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1.  The inhibitory effect of rapamycin on the oval cell response and development of preneoplastic foci in the rat 
Oval cell activation occurs under conditions of severe liver injury when normal hepatocyte proliferation is blocked. Recent studies have shown that a subset of hepatocellular carcinomas expresses oval cell markers, suggesting that these cells are targets of hepatocarcinogens. However, the signaling pathways that control oval cell activation and proliferation are not well characterized. Based on the role of the nutrient signaling kinase complex, mTORC1, in liver development, we investigated the role of this pathway in oval cell activation. Oval cell proliferation was induced in male Fisher rats by a modification of the traditional choline deficient plus ethionine model (CDE) or by 2-acetylaminoflourene treatment followed by 2/3 partial hepatectomy with or without initiation by diethylnitrosamine. To assess the role of mTOR in the oval cell response and development of preneoplastic foci, the effect of the mTORC1 inhibitor, rapamycin, was studied in all models. Rapamycin induced a significant suppression of the oval cell response in both models, an effect that coincided with a decrease in oval cell proliferation. Rapamycin administration did not affect the abundance of neutrophils or natural killer cells in CDE-treated liver or the expression of key cytokines. Gene expression studies revealed the fetal hepatocyte marker MKP-4 to be expressed in oval cells. In an experimental model of hepatic carcinogenesis, rapamycin decreased the size of preneoplastic foci and the rate of cell proliferation within the foci. mTORC1 signaling plays a key role in the oval cell response and in the development of preneoplastic foci. This pathway may be a target for the chemoprevention of hepatocellular carcinoma.
PMCID: PMC3612884  PMID: 22525806
Hepatic progenitor cells; Liver regeneration; Liver injury; mTOR; Hepatocellular carcinoma
2.  Postnatal liver growth and regeneration are independent of c-myc in a mouse model of conditional hepatic c-myc deletion 
BMC Physiology  2012;12:1.
The transcription factor c-myc regulates genes involved in hepatocyte growth, proliferation, metabolism, and differentiation. It has also been assigned roles in liver development and regeneration. In previous studies, we made the unexpected observation that c-Myc protein levels were similar in proliferating fetal liver and quiescent adult liver with c-Myc displaying nucleolar localization in the latter. In order to investigate the functional role of c-Myc in adult liver, we have developed a hepatocyte-specific c-myc knockout mouse, c-mycfl/fl;Alb-Cre.
Liver weight to body weight ratios were similar in control and c-myc deficient mice. Liver architecture was unaffected. Conditional c-myc deletion did not result in compensatory induction of other myc family members or in c-Myc's binding partner Max. Floxed c-myc did have a negative effect on Alb-Cre expression at 4 weeks of age. To explore this relationship further, we used the Rosa26 reporter line to assay Cre activity in the c-myc floxed mice. No significant difference in Alb-Cre activity was found between control and c-mycfl/fl mice. c-myc deficient mice were studied in a nonproliferative model of liver growth, fasting for 48 hr followed by a 24 hr refeeding period. Fasting resulted in a decrease in liver mass and liver protein, both of which recovered upon 24 h of refeeding in the c-mycfl/fl;Alb-Cre animals. There was also no effect of reducing c-myc on recovery of liver mass following 2/3 partial hepatectomy.
c-Myc appears to be dispensable for normal liver growth during the postnatal period, restoration of liver mass following partial hepatectomy and recovery from fasting.
PMCID: PMC3353165  PMID: 22397685
3.  Development and validation of a stability indicating method for the enantioselective estimation of omeprazole enantiomers in the enteric-coated formulations by high-performance liquid chromatography 
Omeprazole is widely prescribed in the form of enteric-coated formulations, due to the rapid degradation of the drug in the acidic condition of the stomach. In the current article, we are reporting the development and complete validation of a stability indicating chiral high-performance liquid chromatography (HPLC) method for the enantioselective analysis of omeprazole in the enteric-coated formulations. A precise and sensitive enantiomeric separation of omeprazole was obtained on Chiralcel OD-H analytical column (250mm × 4.6 mm, 5μm particle size) using normal phase chromatography. The analysis was performed under UV detection at 301nm wavelength. During method development, the addition of methanol to the mobile phase helped in getting the sharp peaks. The developed method showed linear response over a wide concentration range of 0.39-800μg/ml and the regression coefficients value (r2) was obtained more than 0.999 for (S)- and (R)-omeprazole. The lower limit of detection (LLOD) and lower limit of quantification (LLOQ) for (R)-omeprazole were found to be 0.39 and 0.78 μg/ml, respectively for 5 μl injection volume. The percentage recovery of (R)-omeprazole ranged from 93.5 to 104 in spiked formulation samples and omeprazole sample solution and mobile phase were found to be stable for at least 24 h at room temperature. The proposed method was found to be suitable and accurate for the quantitative determination of undesired enantiomer in the enteric-coated omeprazole formulations.
PMCID: PMC3103931  PMID: 21687365
Enantiomeric purity; method development; normal phase chiral HPLC; omeprazole; pharmaceutical formulations; validation
6.  Subnanoradian X-ray phase-contrast imaging using a far-field interferometer of nanometric phase gratings 
Nature Communications  2013;4:2659.
Hard X-ray phase-contrast imaging characterizes the electron density distribution in an object without the need for radiation absorption. The power of phase contrast to resolve subtle changes, such as those in soft tissue structures, lies in its ability to detect minute refractive bending of X-rays. Here we report a far-field, two-arm interferometer based on the new nanometric phase gratings, which can detect X-ray refraction with subnanoradian sensitivity, and at the same time overcomes the fundamental limitation of ultra-narrow bandwidths (Δλ/λ~10−4) of the current, most sensitive methods based on crystal interferometers. On a 1.5% bandwidth synchrotron source, we demonstrate clear visualization of blood vessels in unstained mouse organs in simple projection views, with over an order-of-magnitude higher phase contrast than current near-field grating interferometers.
Phase-contrast imaging has become popular for medical diagnostic purposes because of the ability to see transparent structures at relatively small radiation energy dosed to samples. Wen et al. further develop this technique using nanometric phase gratings to achieve subnanoradian sensitivity.
PMCID: PMC3831282  PMID: 24189696

Results 1-6 (6)