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Abstract: Huperzine A (Hup A) is a lycopodium alkaloid from Huperzia serrata, which has been used as a therapeutic agent in several neurological disorders. Despite the diverse pharmacological activities Hup A has, its role in hippocampal neurogenesis remains to be established. This study showed that Hup A not only promoted the proliferation of cultured mouse embryonic hippocampal neural stem cells (NSCs), but also increased the newly generated cells in the subgranular zone (SGZ) of the hippocampus in adult mice. Furthermore, the in vitro findings indicated that low concentrations of Hup A stimulated the proliferation of cultured NSCs, whereas extremely high concentration of it decreased the cell proliferation. Hup A activated mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway, which was a well-known regulator of biological processes including cell proliferation and differentiation. ERK inhibitor dramatically inhibited the proliferative effect of Hup A on NSCs. Administration of Hup A to adult mice significantly enhanced the cell proliferation in dentate gyrus of hippocampus, and increased the remaining newborn cells 4 weeks after the drug administration. Moreover, the newly generated BrdU+/NeuN+ neurons were also increased by Hup A treatment. These findings suggest a novel role of Hup A in neurogenesis and provide a new insight into its therapeutic effects in neurological disorders via a neurogenesis-related mechanism. [Copyright &y& Elsevier]

Abstract: Oxidative stress has been demonstrated to be involved in the pathogenesis of Alzheimer''s disease (AD). Thus, antioxidant therapy may represent a promising avenue for the treatment of AD. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a potent free radical scavenger and has been shown to provide neuroprotection in both animal models of cerebral ischemia and stroke patients. In the present study, we investigated the protective effect of edaravone against AD-relevant insults in neuroblastoma N2a cells and explored the potential mechanisms involved. N2a/Swe.Δ9 cells were used as the AD model cells, which exhibited reduced cell viability, increased apoptosis and oxidative stress as well as decreased mitochondrial membrane potential compared with N2a/Wt cells. All of these phenotypes were significantly reversed by edaravone treatment. Edaravone treatment significantly elevated cell viability, reduced apoptotic rate, attenuated oxidative stress and improved mitochondrial membrane potential in N2a/Swe.Δ9 cells. Furthermore, edaravone treatment inhibited mitochondria-dependent apoptosis pathways in N2a/Swe.Δ9 cells through decreasing the Bax/Bcl-2 ratio, attenuating cytochrome c release and suppressing the activation of caspase-3. These results demonstrate that edaravone provides neuroprotection in an AD-related in vitro model and therefore, may be a potential complement for AD therapy. [Copyright &y& Elsevier]

Abstract Introduction In this study, a new agent consisting of HER2-specific affibody Z HER2:V2 and chemotherapy drug pemetrexed was synthesized to develop a new targeted drug. Its biological characteristics and anticancer efficacy were assessed in cells level and xenografts models by radiolabeling with technetium-99m. Methods After the Z HER2:V2 -pemetrexed conjugate was synthesized, radiolabeling of the conjugate was performed using its C-terminal 4 amino acids (Gly-Gly-Gly-Cys) as the chelating moiety. The radiochemical yield of the [99mTc]Tc-Z HER2:V2 -pemetrexed was identified by instant thin-layer chromatography (ITLC). Stability of the radiolabeled conjugate was investigated both in vitro and in vivo. In vitro binding affinity and cell internalization study of the probe were performed in A549 cells (HER2-positive). Tumor uptake was evaluated by in vitro uptake assay in A549 cells and H23 cells (HER2-negative), and by in vivo biodistribution and SPECT imaging in A549 and H23 tumor-bearing mice. The antitumor efficacy of the Z HER2:V2 -pemetrexed conjugate was evaluated in cells and xenograft models. Results The Z HER2:V2 -pemetrexed was successfully synthesized and conjugated with technetium-99 m, and acquired the radiochemical yield of 97.0 ± 0.3%. The stability of [99mTc]Tc-Z HER2:V2 -pemetrexed was good in both physiological saline and human serum. The radiolabeled agent displayed excellent HER2-binding specificity and affinity in vitro , and was gradually internalized into the cells. Biodistribution study revealed obvious tumor uptake in A549 xenografts (percentage injected dose per gram, 2.6 ± 1.0%ID/g at 4 h postinjection), while the uptake in HER2-negative H23 tumors was much lower (0.2 ± 0.1%ID/g at 4 h postinjection, P < 0.01). SPECT imaging exhibited an intensity in the A549 xenograft which could be blocked by excess Z HER2:V2 -pemetrexed. Treatment with Z HER2:V2 -pemetrexed significantly impaired the tumor growth (P < 0.05), with less weight loss than pemetrexed. Conclusion [99mTc]Tc-Z HER2:V2 -pemetrexed showed desirable property and HER2-specificity. The Z HER2:V2 -pemetrexed conjugate could inhibit tumor growth of HER2-positive lung adenocarcinoma and may have the potential to become a targeted drug for lung cancer. Advances in knowledge and implications for patient care The compound described herein performs HER2-targeting with favorable anticancer efficacy and offers the potential of novel targeting strategies for further tumor therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] • Magmatism formed during the initial stage (ca. 480Ma) and advanced stage (ca. 450Ma) of exhumation of subducted continental crust have been recognized in South Altyn western China. • Two stages of magmatism exhibits evidence for the partial melting of subducted continental crust during differential exhumation process of South Altyn in Palaeozoic. The early Palaeozoic continental subduction–collisional belt in South Altyn (SA) western China distributes a large amount of (ultra)-high-pressure ((U)HP) metamorphic and granitic rocks associated with subduction, collision, and exhumation. In this study, four granitic rocks were collected from Bashenwake located in eastern SA. The ages of the garnet-bearing alkali-feldspar granite (GAFG), garnet-bearing granitic gneiss (GGG), alkali-feldspar granite (AFG), and syenogranite (SG) are 458.0 ± 4.1, 483.0 ± 4.1, 450.0 ± 2.4, and 482.0 ± 4.9 Ma, respectively. Whole-rock major and trace elements and Sr–Nd–Pb isotope, and zircon Hf isotope compositions for all samples exhibit characteristics of a continental crustal source. Based on partial melting modeling, the source temperature of the GGG, GAFG, AFG and SG was concluded as 750–780 °C, 730–760 °C, 730–770 °C and ca. 800 °C, respectively. The source pressure was estimated as ca. 0.8 GPa for the GGG, GAFG and AFG, and ca. 1.2 GPa for SG. Combined with studies on (U)HP metamorphic rocks in SA, this study reveals that GGG is formed by metamorphism while SG is formed from partial melting of upper crustal rocks heated by upwelling mantle during the initial stage of exhumation (ca. 480 Ma) of subducted continental crust in SA. During further stage of exhumation of the subducted continental crust at ca. 450 Ma, the GAFG and AFG were formed from partial melting of GGG as a result of decreased pressure and further mantle upwelling. Consequently, the exhumation age of subducted continental crust in eastern SA is ca. 30 Myr earlier than that in western SA. Thus, the geochronology and petrogenesis of four granitic samples in this study exhibit one of very few evidence for partial melting of subducted continental crust during the exhumation and also provide magmatism exhibits evidence for the differential exhumation model of eastern SA in Palaeozoic. [ABSTRACT FROM AUTHOR]

[Display omitted] • Clockwise P–T evolution is recorded by the South Altyn Tagh felsic gneiss. • The felsic gneiss was exhumed from eclogite-facies to granulite-facies within 20 Myr. • HP–HT eclogite-facies records were preserved in the weakly deformed felsic gneiss. • The HP mineralogical records were further eliminated by the strong deformation. Felsic gneisses are usually the dominant rock types in most high-pressure (HP) and ultrahigh-pressure (UHP) terranes, although their peak metamorphic conditions and complete P–T paths are rarely known. This lack of knowledge is attributed to the high variance of mineral assemblages at HP/UHP conditions of the felsic gneisses, or to the effects of retrograde-related overprinting. Thus, it is difficult to distinguish whether felsic gneisses underwent HP/UHP metamorphism. In this paper, we focus on the felsic gneiss that has been previously documented as having formed under HP granulite-facies metamorphism with peak P–T of > 1.15 GPa and > 860 °C from the Danshuiquan locality in the South Altyn HP – UHP belt. The Danshuiquan felsic gneiss is strongly deformed and is spatially associated with weakly deformed garnet-rich felsic gneiss. On the basis of detailed microstructure observations on mineral assemblages and phase equilibria modelling, three stages of metamorphic evolution for the weakly deformed garnet-rich felsic gneiss are identified. The first stage is represented by garnet cores, revealing a prograde P–T path from 1.5 GPa/750 °C to 2.1 GPa/900 °C. The second stage is characterized by garnet mantles with multiphase inclusions, defining HP eclogite-facies metamorphic conditions of 2.2–2.6 GPa/950–1100 °C. The third stage is represented by the composition of garnet rims, biotite, and plagioclase, suggesting an HP granulite to amphibolite facies decompression cooling process to 1.1–1.3 GPa/710–770 °C. In contrast, the strongly deformed felsic gneiss just records a deformation-related decompression process from 1.1 to 1.2 GPa/750–760 °C to 0.87–0.98 GPa/760–770 °C, and finally to 0.83 GPa/740 °C. Zircon U–Pb dating yields c. 920 Ma protolith ages, c. 500 Ma eclogite-facies ages, and c. 480 Ma granulite to amphibolite facies retrograde ages for the Danshuiquan felsic gneisses. Our results show that the Danshuiquan felsic gneisses underwent a similar metamorphic evolution process to that of Yinggelisayi HP–UHP rocks in the eastern segment of the South Altyn Tagh. Most HP mineralogical records tend to be eliminated by the strong deformation at crustal depths (∼30 km), meaning that the peak metamorphic conditions of the studied felsic rocks in UHP metamorphic terranes are previously underestimated. [ABSTRACT FROM AUTHOR]

Abstract: β- and γ-secretase cleave the amyloid precursor protein (APP) to release the amyloidogenic β-amyloid peptides (Aβ) and the APP intracellular domain (AICD). Aβ has been widely believed to initiate pathogenic cascades culminating in Alzheimer''s disease (AD). However, the physiological functions of the AICD remain elusive. In this study, we found the AICD to strongly inhibit Wnt-induced transcriptional reporter activity, and to counteract Wnt-induced c-Myc expression. Loss of the AICD resulted in an increased responsiveness to Wnt/β-catenin-mediated transcription. Mechanically, the AICD was found to interact with glycogen synthase kinase 3 beta (GSK3β) and promote its kinase activity. The subsequent AICD-strengthened Axin–GSK3β complex potentiates β-catenin poly-ubiquitination. Functional studies in N2a mouse neuroblastoma cells, rat pheochromocytoma PC12 cells and primary neurons showed that the AICD facilitated neurite outgrowth. And AICD antagonised Wnt3a-suppressed growth arrest and neurite outgrowth in N2a and PC12 cells. Taken together, our results identify the AICD as a novel inhibitory factor of the canonical Wnt signalling pathway and suggest its regulatory role in neuronal cell proliferation and differentiation. [Copyright &y& Elsevier]

[Display omitted] • The mafic granulites in the Kuruksayi area were derived from overprinted eclogites. • Phase modeling suggests that such mafic granulites have undergone UHP metamorphism. • P - T conditions recorded in mafic granulites are comparable to that in HP/UHP eclogites. The South Altyn high-pressure–ultrahigh-pressure (HP–UHP) metamorphic belt in West China records the processes of deep continental subduction (>150–300 km). The HP mafic granulite pods hosted by massive granitic gneiss were for the first time discovered in the Kuruksayi area of the South Altyn Orogen, and they consist mainly of garnet, clinopyroxene, plagioclase, hornblende, biotite, and quartz, with minor rutile, ilmenite, and K-feldspar. The garnets vary in grain size and chemical zoning, and can be divided into three types: subhedral porphyroblastic (g 1), anhedral porphyroblastic (g 2), and neoblastic fine (g 3) grains. Four generations of mineral assemblage (M1–M4) are recognized, and are used to constrain the P–T evolution of the mafic granulites using phase equilibria modeling calculated by THERMOCALC. The first generation (M1) is represented by the core domains of g 1 (g 1C) that have inclusions of rutile and quartz and conspicuous chemical zoning. A pre-peak prograde stage of metamorphism from ~ 15.8 kbar/600 °C to ~ 19.2 kbar/655 °C is recorded by g 1C. The second generation (M2) is inferred to consist of garnet + omphacite + phengite + rutile + quartz and is recorded in the mantle domains of g 1 (g 1M). Modeling suggests that this is representative of conditions that reached a maximum P–T of ~ 36.2 kbar/920 °C. The third generation (M3) is characterized by intergrowths of clinopyroxene + plagioclase and biotite + plagioclase, and this stage is recorded by the compositions of g 2 with modeling suggesting an evolution from ~ 17.8 kbar/820 °C to ~ 11.5 kbar/826 °C, consistent with near-isothermal decompression. The last generation (M4) is characterized by kelyphitic rims of plagioclase + hornblende around garnet and the hornblende coronas that encompass symplectitic clinopyroxene, and is recorded by the compositions of g 3. Modeling suggests evolution from ~ 11.5 kbar/826 °C to ~ 8.7 kbar/735 °C, compatible with near-isobaric cooling. These four stages of metamorphism together establish a clockwise P–T path, which indicates a series of tectonic processes that took the continental slab from subduction to exhumation. Zircon U–Pb dating by LA–ICP–MS yielded two distinct clusters of ages: c. 897 Ma magmatic protolith ages and c. 494 Ma metamorphic ages. The metamorphic ages are interpreted to represent the timing of the eclogite-facies metamorphism, and are similar to the metamorphic ages of other HP/UHP rocks elsewhere in the South Altyn Orogen. Accordingly, we propose that the Kuruksayi mafic granulites underwent UHP metamorphism similar to that recorded in other South Altyn eclogites exposed in Jianggalesayi and Danshuiquan to the west and Yinggelisayi to the east. [ABSTRACT FROM AUTHOR]