Search

Glycogen synthase kinase-3β (GSK-3β) is an important serine/threonine kinase that implicates in multiple cellular processes and links with the neurodegenerative diseases including Alzheimer's disease (AD). In this study, structure-based virtual screening was performed to search database for compounds targeting GSK-3β from Enamine's screening collection. Of the top-ranked compounds, 7 primary hits underwent a luminescent kinase assay and a cell assay using human neuroblastoma SH-SY5Y cells expressing Tau repeat domain (Tau

Decreased BDNF and impaired TRKB signaling contribute to neurodegeneration in Alzheimer's disease (AD). We have shown previously that coumarin derivative LM-031 enhanced CREB/BDNF/BCL2 pathway. In this study we explored if LM-031 analogs LMDS-1 to -4 may act as TRKB agonists to protect SH-SY5Y cells against Aβ toxicity. By docking computation for binding with TRKB using 7,8-DHF as a control, all four LMDS compounds displayed potential of binding to domain d5 of TRKB. In addition, all four LMDS compounds exhibited anti-aggregation and neuroprotective efficacy on SH-SY5Y cells with induced Aβ-GFP expression. Knock-down of TRKB significantly attenuated TRKB downstream signaling and the neurite outgrowth-promoting effects of these LMDS compounds. Among them, LMDS-1 and -2 were further examined for TRKB signaling. Treatment of ERK inhibitor U0126 or PI3K inhibitor wortmannin decreased p-CREB, BDNF and BCL2 in Aβ-GFP cells, implicating the neuroprotective effects are via activating TRKB downstream ERK, PI3K-AKT and CREB signaling. LMDS-1 and -2 are blood-brain barrier permeable as shown by parallel artificial membrane permeability assay. Our results demonstrate how LMDS-1 and -2 are likely to work as TRKB agonists to exert neuroprotection in Aβ cells, which may shed light on the potential application in therapeutics of AD.

We present integrated in situ zircon U–Pb and Hf isotope data, along with whole-rock Sr–Nd isotope and geochemical data for plutonic rocks of the Lohit Plutonic Complex of eastern Himalaya to understand the age distribution and petrogenetic–tectonic evolution of the Transhimalayan batholiths in the eastern Himalaya. The plutonic rocks are gabbro, diorite and quartz-diorite in composition, have calc-alkaline signatures with metaluminous character and have an affinity with Gangdese I-type granitoids of southern Tibet. The enrichment of large ion lithophile elements with highly depleted negative Nb anomalies is consistent with their origin in a subduction-related environment. Our laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) zircon U–Pb ages suggest that two major stages of magmatic emplacement took place at c. 145 Ma (Early Cretaceous) for gabbro and c. 100–90 Ma (early Late Cretaceous) for diorite and quartz-diorite. The zircon Hf isotopes in both the gabbro and diorite samples show high positive eHf(t) values between +11 and +20, suggesting crystallization from juvenile crust or depleted mantle derived melts, as also constrained by the low initial 87Sr/86Sr ratios (0.7038–0.7045) and high positive eNd(t) values (+2.9 to +5.9). Results of REE modelling indicate that the source of these rocks is garnet lherzolite. Field observations and mineralogical and geochemical characteristics in conjunction with the isotopic database suggest that the Transhimalayan magmatic rocks in eastern Himalaya were generated by partial melting of the lithospheric mantle wedge and emplaced into the lower crust (c. 25–30 km) during at least two major magmatic events that took place in the Cretaceous period. Supplementary material: LA-ICP-MS zircon U–Pb and Hf isotope data are available at https://doi.org/10.6084/m9.figshare.c.4665305

The pathogenesis of Alzheimer's disease (AD) is involved in the aggregation of misfolded amyloid β (Aβ), which upregulates the activity of acetylcholinesterase (AChE), increases the production of reactive oxygen species (ROS), enhances neuroinflammation, and eventually leads to neuronal death. Therefore, compounds targeting these mechanisms may be candidates for multitarget drugs in AD treatment. We found that two quinoline derivatives, VB-030 and VB-037, markedly reduced Aβ aggregation and ROS levels in the thioflavin T biochemical assay and Tet-On Aβ-green fluorescent protein (GFP) 293 AD cell model. These compounds further improved neurite outgrowth, reduced AChE activity and upregulated the molecular chaperone heat shock protein family B [small] member 1 (HSP27), whereas knockdown of HSP27 counteracted the compounds' neuroprotective effects on the Tet-On Aβ-GFP SH-SY5Y AD neuronal model. Furthermore, VB-037 attenuated lipopolysaccharide (LPS)/interferon (IFN)-γ-induced activation of BV-2 microglial cells. In addition, VB-037 demonstrated its potential to diminish LPS/IFN-γ-induced upregulation of caspase 1 activity, expression of interleukin (IL)-1β, and active phosphorylation of mitogen-activated protein kinase 14 (P38), mitogen-activated protein kinase 8 (JNK), and Jun proto-oncogene, AP-1 transcription factor subunit (JUN) signalings, as well as improve cell viability in the Tet-On Aβ-GFP SH-SY5Y AD neuronal model. Our findings strongly indicate the potential of VB-037 for modifying AD progression by targeting multiple mechanisms, thereby offering a new drug development avenue for AD treatment.

Abnormal accumulations of misfolded Aβ and tau proteins are major components of the hallmark plaques and neurofibrillary tangles in the brains of Alzheimer’s disease (AD) patients. These abnormal protein deposits cause neurodegeneration through a number of proposed mechanisms, including downregulation of the cAMP-response-element (CRE) binding protein 1 (CREB) signaling pathway. Using CRE-GFP reporter cells, we investigated the effects of three coumarin-chalcone derivatives synthesized in our lab on CREB-mediated gene expression. Aβ-GFP- and ΔK280 tauRD-DsRed-expressing SH-SY5Y cells were used to evaluate these agents for possible antiaggregative, antioxidative, and neuroprotective effects. Blood-brain barrier (BBB) penetration was assessed by pharmacokinetic studies in mice. Of the three tested compounds, (E)-3-(3-(4-(dimethylamino)phenyl)acryloyl)-4-hydroxy-2H-chromen-2-one (LM-021) was observed to increase CREB-mediated gene expression through protein kinase A (PKA), Ca2+/calmodulin-dependent protein kinase II (CaMKII), and extracellular signal-regulated kinase (ERK) in CRE-GFP reporter cells. LM-021 exhibited antiaggregative, antioxidative, and neuroprotective effects mediated by the upregulation of CREB phosphorylation and its downstream brain-derived neurotrophic factor and BCL2 apoptosis regulator genes in Aβ-GFP- and ΔK280 tauRD-DsRed-expressing SH-SY5Y cells. Blockage of the PKA, CaMKII, or ERK pathway counteracted the beneficial effects of LM-021. LM-021 also exhibited good BBB penetration ability, with brain to plasma ratio of 5.3%, in in vivo pharmacokinetic assessment. Our results indicate that LM-021 works as a CREB enhancer to reduce Aβ and tau aggregation and provide neuroprotection. These findings suggest the therapeutic potential of LM-021 in treating AD.

Microtubule‐associated protein Tau, abundant in the central nervous system (CNS), plays crucial roles in microtubule assembly and stabilization. Abnormal Tau phosphorylation and aggregation are a common pathogenic hallmark in Alzheimer's disease (AD). Hyperphosphorylation of Tau could change its conformation and result in self‐aggregation, increased oxidative stress, and neuronal death. In this study, we examined the potential of licochalcone A (a natural chalcone) and five synthetic derivatives (LM compounds) for inhibiting Tau misfolding, scavenging reactive oxygen species (ROS) and providing neuroprotection in human cells expressing proaggregant ΔK280 TauRD‐DsRed. All test compounds were soluble up to 100 μM in cell culture media and predicted to be orally bioavailable and CNS‐active. Among them, licochalcone A and LM‐031 markedly reduced Tau misfolding and associated ROS, promoted neurite outgrowth, and inhibited caspase 3 activity in ΔK280 TauRD‐DsRed 293 and SH‐SY5Y cells. Mechanistic studies showed that LM‐031 upregulates HSPB1 chaperone, NRF2/NQO1/GCLC pathway, and CREB‐dependent BDNF/AKT/ERK/BCL2 pathway in ΔK280 TauRD‐DsRed SH‐SY5Y cells. Decreased neurite outgrowth upon induction of ΔK280 TauRD‐DsRed was rescued by LM‐031, which was counteracted by knockdown of NRF2 or CREB. LM‐031 further rescued the downregulated NRF2 and pCREB, reduced Aβ and Tau levels in hippocampus and cortex, and ameliorated cognitive deficits in streptozocin‐induced hyperglycemic 3 × Tg‐AD mice. Our findings strongly indicate the potential of LM‐031 for modifying AD progression by targeting HSPB1 to reduce Tau misfolding and activating NRF2 and CREB pathways to suppress apoptosis and promote neuron survival, thereby offering a new drug development avenue for AD treatment., Through upregulating HSPB1 chaperone to reduce Tau misfolding, and enhancing NRF2 and CREB pathways to reduce ROS and apoptosis in ΔK280 TauRD‐DsRed SH‐SY5Y cells, as well as promoting neuron survival and cognitive function in hyperglycemic 3×Tg‐AD mice, LM‐031 (3‐benzoyl‐5‐hydroxychromen‐2‐one) displays potential for Alzheimer’s disease treatment.

Before the India–Asia collision, Neotethyan subduction gave rise to an Andean-type convergent margin on the southern margin of Asia. To investigate the spatial and temporal distribution of the subduction-related magmatism, we undertook a combined determination of zircon U–Pb ages and Hf isotopes of Mesozoic to Paleogene intrusive and volcanic rocks from southern Tibet to Myanmar to characterize the two parallel magmatic belts that have previously been considered separately. One belt extends from the Gangdese Batholith in the Southern Lhasa sub-terrane to the Lohit Batholith, the Sodon Pluton and the Popa–Loimye Arc in the West Burma Block, and the other from the Central Lhasa Plutonic Belt to the Bomi–Chayu Batholith, the Dianxi Batholith and the Shan Scarps Batholith in central Myanmar. The Gangdese belt, as the main arc component, consists typically of I-type granitoids that contain magmatic zircons showing positive eHf(t) values. In contrast, the Central Lhasa Plutonic Belt belt is dominated by S-type granites in which most zircons show negative eHf(t) values suggesting the involvement of older continental crust in their petrogenesis. The distinct geochemical characteristics indicate not only distinct tectonic settings of their genesis but also the diverse nature of the crust forming the exotic continental ribbons amalgamated to Asia. Supplementary material: Details of sample locations and analytical results are available at: https://doi.org/10.6084/m9.figshare.c.4311485

Nine autosomal dominant spinocerebellar ataxias (SCAs) are caused by an abnormal expansion of CAG trinucleotide repeats that encodes a polyglutamine (polyQ) tract within different genes. Accumulation of aggregated mutant proteins is a common feature of polyQ diseases, leading to progressive neuronal dysfunction and degeneration. SCA type 3 (SCA3), the most common form of SCA worldwide, is characterized by a CAG triplet expansion in chromosome 14q32.1 ATXN3 gene. As accumulation of the mutated polyQ protein is a possible initial event in the pathogenic cascade, clearance of aggregated protein by ubiquitin proteasome system (UPS) has been proposed to inhibit downstream detrimental events and suppress neuronal cell death. In this study, Chinese herbal medicine (CHM) extracts were studied for their proteasome-activating, polyQ aggregation-inhibitory and neuroprotective effects in GFPu and ATXN3/Q[Formula: see text]-GFP 293/SH-SY5Y cells. Among the 14 tested extracts, 8 displayed increased proteasome activity, which was confirmed by 20S proteasome activity assay and analysis of ubiquitinated and fused GFP proteins in GFPu cells. All the eight extracts displayed good aggregation-inhibitory potential when tested in ATXN3/Q[Formula: see text]-GFP 293 cells. Among them, neuroprotective effects of five selected extracts were shown by analyses of polyQ aggregation, neurite outgrowth, caspase 3 and proteasome activities, and ATXN3-GFP, ubiquitin, BCL2 and BAX protein levels in neuronal differentiated ATXN3/Q[Formula: see text]-GFP SH-SY5Y cells. Finally, enhanced proteasome function, anti-oxidative activity and neuroprotection of catalpol, puerarin and daidzein (active constituents of Rehmannia glutinosa and Pueraria lobata) were demonstrated in GFPu and/or ATXN3/Q[Formula: see text]-GFP 293/SH-SY5Y cells. This study may have therapeutic implication in polyQ-mediated disorders.

A geochemical study was undertaken on basaltic lava flows intercalated with Oligocene to Miocene strata in the Sabzevar region, northern Iran, to examine their petrogenesis in a regional tectonic framework. The lavas are either aphyric or have phenocrysts and micro-phenocrysts of olivine and, to a lesser extent, clinopyroxene. Geochemically, the lavas are silica-undersaturated alkali basalts characterized by relatively high Mg# (~ 57–66) and Na2O/K2O (~ 2.0–6.7). They have distinctive trace element patterns characterized by strong rare-earth element fractionation, negative Nb–Ta and Zr-Hf anomalies and a positive Sr anomaly. Significant contamination by crustal materials either in the magma source or during ascent is ruled out on the basis of trace element compositions and Sr–Nd isotopic compositions (87Sr/86Sr = 0.7037–0.7048 and 143Nd/144Nd = 0.5128–0.5130), both of which differ markedly from continental crustal rocks. Phenocryst assemblage, analysis of multiple saturation points in lherzolite systems, and covariations of La/Yb with MgO of the studied lavas are generally consistent with an origin involving high-pressure fractionation of peridotite-derived melts. Primary magma compositions calculated by reversed fractionation of clinopyroxene and olivine for the relatively primitive samples (> 9 wt.% MgO), however, do not plot on the lherzolite multiple saturation points. Also, high-pressure fractionation predicts increasing trends of silica undersaturation and alkalinitiy with differentiation, and such trends are not indicated by the geochemical data. We suggest that the mixed trends shown by the data might be related to melt generation from both peridotite and silica-deficient pyroxenite sources, superimposed by variable degrees of high-pressure fractionation. The role of pyroxenite in magma genesis is indicated not only by the positive Sr anomaly shown by the trace element patterns, but also first-row transition element systematics of the studied lavas. The silica-deficient pyroxenites contributing to melt generation might have been transformed from mafic–ultramafic cumulates in subducted, lower oceanic crust, or might have formed in the lower crust or mantle lithosphere under continents during earlier magmatic episodes.

Spinocerebellar ataxia type 17 (SCA17) is caused by a CAG/CAA expansion mutation encoding an expanded polyglutamine (polyQ) tract in TATA-box binding protein (TBP), a general transcription initiation factor. Suppression of cAMP-responsive element binding protein- (CREB-) dependent transcription, impaired nuclear factor erythroid 2-related factor 2 (NRF2) signaling, and interaction of AMP-activated protein kinase (AMPK) with increased oxidative stress have been implicated to be involved in pathogenic mechanisms of polyQ-mediated diseases. In this study, we demonstrated decreased pCREB and NRF2 and activated AMPK contributing to neurotoxicity in SCA17 SH-SY5Y cells. We also showed that licochalcone A and the related in-house derivative compound 3-benzoyl-5-hydroxy-2H-chromen-2-one (LM-031) exhibited antiaggregation, antioxidative, antiapoptosis, and neuroprotective effects in TBP/Q79-GFP-expressing cell models. LM-031 and licochalcone A exerted neuroprotective effects by upregulating pCREB and its downstream genes, BCL2 and GADD45B, and enhancing NRF2. Furthermore, LM-031, but not licochalcone A, reduced activated AMPKα. Knockdown of CREB and NRF2 and treatment of AICAR (5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside), an AMPK activator, attenuated the aggregation-inhibiting and neurite outgrowth promoting effects of LM-031 on TBP/Q79 SH-SY5Y cells. The study results suggest the LM-031 as potential therapeutics for SCA17 and probable other polyQ diseases.

The initiation and duration of magmatism in the Tatun Volcano Group (TVG), likely resulting from extensional collapse of the northern Taiwan mountain belt, remains an important issue of debates in the Taiwan orogeny. Here we report a detailed study of U-Pb ages determined by SIMS and LA-ICPMS, together with Hf isotopic data, of zircon separates from a total of 22 extrusive rocks from the TVG lava flow and additional two andesites from Keelungyu (KLY), a volcanic islet off NE Taiwan. Magmatic zircons from the TVG are characterized by uniform and high Hf isotopic ratios, with eHf(T) mostly from +20 to +10. Their overall 206Pb/238U ages suggest that the TVG magmatism was initiated ∼3 Ma but more active ≤0.8 Ma with a flare up ≤0.35 Ma. Magmatic zircons from the two KLY samples reveal identical 206Pb/238U ages (0.41 Ma), coupled with Hf isotopes [eHf(T): +25 to +9] comparable to those of the TVG. Thus, KLY is proposed as part of the TVG. Consequently, we argue that the main body of the TVG formed ≤0.8 Ma by post-collisional volcanism, but the mechanism resulting in the magmatic episodes ≥1.0 Ma remains obscure due to the scarcity of rock exposures.

The origin and geodynamic setting of the Maden Complex, which is situated in the Bitlis-Zagros Suture Zone in the Southeast Anatolian Orogenic Belt, is still controversial due to lack of systematic geological and geochemical data. Here we present new whole rock major-trace-rare earth element and Sr-Nd isotope data from the Middle Eocene volcanic rocks exposed in Maden Complex and discuss their origin in the light of new and old data. The volcanic lithologies are represented mainly by basalt and andesite, and minor dacite that vary from low-K tholeiitic, calc-alkaline, high-K calc-alkaline, and shoshonitic in composition. They exhibit enrichments in large ion lithophile and light rare earth elements, with depletions in high field strength elements. Basaltic rocks have uniform Sr and Nd isotope ratios with high epsilon(Nd)(t) values varying from +5.5 to +6.7, in contrast to, andesitic rocks are characterized by low epsilon(Nd)(t) values ranging from -1.6 to -10. These geochemical and isotopic characteristics indicate that two end-members, a subduction-related mantle source and a continental crust, were involved in the magma genesis. Considering all geological and geochemical data, we suggest that the Eocene Maden magmatism occurred as a post-collisional product by asthenospheric upwelling owing to convective removal of the lithosphere during an extensional collapse of the Southeast Anatolian ranges. (C) 2017, China University of Geosciences (Beijing) and Peking University. Production and hosting by Elsevier B. V.

Spinocerebellar ataxia type 17 (SCA17) is caused by the expansion of translated CAG repeat in the TATA box binding protein (TBP) gene encoding a long polyglutamine (polyQ) tract in the TBP protein, which leads to intracellular accumulation of aggregated TBP and cell death. The molecular chaperones act in preventing protein aggregation to ameliorate downstream harmful events. In this study, we used Tet-On cells with inducible SCA17 TBP/Q79-GFP expression to test five in-house NC009 indole compounds for neuroprotection. We found that both aggregation and polyQ-induced reactive oxygen species can be significantly prohibited by the tested NC009 compounds in Tet-On TBP/Q79 293 cells. Among the five indole compounds, NC009-1 up-regulated expression of heat shock protein family B (small) member 1 (HSPB1) chaperone to reduce polyQ aggregation and promote neurite outgrowth in neuronal differentiated TBP/Q79 SH-SY5Y cells. The increased HSPB1 thus ameliorated the increased BH3 interacting domain death agonist (BID), cytochrome c (CYCS) release, and caspase 3 (CASP3) activation which result in apoptosis. Knock down of HSPB1 attenuated the effects of NC009-1 on TBP/Q79 SH-SY5Y cells, suggesting that HSPB1 might be one of the major pathways involved for NC009-1 effects. NC009-1 further reduced polyQ aggregation in Purkinje cells and ameliorated behavioral deficits in SCA17 TBP/Q109 transgenic mice. Our results suggest that NC009-1 has a neuroprotective effect on SCA17 cell and mouse models to support its therapeutic potential in SCA17 treatment.

To understand the geological control and tectonic forcing on the development of a major river system in SE Asia, new detrital zircon U-Pb and Hf isotopic data from the Salween drainage, Myanmar is reported. Three samples with a range of deposition ages corresponding to different tectonic periods of the Sibumasu Terrane reveal a dramatic change in the drainage system. Differing from the detrital compositions of modern sediments from the Salween river mouth, a Late Triassic sandstone sample shows zircon age distribution implying that the Salween drainage may have been connected at that time to the northeastern part of the Songpan-Ganzi Terrane and western part of the South China Block. U-Pb ages and ɛHf(T) isotopic data of detrital zircons from other major rivers in SE Asia, including the Yangtze, Red, and Mekong Rivers in the east and the Irrawaddy River and the Yalu-Tsangpo in the west are further synthesized. A marked discrepancy in zircons younger than Jurassic ages is identified. Similar to results from the Salween samples, these young zircons from the eastern rivers are overwhelmed by an old, recycled crustal component exhibiting negative ɛHf(T) values. In contrast, those from the western rivers are dominated by juvenile components that are characterized by high and positive ɛHf(T) values. The Salween drainage, therefore, lies in the frontier with its western outline broadly depicting the boundary between mature and juvenile crustal provinces in SE Asia.

The Early Palæogene Silhouette/North Island volcano-plutonic complex was emplaced during the rifting of the Seychelles microcontinent from western India. The complex is thought to have been emplaced during magnetochron C28n. However, the magnetic polarities of the rocks are almost entirely reversed and inconsistent with a normal polarity. In this study we present new in situ zircon U/Pb geochronology of the different intrusive facies of the Silhouette/North Island complex in order to address the timing of emplacement and the apparent magnetic polarity dichotomy. The rocks from Silhouette yielded weighted mean 206Pb/238U ages from 62.4 ± 0.9 Ma to 63.1 ± 0.9 Ma whereas the rocks from North Island yielded slightly younger mean ages between 60.6 ± 0.7 Ma to 61.0 ± 0.8 Ma. The secular latitudinal variation from Silhouette to North Island is consistent with the anticlockwise rotation of the Seychelles microcontinent and the measured polarities. The rocks from Silhouette were emplaced across a polarity cycle (C26r-C27n-C27r) and the rocks from North Island were emplaced entirely within a magnetic reversal (C26r). Moreover, the rocks from North Island and those from the conjugate margin of India are contemporaneous and together mark the culmination of rift-related magmatism.

This paper reports the first systematic analysis of age and geochemical variations in volcanic rocks from the Coastal Range of Taiwan, the Northern Luzon Arc. The rocks, recovered from four main volcanoes, vary from low-K tholeiitic to medium-K calc-alkaline basalts to dacites. The rocks are typical of arc magmatic products, exhibiting enrichment in the large ion lithophile elements and depletion in the high field strength elements. Our new 40Ar/39Ar age data constrain the youngest eruption time in each of the four volcanoes, i.e., from north to south, at ~ 7.2 Ma (Yuemei), ~ 4.2 Ma (Chimei), ~ 6.2 Ma (Chengkuang'ao) and ~ 8.5 Ma (Tuluanshan), respectively. These data indicate that volcanism in the Northern Luzon Arc did not cease progressively from north to south, as previously alleged. The high and broadly uniform Nd isotope ratios [eNd = + 10.1 to + 8.8] and trace element characteristics of the rocks suggest a principal magma source from the depleted mantle wedge. Their overall geochemical variations are ascribed to magma chamber processes. The effects of magmatic differentiation and crustal contamination differ among each volcano, most likely owing to the discrepancy of residence time in individual magma chambers. Consequently, we propose a binary mixing model for the magma generation that involves arc magmas sourced from the depleted mantle wedge and up to ~ 5% crustal contamination with a continental fragment split off from the Eurasian margin.

Polyglutamine (polyQ)-mediated spinocerebellar ataxias (SCA) are caused by mutant genes with expanded CAG repeats encoding polyQ tracts. The misfolding and aggregation of polyQ proteins result in increased reactive oxygen species (ROS) and cellular toxicity. Inflammation is a common manifestation of oxidative stress and inflammatory process further reduces cellular antioxidant capacity. Increase of activated microglia in the pons of SCA type 3 (SCA3) patients suggests the involvement of neuroinflammation in the disease pathogenesis. In this study, we evaluated the anti-inflammatory potentials of indole compound NC009-1, 4-aminophenol-arachidonic acid derivative AM404, quinoline compound VB-037 and chalcone-coumarin derivative LM-031 using human HMC3 microglia and SCA3 ATXN3/Q75-GFP SH-SY5Y cells. The four tested compounds displayed anti-inflammatory activity by suppressing NO, IL-1β, TNF-α and IL-6 production and CD68 expression of IFN-γ-activated HMC3 microglia. In retinoic acid-differentiated ATXN3/Q75-GFP SH-SY5Y cells inflamed with IFN-γ-primed HMC3 conditioned medium, treatment with the tested compounds mitigated the increased caspase 1 activity and lactate dehydrogenase release, reduced polyQ aggregation and ROS and/or promoted neurite outgrowth. Examination of IL-1β- and TNF-α-mediated signaling pathways revealed that the tested compounds decreased IκBα/P65, JNK/JUN and/or P38/STAT1 signaling. The study results suggest the potential of NC009-1, AM404, VB-037 and LM-031 in treating SCA3 and probable other polyQ diseases.

Background The F-box protein 7 ( FBXO7 ) mutations have been identified in families with early-onset parkinsonism and pyramidal tract signs, and designated as PARK15. In addition, FBXO7 mutations were found in typical and young onset Parkinson's disease (PD). Evidence has also shown that FBXO7 plays an important role in the development of dopaminergic neurons and increased stability and overexpression of FBXO7 may be beneficial to PD. Purpose We screened extracts of medicinal herbs to enhance FBXO7 expression for neuroprotection in MPP + -treated cells. Methods Promoter reporter assay in HEK-293 cells was used to examine the cis / trans elements controlling FBXO7 expression and to screen extracts of medicinal herbs enhancing FBXO7 expression. MTT assay was performed to assess cell viability of MPP + -treated HEK-293/SH-SY5Y cells. In addition, proteasome activity, mitochondrial membrane potential and FBXO7/TRAF2/GATA2 protein expression were evaluated. Results We demonstrated that −202–−57 region of the FBXO7 promoter is likely to contain sequences that are bound by positive trans protein factors to activate FBXO7 expression and GATA2 is the main trans protein factor enhancing FBXO7 expression. Extracts of medicinal herbs Oenanthe javanica (Blume) DC. (Umbelliferae), Casuarina equisetifolia L. (Casuarinaceae), and Sorghum bicolor (L.) Moench (Gramineae) improved cell viability of both MPP + -treated HEK-293 and SH-SY5Y cells, rescued proteasome activity in MPP + -treated HEK-293 cells, and restored mitochondrial membrane potential in MPP + -treated SH-SY5Y cells. These protection effects of herbal extracts are acting through enhancing FBXO7 and decreasing TRAF2 expression, which is probably mediated by GATA2 induction. Conclusion Collectively, our study provides new targets, FBXO7 and its regulator GATA2, for the development of potential treatments of PD.

Adakite-like lavas from the Iranian segment of the Arabia–Eurasia collision zone have been considered as partial melts derived from a subducted Neotethyan slab, a hypothesis that cannot be further evaluated due to the lack of systematic age and radiogenic isotopic data. Here, we revisit the Anar region, Iran where such lavas were reported by providing these data to examine their probable origin as slab melts. New SIMS zircon U–Pb ages attest to eruption at ca. 1 to 2 Ma, postdating the Arabia–Eurasia collision. The lavas are characterized by dacitic to rhyolitic, metaluminous to slightly peraluminous and trondhjemitic compositions, and incompatible element patterns similar to continental crustal rocks. Extreme depletion in Nb, Ta, Y and the heavy REE relative to the light and middle REEs reflects control by garnet and rutile. Except one sample presumably affected by secondary gain of radiogenic Sr, the depleted Sr–Nd–Hf isotopic compositions relative to the Bulk Silicate Earth [( 87 Sr/ 86 Sr) i = 0.7040 to 0.7043; eNd( t ) = + 3.2 to + 5.3; eHf( t ) = + 10.5 to + 11.3] indicate magma genesis from juvenile source rocks. A slab melt origin for the Anar lavas is very unlikely and the reason is twofold. First, the Y and HREE of the source rocks estimated by inversed batch melting models assuming garnet pyroxenite residue are far too low compared with MORB-like lithologies and subducted sediments. Second, the low MgO, Ni and Cr of the lavas point to limited interaction with peridotites in a mantle wedge. Fractionation-related models are also unlikely due to the apparent lack of broadly coeval, mafic precursor magmas without adakitic signature. The low-Y and low-HREE source rocks revealed by the melting models, together with the low MgO, Ni and Cr of the Anar lavas, can be explained by lower crustal melting under eclogite-facies conditions. These source rocks were most likely high-pressure cumulates in the root of the Urumieh–Dokhtar magmatic arc, a Neotethyan arc that was active in the Paleogene. Lower crustal melting might be related to localized destruction of the continental mantle, giving rise to the temporally and spatially associated ultrapotassic magmas. The hypothesis of an ‘adakitic province’ near Anar where slab detachment and melting occurred does not hold in light of available data and observations.

SummaryBackground Neurofibrillary tangles formed from tau misfolding have long been considered one of the pathological hallmarks of Alzheimer's disease (AD). The misfolding of tau in AD correlates with the clinical progression of AD and inhibition or reversal of tau misfolding may protect the affected neurons. Methods We generated 293 and SH-SY5Y cells expressing DsRed-tagged pro-aggregation mutant of repeat domain of tau (ΔK280 tauRD) to test indole/indolylquinoline derivatives for reducing tau misfolding and neuroprotection. Results Four of the 10 derivatives tested displayed good misfolding-inhibitory effects on Tet-On 293 cells. Among them, NC009-1 and NC009-7 enhanced heat-shock 27 kDa protein 1 (HSPB1) expression to increase ∆K280 tauRD-DsRed solubility and promoted neurite outgrowth in Tet-On SH-SY5Y cells. Knockdown of HSPB1 resulted in decreased ∆K280 tauRD-DsRed solubility and reduced neurite outgrowth, which were rescued by addition of NC009-1/NC009-7. Treatment with indole/indolylquinoline derivatives also improved neuronal cell viability and neurite outgrowth in mouse hippocampal primary culture under tau cytotoxicity. Conclusion Our results demonstrate how indole/indolylquinoline derivatives are likely to work in tau misfolding reduction, providing insight into the possible working mechanism of indole and indolylquinoline derivatives in AD treatment.

Trehalose, a chemical chaperone and mTOR-independent autophagy enhancer, has shown promise in models of Huntington's disease, Parkinson's disease and tauopathies. In this study, two trehalase analogs, lactulose and melibiose, were examined for their potentials in spinocerebellar ataxia treatment. Using a SCA3 ATXN3/Q75-GFP cell model, we found that the ATXN3/Q75 aggregation was significantly prohibited by lactulose and melibiose because of their abilities to up-regulate autophagy. Meanwhile, lactulose and melibiose reduced reactive oxygen species production in ATXN3/Q75 cells. Both of them further inhibited the ATXN3/Q75 aggregation in neuronally differentiated SH-SY5Y cells. These findings suggest the therapeutic applications of novel trehalose analogs in polyglutamine aggregation-associated neurodegenerative diseases.

Alzheimer's disease (AD) is the most prevalent form of dementia associated with progressive cognitive decline and memory loss. Extracellular β-amyloid (Aβ) is a major constituent of senile plaques, one of the pathological hallmarks of AD. Aβ deposition causes neuronal death via a number of possible mechanisms such as increasing oxidative stress. Therefore therapeutic approaches to identify novel Aβ aggregate reducers could be effective for AD treatment. Using a Trx-His-Aβ biochemical assay, we screened 11 synthetic indolylquinoline compounds, and found NC009-1, -2, -6 and -7 displaying potential to reduce Aβ aggregation. Treating Tet-On Aβ-GFP 293 cells with these compounds reduced Aβ aggregation and reactive oxygen species. These compounds also promoted neurite outgrowth in Tet-On Aβ-GFP SH-SY5Y cells. Furthermore, treatment with above compounds improved neuronal cell viability, neurite outgrowth, and synaptophysin expression level in mouse hippocampal primary culture under oligomeric Aβ-induced cytotoxicity. Moreover, the tested NC009-1 significantly ameliorated Aβ-induced inhibition of hippocampal long-term potentiation in mouse hippocampal slices. Our results demonstrate how synthetic indolylquinoline compounds are likely to work as chemical chaperones in Aβ-aggregation reduction and neuroprotection, providing insight into the possible applications of indolylquinoline compounds in AD treatment.

The continental collision between Arabia and Eurasia which gave rise to the Caucasus-Iran-Anatolia (CIA) volcanic province provides a unique opportunity for understanding collisional zone magmatism. This study reports a comprehensive dataset of ages and geochemical compositions of volcanic rocks formed during the initial phase of post-collisional magmatism in the CIA province. The age data indicate a diachronous onset of volcanism that began ~17 Ma in SE Anatolia, and propagated northward from ~11 to 9 Ma toward NE Anatolia and NW Iran. The rocks are characteristically bimodal, with dominantly basic (SiO2 = 48–52 wt%) and silicic (SiO2 = 58–71 wt%) components that feature significant isotopic variations (eNd = +6 to −5), suggesting two principal magma sources: (1) a juvenile mantle-derived component, and (2) an older continental crust component. We therefore attribute the volcanic initiation to a migrating post-collisional extension regime caused by the successive breakoff of subducted Neo-Tethyan slabs. Subsequent volcanism that began from ~6.5 Ma resulted in a wide spectrum of calc-alkaline and alkaline rocks, with mafic to felsic lithologies in the entire province. From ~2 Ma, volcanism ceased in the western CIA province, and started propagating eastward and southeastward to SE Iran, following the Urumieh-Dokhtar magmatic belt, consistent with the notion of an oblique continental collision between Arabia and Eurasia.

Amyloid [Formula: see text] (A[Formula: see text]) plays a major role in the pathogenesis of Alzheimer’s disease (AD). The accumulation of misfolded A[Formula: see text] causes oxidative and inflammatory damage leading to apoptotic cell death. Chinese herbal medicine (CHM) has been widely used in clinical practice to treat neurodegenerative diseases associated with oxidative stress and neuroinflammation. This study examined the neuroprotection effects of CHM extract Glycyrrhiza inflata (G. inflata) and its active constituents, licochalcone A and liquiritigenin in AD. We examined A[Formula: see text] aggregation inhibition, anti-oxidation and neuroprotection in Tet-On A[Formula: see text]-GFP 293/SH-SY5Y cells and anti-inflammatory potential in lipopolysaccharide (LPS)-stimulated RAW 264.7 and LPS and interferon (IFN)-[Formula: see text] (LPS/IFN-[Formula: see text])-activated BV-2 cells. In addition, we applied conditioned media (CM) of BV-2 cells primed with LPS/IFN-[Formula: see text] to A[Formula: see text]-GFP SH-SY5Y cells to uncover the neuroprotective mechanisms. Our results showed that G. inflata extract and its two constituents displayed potentials of A[Formula: see text] aggregation inhibition and radical-scavenging in biochemical assays, A[Formula: see text] misfolding inhibition and reactive oxygen species (ROS) reduction in A[Formula: see text]-GFP 293 cells, as well as neurite outgrowth promotion, acetylcholinesterase inhibition and SOD2 up-regulation in A[Formula: see text]-GFP SH-SY5Y cells. Meanwhile, both G. inflata extract and its constituents suppressed NO, TNF-[Formula: see text], IL-1[Formula: see text], PGE2 and/or Iba1 productions in inflammation-stimulated RAW 264.7 or BV-2 cells. G. inflata extract and its constituents further protected A[Formula: see text]-GFP SH-SY5Y cells from BV-2 CM-induced cell death by ameliorating reduced BCL2 and attenuating increased IGFBP2, cleaved CASP3, BAD and BAX. Collectively, G. inflata extract, licochalcone A and liquiritigenin display neuroprotection through exerting anti-oxidative and anti-inflammatory activities to suppress neuronal apoptosis.

Misfolded tau proteins induce accumulation of free radicals and promote neuroinflammation by activating microglia-releasing proinflammatory cytokines, leading to neuronal cell death. Traditional Chinese herbal medicines (CHMs) have been widely used in clinical practice to treat neurodegenerative diseases associated with oxidative stress and neuroinflammation. This study examined the neuroprotection effects of formulated CHMs Bai-Shao (made of Paeonia lactiflora), Gan-Cao (made of Glycyrrhiza uralensis), and Shaoyao Gancao Tang (SG-Tang, made of P. lactiflora and G. uralensis at 1 : 1 ratio) in cell model of tauopathy. Our results showed that SG-Tang displayed a greater antioxidative and antiaggregation effect than Bai-Shao and Gan-Cao and a stronger anti-inflammatory activity than Bai-Shao but similar to Gan-Cao. In inducible 293/SH-SY5Y cells expressing proaggregant human tau repeat domain (ΔK280 tauRD), SG-Tang reduced tau misfolding and reactive oxygen species (ROS) level in ΔK280 tauRD 293 cells and promoted neurite outgrowth in ΔK280 tauRD SH-SY5Y cells. Furthermore, SG-Tang displayed anti-inflammatory effects by reducing nitric oxide (NO) production in mouse BV-2 microglia and increased cell viability of ΔK280 tauRD-expressing SH-SY5Y cells inflamed by BV-2 conditioned medium. To uncover the neuroprotective mechanisms of SG-Tang, apoptosis protein array analysis of inflamed tau expressing SH-SY5Y cells was conducted and the suppression of proapoptotic proteins was confirmed. In conclusion, SG-Tang displays neuroprotection by exerting antioxidative and anti-inflammatory activities to suppress neuronal apoptosis in human tau cell models. The study results lay the base for future applications of SG-Tang on tau animal models to validate its effect of reducing tau misfolding and potential disease modification.

Fig. A.5. Plots of εNd (T) values vs. initial Sr isotope ratios for the samples from Myanmar. For comparison, the data of the Tengchong block from Liu et al. (2009), Monywa and Popa volcanos from Yang (2008), and the eastern Transhimalayan batholith, SE Tibet from Lin et al. (2012) are also shown.

Spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, and 17 and dentatorubropallidoluysian atrophy, as well as Huntington disease, are a group of neurodegenerative disorders caused by a CAG triplet-repeat expansion encoding a long polyglutamine (polyQ) tract in the respective mutant proteins. The cytoplasmic and nuclear aggregate formation, a pathological hallmark of polyQ diseases, is probably the initial process triggering the subsequent pathological events. Compromised oxidative stress defense capacity and mitochondrial dysfunction have emerged as contributing factors to the pathogenesis of polyQ diseases. The roots of licorice ( Glycyrrhiza species) have long been used as an herbal medicine. In this study, we demonstrate the aggregate-inhibitory effect of Glycyrrhiza inflata herb extract and its constituents licochalcone A and ammonium glycyrrhizinate (AMGZ) in both 293 and SH-SY5Y ATXN3/Q 75 cells, SCA3 cell models. The reporter assay showed that G. inflata herb extract, licochalcone A, and AMGZ could enhance the promoter activity of peroxisome proliferator-activated receptor γ, coactivator 1α (PPARGC1A), a known regulator of mitochondrial biogenesis and antioxidative response genes. G. inflata extract, licochalcone A, and AMGZ upregulated PPARGC1A expression and its downstream target genes, SOD2 and CYCS, in the 293 ATXN3/Q 75 cell model. The expression of nuclear factor erythroid 2-related factor 2 (NFE2L2), the principal transcription factor that binds to antioxidant-responsive elements (AREs) to promote ARE-dependent gene expression when the cells respond to oxidative stress, and its downstream genes, HMOX1, NQO1, GCLC, and GSTP1, was also increased by G. inflata herb extract, licochalcone A, and AMGZ. Knockdown of PPARGC1A increased aggregates in ATXN3/Q 75 cells and also attenuated the aggregate-inhibiting effect of the tested compounds. G. inflata extract and its constituents significantly elevated GSH/GSSG ratio and reduced reactive oxidative species in ATXN3/Q 75 cells. The study results suggest that the tested agents activate PPARGC1A activity and NFE2L2–ARE signaling to increase mitochondrial biogenesis, decrease oxidative stress, and reduce aggregate formation in SCA3 cellular models.

Spinocerebellar ataxias (SCAs), caused by expanded CAG repeats encoding a long polyglutamine (polyQ) tract in the respective proteins, are characterized by the accumulation of intranuclear and cytoplasmic misfolded polyQ aggregation that leads to cell death. Suppression of aggregate formation can inhibit a wide range of downstream pathogenic events and is expected to be a therapeutic strategy for SCAs. Here we show the anti-aggregation potential of Gardenia jasminoides (G. jasminoides) and its components/metabolite geniposide, crocin, and genipin, in ATXN3/Q75-GFP 293 cells, a putative SCA3 cell model. We found the aggregation can be significantly prohibited by G. jasminoides, genipin, geniposide and crocin. Meanwhile, G. jasminoides, genipin, geniposide, and crocin up-regulated anti-oxidative markers NFE2L2, NQO1, GCLC and GSTP1, and reduced the production of reactive oxidative species (ROS) in the same cell models. All of them further inhibited the aggregation in neurally differentiated SH-SY5Y ATXN3/Q75-GFP cells. Our results demonstrate that G. jasminoides, genipin, geniposide and crocin work on polyQ-aggregation reduction by suppressing ROS. These findings indicate the therapeutic applications of G. jasminoides in treating SCAs. Furthermore, oxidative stress inhibition could be a good target for drug development of anti-polyQ aggregation.

The Neo-Tethyan subduction that operated before the India-Asia collision resulted in an Andean-type convergent margin in South Asia and was associated with extensive arc magmatism that formed the Transhimalayan batholiths. Magmatism in the Gangdese Batholith, the largest batholith exposed in the Lhasa terrane of southern Tibet, is considered to have lasted from the early Jurassic to Eocene. However, eastward correlation of the Gangdese Batholith is uncertain because it is truncated by the eastern Himalayan syntaxis. Here, we report new data from the Lohit Batholith, NE India, including: (i) zircon U-Pb ages of five granitoids from ca. 148 to 96 Ma; and (ii) zircon Hf isotopes of these rocks that yield high and positive eHf(T) values. We argue that the Lohit Batholith is the eastward extension of the Gangdese Batholith, and can be correlated southward to the Wuntho-Popa arc in West Burma, thus linking a prolonged Neo-Tethyan magmatic arc system from southern Tibet to Southeast Asia.

The Ailao Shan–Red River (ASRR) shear zone, one of the most prominent geologic strike-slip shear zones in Southeast Asia, consists of high-grade metamorphic complexes that provide a rare opportunity to sample the mid-crustal rocks along the western margin of the Yangtze Block of South China. Here we report combined, in-situ analyses of zircon U–Pb and Lu–Hf isotopes of eight gneisses from the Diancang Shan and Ailao Shan segments of the ASRR shear zone. Our zircon U–Pb data indicate that the rocks contain abundant magmatic zircons ranging in age from 1785 to 25 Ma, with peak ages at ca. 770, 350 and 240 Ma, suggesting three major periods of protolith formation. The 350-Ma zircons, observed only in an orthogneiss from the Diancang Shan, show uniform initial Hf isotopic ratios marked by high and positive e Hf (T) values from + 16 to + 10. This is in contrast with the other two zircon populations that are more common, occurring in both the Diancang Shan and Ailao Shan, and overall delineate very heterogeneous Hf isotopic compositions, with e Hf (T) values ranging from + 15 to − 16. Many zircons reveal distinctive core-rim age variations. Zircon rims, formed between ca. 34 and 26 Ma, show significant variations in Th/U ratios (5–0.01) and e Hf (T) values (+ 14 to − 10) that suggest complicated magmatic and metamorphic zircon overgrowth during the Oligocene. The presence of both metamorphic and magmatic overgrowths on zircons suggests that the metamorphism reached upper amphibolite facies, corresponding to mid-crustal level P–T conditions, as also suggested by structural and petrologic data. Our data furthermore suggest that the ASRR gneisses were not produced solely by shear heating during the Tertiary strike-slip faulting, but are uplifted, mid-crustal basement rocks that formed essentially during two major stages of magmatism, represented by the Neoproterozoic Kangding Complex and Late Permian Emeishan large igneous province. As a result of the India–Asia collision, these basement rocks underwent regional magmatic and metamorphic overprinting in the Oligocene that, based on our relevant work (Searle et al., 2010, Geosphere, 6, 1–23), predated the initial left-lateral movement along the ASRR shear zone. The 350-Ma protolith, which requires a dominant depleted-mantle input in the petrogenesis, cannot be linked to any major magmatic events in South China but may be interpreted as part of the Paleotethys remnants that were later incorporated into the ASRR shear zone.

Previous isotopic age studies have concluded that the main metamorphism in the Mogok Metamorphic belt (MMB) in Myanmar was Tertiary and caused by collision with or underthrusting by India. We present here results of zircon U–Pb age determinations on 18 samples from Myanmar, largely on intrusive rocks from the north-trending 550 km long Shan Scarps segment of the sickle-shaped MMB. The oldest determination is 491 Ma on orthogneiss north of Mandalay, interpreted as a protolith age and similar to the stratigraphic age of the Bawdwin Volcanics. Augen gneiss at Kyaukse has a 114 Ma protolith age. Our zircon U–Pb ages on undeformed intrusive rocks in the MMB range from Cretaceous to Miocene; the oldest (128 Ma), on a diorite near Yebokson, implies an earliest Cretaceous minimum age for regional metamorphism here. Younger ages on undeformed intrusions include 91 Ma on diorite at Mokpalin, 72 Ma on the weakly foliated garnet-bearing Nattaung granite, 44 and 48 Ma respectively on the MEC and Sedo granites, and 17–20 Ma on granite dykes. For the 128 Ma diorite, Sr and Nd isotopes indicative of a continental crust component, and mapped continuity of metamorphic host rocks, suggest correlation with mid early Cretaceous plutons in the eastern Transhimalayas. Zircon U–Pb ages for the MEC, Sedo and other granites within the MMB and Slate belt help to define a late Cretaceous to early Eocene age range for mostly ilmenite series peraluminous granites within the Western Granite belt and more restricted Western tin belt of Myanmar and southern Thailand. In the Wuntho–Popa arc west of the dextral Sagaing Fault, our new U–Pb zircon age of 105 Ma on diorite at Salingyi supports previous K–Ar ages (106–93 Ma) for pre-Tertiary intrusions. In the Cretaceous this arc may have occupied the Andaman Sea and continued northwards through the Mokpalin diorites and west of the MMB to the 103–80 Ma I-type plutons in the Gandise batholith of southern Tibet. We interpret the MMB and Slate belt as part of a Western Myanmar block separated in the Jurassic from the Shan Plateau to the east by the southwestward continuation of the Bangong–Nujiang–Luxi neo-Tethys I ocean. We relate most intrusive and metamorphic events in and near the MMB to westward subduction of this ocean and end-Jurassic collision of the Plateau with the overriding Western Myanmar-Slate belt block; to orogenic polarity reversal and early Cretaceous westward translation of the Plateau sequence over the suture zone; and to eastward subduction of the ancestral Indian Ocean or neo-Tethys II beneath Myanmar with generation of the Wuntho–Popa arc beginning before the late Cretaceous. The MMB includes meta-Plateau rocks near Mandalay but meta-Slate belt rocks to the north and south. Within the MMB, previous monazite–xenotime–thorite ages of Eocene–Oligocene, and Oligocene-early Miocene cooling ages on micas, with no deformation in Eocene granites, suggest a high-temperature thermal event related to intrusion of these and other granites during a previously proposed regional extension. Our data imply that the main fabric-forming metamorphic event in the MMB pre-dated the India–Asia collision.

We conducted a comprehensive 40Ar/39Ar geochronological study of the Jiali and Gaoligong shear zones to obtain a better understanding of crustal deformation and tectonic evolution around the Eastern Himalayan Syntaxis (EHS). The new age data reveal that the main phase of deformation in the Jiali and Gaoligong shear zones occurred from 22 to 11 Ma and from 18 to 13 Ma, respectively. Structural data collected during this study indicate that the Jiali shear zone underwent a change in shear sense from sinistral to dextral during its movement history. Based on a comparison with the deformation histories of other major shear zones in the region, we argue that the initial sinistral motion recorded by the Jiali shear zone was coincident with that of the Ailao Shan–Red River shear zone, which marked the northern boundary of the southeastward extrusion of the Indochina block during the Early Miocene. From the Middle Miocene (∼18 Ma), the Jiali shear zone changed to dextral displacement, becoming linked with the dextral Gaoligong shear zone that developed as a consequence of continued northward indentation of the Indian continent into Asia. Since this time, the Jiali and Gaoligong shear zones have been united, defining the southwestern boundary of the EHS during clockwise rotation of the eastward-extruding Tibetan block, as revealed by recent GPS data. The temporal change in regional deformation pattern from southeastward block extrusion to clockwise rotation of crustal fragments may have played an important role in the development of the eastern Himalayan drainage system around the EHS.

The NNE-SSW-trending Dien Bien Phu fault, which dextrally displaces the NW-SE-trending Song Ma suture, in northwestern Vietnam, is widely considered one of the most seismically active faults in Indochina. In order to better understand the fault’s activity, this study reports new 40Ar/39Ar geochronological data for mica schists and mylonites from several areas along the Dien Bien Phu fault, showing 40Ar/39Ar ages of 194–212 Ma for mica schists and 158–198 Ma for mylonites. These ages suggest that after the collision of the South China and Indochina blocks, dextral shearing deformation initiated along the Dien Bien Phu fault in the Jurassic, significantly earlier than previously thought. In light of the relevant tectonic events in Indochina, the successive suturing/collision of the Indochina, Simao, and Sibumasu blocks may have been responsible for the initiation of dextral shearing along the Dien Bien Phu fault, which in turn resulted in offset of the Song Ma suture.

Post-collisional magmatism in the Late Miocene Rodna-Bârgau subvolcanic district (East Carpathians) gave rise to a wide variety of rock compositions, allowing recognition of four groups of calcalkaline rocks with distinctive petrography, mineral chemistry, whole-rock geochemistry and Sr-Nd-Hf isotope features. New U-Pb zircon datings, together with literature data, indicate that the emplacement of the four rock groups was basically contemporaneous in the 11.5–8 Ma time span. The low potassium group (LKG) includes the most abundant lithotypes of the area, ranging from basaltic andesite to dacite, characterized by K-poor tschermakitic amphibole, weak enrichment in LILE and LREE, relatively low 87 Sr/ 86 Sr, coupled with relatively high 143 Nd/ 144 Nd and 176 Hf/ 177 Hf. The high potassium group (HKG) includes amphibole-bearing microgabbro, amphibole andesite and amphibole- and biotite dacite, with K-richer magnesio-hastingsite to hastingsite amphibole, more marked enrichments in incompatible elements, higher 87 Sr/ 86 Sr and lower 143 Nd/ 144 Nd and 176 Hf/ 177 Hf. These two main rock groups seem to have originated from similar juxtaposed mantle sources, with the HKG possibly related to slightly more enriched domains (with higher H 2 O reflected by the higher modal amphibole) with respect to LKG (with higher plagioclase/amphibole ratios). The evolution of the two rock series involved also open-system processes, taking place mainly in the upper crust for the HKG, in the lower crust for LKG magmas. In addition, limited occurrences of generally younger strongly evolved peraluminous rhyolites and microgranites (Acid group) and sialic-dominated “leucocratic” andesites and dacites (LAD group) were also recognized to the opposite outermost areas of the district. These two latter rock groups were generated by the melting of a basic metamorphic crustal source (respectively in hydrous and anhydrous conditions), favored by the heat released by mantle melts from the adjoining central area. The peculiar distribution of the products of the four rock groups in well defined sectors argues for a strong control of the local crustal tectonic regime on magmatism, influenced by the change from a transpressional to trastensional stage.

The F-box protein 7 (FBXO7) mutations have been identified in families with early-onset parkinsonism and pyramidal tract signs, and designated as PARK15. In addition, FBXO7 mutations were found in typical and young onset Parkinson's disease (PD). Evidence has also shown that FBXO7 plays an important role in the development of dopaminergic neurons and increased stability and overexpression of FBXO7 may be beneficial to PD.We screened extracts of medicinal herbs to enhance FBXO7 expression for neuroprotection in MPPPromoter reporter assay in HEK-293 cells was used to examine the cis/trans elements controlling FBXO7 expression and to screen extracts of medicinal herbs enhancing FBXO7 expression. MTT assay was performed to assess cell viability of MPPWe demonstrated that -202--57 region of the FBXO7 promoter is likely to contain sequences that are bound by positive trans protein factors to activate FBXO7 expression and GATA2 is the main trans protein factor enhancing FBXO7 expression. Extracts of medicinal herbs Oenanthe javanica (Blume) DC. (Umbelliferae), Casuarina equisetifolia L. (Casuarinaceae), and Sorghum bicolor (L.) Moench (Gramineae) improved cell viability of both MPPCollectively, our study provides new targets, FBXO7 and its regulator GATA2, for the development of potential treatments of PD.

An on-line microdialysis sampling coupled with flow injection (FI) electrothermal atomic absorption spectrometry (ETAAS) method has been developed for in vivo monitoring of extracellular diffusible Mn in brains of living rats. Microdialysates perfused through implanted microdialysis probes were collected with a sample loop of an on-line injection valve and directly introduced into the atomizer of the ETAAS by a FI system. Ultrapure saline solution (0.9% NaCl) was used as the perfusion solution at a flow rate of 1 µl min−1 through the microdialysis probe. The 25 µl of chemical modifier [0.4 g l−1 of Mg(NO3)2] and 25 µl of microdialysate were on-line mixed at a micro-Tee and loaded into a sample loop. A six-port on-line injection valve equipped with a 50 µl of sample loop, a peristaltic pump and an autosampler arm of ETAAS for direct introduction of the sample into the graphite tube were employed to act as a homemade FI system. The optimized conditions of ETAAS were performed for measurement of Mn in microdialysate. The performance characteristics of the on-line microdialysis-FI-ETAAS system for Mn were as follows: linearity range, 0–20 ng ml−1; detection limit (3σ, n = 7), 0.43 ng ml−1; recovery (n = 3), 98%–114%; precision (RSD, n = 20), 7.2%. The accuracy of the proposed on-line method was checked by four spiked artificial cerebrospinal fluid samples and compared with conventional ETAAS. The use of an on-line microdialysis-FI-ETAAS system permitted the in situ, dynamic and continuous in vivo monitoring of extracellular diffusible Mn in brains of living anaesthetized rats after administrated with MnCl2 with a temporal resolution of 25 min.

Pin-Jui Kung,1,* Yu-Chen Tao,1,* Ho-Chiang Hsu,1 Wan-Ling Chen,1 Te-Hsien Lin,1 Donala Janreddy,2 Ching-Fa Yao,2 Kuo-Hsuan Chang,3 Jung-Yaw Lin,1 Ming-Tsan Su,1 Chung-Hsin Wu,1 Guey-Jen Lee-Chen,1 Hsiu-Mei Hsieh-Li1 1Department of Life Science, 2Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan; 3Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan *These authors contributed equally to this work Abstract: In spinocerebellar ataxia type 17 (SCA17), the expansion of a translated CAG repeat in the TATA box binding protein (TBP) gene results in a long polyglutamine (polyQ) tract in the TBP protein, leading to intracellular accumulation of aggregated TBP and cell death. The molecular chaperones act in preventing protein aggregation to ameliorate downstream harmful events. In this study, we used Tet-On SH-SY5Y cells with inducible SCA17 TBP/Q79-green fluorescent protein (GFP) expression to test indole and synthetic derivative NC001-8 for neuroprotection. We found that indole and NC001-8 up-regulated chaperone expression to reduce polyQ aggregation in neuronal differentiated TBP/Q79 cells. The effects on promoting neurite outgrowth and on reduction of aggregation on Purkinje cells were also confirmed with cerebellar primary and slice cultures of SCA17 transgenic mice. Our results demonstrate how indole and derivative NC001-8 reduce polyQ aggregation to support their therapeutic potentials in SCA17 treatment. Keywords: spinocerebellar ataxia type 17, TATA box binding protein, polyQ aggregation, indole and derivative, therapeutics

In polyglutamine (polyQ)-mediated disorders, the expansion of translated CAG repeats in the disease genes result in long polyQ tracts in their respective proteins, leading to intracellular accumulation of aggregated polyQ proteins, production of reactive oxygen species, and cell death. The molecular chaperones act in preventing protein misfolding and aggregation, thus inhibiting a wide range of harmful downstream events. In the circumstance of accumulation of aggregated polyQ proteins, the autophagic pathway is induced to degrade the misfolded or aggregated proteins. In this study, we used Flp-In 293/SH-SY5Y cells with inducible SCA3 ATXN3/Q75-GFP expression to test the effect of indole and synthetic derivatives for neuroprotection. We found that ATXN3/Q75 aggregation can be significantly prohibited in Flp-In 293 cells by indole and derivative NC001-8. Meanwhile, indole and NC001-8 up-regulated chaperones and autophagy in the same cell models. Both of them further promote neurite outgrowth in neuronal differentiated SH-SY5Y ATXN3/Q75-GFP cells. Our results demonstrate how indole and derivative NC001-8 are likely to work in reduction of polyQ-aggregation and provide insight into the possible effectual mechanism of indole compounds in polyQ spinocerebellar ataxia (SCA) patients. These findings may have therapeutic applications in a broad range of clinical situations.

This study was undertaken to examine the effects of nickel (Ni) on human platelet function. In a (concentration-dependent manner, Ni significantly inhibited the function of platelet aggregation induced by collagen. The phenomenon of lipid peroxidation was involved as Ni significantly increased malondialdehyde (MDA) levels with reduction in platelet reduced glutathione (GSH) and alpha-tocopherol content. Further, platelet thromboxane B2, formation was markedly inhibited and the levels of cyclic AMP were significantly elevated by Ni. Treatment with ascorbic acid (Vit C) significantly lowered the levels of MDA and increased the content of alpha-tocopherol and reduced GSH. Vit C also significantly increased platelet aggregation and thromboxane B2 when coincubated with Ni. Data show that Ni is toxic as evidenced by lipid peroxidative damage and inhibition of human platelet aggregation, but that ascorbic acid provides protection, at least partially, against this metal.

The aim of this study was to investigate the effects of chronic, daily, 30-d administration of manganese chloride (MnCl2) to male Sprague-Dawley rats on lipid peroxidation in various tissues. Rats were intraperitoneally injected with MnCl2 (20 mg/kg) once daily for 30 consecutive days. The Mn accumulated in liver, spleen, adrenal glands, heart, kidneys, lung, and testes. This was associated with decreased lipid peroxidation in liver, spleen, and adrenal glands and a decrease in the levels of Fe in these tissues. In a second group of animals, Mn (20 mg/kg/d) and glutathione (GSH, 15 mg/kg/d) were administered ip for 30 d. GSH counteracted the Mn-induced protective fall in lipid peroxidation, but Fe levels remained lower in liver and spleen. Mn decreases lipid peroxidation in certain tissues, which may involve lowering Fe content, but interaction with Fe is not the sole mechanism.

In the present study, the concentrations of copper, iron, zinc, and malondialdehyde in human seminal plasma were measured and correlated with the sperm count and motility in human semen. Copper, iron, and zinc were analyzed by atomic absorption spectrometry, whereas malondialdehyde was measured by high-performance liquid chromatography. The malondialdehyde concentrations in asthenospermia and oligoasthenospermia were significantly higher than in normospermia. Copper and iron levels were higher in asthenospermia, whereas the zinc concentrations in both oligospermia and asthenospermia were lower than in normal controls. A negative correlation (r = -0.28, p < 0.05) between the malondialdehyde concentration and sperm motility was observed in the abnormal groups. There was no association among copper, iron, zinc, and malondialdehyde in seminal plasma. We concluded that changes in trace elements may be related to sperm quality and that lipid peroxidation, although it is not promoted in the seminal plasma by copper or iron or ameliorated by zinc, may be involved in the loss of sperm motility.

The purpose of this study was to evaluate the effects of cadmium-induced peroxidative damage to rat liver, heart, and spleen. Sprague-Dawley rats were injected subcutaneously with a single dose of 25, 125, 500, or 1250 microg Cd/kg and evaluated 6, 12, 24, or 72 h later. Liver, heart, and spleen were analyzed for lipid peroxidation and Fe, Cu, Zn, Se, and Cd concentrations. Data showed that Cd produced enhanced lipid peroxidation in the liver, heart, and spleen. These Cd-induced changes were accompanied by a significant rise in liver, heart, and spleen Fe and Cu, and a fall in spleen Zn and liver, heart, and spleen Se. Concurrent treatment with Se and Cd reduced the Cd-induced alterations in liver, heart, and spleen peroxidation and essential metal levels. Data suggest that lipid peroxidation is associated with cadmium toxicity and that Se was found effective in preventing lipid peroxidation.

The main goal of this study was to investigate the role of cadmium in the promotion of lipid peroxidation in the homogenates of rat testes and the effect of selenium on lipid peroxidation in testes of rats after cadmium injection. Treatment of rats with cadmium resulted in a time- and dose-related accumulation of the metal ions in testes. The concentrations of cadmium, copper, zinc, selenium and iron in the tissues were determined by an atomic absorption spectrophotometer and lipid peroxidation in testes was measured by a spectrophotometer. Cadmium produced enhanced lipid peroxidation in testes. These cadmium-induced changes were accompanied by a significant increase of iron and copper, and a decrease of zinc in testes. Concurrent treatment with selenium and cadmium reduced the cadmium-induced alterations in lipid peroxidation and essential metal levels. Data suggest that lipid peroxidation was associated with cadmium toxicity in testes and that the addition of selenium was found to be effective in attenuation of this effect.