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Ascorbic acid is an essential nutrient commonly regarded as an antioxidant. In this study, we showed that ascorbate at pharmacologic concentrations was a prooxidant, generating hydrogen-peroxide-dependent cytotoxicity toward a variety of cancer cells in vitro without adversely affecting normal cells. To test this action in vivo, normal oral tight control was bypassed by parenteral ascorbate administration. Real-time microdialysis sampling in mice bearing glioblastoma xenografts showed that a single pharmacologic dose of ascorbate produced sustained ascorbate radical and hydrogen peroxide formation selectively within interstitial fluids of tumors but not in blood. Moreover, a regimen of daily pharmacologic ascorbate treatment significantly decreased growth rates of ovarian (P < 0.005), pancreatic (P < 0.05), and glioblastoma (P < 0.001) tumors established in mice. Similar pharmacologic concentrations were readily achieved in humans given ascorbate intravenously. These data suggest that ascorbate as a prodrug may have benefits in cancers with poor prognosis and limited therapeutic options.

Ascorbate (ascorbic acid, vitamin C), in pharmacologic concentrations easily achieved in humans by i.v. administration, selectively kills some cancer cells but not normal cells. We proposed that pharmacologic ascorbate is a prodrug for preferential steady-state formation of ascorbate radical (Asc{bullet}⁻) and H₂O₂ in the extracellular space compared with blood. Here we test this hypothesis in vivo. Rats were administered parenteral (i.v. or i.p.) or oral ascorbate in typical human pharmacologic doses ([almost equal to]0.25-0.5 mg per gram of body weight). After i.v. injection, ascorbate baseline concentrations of 50-100 μM in blood and extracellular fluid increased to peaks of >8 mM. After i.p. injection, peaks approached 3 mM in both fluids. By gavage, the same doses produced ascorbate concentrations of <150 μM in both fluids. In blood, Asc{bullet}⁻ concentrations measured by EPR were undetectable with oral administration and always <50 nM with parenteral administration, even when corresponding ascorbate concentrations were >8 mM. After parenteral dosing, Asc{bullet}⁻ concentrations in extracellular fluid were 4- to 12-fold higher than those in blood, were as high as 250 nM, and were a function of ascorbate concentrations. By using the synthesized probe peroxyxanthone, H₂O₂ in extracellular fluid was detected only after parenteral administration of ascorbate and when Asc{bullet}⁻ concentrations in extracellular fluid exceeded 100 nM. The data show that pharmacologic ascorbate is a prodrug for preferential steady-state formation of Asc{bullet}⁻ and H₂O₂ in the extracellular space but not blood. These data provide a foundation for pursuing pharmacologic ascorbate as a prooxidant therapeutic agent in cancer and infections.

Substitution of fluorine for hydrogen in position 2, 5, or 6 of the aromatic ring of norepinephrine markedly alters the α- and β-adrenergic agonist properties of norepinephrine. The 6-fluoro isomer is an α-adrenergic agonist with virtually no β agonist activity, while the 2-fluoro isomer is a β-adrenergic agonist with little α activity. The 5-fluoro isomer is equipotent with norepinephrine as an α agonist and significantly more potent as a β agonist. The possible physiochemical basis for these differences is discussed.

This chapter contains sections titled: Introduction Fluorinated Heterocycles Containing One Nitrogen Fluorinated Heterocycles Containing Two Nitrogens Fluorinated Triazoles Fluorinated Tetrazoles Perfluorinated Nitrogen‐Containing Heterocycles Summary Acknowledgment References

An amine-functionalized derivative of 1,3-dipropyl-8-phenylxanthine has been prepared in tritiated form as a xanthine amine congener [3H]XAC) for use as an antagonist radioligand for adenosine receptors. [3H]XAC has higher receptor affinity, higher specific activity, lower nonspecific membrane binding, and more favorable hydrophilicity than 1,3-diethyl-8-[3H]phenylxanthine, the xanthine commonly used for adenosine receptor binding. In rat cerebral cortical membranes, [3H]XAC exhibits saturable, specific binding with a Kd of 1.23 nM and a Bmax of 580 fmol/mg of protein at 37 degrees C. N6-(R-Phenylisopropyl)adenosine is a more potent inhibitor of [3XAC binding than is 5′-N-ethylcarboxamidoadenosine, indicating that binding is to an A1-adenosine receptor. In the absence of GTP, the inhibition curves for adenosine agonists versus [3H]XAC binding are biphasic, indicating that [3H]XAC is binding to low- and high-affinity agonist states of the A1 receptor. In the presence of GTP, adenosine analogs exhibit monophasic, low-affinity inhibition of binding of [3H]XAC. Inhibition of [3H]XAC binding by theophylline or by various 8-phenylxanthines is monophasic, and the potencies are commensurate with the potencies of these xanthines as adenosine receptor antagonists. The receptor sites in calf brain membranes exhibit a higher affinity (Kd = 0.17 nM) for [3H]XAC, whereas sites in guinea pig exhibit a slightly lower affinity (Kd = 3.0 nM). Densities of [3H]XAC binding sites are similar in brain membranes from all species.

The intracellular distribution of fluorine has been delineated in human platelets incubated with 4,6-difluoroserotonin, utilizing a scanning-transmission electron microscope equipped with an energy-loss spectrometer. Discrete intracellular structures corresponding in location to dense bodies contained high concentrations of fluorine. Electron energy-loss spectroscopy, which apparently can detect less than 10$^{-20}$ gram of fluorine in an area of 10 square nanometers, can thus localize fluorinated tracer molecules with biological activity.

IL28B and hepatitis C Hepatitis C virus (HCV) infection is the most common blood-borne infection in the United States, leading in many cases to chronic liver disease. Here the authors show that an SNP recently identified to associate with response to HCV drug treatment also associates with viral clearance. This study identifies the strongest and most significant genetic effect associated with natural clearance of HCV, implicating a primary role for IL28B in this process. There are approximately 170 million people infected with hepatitis C virus (HCV) worldwide. About 30% of individuals with persistent HCV infection develop chronic liver disease, with various epidemiological, viral and host factors having been implicated in the differences in HCV clearance or persistence. Here, a single nucleotide polymorphism recently shown to be strongly associated with a difference in response to HCV drug treatment is also shown to be associated with viral clearance. Hepatitis C virus (HCV) infection is the most common blood-borne infection in the United States, with estimates of 4 million HCV-infected individuals in the United States and 170 million worldwide 1 . Most (70–80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma 2 . Epidemiological, viral and host factors have been associated with the differences in HCV clearance or persistence, and studies have demonstrated that a strong host immune response against HCV favours viral clearance 3 , 4 . Thus, variation in genes involved in the immune response may contribute to the ability to clear the virus. In a recent genome-wide association study, a single nucleotide polymorphism (rs12979860) 3 kilobases upstream of the IL28B gene, which encodes the type III interferon IFN-λ3, was shown to associate strongly with more than a twofold difference in response to HCV drug treatment 5 . To determine the potential effect of rs12979860 variation on outcome to HCV infection in a natural history setting, we genotyped this variant in HCV cohorts comprised of individuals who spontaneously cleared the virus ( n = 388) or had persistent infection ( n = 620). We show that the C/C genotype strongly enhances resolution of HCV infection among individuals of both European and African ancestry. To our knowledge, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection.

Antimicrobial resistance is a global health crisis and few novel antimicrobials have been discovered in recent decades. Natural products, particularly from Streptomyces , are the source of most antimicrobials, yet discovery campaigns focusing on Streptomyces from the soil largely rediscover known compounds. Investigation of understudied and symbiotic sources has seen some success, yet no studies have systematically explored microbiomes for antimicrobials. Here we assess the distinct evolutionary lineages of Streptomyces from insect microbiomes as a source of new antimicrobials through large-scale isolations, bioactivity assays, genomics, metabolomics, and in vivo infection models. Insect-associated Streptomyces inhibit antimicrobial-resistant pathogens more than soil Streptomyces . Genomics and metabolomics reveal their diverse biosynthetic capabilities. Further, we describe cyphomycin, a new molecule active against multidrug resistant fungal pathogens. The evolutionary trajectories of Streptomyces from the insect microbiome influence their biosynthetic potential and ability to inhibit resistant pathogens, supporting the promise of this source in augmenting future antimicrobial discovery. Host microbiomes are feasible sources for drug discovery. Here, using large-scale isolations, bioactivity assays and omics, the authors uncover the antimicrobial potential of insect-associated Streptomyces and identify a compound, cyphomycin, active against multidrug-resistant fungal pathogens.

The Cretaceous-Paleogene boundary approximately 65.5 million years ago marks one of the three largest mass extinctions in the past 500 million years. The extinction event coincided with a large asteroid impact at Chicxulub, Mexico, and occurred within the time of Deccan flood basalt volcanism in India. Here, we synthesize records of the global stratigraphy across this boundary to assess the proposed causes of the mass extinction. Notably, a single ejecta-rich deposit compositionally linked to the Chicxulub impact is globally distributed at the Cretaceous-Paleogene boundary. The temporal match between the ejecta layer and the onset of the extinctions and the agreement of ecological patterns in the fossil record with modeled environmental perturbations (for example, darkness and cooling) lead us to conclude that the Chicxulub impact triggered the mass extinction.