(13)C, (31)P and (15)N NMR studies of the ligand exchange reactions of auranofin and chloro(triethylphosphine)gold(I) with thiourea.

The interaction of thiourea (Tu) with auranofin (Et(3)PAuSATg) and its analogue, Et(3)PAuCl has been studied using (13)C, (31)P and (15)N NMR spectroscopy. It is observed that Tu is able to replace both the ligands, Et(3)P and SATg(-) simultaneously from gold(I) in auranofin, forming [Et(3)P-Au-Tu](+) and Tu-Au-SATg complexes. However, no separate resonances for these species were observed either due to their rapid exchange with auranofin and thus giving only the average resonances or because the chemical shifts of either two species are same so that they cannot be resolved. The displaced SATg(-) is oxidized to its disulfide, (SATg)(2). However, some of the displaced Et(3)P is oxidized to Et(3)PO while the remaining reacts with Tu to form Et(3)P-Tu species, characterized by delta 31P of 1.0 ppm, assigned after an independent reaction between Et(3)P and Tu. In an experiment using a 0.05 M solution of auranofin, the Et(3)PO resonance appeared in auranofin spectrum after 4 days of addition of 1.0 equivalent of Tu, showing that the reaction is slow. A resonance for free Et(3)P is also detected in 31P NMR on the addition of CN(-). It is also observed that Tu reacts with Et(3)PAuCl to form [Et(3)P-Au-Tu](+) via displacement of Cl(-), consistent with an upfield shift of 6.2 ppm in >C [double bond] S resonance of Tu in (13)C NMR. In (15)N NMR, a smaller downfield, instead of an upfield shift, in NH(2) resonance of Tu on its addition to auranofin and Et(3)PAuCl indicates that it is not binding to gold(I) through nitrogen.     

Sciatic nerve regeneration by transplantation of menstrual blood-derived stem cells

This is the first study demonstrating the efficacy of menstrual blood-derived stem cell (MenSC) transplantation via a neural guidance conduit, for peripheral nerve regeneration. The synthesized poly (?-caprolactone)/Gelatin conduit, filled with collagen type I and seeded with 3?×?10⁴ MenSCs, was implanted into a rat’s 10 mm sciatic nerve defect. The results of hot plate latency, sciatic functional index and weight-loss percentage of wet gastrocnemius muscle demonstrated that the MenSC transplantation had comparable nerve regeneration outcome to autograft, as the gold standard of nerve bridging. The transplantation of MenSCs via a synthetic conduit could ameliorate the functional recovery of sciatic nerve-injured rats which make them a potential candidate for cell therapy of peripheral nervous system disorders.     

The effect of Trimetazidine and Diazoxide on immunomodulatory activity of human embryonic stem cell-derived mesenchymal stem cell secretome

Comprehensive proteome profiling of the factors secreted by mesenchymal stem cells (MSCs), referred to as secretome, revealed that it consists of cytokines, chemokines, growth factors, extracellular matrix proteins, and components of regeneration, vascularization, and hematopoiesis pathways. Harnessing this MSC secretome for therapeutic applications requires the optimization of production of secretary molecules. A variety of preconditioning methods have been introduced, which subject cells to stimulatory molecules to create the preferred response and stimulate persistent effects. Pharmacological preconditioning uses small molecules and drugs to increase survival of MSCs after transplantation or prolong release of effective secretary factors such as cytokines that improve immune system responses. In this study, we investigated the effect of secretome of human embryonic-derived mesenchymal stem cells (hESC-MSCs) preconditioned with Trimetazidine (TMZ) and Diazoxide (DZ) on immunomodulatory efficiency of these cells in LPS-induced peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from human peripheral blood and treated with concentrated hESC-MSC-derived conditioned medium and then, the secreted levels of IL-10, TNFα and IL-1β were assessed by ELISA after induction with LPS. The results showed that TMZ and DZ-conditioned medium significantly enhanced immunomodulatory potential of hESC-MSCs by increasing the secretion of IL-10, TNFα and IL-1β from LPS- induced PBMCs. We also found that hESC-MSCs did not secrete mentioned cytokines prior to or after the preconditioning with TMZ and DZ. In conclusion, our results implied that TMZ and DZ can be used to promote the immunomodulatory effects of hESC-MSC secretome. It is obvious that for applying of these findings in clinical demands, the potency of different pre-conditioned MSCs secretome on immune response needs to be more clarified.     

Effect of metal chelators on the aggregation of beta-amyloid peptides in the presence of copper and iron

Amyloid β (Aβ) fibrils and amorphous aggregates are found in the brain of patients with Alzheimer’s disease (AD), and are implicated in the etiology of AD. The metal imbalance is also among leading causes of AD, owing to the fact that Aβ aggregation takes place in the synaptic cleft where Aβ, Cu(II) and Fe(III) are found in abnormally high concentrations. Aβ40 and Aβ42 are the main components of plaques found in afflicted brains. Coordination of Cu(II) and Fe(III) ions to Aβ peptides have been linked to Aβ aggregation and production of reactive oxygen species, two key events in the development of AD pathology. Metal chelation was proposed as a therapy for AD on the basis that it might prevent Aβ aggregation. In this work, we first examined the formation of Aβ40 and Aβ42 aggregates in the presence of metal ions, i.e. Fe(III) and Cu(II), which were detected by fluorescence spectroscopy and atomic force microscopy. Second, we studied the ability of the two chelators, ethylenediaminetetraacetic acid and 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol), to investigate their effect on the availability of these metal ions to interact with Aβ and thereby their effect on Aβ accumulation. Our findings show that Fe(III), but not Cu(II), promote aggregation of both Aβ40 and Aβ42. We also found that only clioquinol decreased significantly iron ion-induced aggregation of Aβ42. The presence of ions and/or chelators also affected the morphology of Aβ aggregates.     

Haplotypes inside the beta-globin gene: use as new biomarkers for beta-thalassemia prenatal diagnosis in north of Iran

Background

Beta-thalassemia is common in the Mediterranean area as well as the Middle East and India. Official report in Iran revealed the average prevalence rate of carriers about 4%. More than 20 restriction fragment length polymorphisms (RFLPs) are known in the beta-globin gene cluster and used in the prenatal diagnosis (PND) services. Some of these locations may have low allele frequency and are not informative in the prenatal diagnosis. The current study aims to find new haplotypes and polymorphisms with high allele frequency in the local population.

Methods

Two thousand three hundred fifty samples (1,321 male and 1,029 female) from the northern Iran, whom suspected to be the carriers either for alpha or beta thalassemia and referred to the local diagnostic laboratory as a routine services were investigated during five years, (2010–2015). The beta-globin gene was sequenced for all samples.

Results

Heterozygosity for five SNPs in the beta-globin gene was calculated separately. 383 individuals (16.29%) showed no sign of nucleotide change in the beta-globin gene sequence. In total, codon2 (C/T) 31.72%, IVSII-16 (C/G) 31.72%, IVSII-74 (G/T) 54.71%, IVSII-81 (C/T) 19.47%, and IVSII-666 (T/C) 31.72% were seen respectively. Although all five polymorphisms showed reasonably high heterozygosity, IVSII-74 (G/T) [GG wild type (36.5%), G/T (54.71%) and TT (8.8%)] revealed the highest heterozygosity rate. Four combinations of these five SNPs were defined as new haplotypes named M1 to M4. ARMS-PCR also were designed and applied to detect IVSII-74 (G/T) nucleotide position.

Conclusions

This study represents an intragenic polymorphism, IVSII-74, a reliable position with high heterozygosity rates in Iranian population for PND analysis.

Trial registration

Retrospectively registered.

     

Effect of temporal data aggregation on the perceived structure of a quantitative plant–floral visitor network

Seasonal turnover in plant and floral visitor communities changes the structure of the network of interactions they are involved in. Despite the dynamic nature of plant–visitor networks, a usual procedure is to pool year‐round interaction data into a single network which may result in a biased depiction of the real structure of the interaction network. The annual temporal dynamics and the effect of merging monthly data have previously been described for qualitative data (i.e. describing the occurrence of interactions) alone, while its quantitative aspect (i.e. the actual frequency with which interactions occur) remain little explored. For this, we built a set of 12 monthly networks describing year‐round plant–floral visitor interactions in a 30‐hectare planted forest and its adjacent agricultural landscape at Bahauddin Zakariya University Multan, Pakistan. A total of 80 plant and 162 insect species, which engaged in 1573 unique interactions, were recorded. Most network properties (particularly the number of plants, visitors and unique interactions) varied markedly during the year. Data aggregation showed that while animal species, plant species, unique interaction, weighted nestedness, interaction diversity and robustness increased, connectance and specialization decreased. The only metric which seemed relatively unaffected by data pooling was interaction evenness. In general, quantitative metrics were relatively less affected by temporal data aggregation than qualitative ones. Avoiding data aggregation not only gives a more realistic depiction of the dynamic nature of plant–visitor community networks, but also avoids biasing network metrics and, consequently, their expected response to disturbances such as the loss of species.     

伊朗一沼泽中水生甲虫体长与体重的关系(英文)

本研究所用标本为7种水生甲虫,均采自伊朗Choghakhor沼泽。通过对水生甲虫的体长和体重的测量,研究其体长-体重关系(LWR)。结果表明: LWR参数b的变动范围在2.315~3.117之间。所有被观察的水生甲虫体长与体重关系明显,相关系数(r²)均高。本研究所得到的这种相互关系可被用于确定甲虫体重,并有助于解决其他的一些生态学问题。本研究所提出的体长-体重关系(LWR)限制于所观察到的标本体长范围。     

Slow loss of deoxyribose from the N7deoxyguanosine adducts of estradiol-3,4-quinone and hexestrol-3',4'-quinone. Implications for mutagenic activity

A variety of evidence has been obtained that estrogens are weak tumor initiators. A major step in the multi-stage process leading to tumor initiation involves metabolic formation of 4-catechol estrogens from estradiol (E2) and/or estrone and further oxidation of the catechol estrogens to the corresponding catechol estrogen quinones. The electrophilic catechol quinones react with DNA mostly at the N-3 of adenine (Ade) and N-7 of guanine (Gua) by 1,4-Michael addition to form depurinating adducts. The N3Ade adducts depurinate instantaneously, whereas the N7Gua adducts depurinate with a half-life of several hours. Only the apurinic sites generated in the DNA by the rapidly depurinating N3Ade adducts appear to produce mutations by error-prone repair. Analogously to the catechol estrogen-3,4-quinones, the synthetic nonsteroidal estrogen hexestrol-3',4'-quinone (HES-3',4'-Q) reacts with DNA at the N-3 of Ade and N-7 of Gua to form depurinating adducts. We report here an additional similarity between the natural estrogen E2 and the synthetic estrogen HES, namely, the slow loss of deoxyribose from the N7deoxyguanosine (N7dG) adducts formed by reaction of E2-3,4-Q or HES-3',4'-Q with dG. The half-life of the loss of deoxyribose from the N7dG adducts to form the corresponding 4-OHE2-1-N7Gua and 3'-OH-HES-6'-N7Gua is 6 or 8 h, respectively. The slow cleavage of this glycosyl bond in DNA seems to limit the ability of these adducts to induce mutations.     

Design, synthesis and biological evaluation of novel riccardiphenol analogs

A novel, facile, high yield, and less cumbersome synthesis of riccardiphenol analogs is described. The synthesized compounds were characterized and assessed for its in vitro activity in a panel of human cancer cell lines of differing origin: HuCCT-1, BxPC3, Panc-1, Mia-Paca, A431, Hep2, and HN006. HuCCT-1 was derived from an intrahepatic cholangiocarcinoma; BxPC3, Mia-Paca, and Panc-1 were derived from pancreatic cancers; A431 was derived from a vulvar epithelial carcinoma; and Hep2 and HN006 were derived from squamous cell carcinomas of the head and neck. The cytotoxicity of a newly developed riccardiphenol analog against human cancer cell lines was assessed. The cancer cells exhibited varying sensitivities to the compound, with IC50 values from 30 to 50 microM. This susceptibility was particularly interesting in the case of lines such as Hep2 and BxPC3 that are resistant to classic cytotoxic drugs as well as some targeted agents. These results demonstrate that the novel riccardiphenol analog has effective action against human-derived cancer cell in vitro.