ABSTRACT
Pyrrolizidine alkaloids (PAs) are a group of phytotoxins that can induce human liver injury, particularly hepatic sinusoidal obstruction syndrome (HSOS). To date, the molecular targets of PA-induced HSOS are largely unknown. In this study, retrorsine (RTS), a known hepatotoxic PA, was used as a representative PA for proteomic studies. Toxicological assessment demonstrated that 35 mg/kg RTS (designated as RTS-L) caused early lesions of HSOS at 24 h after dosing. A proteomic approach revealed 17 up-regulated and 31 down-regulated proteins in RTS-L-treated rats. Subsequently, bioinformatic analysis suggested that two proteins, carbamoyl-phosphate synthase (CPS1) (p < 0.05) and ATP synthase subunit beta (ATP5B) (p < 0.01) were associated with RTS-L intoxication. Using immunohistochemical staining, we further verified the down-regulation of CPS1 and ATP5B in RTS-L-treated rats. These findings indicated that CPS1 and ATP5B were altered in the RTS-induced early lesions of HSOS in rats, and therefore, these two proteins and their involved pathways might play important roles in the initiation of HSOS. To the best of our knowledge, our study using a proteomic approach combined with conventional toxicological assessment is the first systems toxicology study on PA-induced HSOS. The results of this study provide novel findings on protein profiles in response to PA exposure, which can serve as a starting point to further investigate potential protein targets and their interactions with PAs to induce HSOS.
Subject(s)
Hepatic Veno-Occlusive Disease/chemically induced , Proteomics , Pyrrolizidine Alkaloids/toxicity , Animals , Cluster Analysis , Male , Rats , Rats, Sprague-DawleyABSTRACT
Annonaceous acetogenins (ACGs) are a group of fatty acid-derivatives with potent anticancer effects. In the present study, we found desacetyluvaricin (Dau) exhibited notable in vitro antiproliferative effect on SW480 human colorectal carcinoma cells with IC50 value of 14 nM. The studies on the underlying mechanisms revealed that Dau inhibited the cancer cell growth through induction of S phase cell cycle arrest from 11.3% (control) to 33.2% (160 nM Dau), which was evidenced by the decreased protein expression of cyclin A Overproduction of superoxide, intracellular DNA damage, and inhibition of MEK/ERK signaling pathway, were also found involved in cells exposed to Dau. Moreover, pre-treatment of the cells with ascorbic acid significantly prevented the Dau-induced overproduction of superoxide, DNA damage and cell cycle arrest. Taken together, our results suggest that Dau induces S phase arrest in cancer cells by firstly superoxide overproduction and subsequently the involvement of various signaling pathways.
Subject(s)
Colorectal Neoplasms/drug therapy , DNA Damage/drug effects , S Phase/drug effects , Superoxides/metabolism , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Division/drug effects , Cell Line, Tumor , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Furans/administration & dosage , HumansABSTRACT
The ethanol extract of Wikstroemia indica was fractionated with organic solvents of different polarities, and various fractions were screened for their antiviral activity against respiratory syncytial virus (RSV) using a cytopathic effect (CPE) reduction assay. The ethyl acetate fraction was most active against RSV with 50% inhibition concentration (IC(50)) value < 3.9 microg/mL and a selectivity index (SI) > 64.1. Further isolation and purification of the fraction led to a purified compound, daphnoretin. Daphnoretin was tested for its anti-RSV activity using a plaque reduction assay and found active against RSV, with an IC(50 )value of 5.87 microg/mL and SI value of 28.17. The mode of antiviral action study revealed that daphnoretin could slightly inhibit the early events of the viral infection but its effect was mainly on the later phase of the replication cycle.
Subject(s)
Antiviral Agents/pharmacology , Coumarins/pharmacology , Plant Extracts/pharmacology , Respiratory Syncytial Viruses/drug effects , Wikstroemia/chemistry , Antiviral Agents/isolation & purification , Cell Line, Tumor , Coumarins/isolation & purification , Drugs, Chinese Herbal/pharmacology , Humans , Inhibitory Concentration 50 , Viral Plaque AssayABSTRACT
OBJECTIVE: To study the chemical constituents of Serissa serissoides. METHOD: Chemical constituents were isolated with the column chromatographic methods including silica gel and sephadex LH -20, and their structures were elucidated on the basis of their spectral and chemical evidences. RESULT: Eight compounds were obtained and were identified as: palmitic acid (1), corosolic acid (2), daucosterol (3), urs-12-en-28-ol (4), oleanolic acid (5), uroslic acid (6), 4-hydroxy-3-methoxybenzoic acid (7), and 2,6-dimethoxy-p-benzoquinone (8). CONCLUSION: Except compound 5, other seven compounds were found from the genus Serissa for the first time.
Subject(s)
Palmitic Acid/isolation & purification , Plants, Medicinal/chemistry , Rubiaceae/chemistry , Sitosterols/isolation & purification , Triterpenes/isolation & purification , Chromatography, Gel/methods , Palmitic Acid/chemistry , Sitosterols/chemistry , Triterpenes/chemistry , Ursolic AcidABSTRACT
The chemical constituents of Adina pilulifera, which were traditionlly used in the area of Yao minority in Southern China, were isolated and characterized. Two compounds were obtained from the ethyl acetate fraction of ethanol extract of Adina pilulifera, and one compound was obtained from the n-butanol fraction of ethanol extract of Adina pilulifera. Their structure were characterized by spectroscopic analysis and comparison with published data to be sarracenin (1), 2-methyl-5, 7-dihydroxychromone (2) and morroniside (3). Except compound 2, other two compounds were isolated from this plant for the first time, and they were also obtained from the Adina genus for the first time.
