Frontiers in Cell and Developmental Biology
·
2021
·
IF 6.684
Wang Meng,Liu Haoyu,Zhang Xu,Zhao Wenbo,Lin Xiaoyan,Zhang Fei,Li Danyang,Xu Chengpeng,Xie Fei,Wu Zhen,Yang Qibing,Li Xiangzhi
Hypoxia-inducible factor-1α (HIF-1α) promotes oncogenesis in hepatocellular carcinoma and is functionally linked to cell proliferation, chemoresistance, metastasis and angiogenesis. It has been confirmed that the low expression level of Males absent on the first (MOF) in hepatocellular carcinoma leads to poor prognosis of patients. However, potential regulatory mechanisms of MOF in response to hypoxia remain elusive. Our results demonstrate that MOF expression is negatively associated with HIF-1α expression in hepatocellular carcinoma tissues and in response to chloride-mimicked hypoxia in hepatocellular carcinoma cell lines. MOF regulates HIF-1α mRNA expression and also directly binds to HIF-1α to mediate HIF-1α N-terminal lysine acetylation, ubiquitination and degradation, with downstream effects on MDR1 levels. Functional inactivation of MOF enhances HIF-1α stability and causes cell tolerance to hypoxia that is insensitive to histone deacetylase inhibitor treatment. Dysfunction of MOF in hepatocellular carcinoma cells also results in chemoresistance to trichostatin A, sorafenib and 5-fluorouracil via HIF-1α. Our results suggest that MOF regulates hypoxia tolerance and drug resistance in hepatocellular carcinoma cells by modulating both HIF-1α mRNA expression and N-terminal acetylation of HIF-1α, providing molecular insight into MOF-dependent oncogenic function of hepatocellular carcinoma cells.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
IMMUNITY
·
2019
·
IF 21.522
Juan Liu,Xiaomin Zhang,Kun Chen,Yujie Cheng,Shuxun Liu,Meng Xia,Yali Chen,Ha Zhu,Zhiqing Li,Xuetao Cao
Summary CCR7 chemokine receptor stimulation induces rapid but transient dendritic cell (DC) migration toward draining lymph nodes, which is critical for the initiation of protective immunity and maintenance of immune homeostasis. The mechanisms for terminating CCR7-mediated DC migration remain incompletely understood. Here we have identified a long non-coding RNA lnc-Dpf3 whose feedback restrained CCR7-mediated DC migration. CCR7 stimulation upregulated lnc-Dpf3 via removing N6-methyladenosine (m 6 A) modification to prevent RNA degradation. DC-specific lnc-Dpf3 deficiency increased CCR7-mediated DC migration, leading to exaggerated adaptive immune responses and inflammatory injuries. Mechanistically, CCR7 stimulation activated the HIF-1α transcription factor pathway in DCs, leading to metabolic reprogramming toward glycolysis for DC migration. lnc-Dpf3 directly bound to HIF-1α and suppressed HIF-1α-dependent transcription of the glycolytic gene Ldha , thus inhibiting DC glycolytic metabolism and migratory capacity. We demonstrate a critical role for CCR7-inducible lnc-Dpf3 in coupling epigenetic and metabolic pathways to feedback-control DC migration and inflammatory responses.
研究领域:
免疫学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2021
·
IF 4.932
Yonglan Ruan,Jinying Ling,Fan Ye,Nuo Cheng,Fei Wu,Zongxiang Tang,Xiaolan Cheng,Hongquan Liu
Background Treatment of chronic inflammatory pain remains a major goal in the clinic. It is thus of prime importance to characterize inherent pathophysiological pathways to design new therapeutic strategies and analgesics for pain management. Paeoniflorin (PF), a monoterpenoid glycoside from Paeonia lactiflora Pallas plants, possesses promising anti-nociceptive property. However, therapeutic effect and underlying mechanism of action of PF on inflammatory pain have not yet been fully elucidated. In this study, we aim to investigate the analgesic effect further and clarify its mechanism of action of PF on complete freund’s adjuvant (CFA)-evoked inflammatory pain. Methods Twenty-four male mice were divided into 3 groups: sham, CFA, and CFA + PF groups (n = 8/group). Mice were treated with normal saline or PF (30 mg/kg) for 11 days. Footpad swelling (n = 8/group), mechanical (n = 8/group) and thermal hypersensitivity (n = 8/group) were measured to evaluate the analgesic effect of PF on CFA-injected mice. At the end of the animal experiment, blood and L4-L6 dorsal root ganglion neurons were collected to assess the therapeutic effect of PF on CFA-induced inflammatory pain. Next, hematoxylin and eosin, quantitative realtime PCR, ELISA, capsaicin and dimethyl succinate induced pain test (n = 8/group), motor coordination test (n = 8/group), tail flicking test (n = 8/group), pyruvate and succinate dehydrogenase assay (n = 6/group), immunohistochemical staining, were performed to clarify the action mechanism of PF on CFA-evoked inflammatory pain. Besides, the effect of PF on TRPV1 was evaluated by whole-cell patch clamp recording on primary neurons (n = 7). Finally, molecular docking further performed to evaluate the binding ability of PF to TRPV1. Results PF significantly relieved inflammatory pain ( P < 0.001 ) and paw edema ( P < 0.001 ) on a complete Freund adjuvant (CFA)-induced peripheral inflammatory pain model. Furthermore, PF inhibited neutrophil infiltration ( P < 0.01 ), IL-1β increase ( P < 0.01 ), and pain-related peptide substance P release ( P < 0.001 ). Intriguingly, CFA-induced succinate aggregation was notably reversed by PF via modulating pyruvate and SDH activity ( P < 0.01 ). In addition, PF dampened the high expression of subsequent succinate receptor SUCNR1 ( P < 0.01 ), HIF-1α ( P < 0.05 ), as well as the activation of NLPR3 inflammasome ( P < 0.05 ) and TRPV1 ( P < 0.05 ). More importantly, both capsaicin and dimethyl succinate supplementation obviously counteracted the pain-relieving effect of PF and TRPV1 ( P < 0.01 or P < 0.001 ). Conclusion Our findings suggest that PF can significantly relieve CFA-induced paw swelling, as well as mechanical and thermal hyperalgesia. PF alleviated inflammatory pain partly through inhibiting the activation of TRPV1 and succinate/SUCNR1-HIF-1α/NLPR3 pathway. Furthermore, we found that PF exerted its analgesic effect without affecting motor coordination and pain-related cold ion-channels. In summary, this study may provide valuable evidence for the potential application of PF as therapeutic strategy for inflammatory pain treatment.
研究领域:
药理学
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疼痛管理
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神经科学
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炎症
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2020
·Vol. 8
·期 8
·2129-2142
·
IF 6.183
Xiaoshuang Guo,Zihan Yuan,Yang Xu,Minyan Wei,Zhiwei Fang,Wei-En Yuan
Hemangioma, one of the most common angiogenic diseases in infants and children, is characterized by the abnormal and aggressive proliferation of vascular endothelial cells. Advanced therapeutic strategies like RNA interference can inhibit the expression of target proteins at the translational level, but they are rarely used in hemangioma treatment owing to the lack of safe carriers. In this study, we showed for the first time that RNAi technology targeting HIF-1α (hypoxia-inducible factor-1 alpha) could benefit hemangioma therapy effectively. Heptafluorobutyric anhydride (HFAA) was used to modify low-molecular-weight PEI (PEI1.8k), and a novel fluorinated polycation carrier named fluorinated PEI (FPEI) was synthesized. Furthermore, HIF-1α-shRNA-pDNA was condensed by FPEI to fabricate FPEI polyplexes. Compared with PEI25k polyplexes, which are usually the gold standard used in gene delivery, FPEI polyplexes showed lower cytotoxicity and higher serum stability, transfection efficiency and gene silencing efficiency both in vitro and in vivo. In addition, we confirmed that FPEI polyplexes could efficiently inhibit the formation of new capillaries and tumor growth in vivo, which may provide a practicable strategy for clinical hemangioma treatment in the future.
研究领域:
药理学
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分子生物学
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生物医学工程
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治疗学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY
·
2023
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IF 4.5
Yujing Wang,Min Xiao,Feng Cai,Yang Li,Tianli Shi,Xiaoyan Zhou,Shuhong Tian,Denggao Huang
Vascular calcification (VC) is a common complication of chronic kidney disease (CKD). VC is a gene-regulated process similar to osteogenic differentiation. There are still no convincing schemes to prevent and reduce the development of VC. It has been reported that hypoxia-inducing factor 1α (HIF-1α) and endothelin-1(ET-1) are related to VC. In this study, we found that the expression of ET-1 and HIF-1α was enhanced after VC, the interaction between HIF-1α and ET-1 was confirmed by CO-IP and luciferase experiments. We found that ET-1 was an upregulated differential gene of calcified vascular smooth muscle cells (VSMCs) through gene sequencing. However, hypoxia-inducing factor 2α (HIF-2α) and HIF-1α have antagonistic effects on each other. HIF-1α is a pro-inflammatory cytokine, and HIF-2α can improve inflammation and fibrosis. Roxadustat, as a selective PHD3 inhibitor, preferentially activates HIF-2α. It is still unclear whether roxadustat improves VC in CKD by regulating the expression of HIF-2α/HIF-1α. Alizarin red staining and western blot as well as immunohistochemical results showed that roxadustat could significantly reduce the degree of vascular and VSMCs calcification in CKD rats. Serum HIF-1α and ET-1 were significantly decreased after roxadustat treatment. In addition, western blot results showed that roxadustat could decrease the expression of HIF-1α and ET-1 in vascular tissues and calcified VSMC, but HIF-2α expression significantly increased. Interestingly, our study confirmed that activation of HIF-1α or inhibition of HIF-2α reversed the ameliorating effect of roxadustat on VC, proving that the effect mediated by roxadustat is HIF-2α/HIF-1α dependent. We have demonstrated for the first time that roxadustat improves VC in CKD rats by regulating HIF-2α/HIF-1α, thus providing a new idea for the application of roxadustat in VC of CKD.
研究领域:
药理学
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肾病学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 25
·期 7
·3735
·
IF 4.9
Jing Sun,Zhengtian Zhao,Jiaqi Lu,Wen An,Yiming Zhang,Wei Li,Li Yang
The unsatisfactory efficacy of immunotherapy for colorectal cancer (CRC) remains a major challenge for clinicians and patients. The tumor microenvironment may promote CRC progression by upregulating the expression of hypoxia-inducing factor (HIF) and PD-L1. Therefore, this study explored the expression and correlation of HIF-1α and PD-L1 in the CRC microenvironment. The expression and correlation of HIF-1α and PD-L1 in CRC were analyzed using bioinformatics and Western blotting (WB). The hypoxia and inflammation of the CRC microenvironment were established in the CT26 cell line. CT26 cells were stimulated with two hypoxia mimics, CoCl2and DFO, which were used to induce the hypoxic environment. Western blotting was used to assess the expression and correlation of HIF-1α and PD-L1 in the hypoxic environment.LPS stimulated CT26 cells to induce the inflammatory environment. WB and bioinformatics were used to assess the expression and correlation of TLR4, HIF-1α, and PD-L1 in the inflammatory environment. Furthermore, the impact of curcumin on the inflammatory environment established by LPS-stimulated CT26 cells was demonstrated through MTT, Transwell, molecular docking, network pharmacology and Western blotting assays. In this study, we found that the HIF-1α/PD-L1 pathway was activated in the hypoxic and inflammatory environment and promoted immune escape in CRC. Meanwhile, curcumin suppressed tumor immune escape by inhibiting the TLR4/HIF-1α/PD-L1 pathway in the inflammatory environment of CRC. These results suggest that combination therapy based on the HIF-1α/PD-L1 pathway can be a promising therapeutic option and that curcumin can be used as a potent immunomodulatory agent in clinical practice.
研究领域:
肿瘤学
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免疫学
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分子生物学
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癌症治疗
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产品关联
DOI
PubMed
高影响因子
MICROBIAL PATHOGENESIS
·
2024
·
IF 3.3
Xiaoye Cheng,Yijin Jiang,Xu Zhao,Nana Ma,Xiangzhen Shen
Lactate has been increasingly recognized for its role in diseases progression, necessitating a deeper understanding of its metabolic processes and regulatory mechanisms. This study aimed to evaluate the impact of lipopolysaccharide (LPS) on lactate accumulation in bovine mammary epithelial cells (BMECs) and to elucidate the underlying regulatory mechanisms. Further optimization of LPS treatment points was achieved by assessing the content of key glycolytic enzymes-hexokinases (HK), pyruvate kinase (PK) and pyruvate dehydrogenase (PDH)-as well as the expression levels of HK2, pyruvate dehydrogenase kinase4 (PDK4) and lactate dehydrogenase (LDHA). Our results indicate that LPS can promote intracellular glycolysis and inhibits pyruvate synthesis, thereby increasing lactate content. BMECs were cultured and divided into a control group (CON) and an LPS-stimulated group (10 μg/mL for 6 h, LPS group). LPS was found to upregulate expression levels of HIF-1α and MCT1, suggesting a role for HIF-1α and MCT1 in cellular glucose metabolism. To explore the effect of HIF-1α on lactate accumulation, BMECs were stimulated with a HIF-1α inducer (COCL 2 ) and HIF-1α inhibitor (DMBPA). COCL 2 was observed to promote lactate accumulation, while DMBPA inhibited it. Additionally, modulation of HIF-1α expression influenced the expression of MCT1, which is a crucial transporter for extracellular lactate influx. To investigate the specific impact of MCT1 on intracellular lactate, we utilized overexpression plasmids and small interfering RNA to modulate MCT1 expression. The findings indicate that while MCT1 expression alone does not affect intracellular lactate levels, it does modulate the changes induced by LPS. In conclusion, our study suggests that LPS regulates lactate accumulation in BMECs through the HIF-1α/MCT1 pathway, providing insights into the metabolic dysregulation associated with LPS-induced stress in dairy cattle.
研究领域:
动物科学
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细胞生物学
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代谢学
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乳品科学
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产品关联
DOI
PubMed
高影响因子
BIOLOGICAL & PHARMACEUTICAL BULLETIN
·
2019
·Vol. 42
·期 6
·886-891
·
IF 1.54
Yangbiao He,Xujun Lang,Dong Cheng,Zhihao Yang
Previous studies implicated the mammalian target of rapamycin (mTOR)/hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway in renal fibrosis and found that curcumin could suppress the expression of mTOR. Therefore, the aim of the present study was to investigate the therapeutic effects of curcumin against chronic renal failure (CRF) in a rat model induced by 5/6 nephrectomy through inhibition of mTOR/HIF-1α/VEGF signaling. A total of 70 male Sprague–Dawley rats were divided into seven groups: a sham group, a CRF group, and five treatment groups. Except for the sham rats, all rats underwent 5/6 nephrectomy to induce CRF. The 5/6 nephrectomized rats received treatment with curcumin vehicle, everolimus vehicle, curcumin, everolimus, or the combination of curcumin and everolimus. Everolimus, a specific inhibitor of mTOR, was used as a positive control. At the end of treatment, blood biochemical indexes, proteinuria and the kidney index were detected. Moreover, histological change was examined by hematoxylin and eosin staining, and protein expression levels were detected by Western blotting. The blood biochemical indexes, proteinuria, and kidney index were increased in the CRF group as compared to the sham group, which was accompanied by marked activation of the mTOR/HIF-1α/VEGF pathway. However, curcumin, as well as everolimus, restored or ameliorated these changes. These results indicate that activation of the mTOR/HIF-1α/VEGF signaling pathway plays an important role in the occurrence and development of CRF, and that curcumin has renoprotective effects by blocking activation of this pathway.
研究领域:
药理学
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肾病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELL PROLIFERATION
·
2024
·
IF 5.9
Yuanchong Chen,Jiangshan Xu,Sirong Shi,Wenjuan Ma,Weitong Cui,Ran Yan,Yunfeng Lin
Since its discovery in 1978, cisplatin-based chemotherapy regimens have served a pivotal role in human cancer treatment, saving millions of lives. However, its high risk still poses a significant challenge for cisplatin-induced acute kidney injury (AKI), which occurs in 30% of cisplatin-treated patients. Unfortunately, no effective solution for preventing or managing this severe complication, which greatly impacts its clinical administration. Kidney is the main organ injured by cisplatin, and the injury is related to cisplatin-induced cell apoptosis and DNA injury. Therefore, to achieve the safe use of cisplatin in tumour treatment, the key lies in identifying a kidney treatment that can effectively minimize cisplatin nephrotoxicity. Here, we successfully synthesized and applied a DNA-nanostructure complex, named TFG, which contains tetrahedral framework nucleic acids (tFNAs) and FG-4592, a novel Hif-1α inducer. As cargo, TFG is composed entirely of DNA strands. It possesses low nephrotoxicity and renal aggregation properties while FG-4592 is able to relieve renal injury by downregulating the apoptosis signal pathways. And it can relieve cisplatin-induced renal injury when taken cisplatin treatment. This work aims to enhance chemotherapy protection in tumour patients by using TFG, a DNA-based nanomedicines to kidney. This work has the potential to revolutionize the treatment of renal diseases, particularly drug-induced kidney injury, leading to improved clinical outcomes.
研究领域:
肿瘤学
·
肾病学
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药学
·
纳米技术
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2018
·Vol. 5
·期 3
·1700392
·
IF 12.441
Yang Wang,Xingyun Liao,Jianguo Sun,Bin Yi,Shenglin Luo,Tao Liu,Xu Tan,Dengqun Liu,Zelin Chen,Xin Wang,Chunmeng Shi
The characterization of cancer stem-like cells (CSCs) has profound implications for elucidating cancer biology and developing treatment strategies. Although surface markers are already used to identify CSCs, the expression of these markers is controversially linked to the phenotypes in different types of tumors and does not represent all functionally relevant of CSCs. Very recently, hyperactive HIF-1α/glycolysis metabolic pathway is recognized as a master regulator of CSCs. In this study, a near-infrared fluorescent small-molecule, IR-780, is identified for the exclusive characterization of human CSCs through the HIF-1α/glycolysis dependent mitochondrial transporter ABCB10's activity. The results identified for the first time that ABCB10 is involved in the preferential uptake of IR-780 in CSCs, which is regulated by HIF-1α via the direct interaction with the binding site of ABCB10 gene promoter region. In addition, IR-780 is demonstrated to conjugate with anticancer drug 5-fluorouracil to act as a potential drug delivery carrier for CSC-targeted therapy. Thus, the studies provide a new rational approach independent of surface markers to characterize CSCs via small-molecule-based imaging of HIF-1α/glycolysis hyperactive metabolic pathway dependent mitochondrial transporter's activity, which holds promise for the further development of CSCs targeted diagnostic and therapeutic strategies.
研究领域:
肿瘤学
·
分子生物学
·
癌症代谢
·
药物递送系统
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DOI
PubMed
高影响因子
Advanced Science
·
2024
·Vol. 11
·期 43
·2408013
·
IF 14.3
Kaicheng Deng,Yuyan Hua,Ying Gao,Houwei Zheng,Yangzi Jiang,Yaping Wang,Changyou Gao,Tanchen Ren,Yang Zhu
HIF-1α (hypoxia induced factor-1α), a vital protective signal against hypoxia, has a short lifetime after myocardial infarction (MI). Increasing HIF-1α stability by inhibiting its hydroxylation with prolyl hydroxylases inhibitors such as DPCA (1,4-dihydrophenonthrolin-4-one-3-carboxylic acid) presents positive results. However, the optimal inhibitor administration profile for MI treatment is still unexplored. Here, injectable, thermosensitive hydrogels with programmable DPCA release are designed and synthesized. Hydrogel degradation and slow DPCA release are coupled to form a feedback loop by attaching pendant DPCA to polymer backbone, which serve as additional crosslinking points through π–π and hydrophobic interactions. Pendant carboxyl groups are added to the copolymer to accelerate DPCA release. Burst release in the acute phase for myocardial protection and extended near zero-order release across the inflammatory and fibrotic phases with different rates are achieved. All DPCA-releasing hydrogels upregulate HIF-1α, decrease apoptosis, promote angiogenesis, and stimulate cardiomyocyte proliferation, leading to preserved cardiac function and ventricular geometry. Faster hydrogel degradation induced by faster DPCA release results in a HIF-1α expression eight times of healthy control and better therapeutic effect in MI treatment. This research demonstrates the value of precise regulation of HIF-1α expression in treating MI and other relevant diseases and provides an implantable device-based modulation strategy.
研究领域:
心血管研究
·
生物材料
·
药学
·
组织工程
✓ 已验证
产品关联
DOI
PubMed
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.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
·
癌症研究
✓ 已验证
DOI
PubMed
高影响因子
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