Gold(I) complexes with thiosemicarbazones: cytotoxicity against human tumor cell lines and inhibition of thioredoxin reductase activity

Complexes [Au(H2Ac4DH)Cl]?MeOH (1) [Au(H₂2Ac4Me)Cl]Cl (2) [Au(H₂2Ac4Ph)Cl]Cl?2H₂O (3) and [Au(H₂2Bz4Ph)Cl]Cl (4) were obtained with 2-acetylpyridine thiosemicarbazone (H2Ac4DH), its N(4)-methyl (H2Ac4Me) and N(4)-phenyl (H2Ac4Ph) derivatives, as well as with N(4)-phenyl 2-benzoylpyridine thiosemicarbazone (H2Bz4Ph). The compounds were cytotoxic to Jurkat (immortalized line of T lymphocyte), HL-60 (acute myeloid leukemia), MCF-7 (human breast adenocarcinoma) and HCT-116 (colorectal carcinoma) tumor cell lines. Jurkat and HL-60 cells were more sensitive than MCF-7 and HCT-116 cells. Upon coordinating to the gold(I) metal centers in complexes (2) and (4), the cytotoxic activity of the H2Ac4Me and H2Bz4Ph ligands increased against the HL-60 and Jurkat tumor cell lines. 2 was more active than auranofin against both leukemia cells. Most of the studied compounds were less toxic than auranofin to peripheral blood mononuclear cells (PBMC). All compounds induced DNA fragmentation in HL-60 and Jurkat cells indicating their pro-apoptotic potential. Complex (2) strongly inhibited the activity of thioredoxin reductase (TrxR), which suggests inhibition of TrxR to be part of its mechanism of action.     

N⁴-Phenyl-substituted 2-acetylpyridine thiosemicarbazones: cytotoxicity against human tumor cells, structure-activity relationship studies and investigation on the mechanism of action

N(4)-Phenyl 2-acetylpyridine thiosemicarbazone (H2Ac4Ph; N-(phenyl)-2-(1-(pyridin-2-yl)ethylidene)hydrazinecarbothioamide) and its N(4)-ortho-, -meta- and -para-fluorophenyl (H2Ac4oFPh, H2Ac4mFPh, H2Ac4pFPh), N(4)-ortho-, -meta- and -para-chlorophenyl (H2Ac4oClPh, H2Ac4mClPh, H2Ac4pClPh), N(4)-ortho-, -meta- and -para-iodophenyl (H2Ac4oIPh, H2Ac4mIPh, H2Ac4pIPh) and N(4)-ortho-, -meta- and -para-nitrophenyl (H2Ac4oNO(2)Ph, H2Ac4mNO(2)Ph, H2Ac4pNO(2)Ph) derivatives were assayed for their cytotoxicity against human malignant breast (MCF-7) and glioma (T98G and U87) cells. The compounds were highly cytotoxic against the three cell lineages (IC(50): MCF-7, 52-0.16 nM; T98G, 140-1.0 nM; U87, 160-1.4 nM). All tested thiosemicarbazones were more cytotoxic than etoposide and did not present any haemolytic activity at up to 10(-5)M. The compounds were able to induce programmed cell death. H2Ac4pClPh partially inhibited tubulin assembly at high concentrations and induced cellular microtubule disorganization.     

Extraordinary growth in tiger sharks Galeocerdo cuvier from the South Atlantic Ocean

Two tagged‐and‐recaptured tiger sharks Galeocerdo cuvier, measuring 172 and 304 cm total length (L_T) and at age 0·75 and 3·50 years, exhibited unmatched growth rates of 118·4 and 55·5 cm year^?1, respectively. The larger fish was nearly mature, indicating that G. cuvier off Brazil could mature considerably earlier than conspecifics from other regions.     

Population genetic structure and social kin associations of franciscana dolphin, Pontoporia blainvillei

We investigated population and social structure of the franciscana dolphin, Pontoporia blainvillei, an endemic and the most endangered cetacean of the southwestern Atlantic Ocean. We analyzed samples from the Rio de la Plata estuary obtained in Uruguayan waters and from the Atlantic Ocean obtained in both Uruguayan and Brazilian waters. Mitochondrial and microsatellite DNA markers were used to study differentiation between the estuary and the ocean and the association between kinship and social group structure. Although multilocus analyses suggested that franciscanas are structured into 2 subpopulations (K = 2, divergence among clusters: F(ST) = 0.06, P = 0.002; R(ST) = 0.3, P = 0.001), mitochondrial markers did not support such divergence (F(ST) = 0.02, P = 0.12; Ф(ST) = 0.06, P =0.06). However, these units are not entirely segregated geographically. Regarding social structure, some groups are composed by first-order related individuals (R ≥ 0.5, P < 0.5). Overall, the data suggest that matrilines could be the social unit in this species. We argue that the divergence found could be associated to local adaptation and social structure, resulting from either feature leading to a recent divergence or reflecting equilibrium between local differentiation and gene flow. This evidence supports considering franciscanas from the Rio de la Plata estuary a discrete management unit.     

Coordination of Thiosemicarbazones and Bis(thiosemicarbazones) to Bismuth(III) as a Strategy for the Design of Metal-Based Antibacterial Agents

Complexes [Bi(2Fo4Ph)Cl(2) ] (1), [Bi(2Ac4Ph)Cl(2) ] (2), [Bi(2Bz4Ph)Cl(2) ] (3), [Bi(H(2) Gy3DH)Cl(3) ] (4), [Bi(H(2) Gy4Et)(OH)(2) Cl] (5), and [Bi(H(2) Gy4Ph)Cl(3) ] (6) were prepared with pyridine-2-carbaldehyde 4-phenylthiosemicarbazone (H2Fo4Ph), 1-(pyridin-2-yl)ethanone 4-phenylthiosemicarbazone (H2Ac4Ph), phenyl(pyridin-2-yl)methanone 4-phenylthiosemicarbazone (H2Bz4Ph), as well as with glyoxaldehyde bis(thiosemicarbazone) (H(2) Gy4DH) and its 4-Et (H(2) Gy4Et) and 4-Ph (H(2) Gy4Ph) derivatives. The complexes exhibited antibacterial activities against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, and Pseudomonas aeruginosa. Coordination to Bi(III) proved to be an effective strategy to increase the antibacterial activity of the thiosemicarbazones and bis(thiosemicarbazones).     

Age and growth of the spotted goatfish, Pseudupeneus maculatus (Bloch, 1793) in Brazil, validated through marginal increment and oxytetracycline dyes in the sagittae

A sample composed of 4973 specimens of the spotted goatfish, Pseudupeneus maculatus (4.5–29.2 cm fork length) was collected off northeastern Brazil from 1999 to 2002. Sagittae (398) were analyzed for age and growth estimation using both annuli and microincrements. For the first approach, the mean monthly marginal increment ratio analysis suggested that one band is formed annually from May to June. With the microincrements analysis, 15 specimens were reared (3–71 days) for validation of periodicity using oxytetracycline. Fluorescent dyes were observed in 10 specimens (7.5–16.9 cm). After testing, one microincrement was found to form daily. Otolith sections were polished and analyzed using a light microscope (100–1200× magnifications). Individuals larger than 22.6 cm (4 years) showed heavily overlaid increments on the otolith edge, which hampered the counts. There was agreement on the size from counts on an annual and daily basis. The von Bertalanffy function provided the following parameters: L_∞ = 33.23 cm; K = 0.265; t₀ = 0.0883 year. The sample was composed of 0⁺ to >5‐year‐old specimens. Age at first maturity was 3.6 years (20 cm), whereas the recruitment age for fisheries was 3.9 years. Juveniles represented about half of the catch (48.7%), which may have implications for population equilibrium.     

Scorched mussels (Brachidontes spp., Bivalvia: Mytilidae) from the tropical and warm‐temperate southwestern Atlantic: the role of the Amazon River in their speciation

Antitropicality is a distribution pattern where closely related taxa are separated by an intertropical latitudinal gap. Two potential examples include Brachidontes darwinianus (south eastern Brazil to Uruguay), considered by some authors as a synonym of B. exustus (Gulf of Mexico and the Caribbean), and B. solisianus, distributed along the Brazilian coast with dubious records north of the intertropical zone. Using two nuclear (18S and 28S rDNA) and one mitochondrial gene (mtDNA COI), we aimed to elucidate the phylogeographic and phylogenetic relationships among the scorched mussels present in the warm‐temperate region of the southwest Atlantic. We evaluated a divergence process mediated by the tropical zone over alternative phylogeographic hypotheses. Brachidontes solisianus was closely related to B. exustus I, a species with which it exhibits an antitropical distribution. Their divergence time was approximately 2.6 Ma, consistent with the intensification of Amazon River flow. Brachidontes darwinianus, an estuarine species is shown here not to be related to this B. exustus complex. We suspect ancestral forms may have dispersed from the Caribbean to the Atlantic coast via the Trans‐Amazonian seaway (Miocene). The third species, B rodriguezii is presumed to have a long history in the region with related fossil forms going back to the Miocene. Although scorched mussels are very similar in appearance, their evolutionary histories are very different, involving major historical contingencies as the formation of the Amazon River, the Panama Isthmus, and the last marine transgression.     

Dexamethasone reverses the memory impairment induced by antagonism of hippocampal gastrin-releasing peptide receptors

Storage of emotionally influenced memory is regulated by activation of glucocorticoid receptors (GRs) as well as of gastrin-releasing peptide receptors (GRPRs) in the dorsal hippocampus. In the present study, male Wistar rats were given a bilateral infusion of saline or the GRPR antagonist (D-Tpi6, Leu13 psi[CH2NH]-Leu14) bombesin (6-14) (RC-3095) (1.0 microg/side) into the dorsal hippocampus 10 min before training on an inhibitory avoidance task, followed by an immediate post-training i.p. injection of vehicle or the GR agonist dexamethasone (0.3 mg/kg). A retention test trial, carried out 24 h after training, indicated that intrahippocampal infusion of RC-3095 impaired inhibitory avoidance retention. Post-training administration of dexamethasone induced an enhancement of retention regardless of whether the animals had received saline or RC-3095 into the hippocampus before training. The findings indicate that hippocampal GRPR blockade does not prevent memory enhancement induced by dexamethasone. Together with previous results, these findings suggest that endogenous activation of GRPRs in the hippocampus modulates the consolidation of emotional memory, but is not a critical receptor system mediating memory formation.     

Genetic and geographic differentiation in the Rio Negro tuco-tuco (Ctenomys rionegrensis): inferring the roles of migration and drift from multiple genetic markers

Among tuco-tucos, Ctenomys rionegrensis is especially amenable to the study of the forces driving population differentiation because of the restricted geographic range it occupies in Uruguay. Within this limited area, the Rio Negro tuco-tuco is limited to sandy soils. It nonetheless exhibits remarkable variation in pelage color, including melanic, agouti, and dark-backed individuals. Two hypotheses have been put forth to explain this pattern: (1) local differentiation and fixation of alternative pelage types by genetic drift under limited gene flow; or (2) fixation by natural selection that may take place even in the presence of gene flow. A previous allozyme study rejected the genetic drift hypothesis on the basis of high inferred levels of migration. New estimates of gene flow from microsatellites and mitochondrial cytochrome b sequences were obtained for C. rionegrensis populations to further test these hypotheses. Much lower levels of gene flow were estimated with these more sensitive markers. Microsatellite-based estimates of gene flow are close to zero and may come closest to estimating current levels of migration. A lack of equilibrium between migration and genetic drift is also strongly suggested by the absence of an isolation-by-distance pattern found in all three genetic datasets. The microsatellite genotype data show that the species is strongly structured geographically, with subpopulations constituting distinct genetic entities. If current levels of gene flow are very low, as indicated by the new data, the local fixation of alternative alleles, including those responsible for pelage color polymorphism, is possible by drift alone. A scenario is thus proposed in which the species expanded in the recent past from a more restricted geographic range and has subsequently differentiated in near isolation, with genetic drift possibly playing a primary role in overall genetic differentiation. The local fixation of pelage color types could also be due to drift, but selection on this trait cannot be ruled out without direct analysis.