Theranostics
·
2018
·
IF 8.537
Zhenyuan Bian,Jin Yan,Simeng Wang,Yijie Li,Yi Guo,Bohan Ma,Hao Guo,Zhijie Lei,Chun Yin,Yi Zhou,Min Liu,Kaishan Tao,Peng Hou,Wangxiao He
Peptides are a rapidly growing class of therapeutics with many advantages over conventional small molecule drugs. Dextrorotary (D)-peptides, with increased enzymatic stability and prolonged plasma half-life in comparison with natural L-peptides, are considered to have great potential as recognition molecules and therapeutic agents. However, the in vivo efficacy of current therapeutic D-peptides is hindered by their inefficient cellular uptake in diseased tissues. Methods: To overcome physiological and cellular barriers to D-peptides, we designed a gold-based ultra-small nanocarrier coupled with polylysine (PLL) and a receptor-targeted peptide to deliver therapeutic D-peptides. Using a D-peptide p53 activator (DPA) as a proof of concept, we synthesized, functionalized and characterized gold- and DPA-based nanoparticles termed AuNP-DPA. Results: AuNP-DPA were effectively enriched in tumor sites and subsequently internalized by cancer cells, thereby suppressing tumor growth via reactivating p53 signaling. More importantly, through a series of in vivo experiments, AuNP-DPA showed excellent biosafety without the common side effects that hinder p53 therapies in clinic trials. Conclusion: The present study not only sheds light on the development of AuNP-DPA as a novel class of antitumor agents for drugging the p53 pathway in vivo, but also supplies a new strategy to use D-peptides as intracellular PPI inhibitors for cancer-targeted therapy.
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Journal of Materials Chemistry B
·
2020
·Vol. 8
·期 19
·4331-4339
·
IF 5.344
Qinan Xu,Xinfang Li,Peng Zhang,Youxiang Wang
The synergistic combination of gene therapy and photothermal therapy (PTT) has been widely investigated as a promising strategy for cancer treatment. To deliver genes and photothermal agents simultaneously and accurately to a tumor site, a microneedle (MN) patch co-loaded with p53 DNA and IR820 was fabricated by a two-step casting method. Hyaluronic acid was chosen as a matrix and p53 DNA and IR820 were mainly loaded into the tips to enhance utilization and reduce waste. The MN patch could efficiently penetrate the stratum corneum, and dissolve rapidly to release p53 DNA and IR820 in the subcutaneous tumor site. Due to the efficient photothermal efficacy of IR820, the temperature of the tumor site where the MN patch was applied increased by 14.7 °C under near-infrared light irradiation. The MN patch showed excellent antitumor effects in vivo owing to the synergistic effect of gene therapy and PTT. Consequently, the p53 DNA/IR820 MN patch may be a promising synergistic strategy for subcutaneous tumor treatments.
研究领域:
生物医学工程
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肿瘤学
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纳米技术
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药学
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高影响因子
Evidence-based Complementary and Alternative Medicine
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2015
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IF 1.88
Ying Chen,Haiyan Sun,Liyong Huang,Juxiang Li,Wenke Zhou,Jingling Chang
Redox homeostasis has been implicated in subarachnoid hemorrhage (SAH). As a result, antioxidants and/or free radical scavengers have become an important therapeutic modality. Considering that radix trichosanthis (RT) saponins exhibited strong antioxidant ability both in vivo and in vitro, the present study aimed to reveal whether the neuroprotective activities of RT saponins were mediated by p38/p53 signal pathway after SAH. An established SAH model was used and superoxide dismutase (SOD), malondialdehyde (MDA), induced nitric oxide synthase (iNOS), nitric oxide (NO), lactate dehydrogenase (LDH), p-p38, and p53 activation were detected after 48 h of SAH. The results showed that RT saponins inhibited iNOS expression to restore NO to basal level. Moreover, compared with Cu/Zn-SOD, RT saponins (2 mg/kg/d dosage) significantly increased Mn-SOD activity after SAH. Accompanied with lowered NO and elevated SOD, decreased p38 phosphorylation and p53 activities were observed, especially for RT saponins at 2 mg/kg/d dosage. In this setting, the neurological outcome was also improved with less neuronal cells damage after RT saponins pretreatment. Our findings demonstrated the beneficial effects of RT saponins in enhancing neuroprotective effects by deducing iNOS activity, normalizing SOD level, and inhibiting p-p38 and p53 expression, hence offering significant therapeutic implications for SAH.
研究领域:
神经科学
·
药理学
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Anti-Cancer Agents in Medicinal Chemistry
·
2024
·Vol. 24
·期 5
·348-357
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IF 2.6
Fan Ning,Zhang Lixiu,Wang Zhiping,Ding Hui,Yue Zhongjin
Background: Bladder cancer is the most common malignant tumor of the urinary system. Nevertheless, current therapies do not provide satisfactory results. It is imperative that novel strategies should be developed for treating bladder cancer. Objectives: To evaluate the effect of
a broad-spectrum anti-parasitic agent, Ivermectin, on bladder cancer cells in vitro and in vivo. Methods: CCK-8 and EdU incorporation assays were used to evaluate cell proliferation. Apoptosis was detected by flow cytometry, TUNEL assay, and western blotting. Flow cytometry
and DCFH-DA assay were used to analyze the reactive oxygen species (ROS) levels. DNA damage was determined by Neutral COMET assay and γ H2AX expression. Proteins related to apoptosis and DNA damage pathways were determined by WB assay. Xenograft tumor models in nude mice were used to
investigate the anti-cancer effect of Ivermectin in vivo. Results: Our study showed that in vitro and in vivo, Ivermectin inhibited the growth of bladder cancer cells. In addition, Ivermectin could induce apoptosis, ROS production, DNA damage, and activate ATM/P53
pathwayrelated proteins in bladder cancer cells. Conclusion: According to these findings, Ivermectin may be a potential therapeutic candidate against bladder cancer due to its significant anti-cancer effect.
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症研究
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高影响因子
Communications Biology
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2025
·Vol. 8
·期 1
·1-14
·
IF 5.1
Sun Wei,Zhao Bo,He Zhong,Chang Lihua,Song Wei,Chen Yingying
Idiopathic pulmonary fibrosis (IPF) is an irreversible lung condition that progresses over time, which ultimately results in respiratory failure and mortality. In this study, we found that PLAC8 was downregulated in the lungs of IPF patients based on GEO data, in bleomycin (BLM)-induced lungs of mice, and in primary murine alveolar epithelial type II (pmATII) cells and human lung epithelial cell A549 cells. Overexpression of PLAC8 facilitated autophagy and inhibited apoptosis of pmATII cells and A549 cells in vitro. Moreover, inhibition of autophagy or overexpression of p53 partially abolished the effects of PLAC8 on cell apoptosis. ATII cell-specific overexpression of PLAC8 alleviated BLM-induced pulmonary fibrosis in mice. Mechanistically, PLAC8 interacts with VCP-UFD1-NPLOC4 complex to promote p53 degradation and facilitate autophagy, resulting in inhibiting apoptosis of alveolar epithelial cells and attenuating pulmonary fibrosis. In summary, these findings indicate that PLAC8 may be a key target for therapeutic interventions in pulmonary fibrosis.
研究领域:
呼吸病学
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细胞生物学
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分子生物学
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药理学
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BIOCHEMICAL PHARMACOLOGY
·
2022
·
IF 6.1
Ge Li,Shan-shan Lin,Ze-lei Yu,Xin-hua Wu,Jing-wen Liu,Gui-hui Tu,Quan-yu Liu,Yuan-ling Tang,Qing-na Jiang,Jian-hua Xu,Qing-ling Huang,Li-xian Wu
Therapeutic targeting of the nuclear enzyme poly (ADP-ribose) polymerase 1 (PARP1) with PARP inhibitors (PARPis) in patients with a homologous recombination (HR)- deficient phenotype based on the mechanism of synthetic lethality has been shown tremendous success in cancer therapy. With the clinical use of various PARPis, emerging evidence has shown that some PARPis offer hope for breakthroughs in triple-negative breast cancer (TNBC) therapy, regardless of HR status. However, similar to other conventional cytotoxic drugs , PARPis are also subject to the intractable problem of drug resistance. Notably, acquired resistance to PARPis caused by point mutations in the PARP1 protein is hard to overcome with current strategies. To explore modalities to overcome resistance and identify patients who are most likely to benefit from PARP1-targeted therapy, we developed a proteolysis-targeted chimaera (PROTAC) to degrade mutant PARP1 in TNBC. Here, we investigated a PARP1 PROTAC termed “ NN3 ″, which triggered ubiquitination and proteasome-mediated degradation of PARP1. Moreover, NN3 degraded PARP1 with resistance-related mutations. Interestingly, compared with other reported PARP1 degraders, NN3 exhibited a unique antitumor mechanism in p53-positive breast cancer cells that effectively promoted ferroptosis by downregulating the SLC7A11 pathway. Furthermore, NN3 showed potent activity and low toxicity in vivo. In conclusion, we propose PROTAC-mediated degradation of PARP1 as a novel strategy against mutation-related PARPi resistance and a paradigm for targeting breast cancer with functional p53 via ferroptosis induction.
研究领域:
癌症生物学
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分子生物学
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药理学
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肿瘤学
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高影响因子
GENERAL PHYSIOLOGY AND BIOPHYSICS
·
2024
·Vol. 43
·期 1
·13-23
·
IF 1.3
Xiao Jin,Ling Jin,Bingxin Wu,Danping Xu
Myocardial ischemia/reperfusion (I/R) causes serious threats to human life. Naringenin, a polyphenolic compound naturally occurring in citrus fruit, has cardioprotective effects against myocardial I/R injury. Besides, miR-24-3p is also reported to have cardioprotective effects. We intended to explore whether the cardioprotective effects of naringenin relate to miR-24-3p and its underlying mechanism. In this study, we used an in vivo rat myocardial I/R model and an in vitro cardiomyocyte H9c2 hypoxia/reoxygenation (H/R) model. Myocardial injury was detected by hematoxylin-eosin staining and ELISA for creatine kinase (CK), malondialdehyde (MDA), and lactate dehydrogenase (LDH). miR-24-3p and cell death inducing p53 target 1 (Cdip1) mRNA expressions were examined by RT-PCR. We find that naringenin pretreatment significantly relieves myocardial I/R injury, reduces LDH, CD, and MDA levels, and increases miR-24-3p expression. Furthermore, miR-24-3p alleviates myocardial I/R injury partially through regulating Cdip1. Moreover, naringenin protects myocardial I/R injury partially by regulating miR-24-3p to inhibit Cdip1 expression. In conclusion, our data suggest naringenin protects myocardial I/R injury partially through miR-24-3p/Cdip1 axis.
研究领域:
心脏病学
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分子生物学
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药理学
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生物医学
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高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2022
·
IF 6.1
Liangping Li,Pingping Li,Xuesong Ma,Shulan Zeng,Yan Peng,Guohai Zhang
p53 inactivation by disabling its function is a hallmark in lung carcinomas , emphasizing the significance of restoring p53 function as an attractive therapeutic strategy. However, the clinical efficacy of existing p53 activators is limited due to their inability to effectively activate p53 within the tumors. Here, we established a p53 activator screening assay in EGFR-driven lung cancer cells and identified a small molecular, MX-C4, as a promising candidate. Using high throughput compound screening and combination analyses, we found that MX-C4 effectively promoted the phosphorylation of p53 at serine-392 (s392). It exhibited potent antitumor activity in a variety of cancer cell lines, but only limited toxicity to NCI-H1299 (p53-null) and normal cell lines such as LX2 and HL-7702. Overexpression of p53 in NCI-H1299 cells by a p53 expressing virus vector sensitized cells to MX-C4 treatment, suggesting a p53-dependent anticancer activity. Furthermore, we demonstrated that MX-C4 bound to p53 and exerted its anticancer activity through cell cycle arrest at G2/M phase and apoptosis induction. Mechanistic study indicated that p53 activation regulated cell cycle and cell survival related targets at protein levels. Moreover, p53 activation raised phospho-p53 translocation to mitochondria and subsequently reorganized the Bcl-xl-Bak complex, thus conformationally activating Bak and inducing apoptosis. It is noteworthy that MX-C4 could effectively activate p53 within the tumors in EGFR-driven xenograft models, where tumor was significantly suppressed without obvious toxicity. Our study identified a promising candidate for lung cancer therapy by restoring p53 function.
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AQUACULTURE
·
2022
·
IF 5.135
Min Li,Xueqin Wu,Jixing Zou,Yingqian Lai,Jiawen Zhang,Xiumei Chen,Xiaotian Niu,Yidi Kong,Guiqin Wang
This study was aimed to evaluate the ameliorative effects of thymol-supplemented diets on the toxicity damage of Channa argus induced by deltamethrin (DEL). After 28 d, the results are as follows: thymol can attenuate DEL-induced oxidative stress by reversing the decrease of the activities of antioxidant enzyme (SOD, CAT , GSH , GST and GSH-Px) and the increase of the MDA content in the tissues (liver and spleen), and also by reversing the decrease of the mRNA expression levels of Nrf2, Cu/Zn SOD and HO-1, and the increase of the Keap1 mRNA expression level in the tissues (liver and spleen). Thymol can attenuate DEL-induced immunotoxicity of fish by reverse the decrease of the levels of humoral immune parameters (C4, C3, IgM and LYS) in the serum, and by reversing the increase of the expression levels of NF-κB p65, TNF-α, IL-1β, IL-8 and IL-6, and the decrease of the IL-10 expression level in the tissues (liver and spleen). Thymol can attenuate DEL-caused apoptosis reversing the increase of the expression levels of pro-apoptosis (p53, Bax and Apaf-1) and the decrease of the expression level of anti-apoptosis Bcl-2 in the tissues (liver and spleen). Therefore, this study reveals that dietary supplementation of thymol alleviates DEL-caused immunotoxicity, oxidative stress, and apoptosis of C. argus in association with the NF-κB/Nrf2/p53 pathway.
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Aging-US
·
2021
·
IF 5.682
Jianhao Xu,Liwei Ni,Fenglun Zhao,Xiaoxiao Dai,Jialong Tao,Jia Pan,Aiming Shi,Zhu Shen,Cunjin Su,Yusong Zhang
Background: This study aimed to investigate the aberrant expression of hsa_circ_0002874 in non-small cell lung cancer (NSCLC) and elucidate associated molecular mechanisms that influence apoptosis and induce paclitaxel (PTX) resistance. Methods: Inhibitors were used to downregulate circRNA or miRNA expression. pCDNA plasmid transfection and mimics were used to upregulate circRNA or miRNA expression. Dual-luciferase reporter assays were conducted to evaluate interactions between miR1273f and MDM2. Xenograft tumor models were used to assess the effect of hsa_circ_0002874 and miR1273f on tumor growth. NSCLC tissues and matched non-cancerous tissues were also collected for correlation analysis. Results: hsa_circ_0002874 acts as a sponge for miR1273f which targets MDM2/P53. The stability of the hsa_circ_0002874/miR1273f/MDM2/P53 pathway was verified by upregulating and downregulating the expression of hsa_circ_0002874 and miR1273f. hsa_circ_0002874 downregulation or miR1273f upregulation reversed the resistance of the A549/Taxol cells in xenograft models. The expression of hsa_circ_0002874 was high, and the level of MDM2 was low in NSCLC tissues. P53 was only weakly expressed in NSCLC tissues with high expression of MDM2. Conclusions: hsa_circ_0002874 is strongly expressed in NSCLC tissues and maybe a potential marker for PTX resistance. hsa_circ_0002874 downregulation could regulate miR1273f/MDM2/P53 signaling pathway to reverse the PTX resistance of NSCLC and induce apoptosis in vitro and vivo .
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BRAZILIAN JOURNAL OF MEDICAL AND BIOLOGICAL RESEARCH
·
2024
·
IF 1.9
Liu Lilong,Wang Yexin,Dong Yanyan,Lin Shan,Guan Wenhui,Song Jia
The clinical application of 5-fluorouracil (5-Fu), a potent chemotherapeutic agent, is often hindered by its well-documented cardiotoxic effects. Nevertheless, natural polyphenolic compounds like resveratrol (RES), known for their dual anti-tumor and cardioprotective properties, are potential adjunct therapeutic agents. In this investigation, we examined the combined utilization of RES and 5-Fu for the inhibition of gastric cancer using both in vitro and in vivo models, as well as their combined impact on cardiac cytotoxicity. Our study revealed that the co-administration of RES and 5-Fu effectively suppressed MFC cell viability, migration, and invasion, while also reducing tumor weight and volume. Mechanistically, the combined treatment prompted p53-mediated apoptosis and autophagy, leading to a considerable anti-tumor effect. Notably, RES mitigated the heightened oxidative stress induced by 5-Fu in cardiomyocytes, suppressed p53 and Bax expression, and elevated Bcl-2 levels. This favorable influence enhanced primary cardiomyocyte viability, decreased apoptosis and autophagy, and mitigated 5-Fu-induced cardiotoxicity. In summary, our findings suggested that RES holds promise as an adjunct therapy to enhance the efficacy of gastric cancer treatment in combination with 5-Fu, while simultaneously mitigating cardiotoxicity.
研究领域:
肿瘤学
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心脏病学
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药理学
·
分子生物学
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高影响因子
REPRODUCTIVE BIOMEDICINE ONLINE
·
2024
·
IF 3.7
Siyuan Xie,Yuyi Wang,Chenxi Zhao,Yugui Cui,Chunyan Gu,Wei Wu
ABSTRACT Research question: Does putrescine improve oocytes from reproductively old mice by promoting mitochondrial autophagy༟ Design: Germinal vesicle (GV) stage cumulus-oocyte complexes (COCs) were obtained from 9-month-old female C57B6L/N mice and divided into three groups: NC (control group), PUT (putrescine group), and DFMO (difluoromethylornithine, inhibitor group). These GV-COCs underwent mouse in vitro maturation (IVM) culture to observe the extrusion of the first polar body in each group. Using JC-1 and DCFH-DA fluorescent probes and a confocal microscope to measure the mitochondrial membrane potential integrity and ROS levels in MII stage oocytes. The expression and cellular localization of the p53 protein were examined by immunofluorescence. RT-qPCR was used to detect the activation of mitochondrial autophagy pathways. The potential mechanisms through which putrescine improves oocytes from reproductively old mice were explored by single-cell transcriptomic analysis. Autophagosomes, autolysosomes, and mitochondria in different groups were directly observed using transmission electron microscopy. Results: The study found that adding exogenous putrescine can promote the in vitro maturation of oocytes from reproductively old mice. Putrescine reduces oxidative stress in oocytes from reproductively old mice by promoting the autophagy of damaged mitochondria, decreasing the levels of reactive oxygen species, and increasing mitochondrial membrane potential. Putrescine affects the expression and subcellular localization of the p53 protein, and increases the expression of TFEB, which may be the potential mechanism behind its promotion of autophagy. Conclusion: This study clarified the target and regulatory pathway of putrescine in oocytes, suggesting that putrescine is an effective small molecule compound with significant potential for non-invasively improving the fertility of elderly women.
研究领域:
生殖生物学
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分子生物学
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老年学
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高影响因子
危险品化学品经营许可证（带存储）