Dataset Information

A Discovery of Clinically Approved Formula FBRP for Repositioning to Treat HCC by Inhibiting PI3K/AKT/NF-?B Activation.

ABSTRACT: Drug repositioning offers new clinical applications for existing drugs with shorter approval processes and lower costs and risks than de novo experimental drug development. The Fufang-Biejia-Ruangan pill (FBRP) is the first clinically approved anti-fibrosis herbal formula in China. Whether FBRP could be used to treat hepatocellular carcinoma (HCC) remains unclear. Herein, a total of 161 FBRP candidate targets against HCC were identified according to the topological importance in the "hepatic fibrosis-cirrhosis-cancer axis-related gene-FBRP putative target" network, and mostly enriched in phosphatidylinositol 3-kinase (PI3K)/AKT/nuclear factor ?B (NF-?B) signaling. Experimentally, FBRP inhibited liver fibrosis and prevented the development of neoplastic lesions at the early stages of hepatocarcinogenesis in a diethylnitrosamine-induced rat HCC model. FBRP inhibited tumor cell proliferation, induced tumor-specific cell death, and suppressed tumor progression in HCC rats while preventing the activation of PI3K, AKT and IK?B proteins, reducing the nuclear accumulation of NF?B1 protein, and decreasing the downstream expression of proteins. Consistently, FBRP suppressed HCC cell proliferation and induced cell cycle arrest in vitro. Co-treatment of FBRP with PI3K inhibitor exhibited an additive inhibitory effect on PI3K/AKT/NF-?B activation. Collectively, our data showed the potentials of FBRP in hepatic fibrosis microenvironment regulation and tumor prevention, suggesting that FBRP may be a promising candidate drug for reduction of fibrogenesis and prevention of HCC.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC6994416 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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A Discovery of Clinically Approved Formula FBRP for Repositioning to Treat HCC by Inhibiting PI3K/AKT/NF-κB Activation.

Zhang Yanqiong Y Mao Xia X Chen Wenjia W Guo Xiaodong X Yu Liangxiang L Jiang Funeng F Wang Xiaoyue X Li Weijie W Guo Qiuyan Q Li Taixian T Lin Na N

Molecular therapy. Nucleic acids 20200110

Drug repositioning offers new clinical applications for existing drugs with shorter approval processes and lower costs and risks than de novo experimental drug development. The Fufang-Biejia-Ruangan pill (FBRP) is the first clinically approved anti-fibrosis herbal formula in China. Whether FBRP could be used to treat hepatocellular carcinoma (HCC) remains unclear. Herein, a total of 161 FBRP candidate targets against HCC were identified according to the topological importance in the "hepatic fib ...[more]

PMID: 31982775

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Project description:Influenza viruses (IVs) tend to rapidly develop resistance to virus-directed vaccines and common antivirals targeting pathogen determinants, but novel host-directed approaches might preclude resistance development. To identify the most promising cellular targets for a host-directed approach against influenza, we performed a comparative small interfering RNA (siRNA) loss-of-function screen of IV replication in A549 cells. Analysis of four different IV strains including a highly pathogenic avian H5N1 strain, an influenza B virus (IBV) and two human influenza A viruses (IAVs) revealed 133 genes required by all four IV strains. According to gene enrichment analyses, these strain-independent host genes were particularly enriched for nucleocytoplasmic trafficking. In addition, 360 strain-specific genes were identified with distinct patterns of usage for IAVs versus IBV and human versus avian IVs. The strain-independent host genes served to define 43 experimental and otherwise clinically approved drugs, targeting reportedly fourteen of the encoded host factors. Amongst the approved drugs, the urea-based kinase inhibitors (UBKIs) regorafenib and sorafenib exhibited a superior therapeutic window of high IV antiviral activity and low cytotoxicity. Both UBKIs appeared to block a cell signaling pathway involved in IV replication after internalization, yet prior to vRNP uncoating. Interestingly, both compounds were active also against unrelated viruses including cowpox virus (CPXV), hantavirus (HTV), herpes simplex virus 1 (HSV1) and vesicular stomatitis virus (VSV) and showed antiviral efficacy in human primary respiratory cells. An in vitro resistance development analysis for regorafenib failed to detect IV resistance development against this drug. Taken together, the otherwise clinically approved UBKIs regorafenib and sorafenib possess high and broad-spectrum antiviral activity along with substantial robustness against resistance development and thus constitute attractive host-directed drug candidates against a range of viral infections including influenza.

Project description:BackgroundLuteolin is widely distributed among a number of vegetal species worldwide. The pharmacological effects of luteolin are diverse and amongst antioxidant, free radical scavenging, and anti-inflammatory activities. Preliminary study showed that luteolin can ameliorate hypertension. However, the precise mechanism needs further investigation. There is no evidence that luteolin affects the paraventricular nucleus of the hypothalamus (PVN), a brain nucleus associated with a critical neural regulator of blood pressure. Our main aim was to explore the effect of luteolin on the PI3K/Akt/NF-κB signaling pathway within the PVN of hypertensive rats.Methodsspontaneously hypertensive rats (SHRs) and corresponding normotensive control rats, the Wistar Kyoto (WKY) rats were divided into four groups and subsequently treated for 4 weeks with bilateral PVN injections of either luteolin (20 µg/0.11 µL, volume: 0.11 µL/h) or vehicle (artificial cerebrospinal fluid).Resultsluteolin infusion to the PVN significantly decreased some hemodynamic parameters including the mean arterial pressure (MAP), heart rate (HR), circulating plasma norepinephrine (NE) and epinephrine (EPI). Additionally, there was a decrease in the expressions of the phosphatidylinositol 3-kinase (p-PI3K) and phosphorylated protein kinase-B (p-AKT), levels of reactive oxygen species (ROS), NAD(P)H oxidase subunit (NOX2, NOX4) in the PVN of SHRs. Meanwhile, the expression of inflammatory cytokines and the activity of nuclear factor κB (NF-κB) p65 in the PVN of SHRs were lowered. Furthermore, immunofluorescence results showed that injection of luteolin in the PVN reduced the expression of tyrosine hydroxylase (TH), and increased that of superoxide dismutase (SOD1) and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN of SHRs.ConclusionOur novel findings revealed that luteolin lowered hypertension via inhibiting NF-κB-mediated inflammation and PI3K/Akt signaling pathway in the PVN.

Dataset Information

A Discovery of Clinically Approved Formula FBRP for Repositioning to Treat HCC by Inhibiting PI3K/AKT/NF-?B Activation.

Publications

A Discovery of Clinically Approved Formula FBRP for Repositioning to Treat HCC by Inhibiting PI3K/AKT/NF-κB Activation.

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