Immp2l Mutation Induces Mitochondrial Membrane Depolarization and Complex Ⅲ Activity Suppression after Middle Cerebral Artery Occlusion in Mice

Objective We previously reported that mutations in inner mitochondrial membrane peptidase 2-like(Immp2l)increase infarct volume,enhance superoxide production,and suppress mitochondrial respiration after transient cerebral focal ischemia and reperfusion injury.The present study investigated the impact of heterozygous Immp2l mutation on mitochondria function after ischemia and reperfusion injury in mice.Methods Mice were subjected to middle cerebral artery occlusion for 1 h followed by 0,1,5,and 24 h of reperfusion.The effects of Immp2l^(+/−)on mitochondrial membrane potential,mitochondrial respiratory complex III activity,caspase-3,and apoptosis-inducing factor(AIF)translocation were examined.Results Immp2l^(+/−)increased ischemic brain damage and the number of TUNEL-positive cells compared with wild-type mice.Immp2l^(+/−)led to mitochondrial damage,mitochondrial membrane potential depolarization,mitochondrial respiratory complex III activity suppression,caspase-3 activation,and AIF nuclear translocation.Conclusion The adverse impact of Immp2l^(+/−)on the brain after ischemia and reperfusion might be related to mitochondrial damage that involves depolarization of the mitochondrial membrane potential,inhibition of the mitochondrial respiratory complex III,and activation of mitochondria-mediated cell death pathways.These results suggest that patients with stroke carrying Immp2l^(+/−)might have worse and more severe infarcts,followed by a worse prognosis than those without Immp2l mutations.

Mitochondrial complex Ⅰ as a therapeutic target for Alzheimer’s disease

Alzheimer’s disease(AD),the most prominent form of dementia in the elderly,has no cure.Strategies focused on the reduction of amyloid beta or hyperphosphorylated Tau protein have largely failed in clinical trials.Novel therapeutic targets and strategies are urgently needed.Emerging data suggest that in response to environmental stress,mitochondria initiate an integrated stress response(ISR)shown to be beneficial for healthy aging and neuroprotection.Here,we review data that implicate mitochondrial electron transport complexes involved in oxidative phosphorylation as a hub for small molecule-targeted therapeutics that could induce beneficial mitochondrial ISR.Specifically,partial inhibition of mitochondrial complex I has been exploited as a novel strategy for multiple human conditions,including AD,with several small molecules being tested in clinical trials.We discuss current understanding of the molecular mechanisms involved in this counterintuitive approach.Since this strategy has also been shown to enhance health and life span,the development of safe and efficacious complex Ⅰ inhibitors could promote healthy aging,delaying the onset of age-related neurodegenerative diseases.

Ag(Ⅰ)与氯苯基苯并咪唑配合物的合成、圆二色性和荧光性质

本文合成了Ag(Ⅰ)与2-(o-氯苯基)苯并咪唑(OCBM)的配合物,采用元素分析、质谱、UV、IR、摩尔电导率等手段进行了表征。圆二色性研究发现,配合物在199nm处呈正科顿效应,而在208nm和247nm处呈负科顿效应。荧光性质研究表明,配合物的特征荧光发射峰出现在601nm和613nm处,荧光寿命τ601和τ613分别为0.40ns和0.35ns。Ag(Ⅰ)配合物可发射橙色荧光和红色荧光,是良好的荧光材料。

MHC-Ⅱ联合MHC-Ⅰ免疫组化染色在特发性炎性肌病诊断中的应用价值探讨

目的探讨主要组织相容性复合体(MHC)-Ⅱ联合MHC-Ⅰ免疫组化染色在特发性炎性肌病(IIM)诊断中的应用价值。方法收集2010年3月至2018年4月在首都医科大学宣武医院神经内科行肌肉活检患者的标本29份,并通过医院电子病历系统收集患者的临床资料,包括4种IIM[皮肌炎(DM)5例,多发性肌炎(PM)5例,散发性包涵体肌炎(IBM)4例及坏死性自身免疫性肌病(NAM)5例]和2种非炎性肌病(NIM)[肌营养不良(MD)5例,dysferlinopathy肌病5例]。将标本进行苏木精-伊红(HE)染色及MHC-Ⅰ、MHC-Ⅱ免疫组化染色。结果免疫组化染色结果显示,PM、DM及IBM患者肌肉标本MHC-Ⅰ阳性率达100.0%,NAM和MD患者肌肉标本MHC-Ⅰ阳性率为80.0%,dysferlinopathy肌病患者肌肉标本MHC-Ⅰ阳性率为20.0%。PM和IBM患者肌肉标本MHC-Ⅱ阳性率分别为40.0%、50.0%,其余类型疾病患者肌肉标本的MHC-Ⅱ免疫组化染色均呈阴性。结论相较于MHC-Ⅰ免疫组化染色,MHC-Ⅱ免疫组化染色在鉴别IIM与NIM中有较高的特异性。MHC-Ⅱ联合MHC-Ⅰ免疫组化染色对不同肌病类型的诊断有较好的临床应用价值。

Mitochondrial protection by low doses of insulin-like growth factor-Ⅰin experimental cirrhosis

AIM: To characterize the mitochondrial dysfunction in experimental cirrhosis and to study whether insulin-like growth factor-Ⅰ(IGF-Ⅰ) therapy (4 wk) is able to induce beneficial effects on damaged mitochondria leading to cellular protection. METHODS: Wistar rats were divided into three groups: Control group, untreated cirrhotic rats and cirrhotic rats treated with IGF-Ⅰtreatment (2 μg/100 g bw/d). Mitochondrial function was analyzed by flow cytometry in isolated hepatic mitochondria, caspase 3 activation was assessed by Western blot and apoptosis by TUNEL in the three experimental groups. RESULTS: Untreated cirrhotic rats showed a mitochon- drial dysfunction characterized by a significant reduction of mitochondrial membrane potential (in status 4 and 3); an increase of intramitochondrial reactive oxigen species (ROS) generation and a significant reduction of ATPase activity. IGF-Ⅰtherapy normalized mitochondrial func-tion by increasing the membrane potential and ATPase activity and reducing the intramitochondrial free radical production. Activity of the electron transport complexes Ⅰand Ⅲ was increased in both cirrhotic groups. In addition, untreated cirrhotic rats showed an increase of caspase 3 activation and apoptosis. IGF-Ⅰtherapy reduced the expression of the active peptide of caspase 3 and resulted in reduced apoptosis.

Depletion of PINK1 sensitizes breast cancer cells to polyphyllin Ⅰ via mitophagy suppression and DRP1-mediated mitochondrial fission

OBJECTIVE To elucidate the molecular mechanism and the anti-breast cancer effect of polyphyllinⅠ,which is a natural compound extracted from Rhizoma of Paris polyphyllin.METHODS Human breast cancer cells were treated with polyphyllinⅠ,after which DRP1-dependent mitochondrial fission and apoptosis,mitophagy and PINK1/PARK2 pathway were evaluated.A genetic approach was employed to determine how knockdown of PINK1 with sh RNA regulates polyphyllinⅠ-induced mitophagy and apoptosis.The inhibitory effect of polyphyllinⅠon tumor growth in a breast cancer cell xenograft mouse model was also examined.RESULTS PolyphyllinⅠenhanced the stabilization of full-length PINK1at the mitochondrial surface,leading to PARK2 recruitment to mitochondria,and culminating in mitophagy.PolyphyllinⅠalso induced dephosphorylation of DRP1 at Ser637 and mitochondrial translocation of DRP1,leading to mitochondrial fission and apoptosis.Knockdown of PINK1 evidently suppressed mitophagy stimulated by polyphyllinⅠ,and markedly enhanced DRP1-dependent mitochondrial fission and apoptosis induced by polyphyl inⅠ.Furthermore,suppression of DRP1 by mdivi-1 or sh RNA inhibits PINK1 knockdown-mediated mitochondrial fragmentation and apoptosis in response to polyphyllinⅠtreatment,suggesting that depletion of PINK1 lead to mitochondrial fragmentation due to excessive fission.Our in vivo study also showed that knockdown of PINK1potentiated polyphyllinⅠ-mediated inhibition of tumor growth in a breast cancer cell xenograft mouse model.CONCLUSION Our study provides a mechanism to support the role of PINK1 in the regulation of polyphyl inⅠ-induced mitophagy and apoptosis,and suggest polyphylinⅠas a potential drug for treatment of breast cancer.

基于Cu(Ⅰ)配合物的OLEDs发光材料研究进展

由于有机材料丰富的发光特性,有机发光二极管(OLEDs)在平面显示器和照明中的应用获得了广泛的关注。传统的有机发光二极管发光层材料主要为有机小分子或贵金属配合物,其中贵金属配合物,如铂(Ⅱ)和铱(Ⅲ),存在热稳定性较差、载流子传输能力有限、获取难度大、性能受限和材料价格高昂等问题,严重限制了其应用和发展。Cu(Ⅰ)配合物具有优异的发光特性、发射可调性和相对较低的成本,为开发金属配合物发光材料提供了新的途径。本文总结了基于Cu(Ⅰ)配合物的OLEDs发光材料的研究进展,探讨了改变配位原子类型和配体结构调节Cu(Ⅰ)配合物电致发光的策略,对Cu(Ⅰ)配合物OLEDs发光材料的发展前景予以展望。

The Genetic Structure and Diversity of Repomucenus curvicornis Inhabiting Liaoning Coast Based on Mitochondrial COⅠ Gene and Control Region

[Object] This study was conducted to explore the genetic diversity and structure of the wild Repomucenus curvicornis inhabiting Liaoning Coast, China. [Method] The mitochondrial COⅠ gene and control region（CR） were PCR amplified from the wild R. curvicornis populations from the Liaodong Bay（n=22） and the northern Yellow Sea（n=18）, sequenced and analyzed for genetic diversity. [Result] The contents of A, T, C and G of 624 bp COⅠ gene were 24.09%, 31.04%, 25.28%, and 19.59%, and those of 460 bp CR fragment were 32.96%, 32.80%, 14.86% and 19.38%, respectively. The total number of variable sites, average number of nucleotide differences（ k）, haplotype diversity（H） and nucleotide diversity（π） based on COⅠ gene were 38, 4.67,（0.96±0.02） and（0.007 5±0.004 2）, and those based on CR fragment were 26, 3.35,（0.97 ±0.02） and（0.007 3±0.004 3）, respectively. Based on mitochondrial COⅠ gene and CR, the genetic diversity of Liaodong Bay population was lower than that of the northern Yellow Sea population. The AMOVA analysis based on CR fragments revealed almost significant genetic divergence between the Liaodong Bay and the northern Yellow Sea populations, while there was no significant genetic divergence based on COⅠ gene. The results showed that CR and COⅠ gene are effective molecular markers for detecting the genetic diversity of R. curvicornis population, while CR is more reliable than COⅠ gene in detecting the genetic structure. [Conclusion] CR is an appropriate marker for genetic analysis of marine fish population.

Structure and Luminescence Property of a Linear Tetranuclear Gold(Ⅰ)-thiolate Complex through Au-Au Interaction

The synthesis,structure and luminescent property of a tetranuclear gold（Ⅰ）complex with doubly bridging diethyldithiocarbamate（Et2dtc）and 1,1-bis（diphenylphosphino）ethene（（Ph2P）2C=CH2）are described.The complex crystallizes in monoclinic space group C2/c with a=26.785（7）,b=25.654（6）,c=12.277（3）A,β=106.879（5）°,V=8073（4）A^3,Z=8,C31H32Au2F6NO3P2S2Sb,Mr=1222.32,Dc=2.011 g/cm^3,F（000）=4592,Rint=0.0529,T=293（2）K,μ=8.157 mm^（-1）,the final R=0.0464 and wR=0.1444 for 5804 observed reflections with I〉2σ（Ⅰ）.The intramolecular and intermolecular Au¨Au distances are 2.8670（9）and 3.2367（9）A,respectively.Weak emission appears at 517 nm at room temperature in the solid state.

The complexes of multiimidazole with copper(Ⅰ) display tyrosinase activity

The six multiimidazole copper（Ⅰ） complexes are utilized to mimic tyrosinase. The main product is 3,5-di-t-butylcatechol from o-hydroxylation of the substrate 2,4-di-t-butylphenol. The highest yield of catechol is up to 82.2% and selectivity 94.8% by [Cu（Ⅰ）2（3b）（MeCN）2]（CIO4）2 and O2 under mild conditions, which are found to be more efficient than that already reported.

Synthesis,Structure and Luminescent Properties of Polymeric Copper(Ⅰ) Halide Complexes Bearing Phosphine and N-donor Bridging Ligands

Three polymeric copper（Ⅰ） halide complexes beating phosphine and N-donor bridging ligands, [（PPh3）2Cu2（μ-Br）2（μ-4,4＇-bipy）]∞ 1 （bipy = bipyridine）, [（PPh3）2Cu2（μ-Br）2（μ- bpe）]∞ 2 （bpe = trans-1,2-bis（4-pyridyl）ethene） and [（PPh3）2Cu2（μ-Cl）2（μ-bpe）]∞ 3, were synthesized by the multilayer diffusion method, and the structures were refined by single-crystal X-ray diffraction. Complex 1 crystallizes in triclinic, space group P1^- with a = 9.122（3）, b = 9.322（3）, c = 13.201（4） A, α = 106.440（4）, β= 105.965（5）, γ= 94.167（5）°, V = 1021.3（6） A^3, Mr= 967.62, Z = 1, De= 1.573 g/cm^3, F（000） = 486, μ = 3.111 mm^-1, the final R = 0.0383 and ωR = 0.0960 for 2792 observed reflections （I 〉 2σ（I））. Complex 2 crystallizes in triclinic, space group P1^- with a = 9.420（3）, b = 10.209（4）, c = 12.407（4） A, α = 104.136（6）, β = 108.132（5）, γ= 95.338（6）°, V = 1081.0（7） A^3, Mr= 496.83, Z = 2, Dc= 1.526 g/cm^3, F（000） = 500, μ = 2.941 mm^-1, the final R = 0.0445 and ωR = 0.1117 for 3251 observed reflections （I 〉 2σ（I））. Complex 3 crystallizes in triclinic, space group P1^- with a = 8.32（1）, b = 11.53（2）, c = 13.94（3） A, α = 109.57（3）, β= 93.85（3）, γ= 97.28（3）°, V= 1242（4） A^3, Mr= 1074.59, Z = 1, Dc = 1.436 g/cm^3, F（000） = 548, μ = 1.279 mm^-1, the final R = 0.0786 and ωR = 0.1586 for 2266 observed reflections （I 〉 2σ（I））. The complexes exhibit intensive solid-state photoluminescence tentatively assigned to an admixture of triplet intraligand （IL） and metal-to-ligand charge-transfer （MLCT） excited state.

Ab Initio Molecular Orbital Calculation on Dinuclear Gold(Ⅰ) Complexes──Metal-Metal Interaction and Electronic Structure of Binuclear Gold(Ⅰ) Complexes with Bridging Bidentate Ligands

The electronic structure and electronic absorption spectra of binuclear Au(Ⅰ) complexes with bidentate phophines and a bidentate ylid ligand have been studied using quasirelativistic pseudopotential ab initio calculations at the HF and MP2 levels by the LANL2DZ basis sets. The electronic properties of the spectral transition and Au(Ⅰ)—Au(Ⅰ) interaction were also discussed.

Studies on A Novel Mixed-Valence Complex of Copper(Ⅰ,Ⅱ)α-Methacrylate with Imidazole and Aqua

A novel mixed-valence copper (Ⅰ,Ⅱ) complex Cu3 [CH2=C(CH3) COO]5 (imH)3 (H2O)has been synthesized and characterized by XPS spectra and single crystal X-ray structural analysis.The title complex crystallized in monoclinic space group P21/c, with α=11 .225 (3), b=13.9023 (12),c=24.559 (2), β=92.372 (10)°and Z=4. Final R=0.0495 for 5546 reflections [I＞2σ (Ⅰ)].

Synthesis and Crystal Structure of a Tetranuclear Cu(Ⅰ) Complex with Vinylidenebis(diphenylphosphine)

The vinylidenebis（diphenylphosphine） （vdpp） reacts with CuBr to give a tetranuclear complex, [Cu4（μ3-Br）2（μ2-Br）2（μ2-vdpp）2（CH3CN）2]·（CH3CN）2 1. The title complex has crystallo- graphically imposed centrosymmetry and presents a CuaBr4 core with distorted stair-like structure. All copper（I） atoms in 1 assume distorted tetrahedral coordination geometry. The distance of 2.7745（11） A between the two copper centers indicates the presence of ligand-supported Cu…Cu interactions. Crystal data for 1： C_60H_56Br_4Cu_4N_4P_4, Mr= 1530.77, triclinic, space group P1, a = 11.6593（9）, b = 11.7181（9）, c = 13.8711（11） А, a = 110.1020（10）, β = 102.0050（10）, γ = 109.8040（10）°, V = 1557.5（2） А^3, Z = 1, Dc = 1.632 g/cm^3, F（000） = 760, λ= 0.71073А, T = 298（2） K, 2θmax = 50.04°,μ= 4.056 mm^-1, S = 1.181, R = 0.0507 and wR = 0.1025.

Crystal Structure of Di[bis(diphenylphosphino)propane]Copper(Ⅰ) Perchlorate Complex

The complex [Cu (dppp)2] (ClO4) was prepared by the reaction ofcopper (Ⅱ) perchlorate wlth bis(diphenylphosphino) propane (dppp) in methanol, andits crystal structure was determlned by X-ray crystallography. The crystal is monoclin-ic, space group P1, M. = 1019. 90 with cell parameters a = 11. 951 (6), b = 12. 178(4), c=18. 413(5) A, α=70. 52(3), β=83. 56(4), γ=77. 61 (4), V=2465. 2 A3,Z = 2, Dc = 1. 371 g/cm3. The structure was solved by direct methods and refined byblock-diagonal and full-matrix least-squares methods to a final R of 0. 043 for 4085 in-dependent reflections of I>3σ(I). In this complex [Cu (dppp)2] (ClO4), dppp func-tions as a bidentate chelate ligand. The four P atoms from two dppp are coordinated tothe tetrahedral copper (P4).

A New Tetranuclear Copper(Ⅰ) Complex of Dithiolate Ligand Fused with TTF Moiety

A tetranuclear copper (I) complex of the ditholate ligand fused with a TTF moiety hasbeen synthesized and characterized crystallographically. This is the first example of a metaJ clustercoordinated with the new type ligand. The complex shows interesting redox and radical properties.

Synthesis,Crystal Structure and Photophysical Properties of Cu(Ⅰ) Complexes Containing 2,5-Bis(pyridyl)-1,3,4-oxadiazole

Four novel Cu（Ⅰ） complexes,[Cu（o-PYO）（PPh3）2]BF4（1）,[Cu（o-PYO）（DPEphos）]BF4（2）,[Cu2 （o-PYO）（PPh3）3（CH3CN）]（BF4）2（3） and [Cu2（o-PYO）（DPEphos）2 ]（BF4）2（4） （o-PYO=2,5bis（pyridyl）-1,3,4-oxadiazole,PPh 3=triphenylphosphine,DPEphos=bis（2-（diphenylphosphanyl）phenyl）ether）,have been synthesized and characterized by 1 H NMR,elemental analysis and single-crystal X-ray diffraction.The central cuprous ions in all complexes are surrounded by N and P atoms to form a distorted tetrahedral geometry,although one of the cuprous ions in complex 3 is coordinated by a PPh3 and an acetonitrile molecule due to the steric hindrance and weak coordination ability from monodentate PPh3 ligand.The UV-vis absorption spectra in CH2Cl2 show the characteristic metal-to-ligand charge transfer （MLCT） absorption bands in the region of 360-480nm.Four Cu（I） complexes exhibit yellow to orange-red phosphorescence with the emission maximum at 572,577,562 and 597nm,respectively in the solid state.

Complete mitochondrial DNA sequence analysis in two southern Chinese pedigrees with Leber hereditary optic neuropathy revealed secondary mutations along with the primary mutation

AIM: To investigate mitochondrial factors associated with Leber hereditary optic neuropathy (LHON) through complete sequencing and analysis of the mitochondrial genome of Chinese patients with this disease. METHODS: Two unrelated southern Chinese families with LHON and 10 matched healthy controls were recruited, and their entire mitochondrial DNA (mtDNA) was amplified and sequenced with the universal M13 primer. Then DNA sequence analysis and variation identification were performed by DNAssist and Chromas 2 software and compared with authoritative databases such as Mitomap. RESULTS: Mutational analysis of mtDNA in these two Chinese pedigrees revealed one common LHON-associated mutation, G11778A (Arg -> His), in the MT-ND4 gene. In addition, there were two secondary mutations in Pedigree 1: C34971 (Ala -> Val), and C3571T (Leu -> Phe) in the MT-ND1 gene, which have not been reported; and two secondary mutations occurred in Pedigree 2: A10398G (Thr -> Ala) in the MT-ND3 gene, and T14502C (Ile -> Val) in the MT-ND6 gene. Three polymorphisms, A73G, G94A and A263G in the mtDNA control region, were also found. CONCLUSION: Our study confirmed that the known MT-ND4* G11778A mutation is the most significant cause of LHON. The C3497T and C3571T mutations in Pedigree 1 were also both at hot-spots of MT-ND1; they may affect the respiratory chain in coordination with the primary mutation G11778A. In Pedigree 2, the two secondary mutations A10398G of MT-ND3 and T14502C of MT-ND6 may influence mitochondrial respiratory complex I, leading to the mitochondrial respiratory chain dysfunction which results in optic atrophy together with G11778A. Therefore, not only the common primary LHON mutation is responsible for the visual atrophy, but other secondary mtDNA mutations should also be considered when giving genetic counseling.

Mitochondrial Signaling in Hypoxia

This paper focuses on a bioenergetic mechanism responding to hypoxia. This response involves hypoxia-induced reprogramming of respiratory chain function and switching from oxidation of complex I (NAD-related substrates) to complex II (succinate oxidation). Transient, reversible, compensatory activation of respiratory chain complex II is a major mechanism of urgent adaptation to hypoxia, which is necessary for 1) succinate-related energy synthesis in the conditions of oxygen shortage and formation of urgent resistance;2) succinate-related stabilization of HIF-1α and initiation of its transcriptional activity related with formation of long-term adaptation;3) succinate-dependent activation of the succinate-specific receptor GPR91. Thus, mitochondria perform a signaling function with succinate as a signaling molecule. Effects of succinate in hypoxia occur at three levels, intramitochondrial, intracellular and intercellular. In these settings, succinate displays antihypoxic activity. The review is focused on tactics and strategy for development of the antihypoxic defense and antihypoxants with energotropic properties.

Investigation of Intermolecular C-H···Halogen Hydrogen Bonded Supramolecular Assemblies in Three Copper(Ⅰ) Complexes Formed by 3,3'-Dimethoxy-6,6'-dimethyl-2,2'-bipyridine Ligand

Three new crystalline compounds 1-3 were successfully obtained by the reactions of 3,3＇-dimethoxy-6,6＇-dimethyl-2,2＇-bipyridine ligand（dmbp） with the corresponding Cu（Ⅰ） salts.Crystal data for 1：orthorhombic Pbca,a = 18.5858（12）,b = 8.1821（5）,c = 20.6066（13） ,V = 3133.7（3） 3,Z = 8,Dc = 1.843 g/cm3,F（000） = 1696,μ = 3.366 mm-1,the final R = 0.0223 and wR = 0.0542.Crystal data for 2：Orthorhombic Pbca,a = 18.7883（16）,b = 8.3249（7）,c = 19.0294（17） ,V = 2976.4（4） 3,Z = 8,Dc = 1.731 g/cm3,F（000） = 1552,μ = 4.154 mm-1,the final R = 0.0279 and wR = 0.0680.Crystal data for 3：monoclinic P21/c,a = 13.812（10）,b = 9.910（7）,c = 23.444（17） ,β = 104.3350（10）°,V = 3090（4） 3,Z = 4,Dc = 1.476 g/cm3,F（000） = 1408,μ = 1.588 mm-1,the final R = 0.0479 and wR = 0.1081.The results of X-ray crystallographic analysis revealed that C14H16ICuN2O2（1） and C14H16BrCuN2O2（2） are isostructural compounds with the dimers connected by C-H···halogen hydrogen bonds to generate a three-dimensional（3D） supramolecular network in 1 and a two-dimensional（2D） sheet structure in 2,respectively,while the mononuclear complex C28H32Cl2Cu2N4O4（3） is ionic.In 3,the [Cu（dmbp）2]＋ cations and [ClCuCl]-anions are connected by C-H···Cl hydrogen bonds to form a one-dimensional（1D） chain along the a axis.Therefore,in the three complexes,the C-H···halogen hydrogen bonds dominate their crystal structures.Additionally,The UV luminescent properties of complexes 1-3 were investigated.