ENVIRONMENTAL TOXICOLOGY
·
2023
·
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
Cell Death & Disease
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2017
·Vol. 8
·期 10
·e3095
·
IF 5.965
Xu Junjie,Zheng Longbo,Chen Jiang,Sun Yin,Lin Hui,Jin Ren-an,Tang Minyue,Liang Xiao,Cai Xiujun
Although sorafenib is currently used as a standard treatment for advanced hepatocellular carcinoma, low response rate, transient and limited efficacy, primary and acquired resistance and negative side-effects gain increasing attentions, suggesting the need for better efficacious combination therapy. Here, we demonstrated that the sorafenib-induced or hypoxia-induced hypoxia inducible factor (HIF)-2 α could bind to an hypoxia responsive element within 500 bp region of androgen receptor (AR) promoter and thus transcriptionally suppress AR. Importantly, In vitro and In vivo studies suggested a specific and potent HIF-2 α inhibitor, PT-2385, could significantly enhance sorafenib efficacy by suppressing HIF-2 α , increasing AR and suppressing downstream pSTAT3/pAKT/pERK pathways. Clinical samples further confirmed the role of HIF-2 α and AR. It is promising that PT-2385 could alleviate the undesirable side-effects of sorafenib treatment by sorafenib-PT-2385 combination therapy, which may shed light for late-stage HCC patients.
研究领域:
肿瘤学
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药理学
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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 PHARMACEUTICS
·
2024
·
IF 5.3
Cheng-Ming Zhang,Yu-Xin Kang,Si-Yu Zheng,Yang Liu,Meng-Rou Liu,Gai-Ge Wu,Li Guo,Peng-Cui Li,Rui-Peng Zhao,Qian-Qian Duan,Shao-Wei Wang,Xiao-Chun Wei
Background Osteoarthritis (OA) is a progressive joint disorder marked by the degradation of cartilage. Elevated concentrations of hypoxia-inducible factor-2α (HIF-2α) are intricately linked to the pathological development of OA. PT2385 has demonstrated effective inhibition of HIF-2α, thereby potentially impeding the initial advancement of OA. Nevertheless, challenges persist, including limited penetration into the deeper layers of cartilage, issues related to charge rejection, and a heightened rate of clearance from the joint. These constraints necessitate further consideration and exploration. Methods It has been demonstrated that PT2385 exhibits efficient inhibition of HIF-2α expression, thereby contributing to the delay in the progression of osteoarthritis. The pH-responsive attributes of carbon quantum dots, specifically those employing m-phenylenediamine (m-CQDs) coated with bovine serum albumin (BSA), have been systematically evaluated. In both in vitro settings involving cartilage explants and in vivo experiments, the efficacy of BSA-m-CQDs-PT2385 (BCP) has been confirmed in facilitating the transport of PT2385 to the middle and deep layers of cartilage. Furthermore, the BCP system demonstrates controlled drug release contingent upon alterations in environmental pH. Results While the use of PT2385 alone provides protective effects on chondrocytes within an inflamed environment, there exists an opportunity for further enhancement in its efficacy when administered via intra-articular injection. The BCP formulation, characterized by appropriate particle size and charge, facilitates seamless penetration into cartilage tissue. Additionally, BCP demonstrates the capability to release drugs in response to changes in environmental pH. In vitro experiments reveal that BCP effectively inhibits Hif-2α expression and catabolic factors in chondrocytes. Notably, cartilage explants and in vivo experiments indicate that BCP surpasses PT2385 alone in inhibiting the expression of HIF-2α and matrix metalloproteinase 13, particularly in the middle and deep layers. Conclusions The BCP drug delivery system exhibits selective release of PT2385 in response to pH changes occurring during the progression of osteoarthritis (OA), thereby inhibiting HIF-2α expression deep within the cartilage. The use of BCP significantly augments the capacity of PT2385 to retard both cartilage degeneration and the progression of osteoarthritis. Consequently, BCP as an innovative approach utilizing m-CQDs to deliver PT2385 into articular cartilage, shows potential for treating osteoarthritis. This strategy opens new avenues for osteoarthritis treatment.
研究领域:
药学
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生物医学工程
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骨科
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Yihao Zhu,Yajian Li,Xuwen Li,Yuan Yu,Lingpu Zhang,Hanchen Zhang,Can Chen,Dong Chen,Mingshuai Wang,Nianzeng Xing,Feiya Yang,Wahafu Wasilijiang,Xiongjun Ye
Immune checkpoint blockers (ICBs) therapy stands as the first-line treatment option for advanced renal cell carcinoma (RCC). However, its effectiveness is hindered by the immunosuppressive tumor microenvironment (TME). Sonodynamic therapy (SDT) generates tumor cell fragments that can prime the host's antitumor immunity. Nevertheless, the hypoxic microenvironment and upregulated autophagy following SDT often lead to cancer cell resistance. In response to these challenges, a hypoxia-responsive polymer (Poly(4,4′-azobisbenzenemethanol-PMDA)-mPEG 5k , P-APm) encapsulating both a HIF-2α inhibitor (belzutifan) and the ultrasonic sensitize (Chlorin e6, Ce6) is designed, to create the nanoparticle APm/Ce6/HIF. APm/Ce6/HIF combined with ultrasound (US) significantly suppresses tumor growth and activates antitumor immunity in vivo. Moreover, this treatment effectively transforms the immunosuppressive microenvironment from “immune-cold” to “immune-hot”, thereby enhancing the response to ICBs therapy. The findings indicate that APm/Ce6/HIF offers a synergistic approach combining targeted therapy with immunotherapy, providing new possibilities for treating RCC.
研究领域:
肿瘤学
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生物医学工程
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免疫学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2025
·
IF 9.6
Yushen Wang,Xinyu Li,Junlei Han,Feng Kong,Zhipeng Xu,Huili Hu,Li Wang
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver disease characterized by lipid zonation, which is closely linked to the functional zonation of liver lobules. However, existing models cannot faithfully replicate the oxygen gradient that regulates liver zonation, hindering a clear understanding of the progression and intervention mechanisms in MASLD. Here, we constructed a MASLD liver-zonation-on-a-chip that utilizes an engineering strategy based on “environmental oxygen convection and diffusion”, achieving a controllable oxygen concentration gradient (3.7%-8.9%) that closely mimics the in vivo hepatic microenvironment. This platform successfully recapitulates the typical features and clinicopathological phenotypes of the liver lobule while enabling continuous monitoring of liver injury. We found that upregulation of the oxygen-sensing factor HIF-2α does not directly promote lipid accumulation. Instead, it indirectly facilitates the progression of MASLD by enhancing the transcriptional activity of β-catenin through the WNT signaling pathway (e.g., AXIN2, DVL1 ). As regulators of the damage process, HIF-2α and β-catenin may be targeted to improve outcomes in MASLD. Significance of statement Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common liver disorder characterized by lipid zonation, which is closely related to the functional zonation of liver lobules. However, existing models are unable to accurately replicate the oxygen (O 2 ) gradients that regulate liver zonation, a limitation that hinders their ability to accurately reflect hepatocyte pathophysiology and obstructs understanding of the mechanisms underlying MASLD progression. This study constructs a liver-zonation-on-a-chip with a controllable physiological O₂ gradient and integrated biosensing for non-destructive injury monitoring. The O 2 gradient chip successfully replicates liver lobule zonation, providing an engineering approach to overcoming the challenge of low regional heterogeneity in liver organoids. The application of the liver-zonation-on-a-chip in pathological assessments has also been thoroughly evaluated, offering potential solutions for MASLD interventions.
研究领域:
生物医学工程
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肝病学
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微生理系统
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分子生物学
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代谢性疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2025
·
IF 16
Yan Fang,Feiyang Shen,Rui Huang,Yao Lin,Yijia Wu,Qian Li,Zhu Xie,Xiaoyu Yang,Zhe Zhang,Xiaoliang Jin,Xianqun Fan,Jianfeng Shen
The von Hippel–Lindau (VHL) tumor suppressor gene product, pVHL, is frequently deficient in a variety of human cancers. In addressing the treatment of pVHL-deficient tumors, hypoxia-inducible factor 2α (HIF-2α) has risen as a promising therapeutic target, culminating in the development of specific inhibitors like PT2385 and its analogues. Nonetheless, the absence of targeted delivery capabilities in these inhibitors heightens the risk of on-target toxicities. To mitigate these limitations, we have engineered a nanoparticle, termed PMMF (PT/MMSN@DSPE-PEG-FA), capable of delivering both a HIF-2α antagonist (PT2385) and manganese directly to tumor sites. PMMF has shown effective targeting of pVHL-deficient clear-cell renal cell carcinoma and melanoma, leading to significant therapeutic benefits and alleviating hypoxic and immunosuppressive traits of the tumor microenvironment. Functionally, PMMF boosts the cyclic GMP–AMP synthase–stimulator of interferon genes signaling pathway, which, in turn, stimulates a robust innate immune response. This response activates natural killer (NK) cells and CD8+ T lymphocytes while curbing the infiltration of regulatory T cells. Notably, the therapeutic efficacy of PMMF is markedly reduced when NK cells are blocked but not affected by neutrophil blockade, highlighting the critical role of NK cells in PMMF-induced antitumor immunity. Additionally, the safety profile of PMMF showed minimal systemic post-treatment cytotoxicity. In summary, our findings position PMMF as a promising platform for treating tumors with pVHL deficiency and underscore the therapeutic potential of metalloimmunotherapy.
研究领域:
肿瘤学
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免疫学
·
纳米医学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2023
·Vol. 21
·期 1
·1-19
·
IF 10.2
Zhang Zi-Jian,Hou Ying-Ke,Chen Ming-Wa,Yu Xue-Zhao,Chen Si-Yu,Yue Ya-Ru,Guo Xiong-Tian,Chen Jin-Xiang,Zhou Quan
The occurrence of osteoarthritis (OA) is highly correlated with the reduction of joint lubrication performance, in which persistent excessive inflammation and irreversible destruction of cartilage dominate the mechanism. The inadequate response to monotherapy methods, suboptimal efficacy caused by undesirable bioavailability, short retention, and lack of stimulus-responsiveness, are few unresolved issues. Herein, we report a pH-responsive metal-organic framework (MOF), namely, MIL-101-NH2, for the co-delivery of anti-inflammatory drug curcumin (CCM) and small interfering RNA (siRNA) for hypoxia inducible factor (HIF-2α). CCM and siRNA were loaded via encapsulation and surface coordination ability of MIL-101-NH2. Our vitro tests showed that MIL-101-NH2 protected siRNA from nuclease degradation by lysosomal escape. The pH-responsive MIL-101-NH2 gradually collapsed in an acidic OA microenvironment to release the CCM payloads to down-regulate the level of pro-inflammatory cytokines, and to release the siRNA payloads to cleave the target HIF-2α mRNA for gene-silencing therapy, ultimately exhibiting the synergetic therapeutic efficacy by silencing HIF-2α genes accompanied by inhibiting the inflammation response and cartilage degeneration of OA. The hybrid material reported herein exhibited promising potential performance for OA therapy as supported by both in vitro and in vivo studies and may offer an efficacious therapeutic strategy for OA utilizing MOFs as host materials.
研究领域:
药学
·
纳米技术
·
生物医学工程
·
风湿病学
✓ 已验证
DOI
PubMed
高影响因子
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