Theranostics
·
2025
·Vol. 15
·期 10
·4734
·
IF 13.3
Zi-Yue Xi,Chuan-Yong Fan,Ying-Ying Jiang,Xin-Ran Xi,Gan-Yu Nie,Shuang Zhu,Jun-Jie Zhang,Lu Xu
Background: Traditional programmed cell death, including ferroptosis, cuproptosis, and apoptosis, has demonstrated excellent anti-tumor effects and declared their complete mechanisms, however, the zinc ion-mediated tumor inhibiting mechanisms remain insufficiently explored. In this study, a self-generated oxygen nanocatalytic system (ZnO@COF@EM, ZCE) was developed to stimulate cascade amplified effect (CAE) of reactive oxygen species (ROS) generation leading to Znproptosis. The underlying Znproptosis mechanism to disrupt mitochondrial (Mito) metabolism was also investigated. Methods: Specifically, the principle of Znproptosis caused by accumulated zinc and ROS, which served as key factors, was declared through western blot analysis and genetic testing. The mechanism of generated ROS (·OH and 1 O 2 ) under NIR irradiation by ZCE was detected by UV scanning curves, confocal laser scanning microscopy (CLSM) images, and density functional analysis. The injury condition of Fe-S protein of mitochondria metabolism, which triggered Znproptosis with FDX2/LIAS pathway by zinc and ROS, was examined by PCR test and MTT assay. Notably, a Mito-targeting strategy for ZCE was proposed by using molecular docking technology, wherein Zn 2+ was recognized by zinc finger proteins (ZFPs) with the Mito. Results: ZCE, along with CAE, produced abundant ROS (2.42-time more than control group). At the quantum chemical level, the CAE mechanism was associated with a narrower highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) gap and increased electronic energy motion within ZCE, which prolonged the excited triplet state (ETS). At the gene level, Znproptosis was achieved by regulating FDX2 and ZIP7 proteins to damage Fe-S protein. The cell cycle was interrupted by Chk2/Cdc25C/Cdc2 and Chk2/p21/Cyclin B1 pathways, leading to the arrest of G1/S and G2/M phases of the cell cycle and inhibition of the Akt/mTOR signaling pathway. Moreover, Znproptosis induced by overloading zinc ions and ROS resulted in a significant antitumor effect (up to 83.81%). Conclusion: Hence, the research reveals a detailed Znproptosis mechanism in nanocatalytic system. Through regulating FDX2/LIAS pathway, Znproptosis could improve the death rate of mitochondria by decreasing the production of Fe-S protein, contributing to advancements in the field of antitumor therapy.
研究领域:
肿瘤学
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细胞生物学
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生物化学
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DOI
PubMed
高影响因子
Frontiers in Microbiology
·
2025
·
IF 4.5
Wencheng Liu,Yanbin Cheng,Xue Han,Junlin Xia,Qingyu Wei,Bing Chang,Quansheng Li
Introduction: Hepatic sinusoidal obstruction syndrome (HSOS) is a vascular liver disease with a high mortality rate, and treatment methods are limited. Rivaroxaban is an oral anticoagulant. This study aimed to investigate the pharmacological effect and potential mechanism of rivaroxaban on HSOS.Methods: In this study, we induced an HSOS mouse model in male C57BL/6J mice by administering monocrotaline orally. The mice were randomly divided into four groups: the control group, the rivaroxaban (RIV) group, the monocrotaline (MCT) group, and the monocrotaline + rivaroxaban (MCT + RIV) group. Liver function and histopathology were evaluated. 16S rDNA sequencing of the small intestinal contents, transcriptomic sequencing of small intestine tissues, real-time qPCR, Western blot analysis of liver tissues, and correlation analysis were conducted. Antibiotic (ABX) treatment and fecal microbiota transplantation (FMT) experiments were also performed to explore the role of the gut microbiota.Results: Compared with the MCT group, rivaroxaban alleviated serum biochemical liver function analysis and liver histopathology in the MCT + RIV group. Additionally, 16S rDNA sequencing of the small intestinal contents revealed that, compared with the MCT group, the MCT + RIV group presented increased relative abundances of Allobaculum and Pediococcus but decreased relative abundances of Streptococcus, Staphylococcus, and Candidatus Arthromitus. Mechanistically, integrated analyses, including transcriptomic sequencing of small intestin e tissues, real-time qPCR, Western blot analysis of liver tissues, and correlation analysis, demonstrated that rivaroxaban protected against MCT-HSOS by inhibiting the PI3K/Akt signaling pathway. In addition, antimicrobial cocktail (ABX) treatment eliminated the beneficial effects of rivaroxaban on liver function and histopathological injury, whereas fecal microbiota transplantation (FMT) from rivaroxaban-treated donors significantly ameliorated liver dysfunction and histological damage in MCT-HSOS mice.Discussion: These findings suggest that rivaroxaban alleviates hepatic sinusoidal obstruction syndrome in mice by modulating the gut microbiota and inhibiting the PI3K/Akt signaling pathway. Rivaroxaban may be a promising therapeutic option for treating HSOS.
研究领域:
肝脏病学
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药理学
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微生物组学
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分子生物学
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转化医学
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产品关联
DOI
PubMed
高影响因子
PeerJ
·
2025
·
IF 2.4
Jia Song,Jinyu Qiao,Mingxue Chen,Jiahui Li,Jixia Wang,Dayong Yu,Huachuan Zheng,Liying Shi
Chaetoglobosin A (ChA) is an antitumor compound produced by Chaetomium globosum . However, the mechanism of its antitumor effect has been rarely reported. In this study, we evaluated the anti-proliferative effect of ChA on T-24 human bladder cancer cells and explored its mechanism of action. ChA was found to have a good inhibitory effect on T-24 cells by MTT assay with an IC50 value of 48.14 ± 10.25 μΜ. Moreover, it was found to have a migration inhibitory ability and a sustained proliferation inhibitory effect on tumor cells by cell aggregation assay and cell migration assay. The cells morphological changes were determined by Hoechst33342 assay. While Annexin V-FITC/PI double-staining assay also demonstrated that the number of apoptotic cells increased with the increase of drug concentration. Flow cytometry results showed that ChA treatment increased reactive oxygen species (ROS) and decreased mitochondrial membrane potential (MMP) in T-24 cells and inhibited cell mitosis, resulting in an increase in the number of sub-G1 phase cells. Further western blot experiments demonstrated that MAPK and PI3K-AKT-mTOR pathways were activated after drug treatment in addition to endogenous and exogenous apoptotic pathways. The addition of the ROS inhibitor N-acetylcysteine (NAC) upregulated the expression level of Bcl-2 protein, decreased p38 phosphorylation, increased ERK phosphorylation and restored the levels of PI3K and p-mTOR after ChA treatment. These suggest that ChA induces apoptosis by regulating oxidative stress, MAPK, and PI3K-AKT-mTOR signaling pathways in T-24 cells.
研究领域:
肿瘤学
·
细胞生物学
·
药理学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2023
·
IF 4.3
Lu Yanyu,Min Qianqian,Zhao Xiaoyan,Li Li,Zhao Guojun,Dong Jianzeng
Eupatilin is a pharmacologically active flavonoid with a variety of biological activities, such as anticancer, anti-inflammatory, antioxidant, neuroprotective, anti-allergic and cardioprotective effects. However, whether eupatilin has protective effects on doxorubicin-induced cardiotoxicity remains unknown. Thus, this study aimed to investigate the role of eupatilin in doxorubicin-induced cardiotoxicity. Mice were exposed to a single dose of doxorubicin (15 mg/kg) to generate doxorubicin-induced cardiotoxicity or normal saline as a control. To explore the protective effects, mice were intraperitoneally injected with eupatilin daily for 7 days. Then, we examined the changes in cardiac function, inflammation, apoptosis, and oxidative stress to evaluate the effects of eupatilin on doxorubicin-induced cardiotoxicity. Additionally, RNA-seq analysis was introduced to explore the potential molecular mechanisms. Eupatilin ameliorated doxorubicin-induced cardiotoxicity by attenuating inflammation, oxidative stress, and cardiomyocyte apoptosis and ameliorated doxorubicin-induced cardiac dysfunction. Mechanistically, eupatilin activated the PI3K-AKT signaling pathway, as evidenced by RNA-seq analysis and Western blot analysis. This study provides the first evidence that eupatilin ameliorates doxorubicin-induced cardiotoxicity by attenuating inflammation, oxidative stress, and apoptosis. Pharmacotherapy with eupatilin provides a novel therapeutic regimen for doxorubicin-induced cardiotoxicity.
研究领域:
药理学
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心脏病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2023
·
IF 4.8
Wei-guang Yang,Ao Sun,Rong Zhu,Nan Liu,Wei-jie He,Lin-lin Liu
Background Artemisinin (ART) is a safe and effective antimalarial drug. In recent years, antimalarial drugs have demonstrated a good therapeutic efficacy in IgA nephropathy, suggesting that this may become a new treatment option.Purpose We aimed to evaluate the effect and mechanism of artemisinin in IgA nephropathy.Methods In this study, CMap database was used to predict the artemisinin therapeutic effect for IgA nephropathy. A network pharmacology approach was applied to explore the unknown mechanism of artemisinin in IgA nephropathy. We used molecular docking to predict the binding affinity of artemisinin with the targets. A mouse model of IgA nephropathy was established to investigate the therapeutic effect of artemisinin on IgA nephropathy. In vitro, the cell counting Kit-8 assay was used to evaluate the cytotoxicity of artemisinin. Flow cytometry and PCR assays were used to detect the effects of artemisinin on oxidative stress and fibrosis in lipopolysaccharide (LPS)-stimulated mesangial cells. Western blot and immunofluorescence were used to detect the expression of pathway proteins.Results CMap analysis showed artemisinin may reverse the expression levels of differentially expressed genes in IgA nephropathy. Eighty-seven potential targets of artemisinin in the treatment of IgA nephropathy were screened. Among them, 15 hub targets were identified. Enrichment analysis and GSEA analysis indicated that response to reactive oxygen species is the core biological process. AKT1 and EGFR had the highest docking affinity with artemisinin. In vivo, artemisinin could improve renal injury and fibrosis in mice. In vitro, artemisinin attenuated LPS-induced oxidative stress and fibrosis promoted AKT phosphorylation and Nrf2 nuclear translocation.Conclusion Artemisinin reduced the level of fibrosis and oxidative stress with IgA nephropathy through the AKT/Nrf2 pathway, which provided an alternative treatment for IgAN.
研究领域:
药理学
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肾病学
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分子生物学
·
生物信息学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Zheng-Meng Jiang,Zhi-Yue Fang,Xing Yang,Xing-Xing Ji,Yuan-Yuan Zhao,Bin-Yan Lin,Ze-Bin Weng,E-Hu Liu
Background Dysbiosis of the gut microbiota is pivotal in the development of gastric mucosa injury (GMI). Glycyrrhetinic acid (GA) is a bioactive triterpenoid compound abundantly present in licorice roots. Although GA's potential in mitigating GMI is recognized, its precise mechanism remains elusive, particularly concerning the role of gut microbiota. Purpose This study aimed to explore the protective effects and mechanisms of GA in preventing HCl/ethanol-induced GMI in rats. Results This study demonstrated the protective effects of GA on gastric mucosa, evidenced by enhanced morphology and structure as revealed through H&E staining. Utilizing fecal microbiota transplantation, GA was found to significantly mitigate oxidative damage, inflammation, and expression of apoptosis-related genes in GMI rats by a gut microbiota-dependent mechanism. 16S rRNA sequencing and metabolomics profiling revealed that GA ameliorated HCl/ethanol-triggered intestinal dysbiosis and imbalances in sphingolipid, arginine, and tryptophan metabolism. By promoting the prevalence of Bifidobacterium longum subsp. infantis ( B. infantis ) in the gut microbiota, GA improved metabolic disturbances linked to injury. Furthermore, its action mechanism was related to the inhibition of the Thbs1/PI3K-Akt/p53 signaling pathway. Conclusion The administration of GA improves GMI by mitigating intestinal dysbiosis and fostering colonization of B. infantis . GA offers therapeutic potential for GMI by modulating the Thbs1/PI3K-Akt/p53 pathway, thus alleviating inflammatory responses associated with gut microbiota imbalance.
研究领域:
药理学
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微生物学
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分子生物学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2019
·
IF 3.845
Peng Mei,Deng Jun,Zhou Sichun,Xiao Di,Long Jiahui,Zhang Nan,He Caimei,Mo Miao,Yang Xiaoping
Activations of Akt or ERK pathway induced by clinical drugs promote therapeutic failure due to decrease of drug response, and no available strategies have been developed to solve these problems. In this study, we found that pirarubicin (THP), one important chemotherapeutic drug for treating bladder cancer intravesically, dramatically elevated phosphorylations of both Akt and Erk1/2 in addition to inducing DNA damage. MK2206 or AZD6244, representative Akt and Erk1/2 inhibitors, respectively, profoundly sensitized bladder cancer cells to THP treatment. Interestingly, we found that inhibition of a single arm of either Akt or Erk1/2 pathway would induce the increase of another arm, indicating the existence of the crosstalk between these two pathways. Thus, simultaneous suppression of both signals may be needed for increasing the sensitivity of THP. On the other hand, we revealed that phenformin efficiently inhibited both Akt and Erk1/2 phosphorylation in a dose-dependent manner. Furthermore, we demonstrated that phenformin, mimicking dual inhibitors, plays dramatically synergistic action with THP both in vitro and in vivo. Our findings suggest that combination therapy of THP with dual inhibitors may constitute a successful strategy for improving chemotherapy response.
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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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2021
·
IF 5.858
Qingming Meng,Junbo Zhou,Fangting You,Yue Wu,Liquan Yang,Yan Wang,Xu Zhang,Shangfeng Gao,Rutong Yu,Xiaoxing Yin
AB38b is a novel biphenyl diester derivative synthesized in our laboratory, and it has been shown to improve the pathology of nephropathy and encephalopathy in diabetic mice. Glioblastoma (GBM) is the most lethal brain tumor, without effective drugs to date. The present study aims at investigating the role of AB38b in GBM growth and revealing the underlying molecular mechanisms. We found that AB38b administration showed a dose- and time-dependent inhibition on cell proliferation in multiple immortalized and primary GBM cell lines, but it had no significant effects on human astrocyte cell line. More importantly, AB38b blocked cell cycle progression, induced early apoptosis , decreased the activity of AKT/mTOR pathway, and increased the generation of reactive oxygen species (ROS) in GBM cells. Interestingly, antioxidant treatments could reverse the AB38b-mediated abovementioned effects; overexpression of constitutively active AKT could partially rescue the suppressive effects of Ab38b on GBM cell proliferation. In addition, AB38b administration inhibited the tumor growth, decreased the activity of AKT/mTOR pathway, and prolonged the survival time in GBM animal models, without any adverse influences on the important organs. These findings suggest that AB38b exerts anti-glioma activity via elevating the ROS generation followed by inhibiting the activity of AKT/mTOR pathway.
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
Orthopaedic Surgery
·
2022
·Vol. 14
·期 10
·2669-2681
·
IF 2.279
Bo-yong Jang,Shi-bing Guo,Rui Bai,Wan-lin Liu,Yu-lin Gong,Zhen-qun Zhao
Objective To study the relationship between vascular endothelial cells (VEC) and autophagy, and its regulatory mechanism in steroid-induced avascular necrosis of the femoral head (SANFH). Methods In cell experiment, VEC were isolated and cultured from the femoral head of Sprague–Dawley rats and divided into three groups: blank control group (Ctrl), methylprednisolone group (MP), and methylprednisolone+mTOR-shRNA group (MP + shmTOR). The autophagy formation was observed by transmission electron microscope. The mRNA expression of PI3K, Akt, mTOR, Beclin1 and MAP1LC3 was detected by RT-PCR and the protein expression was detected by Western blot and immunofluorescence. Expression of the damage marker 6-keto-PGF1α was detected by the ELISA method. In vivo experiment, after establishing the model, the grouping method was the same as cell experiment. Autophagosomes were observed by same method, and the expression of related factors was detected by the same method in cell experiment. Results In the cell experiment, autophagosomes in the MP group were significantly lower than in the Ctrl group, and the autophagosomes in the MP + shmTOR group were intermediate between two groups ( P < 0.05). The mRNA expression levels of PI3K, Akt and mTOR in the MP group were significantly higher than in the Ctrl group, while the MP+ shmTOR group presented intermediate levels between these groups (average gray value were 3837.90, 2996.30, 3005.60, F = 428.64, P < 0.05). MRNA expression levels of Beclin1 and MAP1LC3 in the MP group were significantly lower than that in Ctrl group ( P < 0.05). The content of 6-keto-PGF1α in the MP + shmTOR group was higher than in the Ctrl group and lower than in the MP group at the evaluated time intervals (average absorbance value were 104.98, 206.83, 145.91, F = 352.83, P < 0.01). In vivo experiment, the content of 6-Keto-PGF1α in the hormone group increased as time went on; the mTOR-si group was higher than that in control group, but lower than that in the hormone group ( P < 0.01). The mRNA expressions of Beclin1 and MAP1LC3 in the control group were higher than those in the hormone group, while the mRNA expressions of PI3K, Akt and mTOR were lower than those in the mTOR-si group ( P < 0.05). Conclusion The steroid inhibited the physiological protective effect of autophagy on SANFH by increasing the expression of PI3K/Akt/mTOR signaling pathway related factors and decreasing the expression of Beclin1 and MAP1LC3 in the femoral head VEC.
研究领域:
药理学
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细胞生物学
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骨科
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2024
·
IF 5.7
Lu Li,Kunlu Zhao,Jian Luo,Jinhong Tian,Fengxin Zheng,Xueman Lin,Zijun Xie,Heyang Jiang,Yongmei Li,Zean Zhao,Ting Wu,Jianxin Pang
Uncontrolled hyperuricemia often leads to the development of hyperuricemic nephropathy (HN), characterized by excessive inflammation and oxidative stress. Piperine, a cinnamic acid alkaloid, possesses various pharmacological activities, such as antioxidant and anti-inflammatory effects. In this study, we intended to investigate the protective effects of piperine on adenine and potassium oxonate-induced HN mice and a uric-acid-induced injury model in renal tubular epithelial cells (mRTECs). We observed that treatment with piperine for 3 weeks significantly reduced serum uric acid levels and reversed kidney function impairment in mice with HN. Piperine (5 μM) alleviated uric acid-induced damage in mRTECs. Moreover, piperine inhibited transporter expression and dose-dependently inhibited the activity of both transporters. The results revealed that piperine regulated the AKT/mTOR signaling pathway both in vivo and in vitro. Overall, piperine inhibits URAT1/GLUT9 and ameliorates HN by inhibiting the AKT/mTOR pathway, making it a promising candidate for patients with HN.
研究领域:
药理学
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肾病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INFLAMMOPHARMACOLOGY
·
2025
·
IF 5.3
Xiang Meixian,Wu Songtao,Liu Minxin,Zhang Bin,Xia Xiankun,Tan Wenjing,Xiang Shijian
Iota-carrageenan oligosaccharides (iCOs), derived from marine red algae, are traditionally used as antithrombotic and anti-inflammatory agents in folk medicinal practice. Despite the prevailing emphasis on these aspects in their applications, the potential of iCOs as a prebiotic agent for gut health and its subsequent impact on intestinal disorders such as colitis remains largely unexplored. A DSS-induced colitis model was employed in C57BL/6 male mice to analyze the gut microbiota via 16S rRNA sequencing. Fecal microbiota transplantation (FMT) was used to assess the therapeutic effects of iCOs on colitis. RNA sequencing (RNA-Seq) identified pathways and genes affected by iCOs. ELISA measured inflammatory cytokines, while western blot and RT-qPCR evaluated protein and gene expressions, respectively. The iCOs increased beneficial bacteria, such as Lactobacillus , Bifidobacterium , and Akkermansia . They enhanced short-chain fatty acid production and upregulated GPR41, GPR43, and GPR109A mRNA, influencing cytokine secretion. The iCOs reduced mRNA of SPHK1 , BDKRB1 , LCN2 , and so on, potentially through PI3K-Akt pathway inhibition, and promoted tight junction protein expression. Our findings highlight the novel therapeutic potential of iCOs in colitis, indicating a multifaceted approach to treatment that includes gut microbiota modulation, intestinal barrier restoration, and the suppression of inflammatory responses. Graphical abstract
研究领域:
医学
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微生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2018
·Vol. 8
·期 52
·29637-29644
·
IF 2.936
Minyu Zhu,Jinwei Ying,Chaowei Lin,Yu Wang,Kelun Huang,Yang Zhou,Honglin Teng
β-Escin exhibits anticancer effects on a panel of established cancer cells. However, the effects of β-escin on human osteosarcoma (OS) are still unknown. The aim of the present study was to investigate whether β-escin was effective against OS both in vivo and in vitro. Our results showed that β-escin induced dose- and time-dependent effects against MG-63, OS732, U-2OS, HOS and SAOS-2 cell proliferation. β-Escin also exhibited excellent anti-proliferative and pro-apoptotic effects in an established OS xenograft model. β-Escin and cytotoxic drugs, including cisplatin, methotrexate (MTX), doxorubicin (Dox) and ifosfamide (Ifos), synergistically inhibited proliferation of MG-63 and OS732 cells in vitro. Moreover, β-escin induced apoptotic death, activated caspase-3, caspase-8 and caspase-9, and regulated expression of Bax and Bcl-2 in MG-63 cells. In addition, our results showed that β-escin treatment reduced expression of p-PI3K, p-Akt and p-mTOR both in MG-63 cells and in an MG-63 xenograft OS model. Interestingly, SC79, which is an Akt activator, inhibited the anti-proliferative effects of β-escin on MG-63 cells. Taken together, our data support the conclusion that β-escin effectively inhibits OS proliferation both in vivo and in vitro. The inhibitory effect of β-escin, at least in part, is due to the inactivation of the PI3K/Akt signalling pathway.
研究领域:
肿瘤学
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药理学
·
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
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