Venenum Bufonis induces rat neuroinflammation by activiating NF-κB pathway and attenuation of BDNF

Bi, Qirui; Hou, Jinjun; Pan, Qi; Ma, Chi; Shen, Yao; Ren, Feng; Yan, Bingpeng; Wang, Jianwei; Shi, Xiaojian; Zheng, Yuanyuan; Wu, Wanying; Guo, Dan

doi:10.1016/j.jep.2016.03.049

Cited by 26 publications

(13 citation statements)

References 37 publications

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“…However, further studies are still warranted to evaluate if the antitumor efficacy of cinobufotalin will be enhanced in combination with P-gp inhibitors. As previously reported, over dose of cinobufotalin could resulted in cardiotoxicity and neurotoxicity (Bick et al, 2002; Bi et al, 2016). Hence extensive attention should be attracted with the toxicity of cinobufotalin during the treatment of HCC patients in the future studies, especially in the present of P-gp inhibitors.…”

Section: Discussionsupporting

confidence: 56%

Elucidation of the Differences in Cinobufotalin’s Pharmacokinetics Between Normal and Diethylnitrosamine-Injured Rats: The Role of P-Glycoprotein

et al. 2019

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Cinobufotalin is one of the major anti-tumor components isolated from toad venom and has been used in the clinical therapy of hepatocellular carcinoma (HCC), known as Cinobufacini injection. However, the pharmacokinetic (PK) behaviors of cinobufotalin in vivo with HCC are still unknown. Hence, we have established a HCC model in Sprague Dawley (SD) rats induced by diethylnitrosamine (DEN), named as DEN-injured rats. Then, we developed and validated a sensitive and rapid ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method to quantify cinobufotalin in rat plasma. This UPLC-MS/MS method was successfully used to characterize the PK behaviors of cinobufotalin in normal and DEN-injured rats after intravenous (i.v.) injection at a dosage of 2.5 mg/kg. Cinobufotalin pharmacokinetics was well described by the two-compartment pharmacokinetic model and the PK parameters were calculated using WinNonlin 3.3 software. The transfer rate constant of cinobufotalin from the central compartment to the peripheral compartment (k 12 ) in DEN-injured rats was significantly greater than that in normal rats ( p < 0.01), accompanied by the shorter half-life for the distribution phase (t 1/2α ). Additionally, the elimination rate constant (K 10 ) and clearance (CL) values in DEN-injured rats were significantly higher than that in normal rats ( p < 0.05 for K 10 and p < 0.001 for CL, respectively). Therefore, the values of areas under concentration – time curve (AUC) and the liver concentration of cinobufotalin in DEN-injured rats was obviously lower than that in normal rats ( p < 0.001 and p < 0.01, respectively). This indicated that the PK behaviors of cinobufotalin will be altered in rats with HCC. In addition, P-glycoprotein (P-gp) has shown higher expression in live tissues of DEN-injured rats. Furthermore, cinobufotalin was identified as the substrate of P-gp using MDCK II and MDCK-MDR1 cell models for the first time. Consequently, P-gp will play an important role in the disposition of cinobufotalin in vivo , which provided a new combination therapy for the clinical treatment of HCC.

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Section: Discussionsupporting

confidence: 56%

Elucidation of the Differences in Cinobufotalin’s Pharmacokinetics Between Normal and Diethylnitrosamine-Injured Rats: The Role of P-Glycoprotein

et al. 2019

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“…Importantly, in these cells augmented expression of PTGS2 and IL6 was mediated by NKA inhibition and elevation of the [Na + ]i/[K + ]i ratio. In addition to these findings, the neurotoxicity of Venenum Bufonis has been linked to neural inflammation caused by activation of the NF-κB transcription factor [ 122 ]. However, the literature seems to be divided on this topic.…”

Section: Cts Nka and Inflammationmentioning

confidence: 99%

Cardiotonic Steroids and the Sodium Trade Balance: New Insights into Trade-Off Mechanisms Mediated by the Na+/K+-ATPase

Khalaf

Dube

Mohamed

et al. 2018

IJMS

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In 1972 Neal Bricker presented the “trade-off” hypothesis in which he detailed the role of physiological adaptation processes in mediating some of the pathophysiology associated with declines in renal function. In the late 1990’s Xie and Askari published seminal studies indicating that the Na+/K+-ATPase (NKA) was not only an ion pump, but also a signal transducer that interacts with several signaling partners. Since this discovery, numerous studies from multiple laboratories have shown that the NKA is a central player in mediating some of these long-term “trade-offs” of the physiological adaptation processes which Bricker originally proposed in the 1970’s. In fact, NKA ligands such as cardiotonic steroids (CTS), have been shown to signal through NKA, and consequently been implicated in mediating both adaptive and maladaptive responses to volume overload such as fibrosis and oxidative stress. In this review we will emphasize the role the NKA plays in this “trade-off” with respect to CTS signaling and its implication in inflammation and fibrosis in target organs including the heart, kidney, and vasculature. As inflammation and fibrosis exhibit key roles in the pathogenesis of a number of clinical disorders such as chronic kidney disease, heart failure, atherosclerosis, obesity, preeclampsia, and aging, this review will also highlight the role of newly discovered NKA signaling partners in mediating some of these conditions.

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“…Notably, the GO term results of the 1,237 DEGs were mainly linked to immunity, including ‘immune response’, ‘regulation of immune response’, ‘innate immune response’ and ‘adaptive immune response’. It was reported previously that cinobufotalin activated the nuclear factor-κB pathway and decreased expression levels of brain-derived neurotrophic factor to induce neuroinflammation in rats (60). Nonetheless, no direct evidence has revealed that cinobufotalin was associated with number of immune cells, organism immunity or tumor immunity.…”

Section: Discussionmentioning

confidence: 93%

Differentially expressed gene profile and relevant pathways of the traditional Chinese medicine cinobufotalin on MCF‑7 breast cancer cells

Rong²,

Dang

et al. 2019

Mol Med Report

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Cinobufotalin is a chemical compound extracted from the skin of dried bufo toads that may have curative potential for certain malignancies through different mechanisms; however, these mechanisms remain unexplored in breast cancer. The aim of the present study was to investigate the antitumor mechanism of cinobufotalin in breast cancer by using microarray data and in silico analysis. The microarray data set GSE85871, in which cinobufotalin exerted influences on the MCF-7 breast cancer cells, was acquired from the Gene Expression Omnibus database, and the differentially expressed genes (DEGs) were analyzed. Subsequently, protein interaction analysis was conducted, which clarified the clinical significance of core genes, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used to analyze cinobufotalin-related pathways. The Connectivity Map (CMAP) database was used to select existing compounds that exhibited curative properties similar to those of cinobufotalin. A total of 1,237 DEGs were identified from breast cancer cells that were treated with cinobufotalin. Two core genes, SRC proto-oncogene non-receptor tyrosine kinase and cyclin-dependent kinase inhibitor 2A, were identified as serving a vital role in the onset and development of breast cancer, and their expression levels were markedly reduced following cinobufotalin treatment as detected by the microarray of GSE85871. It also was revealed that the ‘neuroactive ligand-receptor interaction’ and ‘calcium signaling’ pathways may be crucial for cinobufotalin to perform its functions in breast cancer. Conducting a matching search in CMAP, miconazole and cinobufotalin were indicated to possessed similar molecular mechanisms. In conclusion, cinobufotalin may serve as an effective compound for the treatment of a subtype of breast cancer that is triple positive for the presence of estrogen, progesterone and human epidermal growth factor receptor-2 receptors, and its mechanism may be related to different pathways. In addition, cinobufotalin is likely to exert its antitumor influences in a similar way as miconazole in MCF-7 cells.

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Venenum Bufonis induces rat neuroinflammation by activiating NF-κB pathway and attenuation of BDNF

Cited by 26 publications

References 37 publications

Elucidation of the Differences in Cinobufotalin’s Pharmacokinetics Between Normal and Diethylnitrosamine-Injured Rats: The Role of P-Glycoprotein

Elucidation of the Differences in Cinobufotalin’s Pharmacokinetics Between Normal and Diethylnitrosamine-Injured Rats: The Role of P-Glycoprotein

Cardiotonic Steroids and the Sodium Trade Balance: New Insights into Trade-Off Mechanisms Mediated by the Na+/K+-ATPase

Differentially expressed gene profile and relevant pathways of the traditional Chinese medicine cinobufotalin on MCF‑7 breast cancer cells

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