Floral transition is influenced by environmental factors such as light and temperature. Plants are capable of integrating photoperiod and ambient temperature signaling into their developmental program. Despite extensive investigations on individual genetic pathways, little is known about the molecular components that integrate both pathways. Here, we demonstrate that the RING finger–containing E3 ubiquitin ligase CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1) acts as an integrator of photoperiod and ambient temperature signaling. In addition to the role in photoperiodic destabilization of CONSTANS (CO), COP1 also regulates temperature sensitivity by controlling the degradation of GIGANTEA (GI). COP1-impaired mutants showed reduced sensitivity to low ambient temperature. Notably, COP1 is more stabilized at low temperature and accelerates GI turnover in a 26S proteasome-dependent manner. The direct association of GI with the promoter of FLOWERING LOCUS T (FT) was reduced because of its ambient temperature-dependent protein stability control, and thus COP1-triggered GI turnover delays flowering at low temperatures via a CO-independent pathway. Taken together, our findings indicate that environmental conditions regulate the stability of COP1, and conditional specificity of its target selection stimulates proper developmental responses and ensures reproductive success.
Sibutramine [1-(4-chlorophynyl)-N,N-dimethyl-a-(2-methylpropyl)cyclobutane methane amine] is a newer antiobesity drug with a novel mechanism of action.1) It contains a potent inhibitor of the reuptake of noradrenaline (NA), serotonin (5-HT) and may stimulate thermogenesis by its activation of b 3 -adrenoceptors in brown adipose tissue. [2][3][4] In human subjects, sibutramine is rapidly metabolized to an Nmono-desmethyl metabolite (desmethylsibutramine [Metabolite I]) and an N,N-didesmethyl metabolite (didesmethylsibutramine [Metabolite II]). The in vivo effects of sibutramine are predominantly the results of the action of the above 2 metabolites. 4-7)Sibutramine hydrochloride monohydrate is the commercially available formulation of sibutramine with the relatively high solubility of 2.9 mg/ml at pH 5.2 and melting point of 190°C. 4,8) However, sibutramine base with low solubility has not been used in commercial formulation. Various oral formulations of sibutramine such as another salt form such as sibutramine mesylate 9,10) and sibutramine tartrate, 11) solid dispersions with poloxamer [12][13][14] and inclusion complex. 15)One of the well established method for increasing the solubility and bioavailability of poorly water-soluble drugs is solid dispersion.16) Several conventional methods such as melting, solvent evaporation and solvent wetting were reported to prepare solid dispersions. 17,18) However, the solid dispersion prepared by melting method with high temperature might chemically decompose the drugs. 19,20) In the case of solvent evaporation and solvent wetting method, the drug in the solid dispersions changed to amorphous form, resulting that the drug might be unstable. 18) Furthermore, a large amount of hydrophilic carriers against drug in these conventional solid dispersions must be needed to improve the solubility of poorly water-soluble drugs. 21,22) In this study, to improve the bioavailability of poorly water-soluble sibutramine base, various sibutramine baseloaded solid dispersions were prepared with water, hydroxypropylmethyl cellulose (HPMC), poloxamer and citric acid using spray-drying technique. The effect of HPMC, poloxamer and citric acid on the aqueous solubility of sibutramine was then investigated. The physicochemical properties of solid dispersion were investigated using scanning electron microscope (SEM), differential scanning calorimetry (DSC) and X-ray powder diffraction. The dissolution and pharmacokinetics in rats of solid dispersion were evaluated compared to the sibutramine hydrochloride monohydrate-loaded commercial product (Reductil ® ). This commercial product is a conventional capsule which contains 100 mg sibutramine hydrochloride monohydrate and is usually taken multiple times a day. Poloxamer has been employed to enhance the solubility and bioavailability of poorly water-soluble drugs. 19,23) HPMC is frequently used in the preparation of conventional pharmaceutical oral dosage form due to its hydrophilic and soft property. 24,25) To develop a novel sibutramine base-...
To develop a piroxicam-loaded gelatin microcapsule with enhanced bioavailability, a gelatin microcapsule encapsulated ethanol and piroxicam has been formulated by using gelatin as a water-soluble polymer shell. The aqueous solubility and bioavailability of piroxicam in piroxicam-loaded microcapsule in rats were then evaluated compared to piroxicam powder. The piroxicam-loaded gelatin microcapsule spherical in shape with smooth surface showed the geometric mean diameter of about 19 m mm. It had the piroxicam solubility of about 1.87 mg/ml and the amount of ethanol of about 4.37 m mg/mg. Furthermore, it gave significantly higher total plasma concentrations, C max and area under the blood concentration-time curve (AUC ) of piroxicam in rats than did piroxicam powder, indicating that the drug from gelatin microcapsule could be more orally absorbed in rats. In particular, the AUC of piroxicam in gelatin microcapsule was significantly about 2 fold increased compared to piroxicam powder. This enhanced oral relative bioavailability of piroxicam in gelatin microcapsule was contributed by the marked increase in the absorption rate of piroxicam due to the improved solubility of piroxicam. Thus, the piroxicam-loaded gelatin microcapsule developed using spray-drying technique with gelatin, sodium lauryl sulfate and ethanol would be useful to deliver piroxicam in a pattern that allows fast absorption in the initial phase, leading to better absorption.
The circadian clock is a biological time keeper mechanism that regulates biological rhythms to a period of approximately 24 h. The circadian clock enables organisms to anticipate environmental cycles and coordinates internal cellular physiology with external environmental cues. In plants, correct matching of the clock with the environment confers fitness advantages to plant survival and reproduction. Therefore, circadian clock components are regulated at multiple layers to fine-tune the circadian oscillation. Epigenetic regulation provides an additional layer of circadian control. However, little is known about which chromatin remodeling factors are responsible for circadian control. In this work, we analyzed circadian expression of 109 chromatin remodeling factor genes and identified 17 genes that display circadian oscillation. In addition, we also found that a candidate interacts with a core clock component, supporting that clock activity is regulated in part by chromatin modification. As an initial attempt to elucidate the relationship between chromatin modification and circadian oscillation, we identified novel regulatory candidates that provide a platform for future investigations of chromatin regulation of the circadian clock.
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