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Since the introduction of electronic cigarettes (e-cigarettes) in 2003, the technology has advanced allowing for greater user modifications, with users now able to control voltage, battery power, and constituents of the e-cigarette liquid. E-cigarettes have been the subject of a growing body of research with most research justifiably focused on the chemical makeup and risk analysis of chemicals, metals, and particulates found in e-cigarette liquids and vapor. Little research to date has focused on assessing the risks associated with the drug delivery unit itself and its potential for use as an illicit drug delivery system. In light of this, a range of illicit drugs was researched focusing on pharmacodynamics, usual method of administration, the dosage required for toxicity, toxic effects, and evidence of existing use in e-cigarettes in both literature and online illicit drug forums. A systematic literature search found evidence of current use of e-cigarettes to vape almost all illicit drug types analyzed. This presents both a potential population health risk and a management issue for clinicians. It also raises the issue of policing illicit drugs due to potential altered characteristic smells and storage within e-cigarette fluids. E-cigarettes are a viable illicit drug delivery system with evidence both inside and outside of the formal medical literature detailing their potential use for drug delivery of a wide range of illicit and legal drugs.

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A natural product chemistry-based approach was applied to discover small-molecule inhibitors of hypoxia-inducible factor-1 (HIF-1). A Petrosaspongia mycofijiensis marine sponge extract yielded mycothiazole (1), a solid tumor selective compound with no known mechanism for its cell linedependent cytotoxic activity. Compound 1 inhibited hypoxic HIF-1 signaling in tumor cells (IC 50 1 nM) that correlated with the suppression of hypoxia-stimulated tumor angiogenesis in vitro. However, 1 exhibited pronounced neurotoxicity in vitro. Mechanistic studies revealed that 1 selectively suppresses mitochondrial respiration at Complex I (NADH-ubiquinone oxidoreductase). Unlike rotenone, MPP + , annonaceous acetogenins, piericidin A, and other Complex I inhibitors, mycothiazole is a mixed polyketide/peptide-derived compound with a central thiazole moiety. The exquisite potency and structural novelty of 1 suggest that it may serve as a valuable molecular probe for mitochondrial biology and HIF-mediated hypoxic signaling.

Methanosarcina barkeri was adapted to grow on carbon monoxide by sequential transfer of the culture in medium that contained CO (100% of culture headspace). These experiments document the ability of the organism to grow slowly (65-h doubling time) and to produce methane and CO2 either on CO as the sole carbon and energy source or by the simultaneous consumption of methanol and CO. During growth on CO as carbon and energy source, net hydrogen formation occurred when the CO partial pressure in the culture headspace was greater than 20% CO, but hydrogen was consumed when the CO concentration was below this value.Carbon monoxide is an abundant atmospheric pollutant generated by incomplete conbustion of fossil fuels. Carbon monoxide is also formed as a metabolite of microbial metabolism, especially heme degradation by aerobic microorganisms (5,19). The physiological features of anaerobic bacteria that are able to grow on various one-carbon substrates as the sole carbon and electron source (i.e., unicarbonotrophic growth) and to grow mixotrophically on mixtures of onecarbon substrates, including CO, have been reviewed (20). Several genera of anaerobic bacteria have been shown to grow on CO as the energy source, including: Rhodopseudomonas (18), Methanobacterium (2), Butyribacterium (4), Eubacterium (13), Clostridium (9), and Acetobacterium (8).Kluyver and Schnellen (10) demonstrated that Methanosarcina barkeri produced 1 mol of methane and 3 mol of CO2 from 4 mol of CO when cell suspensions were incubated under 1 atm (ca. 101.29 kPa) (100%) of this gas. Later, Daniels et al.(2) showed that M. barkeri oxidized small amounts of added CO during growth on H2-CO2 and that cell extracts contained a methyl viologen-linked CO dehydrogenase activity. The significance of CO metabolism by some anaerobes like Clostridium pasteurianum is enigmatic because this anaerobe consumes CO via CO dehydrogenase activity, but it is not capable of growth on this substrate (3). However, it was established that acetogenic species, like Clostridium thermoaceticum, made acetate during growth with CO as the carbon and energy source (9). Carbon monoxide dehydrogenase has been proposed to function in carbonylation of a methyl group during acetyl-coenzyme Aacetate synthesis in both acetogenic (6) and methanogenic (7, 17) anaerobes. Krzycki and Zeikus (11) reported that the level of this enzyme increased fivefold when M. barkeri was grown on acetate versus on H2-CO2 or methanol as the sole carbon and energy source. This result suggested that CO dehydrogenase of M. barkeri may also function in acetate dissimilation by a biochemical mechanism that involves the production and consumption of a carbonyl group as an intermediary step in methane and CO2 formation. In the present note, we show that M. barkeri is able to grow either * Corresponding author. unicarbonotrophically with CO as the sole carbon and energy source or mixotrophically with CO and methanol.M. barkeri neotype strain MS was routinely cultivated under strictly anoxic conditions in a phosphat...

A natural product chemistry-based approach was employed to discover small molecule inhibitors of the important tumor-selective molecular target hypoxia-inducible factor-1 (HIF-1). Bioassayguided isolation of an active lipid extract of a Saipan collection of the marine sponge Lendenfeldia sp. afforded the terpene-derived furanolipid furospongolide as the primary inhibitor of hypoxiainduced HIF-1 activation (IC 50 2.9 μM, T47D breast tumor cells). The active component of the extract also contained one new cytotoxic scalarane sesterterpene and two previously reported scalaranes. Furospongolide blocked the induction of the downstream HIF-1 target secreted vascular endothelial growth factor (VEGF) and was shown to suppress HIF-1 activation by inhibiting the hypoxic induction of HIF-1α protein. Mechanistic studies indicate that furospongolide inhibits HIF-1 activity primarily by suppressing tumor cell respiration via the blockade of NADH-ubiquinone oxidoreductase (complex I)-mediated mitochondrial electron transfer.Tumor hypoxia (low oxygenation) arises when rapidly proliferating tumor cells demand more oxygen than the tumor vasculature can supply. Clinical studies have indicated that tumor hypoxia is an important prognostic factor for the malignancy of cancers found in ‡ These authors contributed equally to this research ˔ Joint Corresponding Authors to whom correspondence should be addressed: (Y. - NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript many tissues (e.g breast, brain, etc.).1 Hypoxic tumors are more resistant to radiation and chemotherapeutic drugs than their normoxic counterparts.1 -2 Experimental approaches to overcome tumor hypoxia include improving tumor oxygenation via enhanced delivery2 and developing hypoxic radiosensitizers and cytotoxins.3 Currently, there is no approved single method for specifically treating hypoxic tumor masses.1The transcription factor hypoxia-inducible factor-1 (HIF-1) has emerged as an important molecular target for anticancer drug discovery. As a heterodimer of the bHLH-PAS proteins HIF-1α and HIF-1β/ARNT, HIF-1 activates the expression of genes that promote cellular adaptation and survival under hypoxic conditions.1 , 4 The HIF-1α protein is rapidly degraded under normoxic conditions and stabilized under hypoxic conditions, while HIF-1β protein is constitutively expressed.5 Chemicals such as iron chelators (e.g. 1,10-phenanthroline, desferroxamine, etc.) and transition metals can each activate HIF-1 by blocking the Fe(II)-dependent degradation and inactivation of HIF-1α protein. Upon induction and activation, HIF-1 binds to the hypoxia response element (HRE) present in the promoters of target genes and activates transcription. Clinical studies revealed that the oxygen regulated HIF-1α subunit is overexpressed in common human cancers and their metastases, and is associated with poor prognosis and advanced stage cancers.6 -9 In animal models, HIF-1 inhibition retards tumor growth and improves treatment outcome when combined with chemotherape...

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