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Ferroptosis, triggered by discoordination of iron, thiols and lipids, leads to the accumulation of 15-hydroperoxy (Hp)-arachidonoyl-phosphatidylethanolamine (15-HpETE-PE), generated by complexes of 15-lipoxygenase (15-LOX) and a scaffold protein, phosphatidylethanolamine (PE)-binding protein (PEBP)1. As the Ca2+-independent phospholipase A2β (iPLA2β, PLA2G6 or PNPLA9 gene) can preferentially hydrolyze peroxidized phospholipids, it may eliminate the ferroptotic 15-HpETE-PE death signal. Here, we demonstrate that by hydrolyzing 15-HpETE-PE, iPLA2β averts ferroptosis, whereas its genetic or pharmacological inactivation sensitizes cells to ferroptosis. Given that PLA2G6 mutations relate to neurodegeneration, we examined fibroblasts from a patient with a Parkinson's disease (PD)-associated mutation (fPDR747W) and found selectively decreased 15-HpETE-PE-hydrolyzing activity, 15-HpETE-PE accumulation and elevated sensitivity to ferroptosis. CRISPR-Cas9-engineered Pnpla9R748W/R748W mice exhibited progressive parkinsonian motor deficits and 15-HpETE-PE accumulation. Elevated 15-HpETE-PE levels were also detected in midbrains of rotenone-infused parkinsonian rats and α-synuclein-mutant SncaA53T mice, with decreased iPLA2β expression and a PD-relevant phenotype. Thus, iPLA2β is a new ferroptosis regulator, and its mutations may be implicated in PD pathogenesis.

GM1 ganglioside is particularly abundant in the mammalian central nervous system and has shown beneficial effects on neurodegenerative diseases. In this study, we investigated the therapeutic effect of GM1 ganglioside in experimental models of Parkinson’s disease (PD) in vivo and in vitro. Mice were injected with MPTP (30 mg·kg(-1)·d(−1), i.p.) for 5 days, resulting in a subacute model of PD. PD mice were treated with GM1 ganglioside (25, 50 mg·kg(−)(1)·d(−1), i.p.) for 2 weeks. We showed that GM1 ganglioside administration substantially improved the MPTP-induced behavioral disturbance and increased the levels of dopamine and its metabolites in the striatal tissues. In the MPP(+)-treated SH-SY5Y cells and α-synuclein (α-Syn) A53T-overexpressing PC12 (PC12(α-Syn A53T)) cells, treatment with GM1 ganglioside (40 μM) significantly decreased α-Syn accumulation and alleviated mitochondrial dysfunction and oxidative stress. We further revealed that treatment with GM1 ganglioside promoted autophagy, evidenced by the autophagosomes that appeared in the substantia nigra of PD mice as well as the changes of autophagy-related proteins (LC3-II and p62) in the MPP(+)-treated SH-SY5Y cells. Cotreatment with the autophagy inhibitor 3-MA or bafilomycin A1 abrogated the in vivo and in vitro neuroprotective effects of GM1 ganglioside. Using GM1 ganglioside labeled with FITC fluorescent, we observed apparent colocalization of GM1-FITC and α-Syn as well as GM1-FITC and LC3 in PC12(α-Syn A53T) cells. GM1 ganglioside significantly increased the phosphorylation of autophagy regulatory proteins ATG13 and ULK1 in doxycycline-treated PC12(α-Syn A53T) cells and the MPP(+)-treated SH-SY5Y cells, which was inhibited by 3-MA. Taken together, this study demonstrates that the anti-PD role of GM1 ganglioside resulted from activation of autophagy-dependent α-Syn clearance.

We study China’s growth and integration (trade and financial) in a two-country DSGE model with a dynamic exporting decision, pricing-to-market, incomplete financial markets, and aggregate shocks to trade barriers, productivity, and preferences. We estimate the changes in technology, trade costs, and preferences accounting for the dynamics of China’s gross and net trade flows, export participation, real exchange rate, and growth from 1990 to 2014. We find a large unanticipated decline in bilateral trade barriers with persistent, but not permanent, innovations that include an important gradual, phased-in component. Since the Great Recession, average bilateral barriers have stabilized at low levels even as barriers on Chinese imports have risen substantially relative to exports. Trade stagnation since 2011 largely reflects the completed transition to past trade reforms rather than an increase in trade barriers or reversal in the expected pace of future integration. Trade is forecast to decline almost 1 percent per year starting in 2017. Changes in trade barriers are an important determinant of China’s trade balance and its accumulation of foreign assets, accounting for as much as 70 percent of the foreign assets accumulated by 2014. Shocks to trade barriers and in China are found to have increased ROW consumption by 11.9 percent and employment by 0.6 percent but lowered ROW output by less than 1 percent relative to 1990.

Background Oxidative damage of dopaminergic neurons is the fundamental causes of Parkinson's disease (PD) that has no standard cure at present. Theacrine, a purine alkaloid from Chinese tea Kucha, has been speculated to benefit the neurodegeneration in PD, through similar actions to its chemical analogue caffeine, albeit excluding side effects. Theacrine has nowadays gained a lot of interest for its multiple benefits, while the investigations are weak and insufficient. Hypothesis/Purpose It is well-known that tea has a wide range of functions, especially in the prevention and treatment of neurodegenerative diseases. Theacrine is an active monomer compound in Camellia assamica var. kucha Hung T. Chang & H.S.Wang (Kucha), which appears to be effective and safe in PD therapy. The aim of this study is to examine its actions in diverse PD models and explore the mechanisms. Study Design For determination of theacrine's effects, we employed diverse oxidative damage-associated PD models, including 6-OHDA-treated rats, MPTP-treated mice/zebrafish and MPP+-treated SH-SY5Y cells, and using caffeine, selegiline and depranyl as positve control. For investigation and verification of the mechanisms, we utilized approaches testing mitochondrial function-related parameters and enzyme activity as well as applied gene knockdown and overexpression. Methods We employed behavioral tests including spontaneous activity, pole, swimming, rotarod and gait, immunohistochemistry, HPLC, flow cytometry, immunohistochemistry, Western blot, gene knockdown by siRNA and overexpression by plasmid in this study. Results Theacrine is demonstrated to retrieve the loss of dopaminergic neurons and the damages of behavioral performance in multiple animal models of PD (6-OHDA-treated rats and in MPTP-treated mice and zebrafish). The followed data of MPP+-treated SH-SY5Y cells indicate that theacrine relieves apoptosis resulted from oxidative damage and mitochondrial dysfunction. Further investigations illustrate that theacrine activates SIRT3 directly. It is of advantage to prevent apoptosis through SIRT3-mediated SOD2 deacetylation that reduces ROS accumulation and restores mitochondrial function. This concept is elaborated by 3TYP that inhibits SIRT3 enzyme activity and knockdown/overexpression of SIRT3 gene, demonstrating a crucial role of SIRT3 in theacrine-benefited dopaminergic neurons. Conclusion Theacrine prevents apoptosis of dopaminergic neurons through directly activating SIRT3 which deacetylating SOD2 and restoring mitochondrial functions.

Ethnopharmacological relevance Tianma Gouteng granules (TG), a clinical prescription of traditional Chinese medicine, has been clinically applied to treat Parkinson's disease (PD) in combination with Madopar, as included in the Chinese Pharmacopoeia (2015). TG has the potential to decrease the susceptibility of PD pharmacologically, however the mechanisms need detailed demonstration. Aim of the study To evaluate the pharmacological activities, as well as the possible mechanism of TG in diverse models of PD. Materials and methods 6-OHDA-treated rats, MPTP-treated mice, and α-synuclein A53T overexpressed mice, were utilized as PD animal models. Rotarod, locomotor activity, inclined plane and traction tests were used for behavioral assessment. Immunohistochemistry was used for tyrosine hydrolase determination. Western blot were conducted for detection of 4-HNE and 15-lipoxygenase-1 (ALOX15). The interactions of ALOX15 with the components in TG were predicted by molecular docking approach. Results Lipid peroxidation was involved in dopaminergic neuron damage in 6-OHDA-induced rat models. In MPTP-treated mice, the inhibition of lipid peroxidation improved behavioral and pathological symptoms of PD. The lipid peroxidation-related protein, ALOX15 was found to be the key factor in PD process in diverse PD models including 6-OHDA-treated rats, MPTP-treated mice, and α-synuclein A53T overexpressed mice. TG treatment significantly relieved behavioral and pathological symptoms of MPTP-induced PD mouse models with a potential mechanism of alleviating ALOX15-induced lipid peroxidation. Moreover, the results of molecular docking analysis show that compounds in TG might have interactions with ALOX15. Conclusions TG effectively improved the behavioral and dopaminergic neuron damage in diverse PD models. The mechanism of this action may be related to the direct inhibition of ALOX15 and the relief of lipid peroxidation.

Metastasis is the most common cause of death in ovarian cancer patients but remains largely untreated. Epithelial‑mesenchymal transition (EMT) is critical for the conversion of early‑stage ovarian tumors into metastatic malignancies. Thus, investigating the signaling pathways promoting EMT may identify potential targets for the treatment of metastatic ovarian cancer. Lysine demethylase 2A (KDM2A), also known as FBXL11 and JHDM1A, is a histone H3 lysine 36 (H3K36) demethylase that regulates EMT and the metastasis of ovarian cancer. However, the function and underlying mechanisms of EMT suppression in ovarian cancer have not been thoroughly elucidated to date. In the present study, we used Gene Expression Omnibus (GEO) databases to determine that KDM2A is significantly upregulated in human ovarian cancers. KDM2A expression was assessed by immunohistochemistry of epithelial ovarian cancer (EOC) borderline ovarian tumors and normal ovary tissues. Seven fresh EOC tissues and 3 fresh normal ovary tissues were collected for western blot analysis. Kaplan‑Meier survival curves were constructed to identify genes related to EOC prognosis from the TCGA data portal. Stable KDM2A‑knockdown cell lines were established to study the biological functions and underlying mechanisms of KDM2A in EMT in vitro. GEO database analysis revealed that KDM2A was highly upregulated in EOC tissues; this analysis was accompanied by immunochemistry and western blot analysis using samples of human tissues. High expression of KDM2A was associated with poor survival in EOC patients. KDM2A knockdown promoted apoptosis and suppressed the proliferation, migration and invasion of tumor cells in vitro. EMT and the PI3K/AKT/mTOR signaling pathway were suppressed in KDM2A‑silenced cells. Inactivation of the PI3K/AKT/mTOR signaling pathway in A2780 cells induced EMT inhibition. Our data revealed that KDM2A functions as a tumor oncogene, and the downregulation of KDM2A expression regulates EMT and EOC progression, providing a valuable prognostic marker and potential target for the treatment of EOC patients.

To determine the influence of reaction conditions on the formation of metal−organic frameworks, a series of Co(II)/H2tbip/bpp complexes, {[Co2(tbip)2(H2O)6]·8H2O}n (1), {[Co(tbip)(bpp)(H2O)]2·4H2O}n (2), {[Co(tbip)(bpp)]·H2O}n (3), {[Co2(H2O)(tbip)(Htbip)2(bpp)2]·0.5(H2tbip)·0.5H2O}n (4), {[Co3(OH)(tbip)2(Htbip)(bpp)]}n (5) (H2tbip = 5-tert-butyl isophthalic acid, bpp = 1,3-bi(4-pyridyl)propane), have been synthesized through the hydrothermal reaction of cobalt(II) acetate, H2tbip, and bpp under different temperatures and pH conditions. The diverse product structures show the marked sensitivity of the structural chemistry of the aromatic carboxylate ligand to synthesis conditions. Polymer 1, which features a three-dimensional (3D) framework with CdSO4 topology, has carboxylate bridging polymeric chains spanning two different directions and bridging water molecules between these chains, and is formed at pH = 4 at 120 °C. At pH = 6, a one-dimensional tube-like structure of 2 is formed. Further increase of t...

Two novel 3D metal-organic frameworks with cobalt(II) clusters as nodes and mixed bridging ligands as links, {[Co3(OH)(tbip)2(Htbip)(dps)(dpds)0.5]}n (1) and {[Co2 (H2O)(tbip)2(dps)]·CH3OH·2 H2O}2n (2) (dps = 4,4′-dipyridylsulfide, dpds = 4,4′-dipyridyldisulfide, H2tbip = 5-tert-butyl isophthalic acid), were obtained from the same reaction mixture but tuned by different hydrothermal temperatures: at 120 °C, product 1 is a 3D MOF based on the novel triangular trinuclear cluster node, whereas at 160 °C, product 2 is a 3D MOF constructed from both a linear trinuclear cluster node and a mononuclear CoII node. The starting dpds reagent was partly converted into dps ligand in 1 and wholly transferred into dps in 2 via new in situ cleavage of both S−S and S−C bonds and temperature-dependent in situ ligand rearrangement of dpds.

C18H22N2O15S2Zn, orthorhombic, Pnna (no. 52), a = 11.0915(9) A, b = 42.064(4) A, c = 5.0972(4) A, V = 2378.1 A, Z = 4, Rgt(F) = 0.030, wRref(F) = 0.088, T = 292 K. Source of material The mixture of ZnCl2 · 2H2O (1 mmol) and 3-(sulfonyl-glycine)benzoic acid (2 mmol) was stirred into 15mL aqueous solution at room temperature. Then the pH was adjusted to approximately 7 with 1 M KOH solution. And then 5 mL ethanol solution of 4,4 bipyridine (1 mmol) was added. The reaction mixture was then heated on awater bath for 6 h at 70 °C, and then filtered. Colorless crystal were obtained from themother liquor by slow evaporation at room temperature after 6 weeks. Experimental details All hydrogen atoms were first found in the difference electron densitymaps, and then placed in the calculated positions. The hydrogen atoms of carboxylate group and water molecules were found from Fourier difference maps and refined freely. The remaining H atoms were refined by riding model with Ueq(H) = 1.2Ueq(C). Discussion Crystal engineering ofmetal-organic frameworks (MOFs) is realizable by the choice of metals and the numerous choice and design of ligands, which bears the weight of prospective applications in new chemical separation, ion exchange, and gas adsorption [1-6]. In particular, carboxylate ligands have been frequently employed in the construction of microporous inorganic/organic hybrid materials for gas storage purposes. In this context, benzenedicarboxylic acid and their derivatives (such as 1,3-benzenedicarboxylic acid, 1,4-benzenedicarboxylic acid or 5-hydroxyisophtalic acid) are widely used as building blocks to link metal ions to produce interesting metal-organic framework structures and properties [7-10]. However, much fewer studies on coordination chemistry of flexible carboxylate-containing ligands have been carried out. On the other hand, the main strategies used in the field of crystal engineering are basically on the use of either conventional coordinative bonds or weak interactions. Among the non-covalent interactions, hydrogen bonding interactions play important role in designing superstructures and have attracted much interest due to their relative strength and directionality [11-12]. 3-(Sulfonyl-glycine)benzoic acid can act not only as hydrogen bond acceptors but also as hydrogen bond donors,whichmake it a wonderful candidate for the construction of supramolecular networks. The crystal structure consists of the mononuclear molecules. The coordinating 3-(sulfonyl-glycine)benzoic acid exists as a monoanion acting as a monodentate ligand. In the complex, zinc atom is five-coordinated in a distorted trigonal-bipyramidal ZnO5 environment, in which the basal coordination sites are occupied by three oxygen atoms (O1, O1A, O7), with the bond lengths of 1.968(1) A, 1.968(1) A and 2.071(3) A, respectively. The axial position is occupied by two oxygen atoms (O8, O8A) fromwater molecules, with the bond lengths of both 2.076(2) A. There exist intermolecular hydrogen bonds between carboxylate oxygen atoms fromC6H5COOgroup (O···O distances of 2.635A), forming 1D hydrogen bonded chains in which six-membered-ring and mononuclear units are alternately arranged along [100]. These chains are assembled by hydrogen bonds between carboxylate oxygen atoms from amino acid and water molecules from adjacent chains to give rise to 2D layer supramolecular structure (O···O distances of 2.835 A). At the same time, several weaker O–H···O hydrogen bonds are formed: (a) hydrogen bonding between water oxygen atoms and oxygen atoms of sulfonamide groups (O8–H2W···O5) with the bond distance of 3.211(2) A and bond angle of 117(3)°, (b) hydrogen bonding betweenwater oxygen atoms and oxygen atoms of amino acid groups (O7–H3W···O1 and O7–H3W···O2), with the bond distances of 3.117(3) A and 3.035(2)Aandbond angles of 118(3)° and 147(4)°, respectively. Z. Kristallogr. NCS 222 (2007) 435-436 / DOI 10.1524/ncrs.2007.0184 435 © by Oldenbourg Wissenschaftsverlag, Munchen