Introduction of a Fluorine Atom at C3 of 3-Deazauridine Shifts Its Antimetabolic Activity from Inhibition of CTP Synthetase to Inhibition of Orotidylate Decarboxylase, an Early Event in the de Novo Pyrimidine Nucleotide Biosynthesis Pathway

The antimetabolite prodrug 3-deazauridine (3DUrd) inhibits CTP synthetase upon intracellular conversion to its triphosphate, which selectively depletes the intracellular CTP pools. Introduction of a fluorine atom at C3 of 3DUrd shifts its antimetabolic action to inhibition of the orotidylate decarboxylase (ODC) activity of the UMP synthase enzyme complex that catalyzes an early event in pyrimidine nucleotide biosynthesis. This results in concomitant depletion of the intracellular UTP and CTP pools. The new prodrug (designated 3F-3DUrd) exerts its inhibitory activity because its monophosphate is not further converted intracellularly to its triphosphate derivative to a detectable extent. Combinations with hypoxanthine and adenine markedly potentiate the cytostatic activity of 3F-3DUrd. This is likely because of depletion of 5-phosphoribosyl-1-pyrophosphate (consumed in the hypoxanthine phosphoribosyl transferase/adenine phosphoribosyl transferase reaction) and subsequent slowing of the 5-phosphoribosyl-1-pyrophosphate-dependent orotate phosphoribosyl transferase reaction, which depletes orotidylate, the substrate for ODC. Further efficient anabolism by nucleotide kinases is compromised apparently because of the decrease in pK(a) brought about by the fluorine atom, which affects the ionization state of the new prodrug. The 3F-3DUrd monophosphate exhibits new inhibitory properties against a different enzyme of the pyrimidine nucleotide metabolism, namely the ODC activity of UMP synthase.     

How promising is <Emphasis Type="Italic">Lasioseius floridensis</Emphasis> as a control agent of <Emphasis Type="Italic">Polyphagotarsonemus</Emphasis><Emphasis Type="Italic">latus</Emphasis>?

The blattisociid mite Lasioseius floridensis Berlese was found associated with the broad mite, Polyphagotarsonemus latus (Banks), on gerbera leaves in Mogi das Cruzes, State of Sao Paulo, Brazil. Blattisociid mites are not common on aerial plant parts, except under high air humidity levels. Some Lasioseius species have been mentioned as effective control agents of rice pest mites, but nothing is known about the biology of L. floridensis. The objective of this study was to evaluate whether the observed co-occurrence of L. floridensis and P. latus was just occasional or whether the latter could be important as food source for the former, assumed by laboratory evaluation of the ability of the predator to maintain itself, reproduce and develop on that prey. Biological parameters of L. floridensis were compared when exposed to P. latus and to other items as food. The study showed that mating is a pre-requisite for L. floridensis to oviposit and that oviposition rate was much higher on the soil nematode Rhabditella axei (Cobbold) (Rhabditidae) than on P. latus. Ovipositon on the acarid mite Tyrophagus putrescentiae (Schrank) was about the same as on P. latus, but it was nearly zero when the predator was fed the fungi Aspergillus flavus Link or Penicillium sp., or cattail (Typha sp.) pollen. Survivorship was higher in the presence of pollen and lower in the presence of A. flavus or Penicillium sp. than in the absence of those types of food. Life table parameters indicated that the predator performed much better on R. axei than on P. latus. To evaluate the potential effect of L. floridensis as predator of P. latus, complementary studies are warranted to determine the frequency of migration of L. floridensis to aerial plant parts, when predation on P. latus could occur.     

Spectroscopic studies of molecular organization of antibiotic amphotericin B in monolayers and dipalmitoylphosphatidylcholine lipid multibilayers

Amphotericin B (AmB) is considered the gold-standard in the treatment of serious systemic mycoses despite its numerous adverse effects. Both the mechanism of antifungal action and the toxicity of this drug are dependent on its molecular organization. The effect of AmB on the organization of lipid membranes formed with dipalmitoylphosphatidylcholine (DPPC) was studied with application of the Langmuir-Blodgett technique and ATR-FTIR spectroscopy. The aim of this research was to analyze the physical interactions leading to the formation of aggregated forms of AmB molecules in one-component monolayers and lipid multibilayers. Analysis of FTIR spectra of two-component multibilayers suggests the possibility the mutual reorientation of the amino-sugar moiety (mycosamine) and macrolide ring. This effect may be significant in the explanation of the aggregation processes of AmB in biological systems.     

Molecular organization of antibiotic amphotericin B in dipalmitoylphosphatidylcholine monolayers induced by K(+) and Na(+) ions: the Langmuir technique study

The effect of potassium (K(+)) and sodium (Na(+)) ions on the self-association of antibiotic amphotericin B (AmB) in the lipid membrane was reported. Mixed Langmuir monolayers of AmB and dipalmitoylphosphatidylcholine (DPPC) were investigated by recording surface pressure-area isotherms spread on aqueous buffers containing physiological concentration of K(+) and Na(+) ions. The analyses of the π-A isotherms and compressional modulus curves indicate the interactions in the AmB-DPPC system. The strength of the AmB-DPPC interactions and the stability of the mixed monolayers were examined on the basis of the excess free energy of mixing values. The obtained results proved a high affinity of AmB towards lipids induced by the presence of K(+) than Na(+) ions. The most stable monolayers in the presence of K(+) and Na(+) ions were formed by AmB and DPPC with the 1:1 and 2:1 stoichiometry. The understanding of the AmB aggregation processes at the molecular level should contribute to elucidate the mechanisms of action and toxicity of this widely used drug. The presented results are potentially valuable in respect to develop more efficient and less toxic AmB formulations.     

Red wine-dependent reduction of nitrite to nitric oxide in the stomach

Nitrite may be a source for nitric oxide (*NO), particularly in highly acidic environments, such as the stomach. Diet products contribute also with reductants that dramatically increase the production of *NO from nitrite. Red wine has been attributed health promoting properties largely on basis of the reductive antioxidant properties of its polyphenolic fraction. We show in vitro that wine, wine anthocyanin fraction and wine catechol (caffeic acid) dose- and pH-dependently promote the formation of *NO when mixed with nitrite, as measured electrochemically. The production of *NO promoted by wine from nitrite was substantiated in vivo in healthy volunteers by measuring *NO in the air expelled from the stomach, following consumption of wine, as measured by chemiluminescence. Mechanistically, the reaction involves the univalent reduction of nitrite, as suggested by the formation of *NO and by the appearance of EPR spectra assigned to wine phenolic radicals. Ascorbic and caffeic acids cooperate in the reduction of nitrite to *NO. Moreover, reduction of nitrite is critically dependent on the phenolic structure and nitro-derivatives of phenols are also formed, as suggested by caffeic acid UV spectral modifications. The reduction of nitrite may reveal previously unrecognized physiologic effects of red wine in connection with *NO bioactivity.     

Life cycle of the earthworm Octodrilus complanatus (Oligochaeta, Lumbricidae)

The earthworm Octodrilus complanatus (Dugès, 1828) is a large-sized species often found in grasslands and pastures, with a wide distribution area in Europe and North Africa. In order to determine the characteristics of its life cycle, earthworms of this species were cultured from hatching until they reached maturity. Development rates, cocoon production, and incubation period were recorded under controlled conditions. On average, individuals of O. complanatus reared in isolation from hatching reached maturity at day 150 and body weight at maturity ranged between 6 and 8 g. The cocoon incubation period was 66 days, and only one individual hatched from each cocoon, with a mean hatchability of 55%. Reproductive rate showed by O. complanatus after mating was of 52 cocoons per earthworm per year. The results showed that the life cycle of O. complanatus was characterized by both low growth rates and low fecundity. Specific features in life history traits of O. complanatus were compared with those of species of the genus Octodrilus and other related earthworms.     

Mesophyll conductance to CO2 and Rubisco as targets for improving intrinsic water use efficiency in C3 plants

Water limitation is a major global constraint for plant productivity that is likely to be exacerbated by climate change. Hence, improving plant water use efficiency (WUE) has become a major goal for the near future. At the leaf level, WUE is the ratio between photosynthesis and transpiration. Maintaining high photosynthesis under water stress, while improving WUE requires either increasing mesophyll conductance (g_m) and/or improving the biochemical capacity for CO₂ assimilation—in which Rubisco properties play a key role, especially in C₃ plants at current atmospheric CO₂. The goals of the present analysis are: (1) to summarize the evidence that improving g_m and/or Rubisco can result in increased WUE; (2) to review the degree of success of early attempts to genetically manipulate g_m or Rubisco; (3) to analyse how g_m, g_sw and the Rubisco's maximum velocity (V_cmax) co‐vary across different plant species in well‐watered and drought‐stressed conditions; (4) to examine how these variations cause differences in WUE and what is the overall extent of variation in individual determinants of WUE; and finally, (5) to use simulation analysis to provide a theoretical framework for the possible control of WUE by g_m and Rubisco catalytic constants vis‐à‐vis g_sw under water limitations.