Cell Death & Disease
·
2018
·Vol. 9
·期 5
·1-12
·
IF 5.638
Sun Jiahong,Wen Yajie,Zhou Yanying,Jiang Yiming,Chen Yixin,Zhang Huizheng,Guan Lihuan,Yao Xinpeng,Huang Min,Bi Huichang
Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. Inhibition of APAP metabolic activation and promotion in APAP disposition are important to protect against APAP-induced liver injury. Tumor suppressor p53 is traditionally recognized as a surveillance molecule to preserve genome integrity. Recent studies have emerged on discovering its functions in metabolic regulation. Our previous study reported that p53 promoted bile acid disposition and alleviated cholestastic syndrome. Here, we examined the effect of doxorubicin (Dox)-mediated p53 activation on APAP-induced hepatotoxicity in mice and revealed a novel role of p53 in regulating APAP metabolism and disposition. Histopathological and biochemical assessments demonstrated that administration of Dox (10 mg/kg/d) before APAP treatment (400 mg/kg) significantly alleviated APAP-induced hepatotoxicity. Dox treatment prevented APAP-induced GSH depletion and lipid peroxidation. p53-null mice were more susceptible to APAP-induced liver injury. Further, we found that the expression of drug-metabolizing enzymes and transporters CYPs, SULTs and MRPs was regulated by p53. Dox treatment also promoted Nrf2 activation and increased the expression of Nrf2 target genes including GSTα/μ and NQO1, which contribute to APAP detoxification. Overall, this study is the first to demonstrate the protective role of p53 in regulating APAP metabolism and disposition, which provides a potential new therapeutic target for APAP-induced liver injury.
研究领域:
药理学
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毒理学
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分子生物学
·
肝病学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2023
·
IF 5.6
Wang Shuai,Bai Jie,Che Yilin,Qu Weikun,Li Jing
Background: Humans with hypertensive heart disease are more likely to experience heart failure, arrhythmia, myocardial infarction, and sudden death, and it is crucial to treat this condition. Fucoidan (FO) is a natural substance derived from marine algae that has antioxidant and immunomodulatory activities. FO has also been shown to regulate apoptosis. However, whether FO can protect against cardiac hypertrophy is unknown.Methods: We investigated the effect of FO in hypertrophic models in vivo and in vitro. C57BL/6 mice were given an oral gavage of FO (300 mg/kg/day) or PBS (internal control) the day before surgery, followed by a 14-day infusion of Ang II or saline. AC-16 cells were treated with si-USP22 for 4 h and then treated with Ang II (100 nM) for 24 h. Systolic blood pressure (SBP) was recorded, echocardiography was used to assess cardiac function, and pathological changes in heart tissues were assessed by histological staining. Apoptosis levels were detected by TUNEL assays. The mRNA level of genes was assessed by qPCR. Protein expression was detected by immunoblotting.Results: Our data showed that USP22 expression was lowered in Ang II-infused animals and cells, which could promote cardiac dysfunction and remodeling. However, treatment with FO significantly upregulated the expression of USP22 and reduced the incidence of cardiac hypertrophy, fibrosis, inflammation, and oxidative responses. Additionally, FO treatment lowered p53 expression and apoptosis while increasing Sirt 1 and Bcl-2 expression.Conclusion: By reducing the level of Ang II-induced apoptosis through the regulation of USP22/Sirt 1 expression, FO treatment might improve cardiac function. According to this study, FO might be potential targeted approach for treating heart failure.
研究领域:
心脏病学
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药理学
·
分子生物学
·
免疫学
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产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2021
·
IF 5.275
Dongjuan Si,Huijuan Luo,Xiaomeng Zhang,Kundi Yang,Hongmei Wen,Wei Li,Jian Liu
Inhibition of the interactions of the tumor suppressor protein p53 with its negative regulators MDM2 in vitro and in vivo , representing a valuable therapeutic strategy for cancer treatment. The natural product chalcone exhibited moderate inhibitory activity against MDM2, thus based on the binding mode between chalcone and MDM2, a hit unsaturated pyrrolidone scaffold was obtained through virtual screening. Several unsaturated pyrrolidone derivatives were synthesized and biological evaluated. As a result, because the three critical hydrophobic pockets of MDM2 were occupied by the substituted-phenyl linked at the pyrrolidone fragment, compound 4 h demonstrated good binding affinity with the MDM2. Additionally, compound 4 h also showed excellent antitumor activity and selectivity, and no cytotoxicity against normal cells in vitro . The further antitumor mechanism studies were indicated that compound 4 h could successfully induce the activation of p53 and corresponding downstream p21 proteins, thus successfully causing HCT116 cell cycle arrest in the G1/M phase and apoptosis. Thus, the novel unsaturated pyrrolidone p53-MDM2 inhibitors could be developed as novel antitumor agents.
研究领域:
药物化学
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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
MOLECULAR MEDICINE
·
2022
·Vol. 28
·期 1
·1-15
·
IF 6.376
Wang Bingwu,Gao Jian,Zhao Zhongjun,Zhong Xuefei,Cui Hao,Hou Hui,Zhang Yanping,Zheng Junnian,Di Jiehui,Liu Yong
Background Targeting ribosome biogenesis to activate p53 has recently emerged as a therapeutic strategy in human cancer. Among various ribosomal proteins, RPL11 centralizes the nucleolar stress-sensing pathway by binding MDM2, leading to MDM2 inactivation and p53 activation. Therefore, the identification of MDM2-binding RPL11-mimetics would be valuable for anti-cancer therapeutics.Methods Based on the crystal structure of the interface between RPL11 and MDM2, we have identified 15 potential allosteric modulators of MDM2 through the virtual screening.Results One of these compounds, named S9, directly binds MDM2 and competitively inhibits the interaction between RPL11 and MDM2, leading to p53 stabilization and activation. Moreover, S9 inhibits cancer cell proliferation in vitro and in vivo. Mechanistic study reveals that MDM2 is required for S9-induced G2 cell cycle arrest and apoptosis, whereas p53 contributes to S9-induced apoptosis.Conclusion sPutting together, S9 may serve as a lead compound for the development of an anticancer drug that specifically targets RPL11-MDM2-p53 pathway.
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
ARCHIVES OF INSECT BIOCHEMISTRY AND PHYSIOLOGY
·
2022
·Vol. 112
·期 2
·e21970
·
IF 2.454
Pan Zhang,Zi-Yan Liu,Dan Yu,Cui-Xian Xu,Yan Hu,Ya-Ping Liang,Jie Jin,Ming Li
Microplitis bicoloratus parasitism can induce apoptosis of hemocytes in the M. bicolortus host, Spodoptera litura . However, it is unclear how M. bicolortus parasitism regulates host signaling pathways to induce apoptosis. Expression of cyclophilin D (CypD) and p53 was significantly upregulated in S. litura hemocytes at 6 days postparasitization. In the parasitized hemocytes, there was mitochondrial membrane potential (△Ψ m ) loss, cytochrome c (Cyt C) release from mitochondria, and caspase-3 activation. These occurred while hemocytes were undergoing upregulation of CypD and p53. Parasitism also promoted the interaction between CypD and p53. CypD silencing could rescue the apoptotic phenotypes induced by parasitism, but had no effect on apoptosis in unparasitized S. litura . These findings suggest that the CypD-p53 pathway may be an important component of the parasitism-induced immunosuppressive response and establish a basis for further studies of parasitoid/host interactions. Research highlights Microplitis bicoloratus parasitism upregulates the expression of CypD and p53 and induces host hemocyte apoptosis. M. bicoloratus parasitism promotes the CypD-p53 interaction, resulting in Cyt C release from mitochondria and caspase-3 activation.
研究领域:
昆虫学
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分子生物学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Gongxi Qiao,Xuming Pan,Mengyun He,Ruixi Peng,Xiangrong Huang,Cunpeng Nie,Jianhui Jiang,Xia Chu
Tumor protein 53 (Tp53), a key regulator of suppressor genes, is commonly mutated in numerous malignant diseases. Consequently, elimination mutant protein 53 (mutp53) represents an appealing strategy for treating mutp53-related tumors. However, the treatment of these mutations remained challenging due to its formidable limitations. In this study, by loading glucose oxidase (GOX) into Zn-based layered double hydroxides (Zn-LDH) interlayer, a pH-responsive ultrathin nanotherapeutic platform (Zn-LDH@GOX) was created to suppress tumors growth by degrading mutp53. Upon exposure to the acidic environment of lysosomes, the lattice structure of Zn-LDH@GOX was partially disrupted, leading to the release of Zn 2+ ions and GOX into the cytoplasm. The increased intracellular concentration of Zn 2+ facilitated the restoration of wild-type protein 53 (wtp53) conformation, which in turn degraded mutp53 through activated autophagic pathways. Meanwhile, GOX-induced Heat Shock Protein 90 (HSP90) disruption resulted in the liberation of mutp53 from the HSP90/mutp53 complex and reactivated its degradation via the ubiquitination-mediated proteasomal pathway. In vitro and in vivo experiments confirmed the significant suppression of mutp53 expression and inhibition of tumor growth by Zn-LDH@GOX. Our work offers a novel pH-responsive nanotherapeutic platform with immense potential for mutp53 tumor-specific therapy.
研究领域:
肿瘤学
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分子生物学
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纳米技术
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癌症治疗
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产品关联
DOI
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2018
·
IF 3.04
Qi Wan,Hui Chen,Xiaolei Li,Lianqi Yan,Yu Sun,Jingcheng Wang
Fibroblast proliferation is considered to be a major cause in the process of epidural fibrosis formation. Autophagy is a tightly-regulated catabolic process in charge of degrading intracellular components. Although autophagy has been associated with fibrosis of different tissues, the effect of autophagy on epidural fibrosis is still unknown. The aim of this study was to investigate the function and mechanism of autophagy induced by Artesunate (ART), a classical antimalarial agent extracted from the Chinese medicinal herb. In vitro, the effect of ART on inducing fibroblast autophagy was evaluated via LC3 immunofluorescent staining , Transmission Electron Microscopy (TEM) and western blotting analysis. Moreover, the effect of ART on inhibiting fibroblast proliferation was investigated by CCK-8 assay, EdU incorporation assay, flow cytometry and western blotting analysis. Results indicated that ART could induce autophagy and inhibit proliferation in fibroblasts. The inhibitory effect of ART on fibroblast proliferation was associated with the upregulation of p53 and p21 waf1/cip1 proteins. Intriguingly, 3-MA, a classical autophagy inhibitor, attenuated ART-induced p53/p21 waf1/cip1 pathway activation and fibroblast proliferation inhibition. In vivo, the effect of ART on reducing epidural fibrosis was detected by histological macroscopic assessment, hydroxyproline content analysis, histological and immunohistochemical staining. The results revealed that ART had significant suppressive effects on epidural fibrosis following laminectomy in rats. In conclusion, this research demonstrated that ART could inhibit fibroblast proliferation and reduce epidural fibrosis formation after laminectomy, and the potential mechanism might through autophagy cascade-mediated p53/p21 waf1/cip1 pathway. It might provide a novel reagent for reducing epidural fibrosis after spinal laminectomy surgery.
研究领域:
药理学
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神经外科
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细胞生物学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Molecular Biosciences
·
2022
·
IF 6.113
Liu Jing,Li Bin,Li Wenlian,Pan Taowen,Diao Yunpeng,Wang Fangjun
Apoptosis of vascular smooth muscle cells (VSMCs) is closely related to the pathogenesis of cardiovascular diseases, and oxidative stress is an important cause of VSMCs’ death. Inhibiting VSMCs apoptosis is an effective preventive strategy in slowing down the development of cardiovascular disease, especially for atherosclerosis. In this study, we found that oxidation resistance protein 1 (OXR1), a crucial participator for responding to oxidative stress, could modulate the expression of p53, the key regulator of cell apoptosis. Our results revealed that oxidative stress promoted VSMCs apoptosis by overexpression of the OXR1-p53 axis, and 6-shogaol (6S), a major biologically active compound in ginger, could effectively attenuate cell death by preventing the upregulated expression of the OXR1-p53 axis. Quantitative proteomics analysis revealed that the degradation of p53 mediated by OXR1 might be related to the enhanced assembly of SCF ubiquitin ligase complexes, which is reported to closely relate to the modification of ubiquitination or neddylation and subsequent degradation of p53.
研究领域:
药理学
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心脏病学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Pharmacological Reports
·
2020
·Vol. 72
·期 2
·400-417
·
IF 2.754
Li Yingxue,Jiang Bo,Wang Ruiyin,Wang Jingyun,Li Yachen,Bao Yongming
Background Tanshinone IIA (Tan IIA) and andrographolide (Andro) are natural compounds that are reported to exhibit anticancer activities against various types of cancers. The aim of this study is to evaluate the synergistic anticancer effects of the combination of Tan IIA and Andro, and to investigate the mechanisms of pharmacological effect and their potential applications as an anticancer therapy in clinics.
Methods The anticancer effects of the combination of Tan IIA and Andro on MCF7, SMMC7721, and BGC823 cells were explored. The apoptosis of the cancer cells was determined by MTT and AV-PI dual stain assays. The intracellular GSH level was measured by DTNB assay, and the intracellular levels of reactive oxygen species (ROS) were examined by flow cytometry. The expression of the proteins in the apoptosis pathway was determined by immunobloting. Results The combination of Tan IIA and Andro exhibited significant synergistic anticancer effects against cancer cells, especially at low concentrations. Andro reacted with the thiol group of intracellular GSH, thus disrupting the GSH redox cycle and eventually increasing the level of intracellular ROS. Tan IIA triggered p53 responses and apoptosis by binding to the DNA of cancer cells. The crosstalk between ROS and p53 exhibited a synergistic effect on the apoptosis of cancer cells. Conclusion The combination of Tan IIA and Andro showed significant synergistic effects on cancer cell apoptosis by promoting crosstalk between ROS and p53, providing a novel and effective combination that has the potential to be applied in clinical anticancer therapy. Graphic abstract
研究领域:
肿瘤学
·
药理学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
MICROCHIMICA ACTA
·
2020
·Vol. 187
·期 8
·1-9
·
IF 6.232
Wei Yu-ping,Zhang Yi-wen,Chen Jing-Shuai,Mao Chang-jie,Jin Bao-Kang
An ultrasensitive electrochemiluminescence biosensor was established based on the Zn-MOF/GO nanocomposite. Ag(I)-embedded DNA complexes were used as a signal amplification reagent. In this work, 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin (TCPP) and Zn 2+ were integrated into a porphyrin paddlewheel framework (Zn-MOF) by a hydrothermal method. The synthesized Zn-MOF material has electrochemiluminescence property, and the luminescence intensity is improved after being composited with graphene oxide (GO). Based on the composite material, we constructed an ultrasensitive ECL biosensor for the p53 antibody detection. The composite material acted as an admirable substrate and then loaded plenty of p53 antigens to recognize the target (p53 antibody) accurately. Because of the bridging effect of streptavidin and biotin-conjugated goat anti-rabbit IgG (bio-ab2), the rich-C DNA with positive correlation with the target was modified on the electrode and then captured the co-reactant accelerator Ag + to amplify the signal. Therefore, the ECL biosensor response increases with increasing p53 antibody concentration. In the range 0.1 fg/mL–0.01 ng/mL, the response signal of the biosensor has a good linear relationship with the p53 antibody concentration. The detection limit is 0.03 fg/mL (S/ N = 3). Impressively, the biosensor not only featured high sensitivity, good stability, and excellent specificity for the detection of p53 antibody, but also provides a new way for early detection of cancer.
Schematic representation of the electrochemiluminescence sensor based on a Zn-MOF/GO nanocomposite, which can be applied to the determination of p53 antibody.
研究领域:
分析化学
·
生物化学
·
纳米技术
·
癌症研究
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Ke Gong,Jiangtao Lin,Xiaoyan Chen,Yi Duan,Jiali Zhang,Jian Yu,Jing Wang,Ruifang Sun,Jie Li,Yourong Duan
In esophageal cancer (EC), clinical specimen testing has uncovered a significant increase in BTB and CNC homolog 1 (BACH1) expression and a shift towards an immunosuppressive environment, alongside a notable decrease in p53 protein expression. Therefore, therapeutic strategies focusing on BACH1 inhibition and p53 upregulation appear promising. Traditional oral treatments for EC lack precision and efficacy. Here, we propose a novel approach employing tumor-targeted nanoparticles (NPs) for drug delivery. However, the formation of a drug reservoir at the esophageal site, crucial for the sustained release of therapeutics, presents significant challenges in nano-delivery systems for EC treatment. To address this, we developed a thermosensitive hydrogel composed of F127 and tannic acid, serving as a vehicle for NP loading. These NPs, synthesized through the emulsion/volatization methods of mPEG-PLGA-PLL-cRGD, facilitate in situ drug delivery. Upon contacting esophageal tissue, the hydrogel transitions to a gel, adhering to the lining and enabling sustained release of encapsulated therapeutics. The formulation encompasses NPs laden with small interfering RNA targeting BACH1 (siBACH1) and the p53 activator PRIMA-1, creating a cohesive gel-nano system. Preliminary biological assessments demonstrate that this injectable, thermosensitive gel-nano system adheres effectively to esophageal tissue and targets EC cells. For better modeling clinical outcomes, a patient-derived organoid xenograft (PDOX) model was innovated, involving transplantation of EC-derived organoids into humanized mice, reconstructed with peripheral blood mononuclear cells (PBMCs). Post-treatment analysis showed substantial EC growth inhibition (89.51% tumor inhibition rate), significant BACH1 level reduction, restored anti-tumor immune responses, and pronounced tumor apoptosis. In summary, our study introduces a thermosensitive gel-nano system for EC treatment via restoring p53 activity and boosting T-cell immunity, with potential for clinical application.
研究领域:
肿瘤学
·
药学
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生物技术
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2022
·
IF 5.572
Zheng Cao,Jinsong Gao,Wanyue Huang,Juli Yan,Anshan Shan,Xiang Gao
Deoxynivalenol (DON) induces intestinal epithelial barrier disruption, posing a threat to the body. Curcumin (Cur) possesses pharmacological bioactivities such as antioxidant and anti-inflammatory effects that help maintain intestinal health. Here, the protective effects of Cur against DON-induced intestinal epithelial barrier disruption were explored. Cur (75 or 150 mg/kg body weight [B.W.]) alleviated DON-induced (2.4 mg/kg B.W.) inhibition of growth performance and morphological damage to intestinal epithelium in mice. Cur also significantly attenuated DON-induced intestinal epithelial barrier disruption and structural damage to the tight junctions (TJs), as assessed by ultrastructure observation, serum FITC-dextran concentrations and diamine oxidase activity. Cur mitigated the DON-induced increase in reactive oxygen species , malondialdehyde and 8-hydroxy-2′-deoxyguanosine levels; p53, cytoplasmic cytochrome c , Bax , and Bcl-2 expression; and TUNEL-positive cell rate and caspase-3 activity. It decreased the total antioxidant capacity and expression of nuclear Nrf2 and its downstream target genes. Lastly, Cur attenuated the DON-induced increase in MLCK , p-MLC, nuclear NF-κB p65 expression, and the NF-κB downstream target genes; decrease in the expression of TJs proteins (claudin-1, occludin , and zonula occludens-1 [ZO-1]); and abnormal ZO-1 distribution. Overall, Cur mitigated the DON-induced disruption of the intestinal epithelial barrier by regulating the Nrf2/p53-mediated apoptotic pathway and NF-κB/MLCK-mediated TJs pathway in mice.
研究领域:
药理学
·
毒理学
·
胃肠病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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