BIOCHEMICAL PHARMACOLOGY
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2019
·
IF 4.825
Peng-Chao Zhang,Xiao Liu,Man-Mei Li,Yan-Yan Ma,Hong-Tao Sun,Xu-Yan Tian,Yan Wang,Min Liu,Liang-Shun Fu,Yi-Fei Wang,Hong-Yuan Chen,Zhong Liu
The inhibition of angiogenesis is suggested to be an attractive strategy for cancer therapeutics. Heat shock protein 90 (Hsp90) is closely related to tumorigenesis as it regulates the stabilization and activated states of many client proteins that are essential for cell survival and tumor growth. Here, we investigated the mechanism whereby AT-533, a novel Hsp90 inhibitor, inhibits breast cancer growth and tumor angiogenesis. Based on our results, AT-533 suppressed the tube formation, cell migration, and invasion of human umbilical vein endothelial cells (HUVECs), and was more effective than the Hsp90 inhibitor, 17-AAG. Furthermore, AT-533 inhibited angiogenesis in the aortic ring, Matrigel plug, and chorioallantoic membrane (CAM) models. Mechanically, AT-533 inhibited the activation of VEGFR-2 and the downstream pathways, including Akt/mTOR/p70S6K, Erk1/2 and FAK, in HUVECs, and the viability of breast cancer cells and the HIF-1α/VEGF signaling pathway under hypoxia. In vivo, AT-533 also inhibited tumor growth and angiogenesis by inducing apoptosis and the HIF-1α/VEGF signaling pathway in breast cancer cells. Taken together, our findings indicate that the Hsp90 inhibitor, AT-533, suppresses breast cancer growth and angiogenesis by blocking the HIF-1α/VEGF/VEGFR-2 signaling pathway. AT-533 may thus be a potentially useful drug candidate for breast cancer therapy.
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高影响因子
Nutrients
·
2022
·Vol. 14
·期 13
·2591
·
IF 6.706
Cuicui Zhang,Hai Niu,Chengyu Wan,Xiuxian Yu,Guang Xin,Yuda Zhu,Zeliang Wei,Fan Li,Yilan Wang,Kun Zhang,Shiyi Li,Yuman Dong,Yangying Li,Wen Huang
Acute pancreatitis (AP) is one of the most common causes of hospitalization for gastrointestinal diseases, with high morbidity and mortality. Endoplasmic reticulum stress (ERS) and Gasdermin D (GSDMD) mediate AP, but little is known about their mutual influence on AP. Diosgenin has excellent anti-inflammatory and antioxidant effects. This study investigated whether Diosgenin derivative D (Drug D) inhibits L-arginine-induced acute pancreatitis through meditating GSDMD in the endoplasmic reticulum (ER). Our studies were conducted in a mouse model of L-arginine-induced AP as well as in an in vitro model on mouse pancreatic acinar cells. The GSDMD accumulation in ER was found in this study, which caused ERS of acinar cells. GSDMD inhibitor Disulfiram (DSF) notably decreased the expression of GSDMD in ER and TXNIP/HIF-1α signaling. The molecular docking study indicated that there was a potential interaction between Drug D and GSDMD. Our results showed that Drug D significantly inhibited necrosis of acinar cells dose-dependently, and we also found that Drug D alleviated pancreatic necrosis and systemic inflammation by inhibiting the GSDMD accumulation in the ER of acinar cells via the TXNIP/HIF-1α pathway. Furthermore, the level of p-IRE1α (a marker of ERS) was also down-regulated by Drug D in a dose-dependent manner in AP. We also found that Drug D alleviated TXNIP up-regulation and oxidative stress in AP. Moreover, our results revealed that GSDMD-/-mitigated AP by inhibiting TXNIP/HIF-1α. Therefore, Drug D, which is extracted from Dioscorea zingiberensis, may inhibit L-arginine-induced AP by meditating GSDMD in the ER by the TXNIP /HIF-1α pathway.Keywords:acute pancreatitis;L-arginine;Gasdermin D;endoplasmic reticulum stress;TXNIP
研究领域:
药理学
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炎症
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分子生物学
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细胞生物学
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高影响因子
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
·
2019
·Vol. 47
·期 1
·85-94
·
IF 2.336
Ning Han,Haitao Xu,Na Yu,Yazhen Wu,Li Yu
Proliferative diabetic retinopathy (PDR) is a common complication of diabetes mellitus, characterized by abnormal retinal angiogenesis. MicroRNA-203-3p (miR-203-3p) was found to be down-regulated in a murine model of proliferative retinopathy. This study was performed to explore the role of miR-203a-3p in retinal angiogenesis of PDR. Firstly, a rat OIR model, which was used to mimic PDR, was established and the OIR rats were treated with scrambled control or miR-203a-3p agomir by intravitreal injection. The results showed that the level of miR-203a-3p was decreased in OIR rats, and forced over-expression of miR-203a-3p inhibited OIR-induced retinal angiogenesis as evidenced by reduced blood vessel profiles and CD31 expression. OIR-induced up-regulation of VEGFA, HIF-α, PCNA, and MMPs in the retina was also counteracted by miR-203a-3p. Additionally, high glucose (HG)-induced proliferation, migration and tube formation of human retinal microvascular endothelial cells (HRMECs) were also dampened by the up-regulation of miR-203a-3p. Dual-luciferase reporter assay showed that miR-203a-3p could specifically bind to the 3′UTR of VEGFA and HIF-1α. Over-expression of VEGFA or HIF-1α restored the tube formation activity of HRMECs suppressed by miR-203a-3p. In conclusion, our findings demonstrate that up-regulation of miR-203a-3p might inhibit pathological retinal angiogenesis of PDR by targeting VEGFA and HIF-1α.
研究领域:
分子生物学
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眼科学
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糖尿病研究
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微小RNA
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高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
Pingchuan Wang,Tianming Li,Changping Niu,Siyu Sun,Dongyan Liu
Reactive oxygen species (ROS) damage to the intestinal barrier is a side effect of prolonged hyperoxia therapy in neonates, which impairs growth and development of the intestine and promotes intestinal diseases. However, the research on clinical prevention and treatment is lacking. Therefore, we investigated the molecular mechanisms of the neonate intestinal response against hyperoxia-derived ROS to find targets for intestinal barrier damage prevention. Human intestinal epithelial cells were incubated under hyperoxia (85% oxygen) to build an in vitro model. ROS and the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway were inhibited to detect the MAPK/ERK pathway, nuclear factor erythroid factor 2-related factor 2 (Nrf2), hypoxia-inducible factor-1α (Hif-1α), and interleukin-17D (IL-17D) expression. Nrf2 was inhibited to detect Hif-1α and IL-17D expression. Hif-1α was inhibited to detect Nrf2, IL-17D, and tight junction proteins expression and apoptosis. Cells were treated with human recombinant IL-17D to detect TNF-α, IL-1β, IL-10, and tight junction proteins expression. ROS, Nrf2, Hif-1α, and IL-17D were upregulated and the MAPK/ERK pathway was activated under hyperoxia. But ROS inhibition downregulated the MAPK/ERK pathway, Nrf2, Hif-1α, and IL-17D. MAPK/ERK pathway inhibition downregulated Nrf2, Hif-1α, and IL-17D. Nrf2 inhibition downregulated Hif-1α and IL-17D. Hif-1α inhibition downregulated Nrf2, IL-17D, tight junction proteins, and exacerbated apoptosis. The recombinant IL-17D downregulated TNF-α, IL-1β, but upregulated IL-10 and tight junction proteins. We concluded that Hyperoxia-generated ROS activated the MAPK/ERK pathway to regulate Nrf2, Hif-1α, and IL-17D expression. Nrf2 and Hif-1α were interdependent and promoted IL-17D. Importantly, Hif-1α and IL-17D expression protected the intestinal epithelial barrier.
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ENVIRONMENTAL TOXICOLOGY
·
2024
·
IF 4.4
Xuening Ma,Qianchao Shao,Shuxian Huang,Weigao Zhang,Hu Liu,Xu Jiayi,Xunan Zhao,Peiqi Li,Da Shao,YuanQing Bu,Dan Weng
The increasing incidence of cancer underscore the necessity of investigating contributors such as endocrine-disrupting chemicals (EDCs), including bisphenol A (BPA). Although BPA's risks are well-documented, comprehensive studies on its substitutes, such as bisphenol B (BPB), are limited. Dysregulated lipid metabolism is a hallmark of cancer progression. Our previous work demonstrated that BPA and bisphenol S (BPS) disrupt lipid metabolism via the peroxisome proliferator-activated receptor γ (PPARγ) pathway. We hence hypothesized that BPB might similarly perturb lipid metabolism and promote tumor growth. BPB's impact on lipid metabolism was investigated in vitro and in vivo using B16 melanoma cancer cells. Our findings indicate BPB exposure significantly increased lipid metabolism in B16 cells, enhancing cell proliferation and migration, and promoting tumor development in mice. Utilizing siRNA transfection or chemical inhibitor, we found that stearoyl-CoA desaturase-1 (SCD1), a key enzyme in lipid synthesis pathway, was required for BPB-induced lipid accumulation and cancer cell migration. Docking analysis revealed BPB may activate gene expression related to lipid metabolism and angiogenesis by interacting with PPARγ and hypoxia-inducible factor-1α (HIF-1α). This study illuminates BPB's potential role in advancing melanoma through lipid metabolism manipulation, highlighting the need for further research into the safety of BPA substitutes and their impact on cancer development.
研究领域:
肿瘤学
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分子生物学
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环境健康
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细胞生物学
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高影响因子
Nano Today
·
2024
·
IF 13.2
Yuyang Li,Faheem Muhammad,Xiwen Chen,Deao Gu,Wen Li,Jiayi Tang,Mingyue Cheng,Jiang Du,Shuwei Qiao,Yu Deng,Qing Yu,Hui Wei,Leiying Miao
Nanozymes have emerged as promising nanomaterials for the treatment of inflammation-related diseases by eliminating excessive reactive oxide species (ROS) and immunoregulation. However, persistent inflammation invariably causes severe alveolar destruction in periodontitis; and the alleviation of inflammation alone by neglecting the impairment of vascular functions could not effectively realize periodontal regeneration. Herein, a multifunctional copper-ruthenium oxide-based yolk-shell nanozyme (Cu 2 O@RuO 2 , CRNC) is designed to promote effective periodontal regeneration. The ruthenium oxide (RuO 2 ) shell serves to alleviate inflammation by eliminating ROS and triggering macrophage polarization, whereas the cuprous oxide (Cu 2 O) core acts as a responsive Cu 2 + nano-reservoir for promoting angiogenesis and osteogenesis. Results demonstrated that CRNC could activate transforming growth factor β/phosphatidylinositol 3-kinase (TGF-β/PI3K) and hypoxia-inducible factors (HIF-1α) signals, aiding angiogenesis in the human umbilical vein endothelial cells and osteogenesis in periodontal ligament stem cells, respectively. The multifunctional CRNC nanozyme successfully decreased periodontal inflammation and ameliorated alveolar regeneration in a periodontitis model. This study provides promising insights into periodontitis treatment by targeting both angiogenesis and osteogenesis.
研究领域:
牙科学
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纳米医学
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炎症研究
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组织工程
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高影响因子
ACS Nano
·
2024
·
IF 15.8
Yu Ji,Suchen Qu,Gaoyu Shi,Liansheng Fan,Jing Qian,Zhaorui Sun,Feng Lu,Xin Han
Hypoxia is one of the most typical features among various types of solid tumors, which creates an immunosuppressive tumor microenvironment (TME) and limits the efficacy of cancer treatment. Alleviating hypoxia becomes a key strategy to reshape hypoxic TME which improves cancer immunotherapy. However, it remains challenging to perform tumor precision therapy with controllable switches through hypoxia-activated gene editing and prodrugs to alleviate hypoxia. In this study, silica-coated second near-infrared window (NIR-II) emitting silver sulfide quantum dots are used as the carrier to load the Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 (CRISPR/Cas9) system to target hypoxia-inducible factor-1 (HIF-1α) and guide tumor-targeted imaging. To reduce the off-target effects in nontumor cells and better control safety risks, a TME-triggered cascade-activation nanodiagnostic and therapeutic platform (AA@Cas-H@HTS) is designed, which achieves the hypoxia activation of prodrug tirapazamine (TPZ) and spatiotemporal release of CRISPR/Cas9 ribonucleoprotein. Tumor hypoxia is greatly alleviated by the synergistic function of HIF-1α depletion by gene editing and TPZ activation. Importantly, targeting HIF-1α disrupts the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) signaling pathway, which effectively reshapes the immune-suppressive TME and activates T cell-mediated antitumor immunity. Taken together, we have provided a TME-triggered cascade-activation nanoplatform to alleviate hypoxia for improved cancer immunotherapy.
研究领域:
癌症生物学
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免疫学
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纳米技术
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分子生物学
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诊疗学
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高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2020
·Vol. 31
·期 5
·2008515
·
IF 16.836
Lili Sun,Yifan Ma,Haoyi Niu,Yutong Liu,Yuan Yuan,Changsheng Liu
Due to the limited ability for perfusion, traditional intramembranous ossification (IMO) often fails to recapitulate the natural regeneration process of most long bones and craniofacial bones. Alternatively, endochondral ossification (ECO) strategy has emerged and has been evidenced to circumvent the drawbacks in the routine application of IMO. Here, an injectable, poly(glycerol sebacate)- co -poly (ethylene glycol)/polyacrylic acid (PEGS/PAA) hydrogels are successfully developed to induce a hypoxia-mimicking environment and subsequently recapitulate ECO via in situ iron chelation. With the incorporation of PAA, these hydrogels present remarkable viscoelasticity and high efficacy of iron ion-chelating after injection, giving rise to the activation of HIF-1α signaling pathway and suppression of inflammatory responses, and thereby improving chondrogenic differentiation in the early stage and facilitating vascularization in the later stage, which consequently trigger typical ECO. More importantly, through sustained and stable expression of HIF-1α regulated by PEGS/PAA hydrogels throughout the regeneration, a harmonious chondrogenic/osteogenic balance can be struck and thereby accelerating the progress of ECO compared to the PEGS. The findings provide an efficient strategy to achieve in situ ECO via biomaterial-based iron ion-chelating and ensuing hypoxia-mimicking, representing a novel and promising concept for future application in bone regeneration.
研究领域:
生物材料
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组织工程
·
骨科
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再生医学
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高影响因子
Chemical Biology & Drug Design
·
2025
·Vol. 105
·期 6
·e70133
·
IF 3.3
Lin Xu,Dongsheng Yao,Tianying Lan,Yurou Chen,Dongping Chen,Minghai Shao,Yijing Zhou,Chaoyang Ye,Di Huang
Ferulic acid (FA), a natural phenolic compound, shows potential therapeutic effects on renal interstitial fibrosis, although its antifibrotic mechanism remains unclear. This study investigated the molecular mechanisms of FA by focusing on epithelial-mesenchymal transition (EMT) and related signaling pathways. By using a hypoxia-induced HK2 cell model, the optimal FA concentration was determined by CCK-8 assay, and the cells were assigned to low-, medium-, and high-FA groups. Renal fibrosis-associated protein and mRNA levels were evaluated by western blotting (WB) and reverse transcription-quantitative polymerase chain reaction. In a 5/6 nephrectomy-induced chronic renal failure rat model, renal oxygen consumption, serum creatinine, and blood urea nitrogen levels were measured, while ultrastructural and morphological changes in renal tissues were examined by transmission electron microscopy (TEM), hematoxylin–eosin (HE) staining, and Masson's trichrome staining. Renal fibrosis-related indicators were further assessed by Western Blot (WB) and immunofluorescence assay. The results showed that FA treatment significantly reduced fibronectin, HIF-1α, and α-SMA expression; inhibited partial EMT in vivo and in vitro; improved renal function; and attenuated fibrosis in kidney tissues. Combining siTwist or oe-HIF-1α transfection with FA treatment revealed that FA targeted the HIF-1α/Twist signaling pathway, impeding EMT and delaying renal fibrosis. In conclusion, FA inhibited partial EMT of tubular epithelial cells and suppressed the HIF-1α/Twist pathway, thereby mitigating renal interstitial fibrosis and providing a foundation for FA-based treatment of chronic kidney disease.
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2022
·Vol. 20
·期 1
·1-16
·
IF 9.429
Liu Jie,Hu Xiaochun,Feng Lei,Lin Yun,Liang Shujing,Zhu Zhounan,Shi Shuo,Dong Chunyan
Background Non-redundant properties such as hypoxia and acidosis promote tumor metabolic adaptation and limit anti-cancer therapies. The key to the adaptation of tumor cells to hypoxia is the transcriptional and stable expression of hypoxia-inducible factor-1 alpha (HIF-1α). The phosphorylation-activated tumorigenic signal PI3K/AKT/mTOR advances the production of downstream HIF-1α to adapt to tumor hypoxia. Studies have elucidated that acid favors inhibition of mTOR signal. Nonetheless, carbonic anhydrase IX (CAIX), overexpressed on membranes of hypoxia tumor cells with pH-regulatory effects, attenuates intracellular acidity, which is unfavorable for mTOR inhibition. Herein, a drug delivery nanoplatform equipped with dual PI3K/mTOR inhibitor Dactolisib (NVP-BEZ235, BEZ235) and CAIX inhibitor 4‐(2‐aminoethyl) benzene sulfonamide (ABS) was designed to mitigate hypoxic adaptation and improve breast cancer treatment. Results ABS and PEG-NH 2 were successfully modified on the surface of hollow polydopamine (HPDA), while BEZ235 and Chlorin e6 (Ce6) were effectively loaded with the interior of HPDA to form HPDA-ABS/PEG-BEZ235/Ce6 (H-APBC) nanoparticles. The release of BEZ235 from H-APBC in acid microenvironment could mitigate PI3K/mTOR signal and resist HIF-1α-dependent tumor hypoxia adaptation. More importantly, ABS modified on the surface of H-APBC could augment intracellular acids and enhances the mTOR inhibition. The nanoplatform combined with phototherapy inhibited orthotopic breast cancer growth while reducing spontaneous lung metastasis, angiogenesis, based on altering the microenvironment adapted to hypoxia and extracellular acidosis. Conclusion Taken together, compared with free BEZ235 and ABS, the nanoplatform exhibited remarkable anti-tumor efficiency, reduced hypoxia adaptation, mitigated off-tumor toxicity of BEZ235 and solved the limited bioavailability of BEZ235 caused by weak solubility. Graphical Abstract
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高影响因子
Frontiers in Bioengineering and Biotechnology
·
2021
·
IF 5.89
Dong Wenpei,Song Zhicheng,Liu Suihong,Yu Ping,Shen Zhipeng,Yang Jianjun,Yang Dongchao,Hu Qinxi,Zhang Haiguang,Gu Yan
Application of synthetic or biological meshes is the main therapy for the repair and reconstruction of abdominal wall defects, a common disease in surgery. Currently, no ideal materials are available, and there is an urgent need to find appropriate ones to satisfy clinical needs. Electrospun scaffolds have drawn attention in soft tissue reconstruction. In this study, we developed a novel method to fabricate a composite electrospun scaffold using a thermoresponsive hydrogel, poly (N-isopropylacrylamide)-block-poly (ethylene glycol), and a biodegradable polymer, polylactic acid (PLA). This scaffold provided not only a high surface area/volume ratio and a three-dimensional fibrous matrix but also high biocompatibility and sufficient mechanical strength, and could simulate the native extracellular matrix and accelerate cell adhesion and proliferation. Furthermore, rat adipose-derived stem cells (ADSCs) were seeded in the composite electrospun scaffold to enhance the defect repair and regeneration by directionally inducing ADSCs into endothelial cells. In addition, we found early vascularization in the process was regulated by the hypoxia inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway. In our study, overexpression of HIF-1α/VEGF in ADSCs using a lentivirus system promoted early vascularization in the electrospun scaffolds. Overall, we expect our composite biomimetic scaffold method will be applicable and useful in abdominal wall defect regeneration and repair in the future.
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JOURNAL OF PHARMACY AND PHARMACOLOGY
·
2023
·
IF 3.3
Zeng Xiangfeng,Liu Shengyao,Yang Hua,Jia Menglei,Liu Wei,Zhu Wenting
ObjectivesThe most common cause of osteosarcoma (OS) death is lung metastasis. Currently, doxorubicin is the primary chemotherapy drug used to treat OS, however, it is not effective in inhibiting metastasis, and it has obvious cardiotoxicity. The anticancer activity of ginsenoside Rg3 has been demonstrated in a variety of malignant tumours. The aim of this study was to determine the potential role of ginsenoside Rg3 and doxorubicin in OS and the possible mechanism.MethodsThe potential synergistic effects of ginsenoside Rg3 and doxorubicin on human osteosarcoma cells 143B and U2OS, human umbilical vein endothelial cells, and mice receiving 143B xenografts and lung metastases were investigated.Key findingsOur study demonstrated that the combination of ginsenoside Rg3 and doxorubicin significantly inhibited cell proliferation, metastasis and angiogenesis in vitro. Mechanically, the anti-tumour activity of ginsenoside Rg3 and doxorubicin by modulating mTOR/HIF-1α/VEGF and EMT signalling pathways. Furthermore, ginsenoside Rg3 combined with doxorubicin inhibits tumour growth and lung metastasis in 143B-derived murine osteosarcoma models. More importantly, ginsenoside Rg3 can effectively ameliorate doxorubicin-induced weight loss and cardiotoxicity in mice.ConclusionsConsequently, we concluded that the combination of ginsenoside Rg3 and doxorubicin displayed an evidently synergistic effect, which has the potential to be used as an effective and safe therapeutic approach for OS treatment.
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