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Involvement of NF-?B in the reversal of CYP3A down-regulation induced by sea buckthorn in BCG-induced rats.

ABSTRACT: Previous studies reported that sea buckthorn (Hippophae rhamnoides L., Elaeagnaceae, HRP) exhibits hepatoprotective effects via its anti-inflammatory and antioxidant properties as well as its inhibitory effects on collagen synthesis. However, it is unclear whether this hepatoprotective effect is also achieved by regulating liver drug metabolism enzyme pathways. Herein, we examined the regulatory effect of HRP on cytochrome P450 3A (CYP3A) in rats with immune liver injury, and explored the molecular mechanism of its hepatoprotective effect. Rat models of immunological liver injury were induced by intravenous injections of Bacillus Calmette-Guerin (BCG; 125 mg kg-1; 2 wks). Specific protein levels were detected by ELISA or western blot, and CYP3A mRNA expression was detected by RT-PCR. High-performance liquid chromatography (HPLC) detected relative changes in CYP3A metabolic activity based on the rates of 1-hydroxylation of the probe drug midazolam (MDZ). BCG pretreatment (125 mg kg-1) significantly down-regulated liver CYP3A protein expression compared with the control, metabolic activity, and transcription levels while up-regulating liver NF-?B, IL-1?, TNF-? and iNOS. HRP intervention (ED50: 78 mg kg-1) moderately reversed NF-?B, inflammatory cytokines, and iNOS activation in a dose-dependent manner (P < 0.05), and suppressed CYP3A down-regulation (P < 0.05); thereby partially alleviating liver injury. During immune liver injury, HRP may reverse CYP3A down-regulation by inhibiting NF-?B signal transduction, and protect liver function, which involves regulation of enzymes transcriptionally, translationally and post-translationally. The discovery that NF-?B is a molecular target of HRP may initiate the development and optimization of a clinical therapeutic approach to mitigate hepatitis B and other immunity-related liver diseases.

SUBMITTER: Liu F

PROVIDER: S-EPMC7485842 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Involvement of NF-κB in the reversal of CYP3A down-regulation induced by sea buckthorn in BCG-induced rats.

Liu Fengting F Wang Tao T Li Xiaoxia X Jia Jinxue J Lin Qin Q Xue Yongzhi Y

PloS one 20200911 9

Previous studies reported that sea buckthorn (Hippophae rhamnoides L., Elaeagnaceae, HRP) exhibits hepatoprotective effects via its anti-inflammatory and antioxidant properties as well as its inhibitory effects on collagen synthesis. However, it is unclear whether this hepatoprotective effect is also achieved by regulating liver drug metabolism enzyme pathways. Herein, we examined the regulatory effect of HRP on cytochrome P450 3A (CYP3A) in rats with immune liver injury, and explored the molecu ...[more]

PMID: 32915856

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Project description:Puerarin was a major isoflavonoid derived from the Chinese medical herb radix puerariae (Gegen). In present study effect of puerarin on cisplatin nephrotoxicity was evaluated. Rat model of nephrotoxicity was established by a single intraperitoneal injection of cisplatin (7mg/kg). Puerarin was administrated through caudal vein injection once per day at the dose of 10mg/kg, 30mg/kg and 50mg/kg. Biochemical assays showed that after cisplatin treatment the serum urea and creatinine increased significantly compared with control (P<0.05). Cisplatin treatment significantly increased xanthine oxidase (XO) activity and malondialdehyde (MDA) formation, and significantly decreased the levels and /or activities of enzymatic and non-enzymatic antioxidants (GSH, GPx, GST, GR, SOD, CAT), in the kidney tissues. Renal levels of TNF-α and IL-6, two important inflammatory cytokines, were also upregulated by cisplatin. Histopathological examination indicated that cisplatin treatment resulted in severe necrosis and degeneration, hyaline casts in the tubules, intertubular hemorrhage, congestion and swelling in glomerulus and leukocytes infiltration in the kidney tissues. Western blot results demonstrated that cisplatin increased TLR4 and NF-κB protein expression in the kidney tissues. However, all these changes induced by cisplatin were significantly attenuated by puerarin treatment in dose-dependent manner, which indicated the renal protective effect of puerarin. Cell culture experiments illustrated that puerarin alone treatment concentration-dependently inhibited COLO205 and HeLa tumor cell growth and dose-dependently promoted the antitumor activity of cisplatin in COLO205 and HeLa tumor cells. The promotion effects might be attributed to suppression of cisplatin-increased NF-κB p65 expression by puerarin. Taken together, findings in this study suggested that puerarin exhibited renal protection against cisplatin nephrotoxicity via inhibiting TLR4/NF-κB signaling, with no inhibition but promotion effect on the antitumor activity of cisplatin. Puerarin might be a promising adjuvant agent for cisplatin chemotherapy.

Dataset Information

Involvement of NF-?B in the reversal of CYP3A down-regulation induced by sea buckthorn in BCG-induced rats.

Publications

Involvement of NF-κB in the reversal of CYP3A down-regulation induced by sea buckthorn in BCG-induced rats.

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