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This study aimed to investigate halofuginone's inhibitory effect and mechanism on the activity of hepatocellular carcinoma cells. HepG2 cells were used to detect the effects of halofuginone. After treatment, cell activity, cell migration, cell cycle, and cell apoptosis were detected by CCK-8, transwell, and flow cytometry, respectively. The expression levels of growth and metabolism-related factors such as citrate synthase (CS), ketoglutarate dehydrogenase (OGDH), and isocitrate deoxygenase (IDH) were detected by real-time quantitative PCR and Western blot. Compared with the control group, the activity of HepG2 cells was significantly inhibited by halofuginone (P < 0.01), the migration rate of HepG2 cells was decreased (P < 0.01), the apoptosis of HepG2 cells was induced (P < 0.01), and the cell cycle was arrested in S phase (P < 0.01). The expression levels of tricarboxylic acid key enzymes CS, IDH3, and OGDH were up-regulated, the expression level of isocitrate dehydrogenase isoenzymes IDH1 and IDH2 were down-regulation. In conclusion, halofuginone can inhibit the proliferation and migration of HepG2 cells and promote apoptosis in a dose-dependent manner, which may be due to the promotion of the aerobic metabolism of cells.
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Halofuginone (HF) is an extract from the widely used traditional Chinese medicine (TCM) Dichroa febrifugathat facilitates the recovery of wounds and attenuates hepatic fibrosis. However, the role of HF in theepithelial-mesenchymal transition (EMT) of IPEC-J2 cells remains unclear. The current study explored theanti-EMT effect of HF in IPEC-J2 cells and illustrates its molecular mechanism. Transforming growth factorb1 (TGF-b1), as a recognized profibrogenic cytokine, decreased the level of the epithelial marker E-cadherinand increased the level of the mesenchymal markers, such as N-cadherin, fibronectin (FN), vimentin (Vim),and a-smooth muscle actin (a-SMA), in IPEC-J2 cells depending on the exposure time and dose. HF markedlyprevented the EMT induced by TGF-b1. Dissection of the mechanism revealed that HF inhibited IPEC-J2 cellEMT via modulating the phosphorylation of SMAD2/3 and the SMAD2/3-SMAD4 complexnuclear translocation. Furthermore, HF could promote the phosphorylation of eukaryotic translation initiationfactor-2a (eIF2a), which modulates the SMAD signaling pathway. These results suggested that HF inhibitsTGF-b1-induced EMT in IPEC-J2 cells through the eIF2a/SMAD signaling pathway. Our findings suggest thatHF can serve as a potential anti-EMT agent in intestinal fibrosis therapy.
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Objective:To evaluate the regulatory effectsand underlying mechanism of halofuginone (HF) on lipopolysaccharide (LPS)-induced immune disorder of acute lung injury (ALI) in rat. Methods: Rats were treated with LPS and HF. Subsequently,HE staining was performed for pulmonarypathological lesion,apoptosis bodies were calculated by TUNEL assay,the levels of inflammatory factors were confirmed by ELISA assay and the level of CD14 was measured by flow cytometry. Protein levels were determined by Western blot. Results: Treatment of HF dose-dependently alleviated LPS-induced pulmonary injury and inhibited the formation of apoptosis bodies significantly. Meanwhile,HF notably inhibited inflammation of ALI rats,as demonstrated by decreased IL-1β,IL-6 and IL-18. Furthermore,postconditioning with HF markedly decreased CD14+cells. Moreover,HF dose-dependently attenuated the promotive effects of LPS on CD14,TLR4 and NF-κB p65. Conclusion: HF regulates LPS-induced immune disorder of ALI in rat via CD14/NF-κB pathway.
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Halofuginone (HF) is a derivative of dichroine which is the extract of traditional Chinese medicine. It is widely used as an efficient anticoccidial drug. Recent studies have found that HF has unique biological activities, showing great potential capacities in the treatment of autoimmune diseases. In the article, we summarized the therapeutic effects of HF in a variety of autoimmune diseases and its mechanism, providing references for further clinical studies of HF.
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Objective:To investigate the inhibitory effects of halofuginone on radiation-induced pulmonary injury and to explore the therapeutic mechanism of this drug. Methods:A total of 72 healthy female C57BL/6 mice were randomized into 4 groups, namely, control, irradiation, halofuginone, and irradiation plus halofuginone groups, with 18 mice in each group. No treatment was performed in the control group. In the halofuginone group, the halofuginone lavage was conducted once a day, with a continuous course treatment for a month or until sacrifice of the mice. In the therapeutic alliance group, the treatment mode was the same as that in the halofuginone group. Then, a 6MV-X ray single fraction irradiation was performed after the completion of a 15-day intragastric administration. At 24 h, 1 week, 2 weeks, 4 weeks, 12 weeks, and 20 weeks after the irradiation, 3 mice from each group were randomly sacrificed, and total lung tissues were harvested. The lung was dissected to prepare pathological sections. The sections were stained with hematoxylin and eosin staining (H&E) to explore morphologic changes. The protein and mRNA expression levels of TGF-β1 were analyzed by a combi-nation of immunohistochemistry and polymerase chain reaction. The level of hydroxyproline was also measured. Results: The out-comes of H&E staining showed that halofuginone markedly ameliorated the acute pulmonary inflammation and fibrosis induced by irra-diation. The combination group had a lower level of hydroxyproline than the irradiation group, with statistically significant differences at 20 weeks after irradiation (P=0.037). The protein and mRNA expression levels of TGF-β1 were higher in the irradiation and combi-nation groups than in the control group and (or) halofuginone group at different time points (P<0.05). The combination group had lower TGF-β1 protein expression than the irradiation group at different time points, with statistically significant differences at 2, 4, 12, and 20 weeks after the irradiation (P<0.05). Meanwhile, TGF-β1 mRNA level was lower in the combination group than in the irradiation group only at 4 and 12 weeks after the irradiation (P<0.05). Conclusion:Halofuginone can ameliorate the irradiation-induced lung inflamma-tion and fibrosis probably by inhibiting the radiation-induced TGF-β1 expression. Therefore, halofugione is expected to be a therapeu-tic drug for preventing irradiation injury of the lung.
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Objective: To investagate the protective effects of halofuginone against liver injury induced by concanavalin A (Con A) in rats and their mechanism. Methods: Rats were divided into control (G1, 8), model (G2, 14), low- (5 mg/kg, G3, 14) and high-dose (10 mg/kg, G4, 14) halofuginone groups. The rats in G1 were iv injected with 300 μL PBS from tail vain once a week, the rats in other three groups were iv injected with 12.5 mg/kg Con A (in 300 μL PBS) once a week for eight consecutive weeks. Halofuginone was given in the diet for rats in G3 and G4 after molding and continuous administration for eight weeks after the rats were weighted and then were put to execution. The biochemical analysis was used to determine alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein (TP), and album protain (ALB) in serum while enzyme-linked immuno sorbent assay (ELISA) was applied for detecting transforming growth factor β1 (TGF-β1), hyaluronic acid (HA), and procollagen III (PC-III) levels in serum. HE and Masson's trichrome stainings were conducted in liver tissue to observe the pathological variations. Grades of hepatic fibrosis were evaluated according to SSS system. Sirus and immunohistochemical stainings were executed for detecting the deposition and protein expression of collagen 1 (Col I) in liver tissue. Results: Compared with the G2, halofuginone could decrease the levels of ALT, AST, TP, ALB, TGF-β1, HA, and PC-III in serum obviously (P < 0.05, 0.01). Halofuginone could improve the liver pathological variations of fibrotic rats obviously (P < 0.05, 0.01) and reduce the score of hepatic fibrosis significantly (P < 0.05, 0.01). Halofuginone treatment could reduce the deposition and expression of Col I protein (P < 0.05, 0.01). Conclusion: Halofuginone could attenuate the Con A-induced immunological liver injury and the fibrosis level in rats. The mechanisms possibly contribute to down-regulating the deposition and expression of Col I protein in liver of rats.
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BACKGROUND: During normal wound healing the formation of scars and fibrous tissue occurs, which consists largely of collagen fibril, but excessive fibrosis and scar formation become clinical problems. Collagen remodelling during scar formation is dependent on both continued collagen synthesis and collagen catabolism. Halofuginone, a plant alkaloid, is known to inhibit collagen type I synthesis at the transcriptional level. OBJECTIVE: The purposes of this study were to investigate the effects of topical application of halofuginone on the healing of wounds. METHOD: Topical solutions containing halofuginone of variable concentrations were applied on the full-thickness excisional wounds of hairless mice and 0.1% halofuginone ointments applied on the suture site of rats and the normal skin of hairless mice daily. In addition, we performed a one-time intradermal injection of 0.1% halofuginone solution on the normal skin of the hairless mice. We examined the collagen content of the skin of hairless mice and rats treated with halofuginone solutions and ointments during the healing process by performing hematoxylin-eosin and Masson's trichrome stains. We assessed, from time to time, the change in the full-thickness excisional wound size of hairless mice treated with halofuginone solutions of variable concentrations during the healing process and observed clinically the healing process of hairless mice with the full-thickness excisional wound. RESULT: 1. The wound size after daily application of 0.001% and 0.1% halofuginone solutions on the full-thickness excisional wounds of hairless mice decreased more slowly in comparison with the control group (p < 0.05).