pH-Controlled Hydrogen Sulfide Release for Myocardial Ischemia-Reperfusion Injury.

Hydrogen sulfide (H2S) is a critical signaling molecule that regulates many physiological and/or pathological processes. Modulation of H2S levels could have potential therapeutic value. In this work, we report the rational design, synthesis, and biological evaluation of a class of phosphonamidothioate-based H2S-releasing agents (i.e., H2S donors). A novel pH-dependent intramolecular cyclization was employed to promote H2S release from the donors. These water-soluble compounds showed slow, controllable, and pH-sensitive production of H2S in aqueous solutions. The donors also showed significant cytoprotective effects in cellular models of oxidative damage. Most importantly, the donors were found to exhibit potent cardioprotective effects in an in vivo murine model of myocardial ischemia-reperfusion (MI/R) injury through a H2S-related mechanism.

Ammonium tetrathiomolybdate as a water-soluble and slow-release hydrogen sulfide donor.

Ammonium tetrathiomolybdate (TTM) was found to be a slow hydrogen sulfide (H2S) releasing agent. Its H2S generation capability in aqueous solutions was confirmed by UV-vis and fluorescence assays. TTM also showed H2S-like cytoprotective effects in hydrogen peroxide (H2O2)-induced oxidative damage in HaCaT cells.

A Single Fluorescent Probe to Visualize Hydrogen Sulfide and Hydrogen Polysulfides with Different Fluorescence Signals.

Hydrogen sulfide (H2 S) and hydrogen polysulfides (H2 Sn , n>1) are endogenous regulators of many physiological processes. In order to better understand the symbiotic relationship and cellular cross-talk between H2 S and H2 Sn , it is highly desirable to develop single fluorescent probes which enable dual-channel discrimination between H2 S and H2 Sn . Herein, we report the rational design, synthesis, and evaluation of the first dual-detection fluorescent probe DDP-1 that can visualize H2 S and H2 Sn with different fluorescence signals. The probe showed high selectivity and sensitivity to H2 S and H2 Sn in aqueous media and in cells.

Medicinal Chemistry: Insights into the Development of Novel H2S Donors.

Hydrogen sulfide (H2S) was traditionally considered as a toxic gas. However, recent studies have demonstrated H2S is an endogenously generated gaseous signaling molecule (gasotransmitter) with importance on par with that of two other well-known endogenous gasotransmitters, nitric oxide (NO) and carbon monoxide (CO). Although H2S's exact mechanisms of action are still under investigation, the production of endogenous H2S and the exogenous administration of H2S have been demonstrated to elicit a wide range of physiological responses including modulation of blood pressure and protection of ischemia reperfusion injury, exertion of anti-inflammatory effects, and reduction of metabolic rate. These results strongly suggest that modulation of H2S levels could have potential therapeutic values. In this regard, synthetic H2S-releasing agents (i.e., H2S donors) are not only important research tools, but also potential therapeutic agents. This chapter summarizes the knowledge of currently available H2S donors. Their preparation, H2S releasing mechanisms, and biological applications are discussed.

The Development of Fluorescent Probes for Visualizing Intracellular Hydrogen Polysulfides.

Endogenous hydrogen polysulfides (H2Sn; n>1) have been recognized as important regulators in sulfur-related redox biology. H2Sn can activate tumor suppressors, ion channels, and transcription factors with higher potency than H2S. Although H2Sn are drawing increasing attention, their exact mechanisms of action are still poorly understood. A major hurdle in this field is the lack of reliable and convenient methods for H2Sn detection. Herein we report a H2Sn-mediated benzodithiolone formation under mild conditions. This method takes advantage of the unique dual reactivity of H2Sn as both a nucleophile and an electrophile. Based on this reaction, three fluorescent probes (PSP-1, PSP-2, and PSP-3) were synthesized and evaluated. Among the probes prepared, PSP-3 showed a desirable off/on fluorescence response to H2Sn and high specificity. The probe was successfully applied in visualizing intracellular H2Sn.

Fluorescent probes based on nucleophilic substitution-cyclization for hydrogen sulfide detection and bioimaging.

The design, synthesis, properties, and cell imaging applications of a series of 2-pyridyl disulfide based fluorescent probes (WSP1, WSP2, WSP3, WSP4 and WSP5) for hydrogen sulfide detection are reported. The strategy is based on the dual-nucleophilicity of hydrogen sulfide. A hydrogen sulfide mediated tandem nucleophilic substitution-cyclization reaction is used to release the fluorophores and turn on the fluorescence. The probes showed high sensitivity and selectivity for hydrogen sulfide over other reactive sulfur species, including cysteine and glutathione.

Benzothiazole Sulfinate: a Water-Soluble and Slow-Releasing Sulfur Dioxide Donor.

Sulfur dioxide (SO2) has long been considered a toxic environmental pollutant and byproduct of industrial processing. Recently it has become evident that SO2 may also have regulatory functions in mammalian pulmonary systems. However, the study of these effects has proven to be challenging due to the difficulty in administering SO2 in a reliable manner. In this work, we report the discovery of a new pH-dependent and water-soluble SO2 donor, benzothiazole sulfinate (BTS). We have found BTS to have slow and sustained SO2 release at physiological pH. Additionally, we have explored its vasorelaxation properties as compared to the authentic SO2 gas solutions. The slow release of BTS should make it a useful tool for the study of endogenously generated SO2.

Trapping hydrogen sulfide (H2S) with diselenides: the application in the design of fluorescent probes.

Here we report a unique reaction between phenyl diselenide-ester substrates and H2S to form 1,2-benzothiaselenol-3-one. This reaction proceeded rapidly under mild conditions. Thiols could also react with the diselenide substrates. However, the resulted S-Se intermediate retained high reactivity toward H2S and eventually led to the same cyclized product 1,2-benzothiaselenol-3-one. Based on this reaction two fluorescent probes were developed and showed high selectivity and sensitivity for H2S. The presence of thiols was found not to interfere with the detection process.

Design, Synthesis, and Cardioprotective Effects of N-Mercapto-Based Hydrogen Sulfide Donors.

Hydrogen sulfide (H2S) is a signaling molecule which plays regulatory roles in many physiological and/or pathological processes. Therefore, regulation of H2S levels could have great potential therapeutic value. In this work, we report the design, synthesis, and evaluation of a class of N-mercapto (N-SH)-based H2S donors. Thirty-three donors were synthesized and tested. Our results indicated that controllable H2S release from these donors could be achieved upon structural modifications. Selected donors (NSHD-1, NSHD-2, and NSHD-6) were tested in cellular models of oxidative damage and showed significant cytoprotective effects. Moreover, NSHD-1 and NSHD-2 were also found to exhibit potent protective effects in a murine model of myocardial ischemia reperfusion (MI/R) injury.

New fluorescent probes for sulfane sulfurs and the application in bioimaging.

A sulfane sulfur mediated benzodithiolone formation was developed. Based on this reaction, two fluorescent probes (SSP1 and SSP2) for the detection of sulfane sulfur species (persulfide, polysulfide, and elemental sulfur) were prepared and evaluated. The probes showed high selectivity and sensitivity to sulfane sulfurs. Moreover, SSP2 was successfully applied for bioimaging sulfane sulfurs in living cells.

Synthesis and evaluation of phosphorodithioate-based hydrogen sulfide donors.

A series of O-aryl- and alkyl-substituted phosphorodithioates were designed and synthesized as hydrogen sulfide (H2S) donors. H2S releasing capability of these compounds was evaluated using fluorescence methods. O-aryl substituted donors showed slow and sustained H2S release while O-alkylated compounds showed very weak H2S releasing capability. We also evaluated donors' protective effects against hydrogen peroxide (H2O2)-induced oxidative damage in myocytes and donors' toxicity toward B16BL6 mouse melanoma cells.

Controllable hydrogen sulfide donors and their activity against myocardial ischemia-reperfusion injury.

Hydrogen sulfide (H2S), known as an important cellular signaling molecule, plays critical roles in many physiological and/or pathological processes. Modulation of H2S levels could have tremendous therapeutic value. However, the study on H2S has been hindered due to the lack of controllable H2S releasing agents that could mimic the slow and moderate H2S release in vivo. In this work we report the design, synthesis, and biological evaluation of a new class of controllable H2S donors. Twenty-five donors were prepared and tested. Their structures were based on a perthiol template, which was suggested to be involved in H2S biosynthesis. H2S release mechanism from these donors was studied and proved to be thiol-dependent. We also developed a series of cell-based assays to access their H2S-related activities. H9c2 cardiac myocytes were used in these experiments. We tested lead donors' cytotoxicity and confirmed their H2S production in cells. Finally we demonstrated that selected donors showed potent protective effects in an in vivo murine model of myocardial ischemia-reperfusion injury, through a H2S-related mechanism.

Mastectomía radical con conservación del pectoral mayor: nuestra experiencia / Radical mastectomy with preservation of the pectoralis major: our experience

Se presenta una experiencia con la mastectomía radical con preservación del pectoral mayor como tratamiento quirúrgico de elección para los estadios iniciales (I y II) del cáncer de mama, asociada a la radioterapia, con lo cual adquiere criterio de radicalidad en el tratamiento inicial de esta enfermedad. Se destaca que la hormonoterapia quirúrgica y/o médica en el caso de los tumores hormonodependientes y de la quimioterapia en los autónomos quedan reservadas para cuando hay evidencia de progresión de enfermedad en el tiempo

Quistes pericardiocelómicos / Pericardial celomic cysts

Se presentan 4 casos de quistes pericardiocelómicos. Tres de ellos se presentaron clínica y radiológicamente de manera que hicieron posible el diagnóstico presuntivo. Se obtuvo la curación de los mismos mediante tratamiento quirúrgico