Background: Apela, a newly identified peptide hormone, is important during zebrafish embryogenesis. Results: Apela binds directly to APJ and acts through the Gi pathway. Apela is expressed exclusively in adult kidney and regulates fluid homeostasis. Conclusion: Apela regulates fluid homeostasis through Gi signaling pathway. Significance: Apela is a kidney ligand more potent than apelin in regulating fluid homeostasis.

The evolutionary model escape from adaptive conflict (EAC) posits that adaptive conflict between the old and an emerging new function within a single gene could drive the fixation of gene duplication, where each duplicate can freely optimize one of the functions. Although EAC has been suggested as a common process in functional evolution, definitive cases of neofunctionalization under EAC are lacking, and the molecular mechanisms leading to functional innovation are not well-understood. We report here clear experimental evidence for EAC-driven evolution of type III antifreeze protein gene from an old sialic acid synthase (SAS) gene in an Antarctic zoarcid fish. We found that an SAS gene, having both sialic acid synthase and rudimentary ice-binding activities, became duplicated. In one duplicate, the N-terminal SAS domain was deleted and replaced with a nascent signal peptide, removing pleiotropic structural conflict between SAS and ice-binding functions and allowing rapid optimization of the C-terminal domain to become a secreted protein capable of noncolligative freezingpoint depression. This study reveals how minor functionalities in an old gene can be transformed into a distinct survival protein and provides insights into how gene duplicates facing presumed identical selection and mutation pressures at birth could take divergent evolutionary paths.Antarctic eelpouts | thermal hysteresis | tandem repeats | positive selection G ene duplication is well-recognized as an important source of new genes and functions (1), but the underlying evolutionary mechanisms are far from clear (2-5). Most conceptual models propose that mutational changes, whether neutral [mutation during nonfunctionality (MDN) or duplication degeneration complementation (DDC) model] (3, 6, 7) or directional (adaptational models) (3, 4), occur in the daughter duplicate after gene duplication, leading to subfunctionalization (partitioning of ancestral functions and specialization in one of them) and in rare instances, a new function (neofunctionalization). An alternate model, escape from adaptive conflict (EAC), recognizes that an ancestor with an emergent function besides its primary function could be subject to selection and acquire adaptive changes before gene duplication, but inadvertent pleiotropic conflicts between the two functions constrain further improvements (6,8). Gene duplication resolves the conflict, allowing daughter duplicates to separately optimize one of the functions (8-10). Resolution of adaptive conflicts created by natural selection as an intrinsic driving force of gene duplication during sub-or neofunctionalization is elegantly logical and may occur frequently, because it potentially applies whenever the ancestor gene experiencing positive selection is a generalist capable of more than one function. In fact, widespread observations of gene sharing and promiscuous function of many enzymes have raised considerable interest in the EAC model (3,11,12). However, thus far, only two studies provided evidence of gene duplication u...

BackgroundGliosarcoma is one of the most common malignant brain tumors, and anti-angiogenesis is a promising approach for the treatment of gliosarcoma. However, chemotherapy is obstructed by the physical obstacle formed by the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB). Honokiol has been known to possess potent activities in the central nervous system diseases, and anti-angiogenic and anti-tumor properties. Here, we hypothesized that honokiol could cross the BBB and BCSFB for the treatment of gliosarcoma.MethodologiesWe first evaluated the abilities of honokiol to cross the BBB and BCSFB by measuring the penetration of honokiol into brain and blood-cerebrospinal fluid, and compared the honokiol amount taken up by brain with that by other tissues. Then we investigated the effect of honokiol on the growth inhibition of rat 9L gliosarcoma cells and human U251 glioma cells in vitro. Finally we established rat 9L intracerebral gliosarcoma model in Fisher 344 rats and human U251 xenograft glioma model in nude mice to investigate the anti-tumor activity.Principal FindingsWe showed for the first time that honokiol could effectively cross BBB and BCSFB. The ratios of brain/plasma concentration were respectively 1.29, 2.54, 2.56 and 2.72 at 5, 30, 60 and 120 min. And about 10% of honokiol in plasma crossed BCSFB into cerebrospinal fluid (CSF). In vitro, honokiol produced dose-dependent inhibition of the growth of rat 9L gliosarcoma cells and human U251 glioma cells with IC50 of 15.61 µg/mL and 16.38 µg/mL, respectively. In vivo, treatment with 20 mg/kg body weight of honokiol (honokiol was given twice per week for 3 weeks by intravenous injection) resulted in significant reduction of tumor volume (112.70±10.16 mm3) compared with vehicle group (238.63±19.69 mm3, P = 0.000), with 52.77% inhibiting rate in rat 9L intracerebral gliosarcoma model, and (1450.83±348.36 mm3) compared with vehicle group (2914.17±780.52 mm3, P = 0.002), with 50.21% inhibiting rate in human U251 xenograft glioma model. Honokiol also significantly improved the survival over vehicle group in the two models (P<0.05).Conclusions/SignificanceThis study provided the first evidence that honokiol could effectively cross BBB and BCSFB and inhibit brain tumor growth in rat 9L intracerebral gliosarcoma model and human U251 xenograft glioma model. It suggested a significant strategy for offering a potential new therapy for the treatment of gliosarcoma.