A Type I/Type III PKS Hybrid Generates Cinnamomycin A-D.

3,5-Dihydroxybenzoic acid (3,5-DHBA), biosynthesized by type III PKS and tailoring enzymes, is an unconventional starter unit for bacterial type I PKS. Genome mining of 3,5-DHBA-specific biosynthetic gene clusters could lead to discovering new type I/type III PKS hybrids. Herein, we report the discovery and characterization of atypical compounds, namely cinnamomycin A-D, exhibiting selective antiproliferative activity. The biosynthetic pathway of cinnamomycins was proposed based on genetic manipulation, enzymatic reaction, and precursor feeding.

Epidemiological evidence on association between ambient air pollution and stroke mortality.

BACKGROUND: Inconsistent results have been found on the association between air pollution and stroke mortality. Additionally, evidence on people who are potentially sensitive to air pollution-associated stroke mortality is limited. METHODS: Daily stroke mortality of adults aged over 65 between 2003 and 2008 in Shanghai, China were collected. The time-stratified case-crossover approach was used to assess the association between daily concentrations of air pollutants including particles with size <10 µm, sulfur dioxide (SO2) and nitrogen dioxide (NO2) and stroke mortality. RESULTS: Both total-stroke and ischaemic-stroke mortalities were found to be significantly associated with all three air pollutants. Haemorrhagic stroke was significantly associated with SO2 and NO2 only. Substantial differences were observed for effect estimates of ischaemic-stroke mortality in relation to NO2 among people with cardiac diseases compared with those without; for an increase of 10 µg/m(3) in NO2, the increase in ischaemic-stroke mortality was 7.05% (95% CI 1.92% to 12.17%) for people with comorbid cardiac diseases versus 0.60% (95% CI -0.49% to 1.68%) for those without. We did not find evidence of effect modification by hypertension and diabetes. CONCLUSIONS: This study provides new evidence for the association between exposure to ambient air pollution and stroke mortality. Our results also suggest that underlying cardiac disorder may increase the risk for ischaemic-stroke mortality in relation to air pollution exposure, especially NO2. .

Aqueous chemistry of the vanadium(III) (V(III)) and the V(III)-dipicolinate systems and a comparison of the effect of three oxidation states of vanadium compounds on diabetic hyperglycemia in rats.

The aqueous vanadium(III) (V(III)) speciation chemistry of two dipicolinate-type complexes and the insulin-enhancing effects of V-dipicolinate (V-dipic) complexes in three different oxidation states (V(III), V(IV), and V(V)) have been studied in a chronic animal model system. The characterization of the V(III) species was carried out at low ionic strength to reflect physiological conditions and required an evaluation of the hydrolysis of V(III) at 0.20 M KCl. The aqueous V(III)-dipic and V(III)-dipic-OH systems were characterized, and complexes were observed from pH 2 to 7 at 0.2 M KCl. The V(III)-dipic system forms stable 1:2 complexes, whereas the V(III)-dipic-OH system forms stable 1:1 complexes. A comparison of these complexes with the V-pic system demonstrates that a second ligand has lower affinity for the V(III), presumably reflecting bidentate coordination of the second dipic(2)(-) to the V(III). The thermodynamic stability of the [V(III)(dipic)(2)](-) complex was compared to the stability of the corresponding V(IV) and V(V) complexes, and surprisingly, the V(III) complexes were found to be more stable than anticipated. Oral administration of three V-dipicolinate compounds in different oxidation states {H[V(III)(dipic)(2)H(2)O].3H(2)O, [V(IV)Odipic(H(2)O)(2)].2H(2)O, and NH(4)[V(V)O(2)dipic]} and the positive control, VOSO(4), significantly lowered diabetic hyperglycemia in rats with streptozotocin-induced diabetes. The diabetic animals treated with the V(III)- or V(IV)-dipic complexes had blood glucose levels that were statistically different from those of the diabetic group. The animals treated with the V(V)-dipic complex had the lowest blood glucose levels of the treated diabetic animals, which were statistically different from those of the diabetic group at all time points. Among the diabetic animals, complexation to dipic increased the serum levels of V after the administration of the V(V) and V(IV) complexes but not after the administration of the V(III) complex when data are normalized to the ingested dose of V. Because V compounds differing only in oxidation state have different biological properties, it is implied that redox processes must be important factors for the biological action of V compounds. We observe that the V(V)-dipic complex is the most effective insulin-enhancing agent, in contrast to previous studies in which the V(IV)-maltol complex is the most effective. We conclude that the effectiveness of complexed V is both ligand and oxidation state dependent.

Inhibition of yeast growth by molybdenum-hydroxylamido complexes correlates with their presence in media at differing pH values.

The effects of Mo-hydroxylamido complexes on cell growth were determined in Saccharomyces cerevisiae to investigate the biological effects of four different Mo complexes as a function of pH. Studies with yeast, an eukaryotic cell, are particularly suited to examine growth at different pH values because this organism grows well from pH 3 to 6.5. Studies can therefore be performed both in the presence of intact complexes and when the complexes have hydrolyzed to ligand and free metal ion. One of the complexes we examined was structurally characterized by X-ray crystallography. Yeast growth was inhibited in media solutions containing added Mo-dialkylhydroxylamido complexes at pH 3-7. When combining the yeast growth studies with a systematic study of the Mo-hydroxylamido complexes' stability as a function of pH and an examination of their speciation in yeast media, the effects of intact complexes can be distinguished from that of ligand and metal. This is possible because different effects are observed with complex present than when ligand or metal alone is present. At pH 3, the growth inhibition is attributed to the forms of molybdate ion that exist in solution because most of the complexes have hydrolyzed to oxomolybdate and ligand. The monoalkylhydroxylamine ligand inhibited yeast growth at pH 5, 6 and 7, while the dialkylhydroxylamine ligands had little effect on yeast growth. Growth inhibition of the Mo-dialkylhydroxylamido complexes is observed when a complex exists in the media. A complex that is inert to ligand exchange is not effective even at pH 3 where other Mo-hydroxylamido complexes show growth inhibition as molybdate. These results show that the formation of some Mo complexes can protect yeast from the growth inhibition observed when either the ligand or Mo salt alone are present.

Vanadium(IV/V) speciation of pyridine-2,6-dicarboxylic acid and 4-hydroxy-pyridine-2,6-dicarboxylic acid complexes: potentiometry, EPR spectroscopy and comparison across oxidation states.

Evaluation of stability of vanadium(IV) and (V) complexes under similar conditions is critical for the interpretation and assessment of bioactivity of various vanadium species. Detailed understanding of the chemical properties of these complexes is necessary to explain differences observed their activity in biological systems. These studies are carried out to link the chemistry of both vanadium(IV) and (V) complexes of two ligands, 2,6-pyridinedicarboxylic acid (dipicolinic acid, H(2)dipic) and 4-hydroxy-2,6-pyridinedicarboxylic acid (H(2)dipic-OH). Solution speciation of the two 2,6-pyridinedicarboxylic acids with vanadium(IV) and vanadium(V) ions was determined by pH-potentiometry at I=0.2 M (KCl) ionic strength and at T=298 K. The stability and the metal affinities of the ligands were compared. Vanadium(V) complexes were found to form only tridentate coordinated 1:1 complexes, while vanadium(IV) formed complexes with both 1:1 and 1:2 stoichiometries. The formation constant reflects hindered coordination of a second ligand molecule, presumably because of the relatively small size of the metal ion. The most probable binding mode of the complexes was further explored using ambient and low temperature EPR spectroscopy for vanadium(IV) and 51V NMR spectroscopy for vanadium(V) systems. Upon complex formation the pyridinol-OH in position 4 deprotonates with pK approximately 3.7-4.1, which is approximately 6 orders of magnitude lower than that of the free ligand. The deprotonation enhances the ligand metal ion affinity compared to the parent ligand dipicolinic acid. In the light of the speciation and stability data of the metal complexes, the efficiency of the two ligands in transporting the metal ion in the two different oxidation states are assessed and discussed.