In vitro, in vivo and ex vivo characterization of ibrutinib: a potent inhibitor of the efflux function of the transporter MRP1.

BACKGROUND AND PURPOSE: The transporter, multidrug resistance protein 1 (MRP1, ABCC1), plays a critical role in the development of multidrug resistance (MDR). Ibrutinib is an inhibitor of Bruton's tyrosine kinase. Here we investigated the reversal effect of ibrutinib on MRP1-mediated MDR. EXPERIMENTAL APPROACH: Cytotoxicity was determined by MTT assay. The expression of protein was detected by Western blot. RT-PCR and Q-PCR were performed to detect the expression of MRP1 mRNA. The intracellular accumulation and efflux of substrates for MRP1 were measured by scintillation counter and flow cytometry. HEK293/MRP1 cell xenografts in nude mice were established to study the effects of ibrutinib in vivo. KEY RESULTS: Ibrutinib significantly enhanced the cytotoxicity of MRP1 substrates in HEK293/MRP1 and HL60/Adr cells overexpressing MRP1. Furthermore, ibrutinib increased the accumulation of substrates in these MRP1-overexpressing cells by inhibiting the drug efflux function of MRP1. However, mRNA and protein expression of MRP1 remained unaltered after treatment with ibrutinib in MRP1-overexpressing cells. In vivo, ibrutinib enhanced the efficacy of vincristine to inhibit the growth of HEK293/MRP1 tumour xenografts in nude mice. Importantly, ibrutinib also enhances the cytotoxicity of vincristine in primary cultures of leukaemia blasts, derived from patients. CONCLUSIONS AND IMPLICATIONS: Our results indicated that ibrutinib significantly increased the efficacy of the chemotherapeutic agents which were MRP1 substrates, in MRP1-overexpressing cells, in vitro, in vivo and ex vivo. These findings will lead to further studies on the effects of a combination of ibrutinib with chemotherapeutic agents in cancer patients overexpressing MRP1.

[Extraction and analysis of solar-induced chlorophyll fluorescence of wheat with ground-based hyperspectral imaging system].

Dataset simulated with FluorMOD and images of wheat in heading stage taken by a ground-based hyperspectral imaging system with 3.3 nm spectral resolution and 0. 71-0. 74 nm spectral sampling interval were used test the feasibility and accuracy of three FLD methods (named FLD, 3FLD and iFLD). The results show that when spectral resolution is 3.3 nm, solar-induced chlorophyll fluorescence could be extracted effectively in O2-A band (around 760 nm) instead of O2-B band (around 687 nm). As to the extraction results of data with noises, both FLD and 3FLD are stabler than iFLD method. The results of FLD tend to be higher than true value.

[Remote sensing of chlorophyll fluorescence at airborne level based on unmanned airship platform and hyperspectral sensor].

The solar-induced chlorophyll fluorescence (ChlF) has a close relationship with photosynthetic and is considered as a probe of plant photosynthetic activity. In this study, an airborne fluorescence detecting system was constructed by using a hyperspectral imager on board an unmanned airship. Both Fraunhofer Line Discriminator (FLD) and 3FLD used to extract ChlF require the incident solar irradiance, which is always difficult to receive at airborne level. Alternative FLD (aFLD) can overcome the problem by selecting non-fluorescent emitter in the image. However, aFLD is based on the assumption that reflectance is identical around the Fraunhofer line, which is not realistic. A new method, a3FLD, is proposed, which assumes that reflectance varies linearly with the wavelength around Fraunhofer line. The result of simulated data shows that ChlF retrieval error of a3FLD is significantly lower than that of aFLD when vegetation reflectance varies near the Fraunhofer line. The results of hyperspectral remote sensing data with the airborne fluorescence detecting system show that the relative values of retrieved ChlF of 5 kinds of plants extracted by both aFLD and a3FLD are consistent with vegetation growth stage and the ground-level ChlF. The ChlF values of aFLD are about 15% greater than a3FLD. In addition, using aFLD, some non-fluorescent objects have considerable ChlF value, while a3FLD can effectively overcome the problem.

C-reactive protein, vitamin B12 and C677T polymorphism of N-5,10-methylenetetrahydrofolate reductase gene are related to insulin resistance and risk factors for metabolic syndrome in Chinese population.

PURPOSE: Metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) are complex diseases affected by both dietary intake and genetic background. Whether N-5, 10-methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism, high-sensitivity C-reactive protein (hs-CRP) and dietary components folate and vitamin B12 are associated with MS in Asian has not been determined. METHODS: We hypothesized that MTHFR gene C677T, folate, vitamin B12 and hs-CRP are associated with MS and factors related to MS in northern Han Chinese. To test this hypothesis, MTHFR C677T gene polymorphism was determined by PCR-RFLP, serum insulin, folate and vitamin B12 levels by radioimmunoassay, and hs-CRP by immunoturbidimetry in newly diagnosed T2DM patients with MS (118) and without MS (40), and in 55 healthy subjects. RESULTS: Results indicated that MS-associated T2DM accounts for 75% of newly diagnosed T2DM in Han Chinese. Serum hs-CRP was higher and serum vitamin B12 was lower in subjects with TT genotype in comparison with those with CC or CT genotypes. Total T frequency was significantly higher in MS-associated T2DM patients (45.3%) compared to 26.3% in non-MS-associated T2DM patients. MTHFR C677T gene polymorphism and vitamin B12 levels were associated with MS-associated T2DM. CONCLUSION: MTHFR C677T gene polymorphism may contribute to insulin resistance in Han Chinese with MS by increasing hs-CRP and decreasing vitamin B12, and consequently play an important role in development of MS-associated T2DM.