Multidimensional optimization of promising antitumor xanthone derivatives

A promising antitumor xanthone derivative was optimized following a multidimensional approach that involved the synthesis of 17 analogues, the study of their lipophilicity and solubility, and the evaluation of their growth inhibitory activity on four human tumor cell lines. A new synthetic route for the hit xanthone derivative was also developed and applied for the synthesis of its analogues. Among the used cell lines, the HL-60 showed to be in general more sensitive to the compounds tested, with the most potent compound having a GI₅₀ of 5.1 μM, lower than the hit compound. Lipophilicity was evaluated by the partition coefficient (K_p) of a solute between buffer and two membrane models, namely liposomes and micelles. The compounds showed a log K_p between 3 and 5 and the two membrane models showed a good correlation (r² = 0.916) between each other. Studies concerning relationship between solubility and structure were developed for the hit compound and 5 of its analogues.     

Altitudinal variation in growth, photosynthetic capacity and water use efficiency of Abies faxoniana Rehd. et Wils. seedlings as revealed by reciprocal transplantations

Altitudinal variation in morphological, physiological and biochemical characteristics between two provenances of Abies faxoniana Rehd. et Wils. from contrasting elevations (3,500 and 2,850 m) was investigated by reciprocal transplantations in the eastern Qinghai-Tibetan Plateau. From each altitude, 54 seedlings were selected, of which 27 seedlings were simply transplanted at their original altitude, while the other 27 seedlings were reciprocally transplanted to another altitude. The results showed that there is evident altitudinal variation in growth, photosynthetic capacity and water use efficiency among A. faxoniana seedlings. Transplantation of seedlings to a lower altitude decreased the leaf pigment content, leaf N content and water use efficiency, but increased CE, P _n, LMR and PNUE, consequently promoting NAR, the biomass accumulation and branchlet length increment. Besides, the increase in the C/N ratio reduced the risk of pathogen attack. Based on the substantial plasticity in the responses of the seedlings, we infer that the ongoing climate warming might facilitate the growth of A. faxoniana seedlings at high altitudes.     

DNA damage induction and antiproliferative activity of vanadium(V) oxido monoperoxido complex containing two bidentate heteroligands

Several peroxidovanadium(V) complexes have been shown as a potent anticancer agents. The aim of this study was to investigate the interaction of monoperoxidovanadium(V) complex Pr₄N[VO(O₂)(ox)(phen)], (Vphen), [phen = 1,10-phenantroline, ox = oxalate(2?) and Pr₄N = tetra(n-propyl)ammonium(1+)] with DNA. UV–Vis spectrophotometry and the alkaline single-cell gel electrophoresis (SCGE, the comet assay) were used to examine the possibility of the vanadium(V) complex to induce changes in DNA. The interaction of Vphen with calf thymus DNA resulted in absorption hyperchromicity in DNA spectrum and shift of the absorption band of DNA to longer wavelengths for the [complex]/[DNA] concentration ratio equals to 4 and after 60 min of incubation. The rise in DNA absorption (by 34%) and bathochromic shift (Δλ_max = 6 nm) are indicative of the interaction between DNA and the complex molecules. DNA strand breaks in cellular DNA were investigated using the comet assay. The human lymphocytes were exposed to various concentrations of Vphen for 30 min. The results revealed that Vphen contributed to the DNA damage expressed as DNA strand breaks in concentration dependent manner. The used concentrations of Vphen (ranging from 0.1 to 100 μmol/L) caused higher DNA damage in lymphocytes compared to untreated cells (from 1.2 times for 0.1 μmol/L to 1.8 times for 100 μmol/L). Vphen was screened for its potential antitumor activity towards murine leukemia cell line L1210. Vphen exhibited significant antiproliferative activity depending on its concentration and time of exposure. The IC₅₀ values were 0.247 μg/mL (0.45 μmol/L) for 24 h, 0.671 μg/mL (1.21 μmol/L) for 48 h and 0.627 μg/mL (1.13 μmol/L) for 72 h.     

Soybean lecithin-based extender as an alternative for goat sperm cryopreservation

The aim of this study was to evaluate the effect of different concentrations of soybean lecithin (SL) in extenders for sperm goat cryopreservation. Sexually mature male Saanen goats (n = 4) were used, and the ejaculates were obtained using an artificial vagina method. The semen samples were pooled and diluted in a skim milk-based extender (control group; CG) or Tris extender supplemented with SL at different concentrations (G1 = 0.04%, SL G2 = 0.08% SL and G3 = 0.16%) for a final concentration of 240 × 10⁶ spermatozoa/mL. The semen samples were packed in straws (0.25 mL), frozen using an automated system and stored in liquid nitrogen (?196 °C). After thawing (37 °C/30 s), the samples were evaluated for sperm quality parameters, including sperm motility, membrane integrity, acrosome integrity and mitochondrial activity. No significant difference was observed among the experimental and control groups for all of the parameters (P > 0.05). However, even though the control group presented a significantly lower mitochondrial membrane potential compared to fresh semen (P < 0.05), the same did not occur for the extender supplemented with soybean lecithin, that is, it did not differ from fresh sperm (P > 0.05). The extender containing soybean lecithin at different concentrations preserved the sperm quality parameters in a manner similar to the conventional skim milk-based extender. Thus, it is concluded that an extender containing soybean lecithin as the lipoprotein source can be used for freezing goat semen.     

Modelling shifts in agroclimate and crop cultivar response under climate change

This paper aims: (i) to identify at national scale areas where crop yield formation is currently most prone to climate‐induced stresses, (ii) to evaluate how the severity of these stresses is likely to develop in time and space, and (iii) to appraise and quantify the performance of two strategies for adapting crop cultivation to a wide range of (uncertain) climate change projections. To this end we made use of extensive climate, crop, and soil data, and of two modelling tools: N‐AgriCLIM and the WOFOST crop simulation model. N‐AgriCLIM was developed for the automatic generation of indicators describing basic agroclimatic conditions and was applied over the whole of Finland. WOFOST was used to simulate detailed crop responses at four representative locations. N‐AgriCLIM calculations have been performed nationally for 3829 grid boxes at a 10 × 10 km resolution and for 32 climate scenarios. Ranges of projected shifts in indicator values for heat, drought and other crop‐relevant stresses across the scenarios vary widely – so do the spatial patterns of change. Overall, under reference climate the most risk‐prone areas for spring cereals are found in south‐west Finland, shifting to south‐east Finland towards the end of this century. Conditions for grass are likely to improve. WOFOST simulation results suggest that CO₂ fertilization and adjusted sowing combined can lead to small yield increases of current barley cultivars under most climate scenarios on favourable soils, but not under extreme climate scenarios and poor soils. This information can be valuable for appraising alternative adaptation strategies. It facilitates the identification of regions in which climatic changes might be rapid or otherwise notable for crop production, requiring a more detailed evaluation of adaptation measures. The results also suggest that utilizing the diversity of cultivar responses seems beneficial given the high uncertainty in climate change projections.     

Phenotypic divergence in reproductive traits of a moth population experiencing a phenological shift

Allochrony that is reproductive isolation by time may further lead to divergence of reproductive adaptive traits in response to different environmental pressures over time. A unique “summer” population of the pine processionary moth Thaumetopoea pityocampa, reproductively isolated from the typical winter populations by allochronic differentiation, is here analyzed. This allochronically shifted population reproduces in the spring and develops in the summer, whereas “winter” populations reproduce in the late summer and have winter larval development. Both summer and winter populations coexist in the same pine stands, yet they face different climatic pressures as their active stages are present in different seasons. The occurrence of significant differences between the reproductive traits of the summer population and the typical winter populations (either sympatric or allopatric) is thus hypothesized. Female fecundity, egg size, egg covering, and egg parasitism were analyzed showing that the egg load was lower and that egg size was higher in the summer population than in all the studied winter populations. The scales that cover the egg batches of T. pityocampa differed significantly between populations in shape and color, resulting in a looser and darker covering in the summer population. The single specialist egg parasitoid species of this moth was almost missing in the summer population, and the overall parasitism rates were lower than in the winter population. Results suggest the occurrence of phenotypic differentiation between the summer population and the typical T. pityocampa winter populations for the life‐history traits studied. This work provides an insight into how ecological divergence may follow the process of allochronic reproductive isolation.     

An in vivo control map for the eukaryotic mRNA translation machinery

Rate control analysis defines the in vivo control map governing yeast protein synthesis and generates an extensively parameterized digital model of the translation pathway. Among other non‐intuitive outcomes, translation demonstrates a high degree of functional modularity and comprises a non‐stoichiometric combination of proteins manifesting functional convergence on a shared maximal translation rate. In exponentially growing cells, polypeptide elongation (eEF1A, eEF2, and eEF3) exerts the strongest control. The two other strong control points are recruitment of mRNA and tRNA_i to the 40S ribosomal subunit (eIF4F and eIF2) and termination (eRF1; Dbp5). In contrast, factors that are found to promote mRNA scanning efficiency on a longer than‐average 5′untranslated region (eIF1, eIF1A, Ded1, eIF2B, eIF3, and eIF5) exceed the levels required for maximal control. This is expected to allow the cell to minimize scanning transition times, particularly for longer 5′UTRs. The analysis reveals these and other collective adaptations of control shared across the factors, as well as features that reflect functional modularity and system robustness. Remarkably, gene duplication is implicated in the fine control of cellular protein synthesis.     

Emerging Role of Angiotensin Type 2 Receptor (AT2R)/Akt/NO Pathway in Vascular Smooth Muscle Cell in the Hyperthyroidism

Hyperthyroidism is characterized by increased vascular relaxation and decreased vascular contraction and is associated with augmented levels of triiodothyronine (T3) that contribute to the diminished systemic vascular resistance found in this condition. T3 leads to augmented NO production via PI3K/Akt signaling pathway, which in turn causes vascular smooth muscle cell (VSMC) relaxation; however, the underlying mechanisms involved remain largely unknown. Evidence from human and animal studies demonstrates that the renin-angiotensin system (RAS) plays a crucial role in vascular function and also mediates some of cardiovascular effects found during hyperthyroidism. Thus, in this study, we hypothesized that type 2 angiotensin II receptor (AT2R), a key component of RAS vasodilatory actions, mediates T3 induced-decreased vascular contraction. Marked induction of AT2R expression was observed in aortas from T3-induced hyperthyroid rats (Hyper). These vessels showed decreased protein levels of the contractile apparatus: α-actin, calponin and phosphorylated myosin light chain (p-MLC). Vascular reactivity studies showed that denuded aortic rings from Hyper rats exhibited decreased maximal contractile response to angiotensin II (AngII), which was attenuated in aortic rings pre-incubated with an AT2R blocker. Further study showed that cultured VSMC stimulated with T3 (0.1 µmol/L) for 24 hours had increased AT2R gene and protein expression. Augmented NO levels and decreased p-MLC levels were found in VSMC stimulated with T3, both of which were reversed by a PI3K/Akt inhibitor and AT2R blocker. These findings indicate for the first time that the AT2R/Akt/NO pathway contributes to decreased contractile responses in rat aorta, promoted by T3, and this mechanism is independent from the endothelium.