2,4-dinitrophenyl ether-containing chemodosimeters for the selective and sensitive 'in vitro' and 'in vivo' detection of hydrogen sulfide

[EN] Four probes (i.e. D1¿D4) for the selective and sensitive fluorogenic detection of HS2 have been prepared and characterised. HEPES (10 mM, pH 7.4)¿DMSO 99:1 v/v solutions of D1¿D4 are essentially non-fluorescent. Changes in the emission using D1¿D4 in the presence of anions (F2, Cl2, Br2, I2, N2 3 , CN2, SCN2, AcO2, CO22 3 , PO22 4 , SO22 4 , HS2 and OH2), biothiols (GSH, Cys, Hcy, Me ¿Cys and lipoic acid), reducing agents (SO22 3 and S2O22 3 ) and oxidants (H2O2) demonstrated that only HS2 is able to induce the appearance of intense emission bands in the 400¿ 520 nm range in the four probes. The selectivity observed was ascribed to a unique hydrogen sulfide-induced hydrolysis of the 2,4-dinitrophenyl ether moiety that yielded the corresponding free highly fluorescent alcohols. The potential detection of intracellular HS2 was also studied.Financial support from the Spanish Government (Project MAT2012-38429-C04-01) and the Generalitat Valencia (Project PROMETEO/2009/016) is gratefully acknowledged. S.E. is grateful to the Generalitat Valenciana for his Santiago Grisolia fellow. L.E.S.F. also thanks the Carolina Foundation and UPNFM-Honduras for his doctoral grant.El Sayed Shehata Nasr, S.; De La Torre, C.; Santos Figueroa, LE.; Martínez-Máñez, R.; Sancenón Galarza, F.; Orzáez, M.; Costero, AM.... (2015). 2,4-dinitrophenyl ether-containing chemodosimeters for the selective and sensitive 'in vitro' and 'in vivo' detection of hydrogen sulfide. Supramolecular Chemistry. 27(4):244-254. https://doi.org/10.1080/10610278.2014.977286S24425427

Solubility and Permeation of Hydrogen Sulfide in Lipid Membranes

Hydrogen sulfide (H2S) is mainly known for its toxicity but has recently been shown to be produced endogenously in mammalian tissues and to be associated with physiological regulatory functions. To better understand the role of biomembranes in modulating its biological distribution and effects; we measured the partition coefficient of H2S in models of biological membranes. The partition coefficients were found to be 2.1±0.2, 1.9±0.5 and 2.0±0.6 in n-octanol, hexane and dilauroylphosphatidylcholine liposome membranes relative to water, respectively (25°C). This two-fold higher concentration of H2S in the membrane translates into a rapid membrane permeability, Pm = 3 cm s−1. We used a mathematical model in three dimensions to gain insight into the diffusion of total sulfide in tissues. This model shows that the sphere of action of sulfide produced by a single cell expands to involve more than 200 neighboring cells, and that the resistance imposed by lipid membranes has a significant effect on the diffusional spread of sulfide at pH 7.4, increasing local concentrations. These results support the role of hydrogen sulfide as a paracrine signaling molecule and reveal advantageous pharmacokinetic properties for its therapeutic applications

Enhancement of endogenous neurogenesis in ephrin-B3 deficient mice after transient focal cerebral ischemia

Cerebral ischemia stimulates endogenous neurogenesis. However, the functional relevance of this phenomenon remains unclear because of poor survival and low neuronal differentiation rates of newborn cells. Therefore, further studies on mechanisms regulating neurogenesis under ischemic conditions are required, among which ephrin-ligands and ephrin-receptors (Eph) are an interesting target. Although Eph/ephrin proteins like ephrin-B3 are known to negatively regulate neurogenesis under physiological conditions, their role in cerebral ischemia is largely unknown. We therefore studied neurogenesis, brain injury and functional outcome in ephrin-B3−/− (knockout) and ephrin-B3+/+ (wild-type) mice submitted to cerebral ischemia. Induction of stroke resulted in enhanced cell proliferation and neuronal differentiation around the lesion site of ephrin-B3−/− compared to ephrin-B3+/+ mice. However, prominent post-ischemic neurogenesis in ephrin-B3−/− mice was accompanied by significantly increased ischemic injury and motor coordination deficits that persisted up to 4 weeks. Ischemic injury in ephrin-B3−/− mice was associated with a caspase-3-dependent activation of the signal transducer and activator of transcription 1 (STAT1). Whereas inhibition of caspase-3 had no effect on brain injury in ephrin-B3+/+ animals, infarct size in ephrin-B3−/− mice was strongly reduced, suggesting that aggravated brain injury in these animals might involve a caspase-3-dependent activation of STAT1. In conclusion, post-ischemic neurogenesis in ephrin-B3−/− mice is strongly enhanced, but fails to contribute to functional recovery because of caspase-3-mediated aggravation of ischemic injury in these animals. Our results suggest that ephrin-B3 might be an interesting target for overcoming some of the limitations of further cell-based therapies in stroke

Mutations in SELENBP1, encoding a novel human methanethiol oxidase, cause extraoral halitosis

Selenium-binding protein 1 (SELENBP1) has been associated with several cancers, although its exact role is unknown. We show that SELENBP1 is a methanethiol oxidase (MTO), related to the MTO in methylotrophic bacteria, that converts methanethiol to H2O2, formaldehyde, and H2S, an activity not previously known to exist in humans. We identified mutations in SELENBP1 in five patients with cabbage-like breath odor. The malodor was attributable to high levels of methanethiol and dimethylsulfide, the main odorous compounds in their breath. Elevated urinary excretion of dimethylsulfoxide was associated with MTO deficiency. Patient fibroblasts had low SELENBP1 protein levels and were deficient in MTO enzymatic activity; these effects were reversed by lentivirus-mediated expression of wild-type SELENBP1. Selenbp1-knockout mice showed biochemical characteristics similar to those in humans. Our data reveal a potentially frequent inborn error of metabolism that results from MTO deficiency and leads to a malodor syndrome.info:eu-repo/semantics/publishedVersio