Autophagy
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2025
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IF 14.3
Mi Zhou,Minyu Chen,Zhousan Zheng,Qihao Li,Lican Liao,Yunfei Wang,Yi Xu,Guannan Shu,Junhang Luo,Taowei Yang,Jiaxing Zhang
The tumor microenvironment (TME) in renal cell carcinoma (RCC) frequently exhibits significant immune cell infiltration. However, tumor cells often manage to evade immune surveillance. This study revealed the mechanism by which circular RNA circGRAMD4 regulates NBR1. CircGRAMD4 is markedly elevated in RCC, and its high levels are correlated with a poor prognosis. Notably, the absence of circGRAMD4 has been demonstrated to result in a significant inhibition of renal cancer cell growth. This inhibition has been attributed to an enhanced anti-tumor immunity mediated by CD8+ T cells. Mechanistically, circGRAMD4 interacts with the RBM4 protein, stabilizing the autophagic cargo receptor NBR1 mRNA. This interaction promotes NBR1 expression, which in turn leads to the degradation of MHC-I molecules through macroautophagy/autophagy pathways. Consequently, this process affects renal cancer cell antigen presentation, induces CD8+ T cell dysfunction, and contributes to tumor immune escape. Moreover, by inhibiting circGRAMD4 and using immune checkpoint blockers (ICB), the immunosuppressive TME is altered to prevent tumor immune evasion, ultimately increasing the effectiveness of ICB treatment. The discovery highlights the significant impact of circGRAMD4 on RCC immune escape and proposes that blocking circGRAMD4 could serve as a promising immunotherapy strategy when combined with ICB to enhance patient outcomes.
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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DOI
PubMed
高影响因子
Cancers
·
2022
·Vol. 14
·期 10
·2551
·
IF 6.575
Qingwen Xu,Yuxi Liu,Wen Sun,Tiantian Song,Xintong Jiang,Kui Zeng,Su Zeng,Lu Chen,Lushan Yu
Simple SummaryThe transformation and mechanism of methionine metabolism of renal cell carcinoma (RCC) under a hypoxic microenvironment is not well understood as yet. This study illustrated that the reprogramming of methionine metabolism and the subsequent glutathione (GSH) synthesis were mediated by amino acid transporter 1 (LAT1). Correspondingly, we proposed a combination strategy of LAT1 inhibitor JPH203 and oxaliplatin, which presented an enhanced therapeutic efficacy for RCC both in vivo and in vitro.AbstractHypoxic microenvironment and metabolic dysregulation of tumor impairs the therapeutic efficacy of chemotherapeutic drugs, resulting in drug resistance and tumor metastasis, which has always been a challenge for the treatment of solid tumors, including renal cell carcinoma (RCC). Herein, starting from the evaluation of methionine metabolism in RCC cells, we demonstrated that the increased methionine accumulation in RCC cells was mediated by L-type amino acid transporter 1 (LAT1) under hypoxia. Glutathione (GSH), as a methionine metabolite, would attenuate the therapeutic efficacy of oxaliplatin through chemical chelation. Reducing methionine uptake by LAT1 inhibitor JPH203 significantly enhanced the sensitivity of RCC cells to oxaliplatin by reducing GSH production in vitro and in vivo. Therefore, we proposed an effective and stable therapeutic strategy based on the combination of oxaliplatin and LAT1 inhibitor, which is expected to solve the resistance of RCC to platinum-based drugs under hypoxia to a certain extent, providing a meaningful insight into the development of new therapeutic strategies and RCC treatmentKeywords:renal cell carcinoma;hypoxia;methionine metabolism;LAT1;drug combination
研究领域:
肿瘤学
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癌症生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2023
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IF 3.3
Miao Xing,Xiaoyu Ma,Xi Wang,Haoze Wang,Minjuan Xie,Ziwen Zhang,Jie Zhou
Emodin has been demonstrated to possess multiple pharmacological activities. However, emodin has also been reported to induce nephrotoxicity at high doses and with long-term use, and the underlying mechanism has not been fully disclosed. The current study aimed to investigate the roles of oxidative stress and ferroptosis in emodin-induced kidney toxicity. Mice were intraperitoneally treated with emodin, and NRK-52E cells were exposed to emodin in the presence or absence of treatment with Jagged1, SC79, or t-BHQ. Emodin significantly upregulated the levels of blood urea nitrogen, serum creatinine, malondialdehyde, and Fe 2+ , reduced the levels of superoxide dismutase and glutathione, and induced pathological changes in the kidneys in vivo. Moreover, the viability of NRK-52E cells treated with emodin was reduced, and emodin induced iron accumulation, excessive reactive oxygen species production, and lipid peroxidation and depolarized the mitochondrial membrane potential ( ΔΨm ). In addition, emodin treatment downregulated the activity of neurogenic locus notch homolog protein 1 (Notch1), reduced the nuclear translocation of nuclear factor erythroid-2 related factor 2 (Nrf2), and decreased glutathione peroxidase 4 protein levels. However, Notch1 activation by Jagged1 pretreatment, Akt activation by SC79 pretreatment, or Nrf2 activation by t-BHQ pretreatment attenuated the toxic effects of emodin in NRK-52E cells. Taken together, these results revealed that emodin-induced ferroptosis triggered kidney toxicity through inhibition of the Notch1/Nrf2/glutathione peroxidase 4 axis.
研究领域:
药理学
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毒理学
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细胞生物学
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肾脏生理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF INORGANIC BIOCHEMISTRY
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2018
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IF 3.063
Jiajing Diao,Feng Bai,Ying Wang,Qianqian Han,Xi Xu,Hongmei Zhang,Qiang Luo,Yanqing Wang
In this work, we designed polysaccharide-metal complex of dopamine-modified pectin linking ruthenium compound, which exhibited a certain inhibition specificity to human renal cell adenocarcinoma cell line 786-O. The chemical structure and physical properties of the polysaccharide-metal complex were well characterized by multiple analysis methods. The multi-spectral results revealed that pectin-dopamine have been successfully coordinated by ruthenium complex to form nano-conjugates, which self-assembled into relatively regular nanospheres of approximately 200 nm. The polysaccharide-metal complex has more amorphous and less viscosity than pectin, and cannot withstand as much strain as the pectin and pectin-dopamine systems. Pectin-dopamine can decrease the toxicity effect of Ru complex in normal cell line such as human normal renal epithelial cell line 293A.
研究领域:
生物医学工程
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药剂学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
Nano Select
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2020
·Vol. 2
·期 2
·303-312
·
IF 0
Xin Tian,Yue Lang,Dexuan Gao,Xiang-Xiang Zhang,Hai-Yue Dong,Meng-Meng Gu,Lan Yu,Zeng-Fu Shang
Targeted anti-cancer therapy selectively inhibits the growth of malignant cells by interfering with cancer-specific signaling pathways, and inflicts minimal toxicity to normal tissues. Here, the current study demonstrates black phosphorus quantum dots (BPQDs) can target histone deacetylase 1 (HDAC1), which is overexpressed in multiple tumors and involved in cancer progression. The BPQDs inhibit HDAC1 activity and impair HDAC1-mediated deacetylation of the mitotic spindle protein Eg5 in human renal cell carcinoma (RCC) cells, thereby disrupting the mitotic spindle structure and stalling cell cycle progression. Since HDAC1 regulates multiple aspects of cancer progression, BPQDs can neutralize the malignant potential of cancer cells by suppressing their proliferation and migration, and inducing apoptosis. Further in vitro assays demonstrate BPQDs significantly increase the sensitivity of RCC cells to the clinical chemotherapeutic agent, paclitaxel (PTX). Moreover, animal experiments also indicate the combined approach with both BPQDs and PTX displays better efficacy than PTX alone. These findings demonstrate that BPQDs have potential applications in targeted anti-cancer therapy and can be more effectively treated with chemotherapy.
研究领域:
肿瘤学
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生物医学
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药理学
✓ 已验证
DOI
International Journal of Nanomedicine
·
2023
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IF 8
Shaohui Zheng,Min Zhang,Hongyan Bai,Meijuan He,Lina Dong,Lulu Cai,Mingming Zhao,Qi Wang,Kai Xu,Jingjing Li
Background Early diagnosis of renal cell carcinoma is extremely significant for the effective treatment of kidney cancer. The development of AS1411 aptamer modified Mn-MoS2 QDs provides a promising fluorescence/magnetic resonance (MR) dual-modal imaging probe for the precise diagnosis of renal clear cell carcinoma.Methods In this work, Mn-MoS2 QDs were synthesized through a simple “bottom-up” one-step hydrothermal method. AS1411 aptamer was modified on the Mn-MoS2 QDs to improve the specificity to renal cell carcinoma. The characteristics of Mn-MoS2 QDs were confirmed by transmission electronic microscopy (TEM), atomic force microscope (AFM), X-ray photoelectron spectrometer (XPS), photoluminescence (PL) emission spectra, etc. Cellular fluorescence labelling was investigated using the Mn-MoS2 QDs and AS1411-Mn-MoS2 QDs. The T1-weighted MR imaging was assessed by the in vitro MR cell imaging and in vivo MR imaging. Finally, the long-term toxicity of Mn-MoS2 QDs was investigated by the hematology and histological analysis.Results The prepared Mn-MoS2 QDs exhibited excellent aqueous property, intense fluorescence, low toxicity, high quantum yield of 41.45% and high T1 relaxivity of 16.95 mM−1s−1. After conjugated with AS1411 aptamer, the AS1411-Mn-MoS2 QDs could specifically fluorescently label the renal carcinoma cells and present a specific MRI signal enhancement in the tumor region of mice bearing renal carcinoma tumors. Furthermore, Mn-MoS2 QDs revealed low toxicity to the mice via hematology and histological analysis.Conclusion These results demonstrated the potential of AS1411-Mn-MoS2 QD as a novel nanoprobe for targeted MR imaging and fluorescence labelling of renal cell carcinoma.
研究领域:
医学影像学
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纳米医学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2024
·Vol. 25
·期 5
·2458
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IF 4.9
Lixing Cao,Kai Han,Lihong Fan,Chong Zhao,Shutao Yin,Hongbo Hu
Acute kidney injury (AKI) is a common clinical problem with high morbidity and mortality. The discovery of ferroptosis has provided novel insights into the mechanisms underlying AKI and paves the way for developing ferroptosis-based approaches to treat AKI. Glycyrol (GC) is a representative coumarin compound isolated from licorice that demonstrates various pharmacological activities. However, its potential for a protective effect against kidney injury remains unknown. We hypothesized that GC might be able to protect against AKI via suppression of ferroptosis. This hypothesis was tested in a cell-culture model of RSL3-induced nephrocyte ferroptosis and a mouse model of folic acid-induced AKI. The results showed that GC exerted a significant protective effect against nephrocyte ferroptosis in vitro and was effective against folic acid-induced AKI in vivo, where it was mechanistically associated with suppressing HO-1-mediated heme degradation. Collectively, the findings of the present study support the hypothesis that GC holds considerable potential to be developed as a novel agent for treating ferroptosis-related AKI.
研究领域:
药理学
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肾病学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·
IF 10.6
Zifei Wu,Xie Huang,Chuan Wu,Yan Zhou,Mingquan Gao,Shenglin Luo,Qiang Xiang,Weidong Wang,Rong Li
Enhancing the sensitivity of radiotherapy (RT) towards renal cell carcinoma (RCC) remains a challenge because RCC is a radioresistant tumor. In this work, we design and report asymmetrically Polyethylene Glycol (PEG)ylated and amphipathic heptamethine indocyanine dyes for efficient radiosensitization of RCC treatment. They were synthesized by modifying different lengths of PEG chains as hydrophilic moieties on one N -alkyl chain of a mitochondria-targeting heptamethine indocyanine dye (IR-808), and a radiosensitizer 2-nitroimidazole (NM) as a hydrophobic moiety on another N -alkyl chain. The PEG modification significantly improved water solubility, decreased the intermolecular π–π large aggregates, thereby enhanced renal excretion. The asymmetrical and amphipathic modification enhanced the preferential accumulation in renal tumors through self-assembly into small-size nanoparticles in aqueous environment. Radiosensitization was further improved by preferential accumulation in renal tumor cells and their mitochondria as mitochondria play a crucial role in rapid cancer cell growth, metastasis, and RT resistance. Additionally, the modification also increased the abilities of fluorescence emission and photostability, which is meaningful for imaging-guided precise RCC RT. Therefore, our findings may present a theranostic radiosensitizer for renal tumor-targeted imaging and radiosensitization.
研究领域:
肿瘤学
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药理学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY
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2024
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IF 4.8
Hong-Yu Fu,Yue Li,Han Cui,Jiu-Zhi Li,Wan-Xue Xu,Xi Wang,Rui-Feng Fan
Mercuric chloride (HgCl 2 ), a widespread environmental pollutant, induces ferroptosis in chicken embryonic kidney (CEK) cells. Whereas activating transcription factor 4 (ATF4), a critical mediator of oxidative homeostasis, plays a dual role in ferroptosis, but its precise mechanisms in HgCl 2 -induced ferroptosis remain elusive. This study aims to investigate the function and molecular mechanism of ATF4 in HgCl 2 -induced ferroptosis. Our results revealed that ATF4 was downregulated during HgCl 2 -induced ferroptosis in CEK cells. Surprisingly, HgCl 2 exposure has no significant impact on ATF4 mRNA level. Further investigation indicated that HgCl 2 enhanced the expression of the E3 ligase beta-transducin repeat-containing protein (β-TrCP) and increased ATF4 ubiquitination. Subsequent findings identified that miR-15b-5p as an upstream modulator of β-TrCP, with miR-15b-5p downregulation observed in HgCl 2 -exposed CEK cells. Importantly, miR-15b-5p mimics suppressed β-TrCP expression and reversed HgCl 2 -induced cellular ferroptosis. Mechanistically, HgCl 2 inhibited miR-15b-5p, and promoted β-TrCP-mediated ubiquitin degradation of ATF4, thereby inhibited the expression of antioxidant-related target genes and promoted ferroptosis. In conclusion, our study highlighted the crucial role of the miR-15b-5p/β-TrCP/ATF4 axis in HgCl 2 -induced nephrotoxicity, offering a new therapeutic target for understanding the mechanism of HgCl 2 nephrotoxicity.
研究领域:
毒理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-22
·
IF 12.6
Liu Yanhong,Gong Liming,Feng Jing,Xiao Congcong,Liu Chenfei,Chen Bohan,Chen Liqing,Jin Mingji,Guan Youyan,Gao Zhonggao,Huang Wei
Immune checkpoint inhibition (ICI) has become the mainstay of immunotherapy for the treatment of renal cell carcinoma (RCC). However, only a small portion of patients exhibit a positive response to PD-1/PD-L1 blockade therapy and the key reason is that RCC belongs to a vascular-rich tumor for promoting immunosuppression. Specifically, the dysfunctional tumor vasculature hinders effector T cell infiltration and induces immunosuppressive tumor microenvironment via the release of cytokine, which attenuates the therapeutic efficacy of ICI. Therefore, regulating abnormal tumor vasculature may be a promising strategy to overcome the immunosuppressive microenvironment and enhance ICI therapy. Here, we propose an NGR peptide-modified actively targeted liposome (Axi/siRNA PD−L1 @NGR-Lipo) to encapsulate the anti-angiogenic agents Axitinib and PD-L1 siRNA to promote tumor vasculature normalization and relieve immune evasion for enhanced anti-tumor immunotherapy. With NGR-mediated tumor homing and active targeting, Axi/siRNA PD−L1 @NGR-Lipo could act on tumor vascular endothelial cells to inhibit neo-angiogenesis, increase pericyte coverage and vascular perfusion, and normalize the structure and function of tumor blood vessels. Meanwhile, it also enhanced immune effector T cells and NK cells infiltration and reduced the proportion of immunosuppressive T cells including MDSC cells and Tregs, thus improving the tumor immunosuppressive microenvironment. Moreover, Axi/siRNA PD−L1 @NGR-Lipo reduced the expression of PD-L1 protein in tumor cells, restored the recognition and killing ability of cytotoxic T cells, and relieved immune evasion. As expected, Axi/siRNA PD−L1 @NGR-Lipo displayed superior anti-tumor and anti-metastatic efficacy in mice bearing RCC. Overall, this study demonstrated the important potential of regulating abnormal tumor vasculature to reshape the immunosuppressive microenvironment and boost ICI therapy, which represents a promising avenue for the synergistic anti-tumor with cancer immunotherapy. Graphical
研究领域:
肿瘤学
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免疫学
·
药剂学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2024
·
IF 4.7
Bo Liu,Lei Luo,Bixin Yu,Taotao Que,Yujiao Zhang
Background The incidence of renal cell carcinoma (RCC) is already in the top ten of all types of cancers, with more than 4%. Epigallocatechin gallate (EGCG), a polyphenolic compound extracted from green tea, has been shown to be effective in the treatment of various tumors. However, limited studies have demonstrated the effect of EGCG on RCC and its underlying molecular mechanisms. Methods After exposure to gradient concentration ( 0,5,10,20,40,60,80,100 μM ) of EGCG, the cell viability of RCC cells was determined by MTT assay. The migration and invasion abilities of RCC cells were investigated by wound healing and transwell assays. The expression levels of proteins involved in the epithelial-mesenchymal transition (EMT) and autophagy were explored by Western blotting assays. The formation of autophagosome was detected by electron microscope and LC3 puncta assays. Nude mouse xenograft model was used as the model system in vivo. Results In the present study, EGCG significantly inhibited the migration, invasion and EMT of RCC cells in a concentrated manner. Further exploration of its mechanism indicated that autophagy is involved in EGCG-mediated metastasis inhibition and EMT inhibition of RCC cells. In addition, EGCG could significantly up-regulate the transcription factor EB (TFEB) and promotes its nuclear localization. The incorporation of TFEB into the nucleus enhanced the transcriptional levels of molecules associated with autophagy. TFEB knockdown inhibited EGCG-mediated autophagy activation, metastasis and EMT inhibition in RCC cells. Conclusions In conclusion, these findings demonstrate for the first time that EGCG inhibits migration, invasion, and EMT of RCC by activating TFEB-mediated autophagy. Therefore, the combination of EGCG and TFFB activators or EMT inhibitors is expected to be a promising therapeutic strategy for RCC.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
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2025
·
IF 7.7
Zhi-Li Yao,Qing-Nan Li,Yong-Ji Li,Hao-Rui Li,Si-Wei Yang,Chen-Yu Wang,Jia-Yi Shi,Shun-Li Wu,Shuang-Qing Liu,Gui-Mei Han,Jing Wang,Li-Yong Xing,Yan Zhao,De-Ming Kong,Qi-Liang Cai
Clear cell renal cell carcinoma (ccRCC) is the most prevalent form of kidney cancer in adults, with rising global incidence and mortality rates. Early diagnosis is critical for improving patient outcomes. However, current diagnostic techniques often rely on expensive and complex instrumentation, which limits their accessibility. This creates an urgent need for affordable, sensitive, and user-friendly diagnostic methods. MiR-210–3p, a biomarker significantly upregulated in ccRCC, shows promise for non-invasive diagnostic applications. In this study, we innovatively developed a fluorescence-colorimetric dual-mode platform for miR-210–3p detection by utilizing a recently identified hemin aptamer with a stem-loop structure and by combining the trans -cleavage activity of the CRISPR/Cas12a system with the peroxidase-like activity of the aptamer/hemin complex. Moreover, using fluorescently labeled aptamer or its complementary sequence as cleavage substrates for CRISPR/Cas12a allows us to achieve two types of dual-mode detection: fluorescence “turn on” combined with colorimetric “turn off”, and fluorescence “turn on” combined with colorimetric “turn on”. This dual-mode detection platform combines sensitive quantification (with a detection limit for miR-210-3p of 0.95 pM) with rapid and visually interpretable on-site analysis, significantly enhancing the reliability and accuracy of test results. The platform has good scalability, as it is capable of detecting miR-210-3p and can also be extended to detect other tumor biomarkers. This versatility holds great potential for integration with big data analytics to personalize miRNA profiles, aiding in tumor staging, monitoring, and the development of treatment strategies, thereby advancing the field of precision medicine.
研究领域:
分子生物学
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肿瘤学
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诊断学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）