Effect of Complexes of Cobalt With Aminoacids on the Replication of Herpes Simplex Virus Type 1 (HSV-1)

Cobalt, being essential metal, influences different physiological and enzymatic functions. As cobalt does not accumulate in the body, Co-compounds have relatively low toxicity. The aim of the present study is the effect of complexes of Co(II) with aminoacids - lysine, arginine, histidine and serine on HSV-1 replication. No effect of [O(2)Co(his)(4)].nH(2)O and [O(2)Co(arg)(2)].nH(2)O on HSV-1 infection in vitro was found. Both, [O(2)Co(lys)(2)].nH(2)O and [O(2)Co(ser)(2)].nH(2)O suppress the attachement of HSV-1 particles onto target cells and the viral replication as well. Moreover, the properties of the particular Co-complex (charge, stability, structure) are manifestated by their virucidal effect. Thus, [O(2)Co(ser)(2)].nH(2)O irreversibly inhibits the infectious activity of free HSV-1 virions, while virucidal effect of [O(2)Co(lys)(2)].nH(2)O is completely reversible after the 2h of contact.     

Effect of Copper Acyclovir Complexes on Herpes Simplex Virus Type 1 and Type 2 (HSV-1, HSV-2) Infection in Cultured Cells

We have found that when copper, zinc or cobalt is bound to a suitable ligand, the appropriate complex exhibited a significant anti-HSV effect (Varadinova et al., 1993; 1996). Recently published data by Sagripanti et al. (1997) also show that the inhibition of HSV by copper was enhanced by reducing agents and that mechanism of the inactivation is similar as for copper-mediated DNA damage (Aruoma, et al. 1991; Dizdaroglu, et al., 1991; Toyokuni and Sagripanti, 1994). Therefore it was interesting to study the efect of Cu(ll) coordination compounds with acyclovir (ACV) on the replication of HSV in cultured cells. The experiments on cytotoxicity as well as on the activity of three different Cu-ACV complexes [Cu(ACV)(2)Cl(2)(H(2)O)(2)] = (A); [Cu(ACV)(2)(H(2)O)(3)](NO(3))(2).H(2)O = (B) and [Cu(ACV)(2)(H(2)O)(2)](NO(3))(2)] = (C) towards virus replication, with special attention on the growth of ACV-resistant strain R-100 were performed on MDBK cells. ACV was used as a reference compound. The following results were obtained: 1) Increased cell's viability in the presence of 20-40(g/ml ACV and decreased one in the presence of Cu-ACV complexes with relative level (A) > (B) > (C); 2) Cu-ACV complexes are more cytotoxic than the ligand - ACV and the relative level is (C)>(B)>(A); 3) The anti-HSV effect of ACV can be modulated by copper at levels depending on the specificity of the particular virus strain: (i) for the ACV sensitive strain DA (HSV-1) - ACV ((A) > (C) > (B); (ii) for the ACV sensitive strain Bja (HSV-2) (A) > ACV > (C) > (B); (iii) for strain R-100 (ACV(R), TK(a)) - (A) > ACV > (C) > (B). This findings are consistent with previously published data and undoubtedly show that Cu-ACV complexes could be useful in the treatment of HSV infections, especially when the causative agent is a resistant to ACV mutant.     

Zinc(II) Complexes - A New Group of Non-Mutagenic Herpes Simplex Virus Inhibitors

Former studies showed that complexes of Zn(II) with picolinic and with aspartic acids, Zn(pic)(2) and Zn(asp)(2), are able to inhibit HSV infection in cultured cells by affecting key steps of virus replication. As these complexes are candidates for a novel class anti-HSV drugs, further studies on their mutagenicity are of particular interest. In the present paper we present data showing that Zn(pic)(2) and Zn(asp)(2) do not express mutagenic effect in both prokaryotic (Salmonella typhimurium) and eukaryotic (Saccharomices cerevisiae) test systems.     

Increased Efficacy of Zinc Complexes With Picolinic and Aspartic Acids Against Herpes Simplex Virus (HSV) Infection When Combined With the Pavine Alkaloid (-)-Thalimonine

Complexes of zinc with picolinic and aspartic acids inhibit key steps of HSV-1 replication affecting different virus-specific targets. As was recently demonstrated by us, the pavine alkaloid (-)-thalimonine irreversibly inhibits HSV-1 infection in cultured cells. The aim of the present study was the evaluation of the combined effect of zinc complexes and (-)-thalimonine on uninfected and HSV-1 infected cells. The data obtained have shown that zinc complexes and the alkaloid exert decreased cytotoxicity (antagonistic effect) and significantly increased anti-HSV-1 activity (synergistic effect) when applied in dual chess-board combinations as compared to the individual effects of compounds tested. These combinations are also effective against the infection caused by a resistant to acyclovir (ACV) HSV-1 mutant and the effect has been recognised as synergistic.     

Recurrent Herpes Simplex Virus Type 1 (HSV-1) Infection Modulates Neuronal Aging Marks in In Vitro and In Vivo Models

Herpes simplex virus 1 (HSV-1) is a widespread neurotropic virus establishing a life-long latent infection in neurons with periodic reactivations. Recent studies linked HSV-1 to neurodegenerative processes related to age-related disorders such as Alzheimer’s disease. Here, we explored whether recurrent HSV-1 infection might accelerate aging in neurons, focusing on peculiar marks of aged cells, such as the increase in histone H4 lysine (K) 16 acetylation (ac) (H4K16ac); the decrease of H3K56ac, and the modified expression of Sin3/HDAC1 and HIRA proteins. By exploiting both in vitro and in vivo models of recurrent HSV-1 infection, we found a significant increase in H4K16ac, Sin3, and HDAC1 levels, suggesting that the neuronal response to virus latency and reactivation includes the upregulation of these aging markers. On the contrary, we found a significant decrease in H3K56ac that was specifically linked to viral reactivation and apparently not related to aging-related markers. A complex modulation of HIRA expression and localization was found in the brain from HSV-1 infected mice suggesting a specific role of this protein in viral latency and reactivation. Overall, our results pointed out novel molecular mechanisms through which recurrent HSV-1 infection may affect neuronal aging, likely contributing to neurodegeneration.     

Studies on Some Biologically Cobalt(II), Copper(II) and Zinc(II) Complexes With ONO, NNO and SNO Donor Pyrazinoylhydrazine-Derived Ligands

Biologically active complexes of Co(II), Ni(II), Cu(II) and Zn(II) with novel ONO, NNO and SNO donor pyrazinoylhydrazine-derived compounds have been prepared and characterized on the basis of analytical data and various physicochemical studies. Distorted octahedral structures for all the complexes have been proposed. The synthesized ligands and their complexes have been screened for their antibacterial activity against bacterial species Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Klebsiella pneumonae. The activity data show the metal complexes to be more active than the parent free ligands against one or more bacterial species.     

重组人干扰素α2b阴道泡腾片抗豚鼠单纯疱疹病毒性阴道炎的疗效

目的观察重组人干扰素α2b阴道泡腾片对单纯疱疹病毒性阴道炎动物模型的疗效。方法采用单纯疱疹病毒感染建立豚鼠实验性阴道炎模型,并分别用重组人干扰素α2b阴道泡腾片600、3 000和15 000 IU/只进行治疗。以阿昔洛韦(无环鸟苷)和干扰素α2b栓剂15 000 IU/只作为对照。对治疗前后豚鼠阴道外观及组织切片进行评分。结果应用重组人干扰素α2b阴道泡腾片对豚鼠实验性单纯疱疹病毒性阴道炎进行治疗后,豚鼠阴道外观病变与组织切片病变评分均显著降低,其中15 000 IU/只效果最好。同样剂量的α2b泡腾片药效优于栓剂。结论重组人干扰素α2b阴道泡腾片对实验性单纯疱疹病毒性阴道炎有明显的疗效。     

Disrupting Neurons and Glial Cells Oneness in the Brain—The Possible Causal Role of Herpes Simplex Virus Type 1 (HSV-1) in Alzheimer’s Disease

Current data strongly suggest herpes simplex virus type 1 (HSV-1) infection in the brain as a contributing factor to Alzheimer’s disease (AD). The consequences of HSV-1 brain infection are multilateral, not only are neurons and glial cells damaged, but modifications also occur in their environment, preventing the transmission of signals and fulfillment of homeostatic and immune functions, which can greatly contribute to the development of disease. In this review, we discuss the pathological alterations in the central nervous system (CNS) cells that occur, following HSV-1 infection. We describe the changes in neurons, astrocytes, microglia, and oligodendrocytes related to the production of inflammatory factors, transition of glial cells into a reactive state, oxidative damage, Aβ secretion, tau hyperphosphorylation, apoptosis, and autophagy. Further, HSV-1 infection can affect processes observed during brain aging, and advanced age favors HSV-1 reactivation as well as the entry of the virus into the brain. The host activates pattern recognition receptors (PRRs) for an effective antiviral response during HSV-1 brain infection, which primarily engages type I interferons (IFNs). Future studies regarding the influence of innate immune deficits on AD development, as well as supporting the neuroprotective properties of glial cells, would reveal valuable information on how to harness cytotoxic inflammatory milieu to counter AD initiation and progression.     

Interplay between Autophagy and Herpes Simplex Virus Type 1: ICP34.5, One of the Main Actors

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus that occasionally may spread to the central nervous system (CNS), being the most common cause of sporadic encephalitis. One of the main neurovirulence factors of HSV-1 is the protein ICP34.5, which although it initially seems to be relevant only in neuronal infections, it can also promote viral replication in non-neuronal cells. New ICP34.5 functions have been discovered during recent years, and some of them have been questioned. This review describes the mechanisms of ICP34.5 to control cellular antiviral responses and debates its most controversial functions. One of the most discussed roles of ICP34.5 is autophagy inhibition. Although autophagy is considered a defense mechanism against viral infections, current evidence suggests that this antiviral function is only one side of the coin. Different types of autophagic pathways interact with HSV-1 impairing or enhancing the infection, and both the virus and the host cell modulate these pathways to tip the scales in its favor. In this review, we summarize the recent progress on the interplay between autophagy and HSV-1, focusing on the intricate role of ICP34.5 in the modulation of this pathway to fight the battle against cellular defenses.     

6-羟基-2-萘磺酸铜、镁、锌、钴、镍配合物的合成和结构表征

6-羟基-2-萘磺酸钠分别和CuSO4,MgSO4,ZnSO4、Co(phen)3Cl2反应,物质的量比为5∶1,得到一系列铜、镁、锌、钴、镍配合物并通过红外和元素分析确定结构。测定了钴的配合物的单晶结构,结果表明,钴配合物1属于三斜晶系,P-1空间群,a=12.4120(15),b=12.4711(16),c=20.090(2),α=90.0450(10)°,β=103.161(2)°,γ=113.519(2)°,V=2761.9(6)3,Z=2。     

Synthesis, Ligational and Biological Properties of Cobalt(II), Copper(II), Nickel(II) and Zinc(II) Complexes With Pyrazinedicarboxaimide Derived Furanyl, Thienyl and Pyrrolyl Compounds

Preparation, ligational and biological properties of some pyrazinedicarboxaimide derived furanyl, thienyl and pyrrolyl compounds with Co(ll), Cu(ll), Ni(ll) and Zn(ll) metals are described. Magnetic moments, electronic, infrared, nuclear magnetic resonance spectra and elemental analysis data indicate that co-ordination of the ligands with the metal ions take place through the pyrazine ring nitrogen, azomethine nitrogen and heteroatom of heterocyclic ring system. The compounds are all novel and are proposed to possess an octahedral geometry for Co(ll) and Ni(ll), and a distorted octahedral geometry for Cu(ll) and Zn(ll) complexes. The comparative biological properties of the title ligands and their metal chelates against different bacterial species are also described.     

铜离子在硫酸锌电解液深度净化除钴中的作用

对Cu2+在湿法炼锌浸出液锑盐法深度净化除钴过程中的作用进行了研究. 考察了钴离子浓度达到深度净化浓度([Co2+]<0.1 mg/L)的时间、低于该浓度的持续时间及所需初始铜离子浓度([Cu2+]0)等因素,综合衡量除钴效果,得到优化实验条件为：[Co2+]0=15 mg/L时,钴/锑质量比(Co/Sb)=2:1,[Cu2+]0=200 mg/L,达到深度净化浓度的时间和保持该浓度的时间分别是25和70 min;[Co2+]0=7.5 mg/L时,Co/Sb=2:1,[Cu2+]0=100 mg/L,达到和保持深度净化浓度的时间分别是40和55 min. 搅拌转速对除钴效果影响不大,高转速有利于钴返溶,返溶的原因可能是沉积的碱式钴盐溶解.     

Oncolytic Herpes Simplex Virus Type 1 Induces Immunogenic Cell Death Resulting in Maturation of BDCA-1+ Myeloid Dendritic Cells

Recently, a paradigm shift has been established for oncolytic viruses (OVs) as it was shown that the immune system plays an important role in the specific killing of tumor cells by OVs. OVs have the intrinsic capacity to provide the right signals to trigger anti-tumor immune responses, on the one hand by delivering virus-derived innate signals and on the other hand by inducing immunogenic cell death (ICD), which is accompanied by the release of various damage-associated molecules from infected tumor cells. Here, we determined the ICD-inducing capacity of Talimogene laherparepvec (T-VEC), a herpes simplex virus type 1 based OV, and benchmarked this to other previously described ICD (e.g., doxorubicin) and non-ICD inducing agents (cisplatin). Furthermore, we studied the capability of T-VEC to induce the maturation of human BDCA-1⁺ myeloid dendritic cells (myDCs). We found that T-VEC treatment exerts direct and indirect anti-tumor effects as it induces tumor cell death that coincides with the release of hallmark mediators of ICD, while simultaneously contributing to the maturation of BDCA-1⁺ myDCs. These results unequivocally cement OVs in the category of cancer immunotherapy.     

HSV-1 stocker株糖蛋白G基因膜外区毕赤酵母表达载体的构建及序列分析

目的构建Ⅰ型单纯疱疹病毒型特异性包膜糖蛋白G基因膜外区毕赤酵母表达载体,并进行序列分析。方法PCR扩增HSV-1-gG基因的膜外区,克隆于pGEM-T载体,转化DH5α,提取质粒酶切鉴定后,与pPIC9K载体连接,转化DH5α,筛选阳性克隆,鉴定后转化GS115菌,构建酵母表达载体。对克隆的序列进行分析,预测表达产物的理化特性、抗原性及表达形式。结果获得的重组酵母表达载体pPIC9K-gG,测序结果证实为HSV-1-gG基因,序列分析其高度保守,预测蛋白相对分子质量15870,等电点pI为4.72,包含全部膜外区分值达1.7的6个强抗原决定簇,将以可溶性形式分泌表达于胞外。结论已成功构建HSV-1stocker株糖蛋白G基因膜外区毕赤酵母表达载体。     

Cobalt(II), Zinc(II) and Cadmium(II)-Squarate Complexes with N-Methylimidazole

Three M(II)-squarate complexes, [Co(sq)(H₂O)(Nmim)₄] (1), [Zn(μ_1,3-sq)(H₂O)₂ (Nmim)₂] _n (2) and [Cd(μ_1,3-sq)(H₂O)₂(Nmim)₂] _n (3) (sq = squarate, Nmim = N-methylimidazole) have been synthesized and characterized by elemental, spectral (IR and UV–Vis.) and thermal analyses. The molecular structures of the complexes have been investigated by single crystal X-ray diffraction technique. The squarate ligand acts as two different coordination modes as a monodentate (in 1) and bis(monodentate) (O ^1– O ³ ) bridging ligand (in 2, 3). The Co(II) atom has a distorted octahedral geometry with the basal plane comprised of three nitrogen atoms of Nmim ligands and a oxygen atom of squarate ligand. The axial position is occupied by a nitrogen atom of Nmim and one aqua ligand. The crystallographic analysis reveals that the crystal structures of 2 and 3 are one-dimensional linear chain polymers along the c and b axis, respectively. The configuration around each metal(II) ions are distorted octahedral geometry with two nitrogen atoms of trans-Nmim, two aqua ligands and two oxygen atoms of squarate-O¹,O³ ligand. These chains are held together by the C–H···π, π···π and hydrogen-bonding interactions, forming three-dimensional network.     

Pharmacological Role of Anions (Sulphate, Nitrate, Oxalate and Acetate) on the Antibacterial Activity of Cobalt(II), Copper(II) and Nickel(II) Complexes With Nicotinoylhydrazine-Derived ONO, NNO and SNO Ligands

Mixed ligands biologically active complexes of cobalt(II), copper(II) and nickel(II) with nicotinoylhydrazine-derived ONO, NNO and SNO donor schiff-base ligands having the same metal ion but different anions such as sulphate, nitrate, oxalate and acetate have been synthesised and characterised on the basis of their physical, analytical and spectral data. In order to evaluate the role of anions on their bioability, these ligands and their synthesised metal complexes with various anions have been screened against bacterial species such as Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus and the title studies have proved a definative role of anions in increasing the biological activity.     

阴离子交换色谱法分离含钴溶液中锌、镉、铜等杂质

采用阴离子交换色谱法,研究了某锌厂冶炼废渣的硫酸化焙砂浸出液中钴与锌、镉、铜等杂质离子的分离工艺,确定了最佳工艺参数：将料液配制成含2 mol/L Cl–1和0.1 mol/L Na2SO3的溶液,调节pH值为 4.5,搅拌数分钟,料液pH值降低至 4.0后,用201?7阴离子交换色谱柱进行分离,柱后流出液中锌、镉、铜等杂质的含量达到钴冶金工艺要求,钴的损失为0.7%左右.     

A kinetic study of precipitate flotation of Zinc(II), Cobalt(II) and Copper(II) hydroxides

An experimental kinetic study has been completed on precipitate flotation of Zn(II), Co(II) and Cu(II) hydroxides (initial metal concentration 1 × 10^?-2M) with the anionic surfactant, sodium dodecyl benzenesulphonate (1 × 10^?-4M), at varying equilibrium pH. An original radioactive isotope procedure was applied and proved to be sufficiently accurate. Kinetic equations of Rubin and co-workers were found to be relevant for precipitate flotation of hydroxides. From the flotation rate constant (k_p) determined at varying equilibrium pH of floated suspensions it appeared that the selective flotation of individual compounds from mixed precipitate was possible as a result of the ‘kinetic effect’.