect of EPO in regulating ZnT8 and protecting retinal cells in diabetic rats and possible mechanisms.Methods:Diabetes was induced in Sprague-Dawley rats. Intravitreal injection of EPO was performed 1 month after diabetes onset. The CoCl2-treated rat Müller cell line (rMC-1) was cotreated with EPO, soluble EPO receptor (sEPOR), digoxin, or U0126. Cell viability, cell death, and intracellular zinc level were examined. The expression of ZnT8, HIF-1α, AKT, and ERK was studied.Results:In diabetic rat retinas, EPO significantly decreased HIF-1α expression and increased ZnT8 expression. In CoCl2-treated rMC-1 cells, EPO increased cell viability and decreased intracellular zinc. Erythropoietin or digoxin could activate ERK pathway, downregulate HIF-1α, and upregulate ZnT8. The effect of EPO was abolished by sEPOR and U0126. Transient knockdown of ZnT8 increased intracellular zinc level, but not to a degree that would decrease cell viability or cause cell death.Conclusions:In diabetic retinas, EPO maintains zinc homeostasis through activating the ERK pathway and downregulating HIF-1α, and thus upregulating ZnT8 expression. This work proposed a possible new protective mechanism for EPO in, and indicated a potential target for, the treatment of diabetic retinopathy.
研究领域:
眼科学
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内分泌学
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细胞生物学
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分子生物学
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糖尿病研究
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DOI
PubMed
高影响因子
BIOLOGICAL TRACE ELEMENT RESEARCH
·
2026
·
IF 4.3
Liu Bai Han,Zhang Jin Ge,Peng Dong Qiao,Jin Yong Cheng
Copper is an essential trace element for beef cattle, yet its muscle developmental regulatory mechanism remains unclear. This study investigated the effects of copper sulfate (CuSO₄) on myogenic differentiation of bovine skeletal muscle-derived cells (BSMC) and the underlying molecular mechanisms. BSMC were isolated from the longissimus thoracis muscle of three 30-month-old crossbred steers, with each steer defined as an independent experimental unit corresponding to a separate biological replicate ( n = 3). Based on cell viability, CuSO₄ was used at 0, 0.1, 1, and 10 µM. All cell samples were harvested at differentiation day 6 (D6). The 0.1 µM CuSO₄ treatment during cell growth significantly promoted D6 myotube formation ( P = 0.049), and upregulated mRNA and protein expression of myogenic differentiation 1 (MyoD) ( P = 0.044, P = 0.030), as well as protein expression of hypoxia-inducible factor-1α (HIF-1α) ( P = 0.037) and β-catenin ( P = 0.050). During differentiation, 1 µM CuSO₄ significantly facilitated D6 myotube formation ( P = 0.0004), increased myogenic factor 5(Myf5) mRNA and protein expression ( P = 0.030, P = 0.006), and elevated HIF-1α ( P = 0.025) and β-catenin ( P = 0.004) protein levels, whereas Wnt10b protein expression remained unaltered ( P = 0.930). Single or combined pharmacological inhibition of HIF-1α and β-catenin markedly reversed copper’s pro-myogenic effect on BSMC. In conclusion, copper modulates BSMC myogenic differentiation via the HIF-1α/β-catenin axis by enhancing β-catenin protein stability independent of Wnt10b transcription. HIF-1α acts upstream to drive β-catenin, and a reciprocal regulatory relationship may exist in which β-catenin in turn helps sustain HIF-1α abundance, thereby supporting cascade signaling and downstream myogenic transcription. This study elucidates copper’s molecular mechanism governing muscle development and provides theoretical support for precise copper supplementation to improve beef production performance.
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高影响因子
INFLAMMATION
·
2018
·Vol. 41
·期 6
·2068-2078
·
IF 2.884
Zhou Qin,Gong Xia,Kuang Ge,Jiang Rong,Xie Tianjun,Tie HongTao,Chen XiaHong,Li Ke,Wan JingYuan,Wang Bin
Ferulic acid (FA), derived from fruits and vegetables, is well-known as a potent antioxidant of scavenging free radicals. However, the role and underlying mechanism of FA on kidney ischemia reperfusion (I/R) injury are limited. Here, we explored the effects of FA on kidney I/R injury. The kidney I/R injury models were carried out by clamping bilateral pedicles for 35 min followed by reperfusion for 24 h. Mice were orally pretreated with different doses of FA for three times 24 h before I/R. The renal function was assessed by serum creatine (Scr) and blood urea nitrogen (BUN). Kidney histology was examined by hematoxylin and eosin (HE) staining and terminal deoxynucleotidly transferased UTP nick-end labeling (TUNEL) assay. Proinflammatory cytokines, caspase-3 activity, adenosine generation, adenosine signaling molecules, and hypoxia inducible factor-1 alpha (HIF-1α) were also detected, respectively. The siHIF-1α adenovirus vectors were in vivo used to inhibit the expression of HIF-1α. The results showed that FA significantly attenuated kidney damage in renal I/R-operated mice as indicated by reducing levels of Scr and BUN, ameliorating renal pathological structural changes, and tubular cells apoptosis. Moreover, FA pretreatment inhibited I/R-induced renal proinflammatory cytokines and neutrophils recruitment. Interestingly, the levels of HIF-α, CD39, and CD73 mRNA and protein as well as adenosine production were all significantly increased after FA pretreatment in the kidney of I/R-performed mice, and inhibiting HIF-α expression using siRNA abolished this protection of FA on I/R-induced acute kidney injury as evidenced by more severe renal damage and reduced adenosine production. Our findings indicated that FA protected against kidney I/R injury by reducing apoptosis, alleviating inflammation, increasing adenosine generation, and upregulating CD39 and CD73 expression, which might be mediated by HIF-1α.
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DOI
PubMed
高影响因子
NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL
·
2025
·
IF 2.4
Jingjing Lu,Dongxuan Wang,Hongjin Huo,Hao Jiang,Wei Wei,Jie Sun,Fei Jiang
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high metastatic potential and limited therapeutic options. This study investigates the effects of calcitriol, an active metabolite of vitamin D, on TNBC progression by targeting the vitamin D receptor (VDR)-mediated hypoxia-inducible factor-1α (HIF-1α) axis. We established in vivo TNBC xenograft models using 4T1 cells and in vitro models with MDA-MB-231 and 4T1 cells overexpressing HIF-1α. Results showed that calcitriol inhibited lung metastasis and downregulated glycolytic activity in TNBC xenografts without affecting primary tumor growth. In vitro, calcitriol reduced cell viability, migration, and invasion by suppressing HIF-1α expression. It also decreased glucose uptake, lactate production, and ATP levels while downregulating key glycolytic regulators. VDR knockdown abolished these effects, confirming VDR as the critical mediator. Our findings suggest that calcitriol exerts anti-metastatic effects in TNBC by modulating the VDR-HIF-1α axis, inhibiting glycolysis, and suppressing the epithelial-mesenchymal transition. This study highlights the potential therapeutic role of calcitriol in TNBC treatment by targeting both metabolic reprogramming and invasive capacity. Future research should further explore the mechanisms underlying calcitriol-mediated HIF-1α suppression and its clinical application in TNBC.
研究领域:
肿瘤学
·
分子生物学
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内分泌学
·
癌症代谢
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转化医学
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2024
·Vol. 14
·期 1
·1-13
·
IF 3.8
Zhu Dongsheng,Chen Feng,Qiang Hongjia,Qi Han
To clarify the impact of SETD2 on macrophage function in pediatric patients with acute suppurative osteomyelitis and to elucidate the precise underlying mechanism. To gain insights into the potential functions of SETD2, a comprehensive study was conducted utilizing a co-culture model of human bone mesenchymal stem cells (hBMSCs) and bone marrow-derived macrophages (THP-1). A range of techniques were employed, including quantitative polymerase chain reaction, western blotting, ELISA, alkaline phosphatase activity assays, alizarin red S staining, luciferase reporter gene assays, and chromatin immunoprecipitation, to unravel the intricate interactions and molecular mechanisms involving SETD2 in this system. It was observed that SETD2 expression was reduced in THP-1 cells stimulated by staphylococcal protein A (SPA). Furthermore, the downregulation of SETD2 resulted in elevated M1 macrophage polarization and glycolysis, effects that were mitigated by SPA stimulation. Notably, SPA-stimulated THP-1 cells exhibited an increase in HIF-1α expression, which exhibited an inverse correlation with SETD2 levels. Moreover, it was discovered that SETD2 functioned as a catalyst for H3K36me3 and bound to the HIF-1α gene, which, in turn, regulated HIF-1α expression. Furthermore, the suppression of HIF-1α abrogated the consequences of SETD2 downregulation on glycolysis and M1 macrophage polarization. Lastly, the study demonstrated that M1 macrophage polarization serves as a mediator for BMP4’s inhibitory effect on osteogenic differentiation of hBMSCs. This research has uncovered a previously unknown role of SETD2 in macrophages during osteomyelitis, revealing its significance in the pathogenesis of this condition. These findings suggest SETD2 as a novel target for the treatment of osteomyelitis.
研究领域:
免疫学
·
分子生物学
·
细胞生物学
·
骨科
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DOI
PubMed
高影响因子
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