BRAZILIAN JOURNAL OF MEDICAL AND BIOLOGICAL RESEARCH
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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
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分子生物学
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PubMed
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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PubMed
高影响因子
Materials Science & Engineering C-Materials for Biological Applications
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2016
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IF 3.42
Fangrong Zhang,Min Li,Yujie Su,Jianping Zhou,Wei Wang
Regulation of gene expression using p53 is a promising strategy for treatment of numerous cancers, and chemotherapeutic drug dichloroacetate (DCA) induces apoptosis and growth inhibition in tumor, without apparent toxicity in normal tissues. Combining DCA and p53 gene could be an effective way to treat tumors. The progress towards broad applications of DCA/p53 combination requires the development of safe and efficient vectors that target to specific cells. In this study, we developed a DSPE-PEG-AA (1,2-distearoryl- sn -glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol-2000)] ammonium salt-anisamide) modified reconstituted high-density lipoprotein-based DCA/p53-loaded nanoparticles (DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes), which was fabricated as a drug/gene dual-targeting co-delivery system for potential cancer therapy. Here, DCA-PEI was utilized to effectively condense the p53 plasmid, to incorporate the plasmid into rHDL and to act as an antitumor drug to inhibit tumor cell growth. The DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes exhibited desirable and homogenous particle size, neutral surface charge and low cytotoxicity for normal cells in vitro . The results of confocal laser scanning microscopy (CLSM) and flow cytometry confirmed that the scavenger receptor class B type I (SR-BI) and sigma receptor mediated dual-targeting function of the complexes inducing efficient cytoplasmic drug delivery and gene transfection in human lung adenocarcinoma cell line A549. And in vivo investigation on nude mice bearing A549 tumor xenografts revealed that DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes possessed specific tumor targeting and strong antitumor activity. The work described here demonstrated that the DSPE-PEG-AA/rHDL/DCA-PEI/p53 complexes might offer a promising tool for effective cancer therapy.
研究领域:
肿瘤学
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药剂学
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分子生物学
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DOI
PubMed
高影响因子
3 Biotech
·
2025
·Vol. 15
·期 12
·412
·
IF 2.9
Fang Zhiruo,Zhu Haojun,Gao Jiancao,Cao Liping,Yao Yu,Li Quanjie,Dai Fei,Yang Xiwei,Du Jinliang,Xu Gangchun
Silymarin has proven antioxidant activity and hepatoprotective effects, but no study to date has investigated the potential protective effect on deltamethrin-induced hepatopancreas injury in Chinese mitten crabs Eriocheir sinensis . This study investigated the protective effect of silymarin pretreatment on deltamethrin-induced hepatopancreas injury in E.sinensis . Healthy crabs (n = 150) were randomly divided into five experimental groups: the control, a deltamethrin exposure group (Basal feed without silymarin), and three silymarin groups (addition of 0.1, 0.5, or 1.0 g/kg diet to the basal feed). After 6 weeks of feeding (no deltamethrin exposure), the crabs were exposed to a deltamethrin concentration of 4.317 μg/L for 48 h. Histopathological results showed that the hepatopancreas remained relatively intact in the silymarin pretreatment groups. Furthermore, metabolites annotated by LC–MS were mainly enriched in signaling pathways related to cytochrome P450, terpenoid alkaloid biosynthesis and phospholipid metabolism. Silymarin at 0.1, 1.0 and/or 0.5 g/kg were significantly increased AKP, ACP, GSH activities and T-AOC levels, and significantly decreased AST, ALT, TNF-α, IL-6, NO, TC, MDA, CYP3A and CYP2E1 levels ( P < 0.05). Silymarin at the concentation of 0.1, 0.5 and 1.0 g/kg could significantly up-regulated the expressions of immune-related genes ( propo , alf3 , crustin1 , hsp70 , hsp90 , relish ), anti-apoptotic gene ( bcl-2 ), and significantly down-regulated the lipid metabolism-related genes ( cpt1 , srebp , acc ) and apoptosis-related genes ( caspase3 , caspase8 , p53 , cyt-c ) ( P < 0.05). Silymarin at 0.5 and/or 1.0 g/kg significantly down-regulated the mRNA expression of inflammation-related genes ( tnf-α , il-16 ) and drug metabolism-related genes ( cyp2a , cyp2e1 , cyp3a ) ( P < 0.05). The results demonstrate a good protective effect of 1.0 g/kg silymarin on deltamethrin-induced hepatopancreas injury induced by deltamethrin in a crustacean species.
研究领域:
水产毒理学
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环境科学
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分子生物学
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渔业科学
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药理学
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DOI
PubMed
高影响因子
CELLULAR SIGNALLING
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2023
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IF 4.8
Yingying Chen,Zhong He,Bo Zhao,Rui Zheng
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease and a severe form of pulmonary fibrosis. Epithelial-mesenchymal transition (EMT) of alveolar epithelial cells is induced in response to epithelial injury, which leads to the accumulation of extracellular matrix in the lung parenchyma and contributes to pulmonary fibrosis. NPAS2 (neuronal PAS domain protein 2) is significantly increased in the lung tissues of IPF patients according to microarray dataset GSE10667 and NPAS2 is downregulated in differentiated human pulmonary type 2 epithelial cells in vitro based on microarray dataset GSE3306 from Gene Expression Omnibus (GEO). In this study, we demonstrated that NPAS2 was increased in bleomycin (BLM)- induced fibrotic lungs in mice. Knockdown of NPAS2 inhibited EMT in primary mouse lung alveolar type 2 epithelial (pmATII) cells and human lung alveolar type 2 epithelial cell line A549 cells under BLM challenge in vitro. Moreover, the silence of NPAS2 alleviated the BLM-induced pulmonary fibrosis in a murine model. Mechanistically, NPAS2 promotes EMT through positively regulating hairy and enhancer of split 1 (HES1) expression. In this study, we present novel findings that have not been previously reported, emphasizing that p53 transcriptionally activates NPAS2 in ATII cells and overexpression of NPAS2 weakens the effects of TP53 knockdown on EMT of pmATII and A549 cells. Our results suggest NPAS2 is a novel target gene of p53 in regulating BLM-mediated EMT in ATII cells and pulmonary fibrosis.
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高影响因子
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY
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2022
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IF 3.915
Qingfa Guo,Fanyuan Kong,Xiaoru Pan,Shuhua Cao
Recent findings revealed that low-concentration paclitaxel(DTX) could enhance cytotoxicity by upregulating p53 expression in lung cancer cell lines. So, co-delivery of DTX and RFP-p53 gene with PEA nanoparticles (NPs) was studied. The prepared DTX loaded PEA NPs (PEA/DTX) were characterized by particle size distribution, morphology, zeta potential, and crystallography and cytotoxicity. Results showed that the PEA/DTX NPs had a mall particle size (≤100 nm), moderate zeta potential (≥40 mV) and drug loading of 9.0%, DTX was released from PEA/DTX NPs in an extended period in vitro. More important, agarose gel electrophoresis showed that PEA/DTX cationic NPs were able to completely bind RFP-p53 gene with mean particles size and zeta potential. Studies on cellular uptake of (PEA/DTX)/RFP-p53 NPs demonstrated that both drug and gene were effectively taken up by A549 tumor cells. It was found that intravenous injection of (PEA/DTX)/RFP-p53 NPs efficiently inhibited growth of subcutaneous A549 carcinoma in vivo (p < 0.05) and was significantly less side effect than that of mice treated with the other groups. Therefore, the (PEA/DTX)/RFP-p53 NPs might be a promising candidate for A549 cancer therapy.
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高影响因子
ENVIRONMENTAL RESEARCH
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2017
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IF 3.835
Ping Xiang,Rong-Yan Liu,Hong-Jie Sun,Yun-Wen Yang,Xin-Yi Cui,Lena Q. Ma
As a replacement for polybrominated diphenyl ethers , bis-(2-ethylhexyl) tetrabromophthalate (TBPH) is widely used as a novel flame retardant and has been detected in many environmental matrix including human blood. TBPH can be metabolized into mono-(2-ethyhexyl) tetrabromophthalate (TBMEHP) by carboxylesterase. However, their adverse effects on human vascular endothelium and their potential impacts on human cardiovascular disease are unknown. In this study, their adverse effects and associated molecular mechanisms on human vascular endothelial cells (HUVECs) were investigated. A concentration-dependent inhibition on HUVECs' viability and growth was observed for TBMEHP but not for TBPH. TBMEHP induced a marked G 0 /G 1 cell cycle arrest and robust cell apoptosis at 1 μg/mL by inducing expression of p53, GADD45α and cyclin dependent kinase (CDK) inhibitors ( p21 and p27 ) while suppressing the expression of cyclin D1, CDK2, CDK6, and Bcl-2. Unlike TBMEHP, TBPH caused early apoptosis after G 2 /M phase arrest only at 10 μg/mL via up-regulation of p21 and down-regulation of CDK2 and CDK4. TBMEHP decreased mitochondrial membrane potential and increased caspase-3 activity at 1 μg/mL, suggesting that activation of p53 and mitochondrial pathway were involved in the cell apoptosis. The data showed that TBPH and TBMEHP induced different cell cycle arrest and apoptosis through different molecular mechanisms with much higher toxicity for TBMEHP. Our study implies that the metabolites of TBPH, possibly other novel brominated flame retardants, may be of potential concern for human cardiovascular disease.
研究领域:
毒理学
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环境健康
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细胞生物学
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分子生物学
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PubMed
高影响因子
Journal of Materials Chemistry B
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2024
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IF 6.1
Yuhan Zheng,Qingyun Wei,Xuan Han,Xiangmin Tao,Tao Cao,Tianbao Chen,Peng Cao,Qichen Zhan
Despite exhibiting potent anticancer activity, the strong hemolytic properties of melittin (MEL) significantly restrict its delivery efficiency and clinical applications. To address this issue, we have devised a strategy wherein homologous dopamine (DA), an essential component of bee venom, is harnessed as a vehicle for the synthesis of MEL–polydopamine (PDA) nanoparticles (MP NPs). The ingenious approach lies in the fact that MEL is a basic polypeptide, and the polymerization of DA is also conducted under alkaline conditions, indicating the distinctive advantages of PDA in MEL encapsulation. Furthermore, MP NPs are modified with folic acid to fabricate tumor-targeted nanomedicine (MPF NPs). MPF NPs can ameliorate the hemolysis of MEL in drug delivery and undergo degradation triggered by high levels of reactive oxygen species (ROS) within solid tumors, thereby facilitating MEL release and subsequent restoration of anticancer activity. After cellular uptake, MPF NPs induce cell apoptosis through the PI3K/Akt-mediated p53 signaling pathway. The tumor growth inhibitory rate of MPF NPs in FA receptor-positive 4T1 and CT26 xenograft mice reached 78.04% and 81.66%, which was significantly higher compared to that in FA receptor-negative HepG2 xenograft mice (45.79%). Homologous vehicles provide a new perspective for nanomedicine design.
研究领域:
纳米医学
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癌症治疗
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药学
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生物材料
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产品关联
DOI
PubMed
高影响因子
Cell Death Discovery
·
2025
·Vol. 11
·期 1
·1-20
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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
Antioxidants
·
2026
·Vol. 15
·期 3
·
IF 8.2
Jianhong Wang,Ting Jiang,Siqi Chen,Yajing Li,Qing Li,Lan Xiang,Jianhua Qi
Traditional Chinese medicine plays an important role in human health, but due to the complexity of its active fraction, its therapeutic mechanism still needs further clarification.Polygalae Radixis one of the traditional Chinese medicines, which was recorded inShennong Classic of Materia Medicawith the effect of prolonging life. In the present study, we isolated a small molecule compound with anti-aging effects, 3,6′-disinapoyl sucrose (DISS), fromPolygalae Radixunder the guidance of the replicative lifespan assay of K6001 yeast strain. It extended the lifespan of yeast and alleviated etoposide-induced aging in 3T3 cells. Furthermore, this compound increased the telomerase activity and the length of telomeres, and targeted the SIRT1 signaling pathway, respectively. In addition, it improved the survival ability of yeast under oxidative stress conditions, decreased ROS and MDA levels, and increased the activity of SOD, CAT and GPx enzymes. Moreover, DISS enhanced autophagic flux, as demonstrated by assay of the YOM38-GFP-ATG8 yeast strain. In conclusion, DISS fromPolygalae Radixexerts anti-aging effects by protecting telomeres, regulating the SIRT1/p53/p21 signaling pathway, mitigating oxidative stress and modulating autophagy. Thus, this study provides scientific evidence for the use ofPolygalae Radixas an anti-aging herb.
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PubMed
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
International Journal of Nanomedicine
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2011
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IF 4.976
Wei Zhou,Yingyi Ma,Huan Yang,Yi Ding,Xiangang Luo
By using triangular silver (Ag) nanoparticle array, a localized surface plasmon resonance (LSPR) nanosensor was fabricated and shown to sense serum p53 protein in vitro, which is involved in head and neck squamous cell carcinoma (HNSCC). The nanosensor consists of a triangular Ag nanoparticles array with single particle dimension of 120 nm in-plane width and 45 nm out-of-plane height. When examined using LSPR nanobiosensor, the results indicated significant difference in LSPR shifts (Δλ max ) between HNSCC patient and control. Although there is need for precise quantification and large-scale prospective, this report shows that the LSPR nanobiosensor provides a promising platform with attractive advantages for serological diagnosis or molecular diagnosis in tumor, such as HNSCC. This is the first clinical application of the LSPR nanosensor in HNSCC.
研究领域:
纳米技术
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生物传感
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癌症诊断
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临床化学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）