Cell Death Discovery
·
2025
·Vol. 11
·期 1
·1-20
·
IF 7
Li Hao,Ju Shuguang,Wang Jiacheng,Kuang Donglin,Chen Pengfei,Zhang Mengfan,Qian Ruijie,Liang Chao,Han Daqian,Duan Xuhua
Thermal ablation offers minimally invasive treatment options for hepatocellular carcinoma (HCC) therapy. However, local recurrence due to sublethal temperatures enhances tumor cell survival. This study aims to investigate the tumor-promoting effects of hyperthermia on HCC cells, the role of tanshinone IIA (Tan IIA) in mitigating these effects, and the underlying mechanisms involved. We observed that temperature at 44 °C increased the aggressiveness of HCC cells, and Tan IIA inhibited cell viability and cell invasion, and induced cell cycle arrest and apoptosis of heat-pretreated HCC cells. ALDH7A1 was identified as a target of Tan IIA, and its altered expression resulted in dysregulation of cell viability, invasion, apoptosis, ATP production, glycolysis, osmolyte levels, and reactive oxygen species (ROS). Under hyperosmotic conditions, ALDH7A1 knockdown sensitized heated Huh-7 cells, while its overexpression promoted cell survival and invasion, with corresponding changes in energy metabolism and enzymatic products. Tan IIA and the specific ALDH7A1 inhibitor, 4-diethylaminobenzaldehyde, demonstrated similar effects on gene expression patterns, glycolysis, osmotic regulation, and ROS levels in heated Huh-7 cells. Moreover, Tan IIA is able to direct interact with ALDH7A1 protein. In vitro, Tan IIA combined with hyperosmotic stress significantly inhibited cell invasion and induced apoptosis in heat-induced Huh-7 cells and ALDH7A1 overexpression partially reversed the effects of Tan IIA. In vivo, Tan IIA combined with hyperosmotic stress or glycolysis inhibitor yielded better therapeutic efficacy for HCC. In conclusion, Tan IIA sensitizes HCC cells to sublethal heat by targeting ALDH7A1, leading to disrupted glycolytic and osmolytic balance, subsequently hindering tumor cell survival and increasing apoptosis. These findings highlight a potentially novel strategy for preventing or treating recurrent HCC post-thermal ablation using Tan IIA with hyperosmotic reagents.
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高影响因子
Frontiers in Immunology
·
2025
·
IF 5.9
Maolin Chu,Suna Jiang,Jiawei Xue,Wenjing Li,Guanhua Jing,Hongying Li,Juan Zhang,Wanhai Xu
Introduction: Premature senescence of renal tubular epithelial cells (RTECs) can be caused by oxidative stress related to calcium oxalate (CaOx) kidney stones (KSs), but the role and mechanisms of cellular senescence of RTECs in the pathogenesis of kidney stones have not been fully determined. Macrophages, the most prevalent leucocyte found in nephrolithiasis, have been implicated in the pathogenesis of kidney stones.Methods: Using oxalate (Ox) induction to simulate the hyperoxaluria microenvironment in vivo, fisetin was administered to human renal proximal tubular epithelial cells (HK-2 cells). The senescence of HK-2 cells was evaluated by detecting SA-β-gal staining, expression of senescence markers p16 and p53, and levels of senescence-associated secretory phenotype (SASP) molecules. THP-1 cells were differentiated into macrophages (M0-MΦs) using PMA induction, and macrophages in different polarization states (M1-like phenotype, M2-like phenotype) were treated with the supernatant from HK-2 cell culture. siRNA gene knockdown technology was applied to evaluate the activity of the LXN/Rps3/p53 pathway during oxalate-induced senescence in HK-2 cells. A rat model of calcium oxalate crystal-induced kidney injury was established, and the rats were divided into following groups: PBS, oxalate, oxalate + fisetin, oxalate + transfection with LXN-knockdown adeno-associated virus (AAV-shLXN), and oxalate + fisetin + AAV-shLXN, Histological assessment was performed using HE staining and Von Kossa staining of kidney tissues. The expression levels of LXN, Rps3, p53, iNOS, and CD163 in renal tissues were evaluated by immunohistochemical staining.Results: The onset of RTEC senescence was increased after treatment with oxalate, and the increase in RTEC senescence was reduced by fisetin treatment. Interestingly, the changes in proinflammatory M1-like phenotype polarization induced by culture medium from HK-2 cells treated with Ox+/-fisetin were consistent with the proportion of senescent HK-2 cells cultured. Furthermore, reducing cellular LXN/Rps3/p53 signaling significantly decreased SASP factors in the culture medium and simultaneously abolished M1-like phenotype macrophage polarization. More importantly, silencing renal LXN reduced RTEC senescence and M1-like phenotype macrophage polarization and consequently decreased intrarenal CaOx crystal deposition in a rat kidney stone model.Discussion: Our results demonstrate that kidney macrophage phenotype changes are related, at least in part, to RTEC senescence, and a strategy to modulate the cellular senescence of RTECs is promising as a new target for immunotherapy to treat nephrolithiasis and other age-related diseases.
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高影响因子
ANALYST
·
2023
·Vol. 148
·期 5
·1005-1015
·
IF 4.2
Yali Wang,Shuai Liu,Dongyou Zhang,Qi Xiao,Shan Huang
As an important tumor suppressor gene, the p53 gene is considered to be a typical biomarker for the early diagnosis and prognosis evaluation of severe cancer. Herein, an electrochemical biosensor was proposed for the ultrasensitive detection of the p53 gene based on molecular beacon-mediated circular strand displacement polymerization combined with terminal deoxynucleotide transferase-mediated template-free DNA extension. Firstly, the p53 gene opened the hairpin structure of the molecular beacon, thereby exposing the binding sequence region of the primer DNA. The circular strand displacement polymerization occurred in the presence of the primer DNA and phi29 DNA polymerase, subsequently resulting in the circulation of the p53 gene. With the catalysis of the terminal deoxynucleotide transferase, the 3′-OH terminal sequence of the molecular beacon elongated to produce long single-stranded DNA under the template-free DNA extension. Methylene blue bound with such DNA strands generated a strong differential pulse voltammetry (DPV) signal with a peak potential of −0.28 V. Under the optimal detection conditions, the DPV signal of methylene blue showed good linear relationships with the logarithm value of the p53 gene in two concentration ranges of 0.05 fM to 3 pM and 5 fM to 100 fM, and the detection limit of the p53 gene was as low as 0.018 fM. This electrochemical biosensor possessed high recognition ability for the p53 gene in its analogues and was successfully applied for p53 gene analysis in human serum samples.
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高影响因子
RSC Advances
·
2015
·Vol. 5
·期 115
·94719-94731
·
IF 3.84
Lili Chen,Xiaohong Wang,Fangling Ji,Yongming Bao,Jingyun Wang,Xianwu Wang,Lianying Guo,Yachen Li
Combined treatment of drugs and therapeutic genes has emerged as a new modality of anticancer therapy. In this study, a new amphiphilic bifunctional pullulan derivative (named as PSP) containing stearic acid and low-molecular weight (1 kDa) branched polyethylenimine was prepared and evaluated as a nano-carrier for the co-delivery of a drug and gene for potential cancer therapy. The amphiphilic PSP could self-assemble into cationic core–shell nano-micelles in water, with a critical micelle concentration of around 58.9 mg L−1. PSP nanomicelles had an average size of 188.75 ± 3.18 nm, and a positive zeta potential of 17.83 ± 0.75 mV. The drug loading content and encapsulation efficiency of the PSP nanomicelles for doxorubicin (DOX), an anti-tumor drug, were about 5.10% and 56.07%, respectively, and DOX in PSP nanomicelles showed sustained release. The flow cytometry and confocal laser scanning microscopy showed that PSP/DOX nanomicelles could be successfully internalized by MCF-7 cells. The in vitro IC50 of PSP/DOX nanomicelles was slightly lower than that of free DOX against MCF-7 cells. Additionally, PSP nanomicelles condensed DNA efficiently to form compact structures, and induced comparable GFP gene expression level to Lipo2000 at N/P = 10 in gene transfection studies. In comparison with single DOX or p53 delivery, the co-delivery of DOX and therapy gene p53 using PSP micelles displayed higher cytotoxicity and induced a higher apoptosis rate of tumor cells in vitro. Moreover, PSP exhibited good blood compatibility and low cytotoxicity in the hemolysis and MTT assays, respectively. Altogether, PSP nanomicelles have a great potential in delivering hydrophobic anticancer drugs and therapeutic genes simultaneously for improved cancer therapy.
研究领域:
药学
·
生物材料科学
·
肿瘤学
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高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 19
·14503
·
IF 5.6
Zhiye Zhao,Ye Li,Shancheng Guo,Yuxu Chen,Haiaolong Yin,Yaxian Li,Guiguang Cheng,Lei Tian
Acute hepatitis (AH) is a common liver disease with an increasing number of patients each year, requiring the development of new treatments. Hence, our work aimed to evaluate the therapeutic effect ofOryza sativaL. indica (purple rice) seed coat on concanavalin A (ConA)-induced AH and further reveal its potential mechanisms. Purple rice seed coat extract (PRE) was extracted with hydrochloric acid ethanol and analyzed through a widely targeted components method. We evaluated the effects of PRE on AH through histopathological examination, liver function, gut microbiota composition, and the intestinal barrier. The potential targets of PRE on AH were predicted by bioinformatics. Western blotting, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining, and corresponding kits were used to investigate PRE effects on predicting targets and associated signaling pathways in AH mice. In AH model mice, PRE treatment increased transformed mouse 3T3 cell double minute 2 (MDM2) expression to inhibit apoptosis; it also markedly downregulated protein kinase C alpha (PKCα), prostaglandin-endoperoxide synthase 1 (PTGS1), and mitogen-activated protein kinase 1 (MAPK1) activity to alleviate inflammation. Thus, PRE treatment also recovered the intestinal barrier, decreased the lipopolysaccharide (LPS) levels of plasma and the liver, enhanced liver function, and improved the composition of intestinal microbiota. In general, PRE targeting MDM2, PKCα, MAPK1, and PTGS1 ameliorated ConA-induced AH by attenuating inflammation and apoptosis, restoring the intestinal barrier, enhancing the liver function, and improving the gut microbiota, which revealed that the purple rice seed coat might hold possibilities as a therapeutic option for AH.Keywords:Oryza sativaL. indica;acute hepatitis;MDM2;PKCα;PTGS1;gut microbiota
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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
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高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6
Yuxin Feng,Xuan Xuan,Yuemiao Hu,Jiaguo Lu,Zhiwen Dong,Ziqiang Sun,Hongying Yao,Lei Hu,Qikun Yin,Yi Liu,Hongbo Wang
Murine double minute 2 (MDM2) and homologous protein murine double minute X (MDMX) are p53 negative regulators that perform significant driving effects in tumorigenesis, and targeting these oncoproteins has became an efficient strategy in treating cancers. However, the definite antitumor activity and significance ordering of each protein in MDM family is still unclear due to the similar structure and complicated regulation. Herein, we identified two G-rich sequences ( G 1 and G 5 ) located in the promoter that could assemble the G-quadruplex to respectively inhibit and promote the transcription of the MDM2 and MDMX. Based on this target, we designed and synthesized a novel G-quadruplex ligand A3f and achieved the differentiated regulation of MDM protein. In triple-negative breast cancer (TNBC) cells, A3f could induce MDM2-dependent proliferation arrest and exhibit additive therapeutic effect with MDMX inhibitors. Overall, this study provided a novel strategy to regulate the transcription of MDM genes by targeting certain G-rich sequences, and discovered an active antitumor molecule for use in TNBC treatment.
研究领域:
肿瘤学
·
分子生物学
·
癌症治疗
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高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Run Chen,Pengchao Sun,Xiao Chu,Xiaorong Pu,Yang Yang,Nan Zhang,Yongxing Zhao
Background Aptamers have been widely used as targeted therapeutic agents due to its relatively small physical size, flexible structure, high specificity, and selectivity. Aptamers functionalized nanomaterials, not only enhance the targeting of nanomaterials, but can also improve the stability of the aptamers. We developed aptamer C2NP (Apt) conjugated straight DNA nanotubes (S-DNT-Apt) and twisted DNA nanotubes (T-DNT-Apt) as nanocarriers for doxorubicin (DOX).Methods The twisted DNA nanotubes (T-DNT) and straight DNA nanotubes (S-DNT) were assembled with a scaffold and hundreds of staples. Apt was site-specifically anchored on DNA nanotubes with either different spatial distribution (3 or 6 nm) or varied stoichiometry (15Apt or 30Apt). The developed nanocarriers were characterized with agarose gel electrophoresis and transmission electron microscopy. The drug loading and release in vitro were evaluated by measuring the fluorescence intensity of DOX using a microplate reader. The stability of DNT in cell culture medium plus 10% of FBS was evaluated by agarose gel electrophoresis. The cytotoxicity of DNA nanostructures against K299 cells was tested with a standard CCK8 method. Cellular uptake, cell apoptosis, cell cycle and reactive oxygen species level were investigated by flow cytometry. The expression of p53 was examined by Western Blot.Results T-DNT-30Apt-6 exhibited the highest cytotoxicity when the concentration of Apt was 120 nM. After intercalation of DOX, the cytotoxicity of DOX@T-DNT-30Apt-6 was further enhanced due to the combination of chemotherapy of DOX and biotherapy of Apt. The enhanced cytotoxicity of DOX@T-DNT-30Apt-6 can be explained by the increase in the cellular uptake, cell apoptosis and intracellular ROS levels. Additionally, the interaction between Apt and its receptor CD30 could upregulate the expression of p53.Conclusion These results demonstrate that both stoichiometry and spatial arrangement of Apt on T-DNT-Apt influence the anticancer activity. The developed twisted DNA nanotubes may be a solution for the synergistic treatment of cancer.
研究领域:
纳米技术
·
生物医学工程
·
药学
·
癌症研究
·
分子生物学
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高影响因子
Molecular Genetics & Genomic Medicine
·
2023
·Vol. 11
·期 5
·e2150
·
IF 2
Fang Wang,Haiqin Cheng,Qin Zhang,Jin Guo
Background Rare mutations in multiple genes have been associated with human neural tube defects (NTDs), but their causative roles in NTDs disease are poorly understood. Insufficiency of the ribosomal biogenesis gene treacle ribosome biogenesis factor 1( Tcof1 ) results in cranial NTDs and craniofacial malformations in mice. Here, we aimed to identify genetic association of TCOF1 with human NTDs. Methods High-throughput sequencing targeted on TCOF1 was performed on samples from 355 human cases affected by NTDs and 225 controls from a Han Chinese population. Results Four novel missense variants were found in the NTD cohort. Cell-based assays indicated that the p.(A491G) variant carried by an individual, who shows anencephaly and single-nostril abnormality, attenuates production of total proteins, suggesting a loss-of-function mutation in ribosomal biogenesis. Importantly, this variant promotes nucleolar disruption and stabilizes p53 protein, highlighting an unbalancing effect on cell apoptosis. Conclusions This study explored the functional impact of a missense variant in TCOF1 , implicating a set of novel causative biological factors involved in the pathogenicity of human NTDs, particularly whom combined with craniofacial abnormality.
研究领域:
遗传学
·
分子生物学
·
神经发育障碍
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高影响因子
ANTIVIRAL RESEARCH
·
2024
·
IF 4.5
Liang Zhao,Wei-Ze Wang,Tian-Tian Jiang,Tian-Zi Sun,Bo Liu,Bin Zhu
Spring viremia of carp virus (SVCV), as a high pathogenicity pathogen, has seriously restricts the healthy and sustainable development of cyprinid farming industry. In this study, we selected 5-Fluorouracil (5-Fu) as the drug model based on zeolitic imidazolate framework-8 (ZIF-8) to construct a drug delivery system (5-Fu@ZIF-8), and the anti-SVCV activity was detected in vitro and in vivo . The results showed 5-Fu@ZIF-8 was uniform cubic particle with truncated angle and smooth surface, and the particle size was 90 nm. The anti-SVCV activity in vitro results showed that the highest inhibition rate of 5-Fu was 77.93% at 40 mg/L and the inhibitory concentration at half-maximal activity (IC 50 ) was 20.86 mg/L. For 5-Fu@ZIF-8, the highest inhibition rate was 91.36% at 16 mg/L, and the IC 50 value was 5.85 mg/L. In addition, the cell viability was increased by 18.1% after 5-Fu treatment. Similarly, after 5-Fu@ZIF-8 treatment, the cell viability increased by 27.3%. Correspondingly, in vivo experimental results showed the viral loads reduced by 18.1% on the days 7 and the survival rate increased to 19.4% at 80 mg/L after 5-Fu treatment. For 5-Fu@ZIF-8, the viral loads reduced by 41.2% and the survival rate increased to 54.8%. Mechanistically, 5-Fu inhibits viral replication by regulating p53 expression and promoting early apoptosis in infected cells. All results indicated that 5-Fu@ZIF-8 improved the anti-SVCV activity; it may be a potential strategy to construct a drug-loaded system with ZIF-8 as a carrier for the prevention and treatment of aquatic diseases.
研究领域:
水产养殖
·
药学
·
病毒学
·
纳米技术
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高影响因子
Food & Function
·
2015
·Vol. 6
·期 5
·1518-1525
·
IF 2.791
Qiang Zhang,Guangdong Cheng,Hongbin Qiu,Liling Zhu,Zhongjuan Ren,Wei Zhao,Tao Zhang,Lei Liu
Flavonoids have been reported to exhibit prooxidant cytotoxicity against cancer cells, but the underlying mechanism is still poorly understood. Here we investigated the potential mechanism that p53-inducible gene 3 (PIG3), a NADPH:quinone oxidoreductase, mediated the prooxidant cytotoxicity of flavonoids on human hepatoma HepG2 cells. The results showed that flavonoids (apigenin, luteolin, kaempferol, and quercetin) inhibited the growth of HepG2 cells in a dosage- and time-dependent manner, and induced the morphological changes characteristic of apoptosis in HepG2 cells. We also found that expression of PIG3 was increased markedly in HepG2 cells treated with flavonoids at both mRNA and protein levels, which was accompanied by increased intracellular ROS production and a decreased mitochondrial membrane potential (ΔΨm). All these effects were largely reversed through knockdown of the PIG3 gene in HepG2 cells. Western blotting indicated that flavonoids increased cytochrome c release, upregulated the ratio of Bax/Bcl-2, and activated the caspases-9 and -3. Moreover, knockdown of PIG3 could reverse the changes of these apoptotic-related proteins. These results suggest that PIG3 plays an important role in regulating the prooxidant activity and apoptosis-inducing action of flavonoids on HepG2 cells though the ROS-triggered mitochondrial apoptotic pathway.
研究领域:
肿瘤学
·
分子生物学
·
药理学
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高影响因子
TOXICOLOGY
·
2021
·
IF 4.221
Zixuan Liu,Qiushuang Zhu,Erqun Song,Yang Song
Polybrominated diphenyl ethers (PBDEs) are world-wide used flame retardants before they were listed as Persistent Organic Pollutants (POPs) by the Stockholm Convention. Previously, our studies indicated that a quinone type of PBDE metabolite (PBDEQ) exposure was linked with neurotoxicity via excess free radical formation and oxidative stress. However, it is current unknown the effect of PBDEQ on genetic biomacromolecules DNA and corresponding biological consequences in neurological cells. Here, by employing phosphorylated histone H2AX in Serine 139 (γ-H2AX) and comet assay in microglia BV2 cells, our data suggested PBDEQ could triggered DNA damage. Furthermore, PBDEQ exposure led to the caspase 3-dependent cell apoptosis. Moreover, PBDEQ induced G2/M-phase cell arrest in a p53-dependent manner. Notably, p53 activation coordinated cell cycle progression, alleviated DNA damage and ultimately mitigated apoptosis in BV2 cells. Finally, antioxidant N -acetyl- l -cysteine (NAC) inhibited p53 activation upon PBDEQ exposure, and then ameliorated PBDEQ-induced DNA damage, cell cycle arrest and apoptosis, which illustrated that PBDEQ-induced DNA damage and p53 activation were mediated by reactive oxygen species (ROS). Together, the current findings unveil the fundamental toxicological mechanisms of PBDEQ, which propose a potential therapeutic strategy against the adverse effect caused by PBDE exposure.
研究领域:
毒理学
·
神经科学
·
细胞生物学
·
分子生物学
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高影响因子
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