Gold(I) ion and the phosphine ligand are necessary for the anti-Toxoplasma gondii activity of auranofin.

Auranofin, an FDA-approved drug for rheumatoid arthritis, has emerged as a promising antiparasitic medication in recent years. The gold(I) ion in auranofin is postulated to be responsible for its antiparasitic activity. Notably, aurothiomalate and aurothioglucose also contain gold(I), and, like auranofin, they were previously used to treat rheumatoid arthritis. Whether they have antiparasitic activity remains to be elucidated. Herein, we demonstrated that auranofin and similar derivatives, but not aurothiomalate and aurothioglucose, inhibited the growth of Toxoplasma gondii in vitro. We found that auranofin affected the T. gondii biological cycle (lytic cycle) by inhibiting T. gondii's invasion and triggering its egress from the host cell. However, auranofin could not prevent parasite replication once T. gondii resided within the host. Auranofin treatment induced apoptosis in T. gondii parasites, as demonstrated by its reduced size and elevated phosphatidylserine externalization (PS). Notably, the gold from auranofin enters the cytoplasm of T. gondii, as demonstrated by scanning transmission electron microscopy-energy dispersive X-ray spectroscopy (STEM-EDS) and Inductively Coupled Plasma-Mass Spectrometry (ICP-MS).IMPORTANCEToxoplasmosis, caused by Toxoplasma gondii, is a devastating disease affecting the brain and the eyes, frequently affecting immunocompromised individuals. Approximately 60 million people in the United States are already infected with T. gondii, representing a population at-risk of developing toxoplasmosis. Recent advances in treating cancer, autoimmune diseases, and organ transplants have contributed to this at-risk population's exponential growth. Paradoxically, treatments for toxoplasmosis have remained the same for more than 60 years, relying on medications well-known for their bone marrow toxicity and allergic reactions. Discovering new therapies is a priority, and repurposing FDA-approved drugs is an alternative approach to speed up drug discovery. Herein, we report the effect of auranofin, an FDA-approved drug, on the biological cycle of T. gondii and how both the phosphine ligand and the gold molecule determine the anti-parasitic activity of auranofin and other gold compounds. Our studies would contribute to the pipeline of candidate anti-T. gondii agents.

Exposición a fluidos corporales en trabajadores de salud del Hospital Universitario de Caracas: primer reporte: años 1991-1999 Caracas República de Venezuela / Exposure to body fluids in health workers the Hospital Universitario de Caracas: first report: years 1991-1999 Caracas República de Venezuela

Estudio prospectivo diseñado con el fin de evaluar a los trabajadores de salud del Hospital Universitario de Caracas que notificaran exposición a fluidos corporales al Sistema de Vigilancia de Virus de Inmunodeficiencia Humana y Hepatitis Viral, desde los años 1991 hasta 1999. Las variables estudiadas fueron: fecha y sitio del accidente, categoría del personal, edad, género, fluido involucrado, tipo de exposición, instrumento utilizado, serología basal para Virus de Inmunodeficiencia Humana y hepatitis viral del paciente índice y del TS, tipo de profilaxis antirretroviral, efectos adversos y seroconversión al Virus de Inmunodeficiencia Humana. Se utilizó el método descriptivo serie de casos los cuales fueron analizados por Epi-info. Versión 5. Durante el período de estudio fueron evaluados 242 trabajadores de la salud con exposición a fluidos corporales, 65% accidentes fueron notificados los dos últimos años. Ciento sesenta y tres femeninos y 79 masculinos, edad promedio 43 años (rango de 21-65 años). Los trabajadores de la salud que notificaron exposición a fluidos corporales procedían principalmente de los servicios de medicina interna, emergencia y cirugía. El mayor número de los accidentes correspondió a los médicos, principalmente residentes de posgrado. Exposición de tipo parenteral fue observada en 197 casos (179 percutáneas, y 18 salpicaduras en mucosas). Exposición cutánea se observó en 14 y combinada (piel y mucosas) 23 casos. El instrumento utilizado en 179 exposiciones percutáneas fue aguja con lumen en 48%. El fluido corporal involucrado fue la sangre en el 73% de los casos. La fuente fue conocida en 65% de las exposiciones. La profilaxis antirretroviral posexposición fue indicada inicialmente en 52% de los TS. Los efectos adversos se presentaron en 40%, en 7 casos fue motivo de abandono de tratamiento. El seguimiento se realizó en el 80% de los casos. Un trabajador de salud presentó Virus de Inmunodeficiencia Humana ocupacional...

Prospective study designed to assess the health workers at the Hospital Universitario de Caracas to notify body fluid exposure to Human Immunodeficiency Virus Surveillance System and Viral Hepatitis, from the years 1991-1999. The variables studied were: date and place of the accident, staff category, age, gender, fluid involved, type of exposure, instrument used, and baseline serology for Human Immunodeficiency Virus and Viral Hepatitis of health workers and index patient, type of prophylaxis antiretroviral, side effects and Human Immunodeficiency Virus seroconversion. Descriptive method was used series of cases which were analyzed by Epi-info. Version 5. During the study period were evaluated health workers 242 with body fluid exposure, 65% accidents were reported the past two years. 163 female and 79 male, mean age 43 years (range 21-65 years). Health workers who reported exposure to body fluids were mainly of Internal Medicine, Emergency and Surgery. The greatest numbers of injuries were doctors, mainly postgraduate residents. Parenteral exposure rate was observed in 197 cases (179 percutaneous, splash to mucous membranes 18). Dermal exposure was observed in 14 and combined (skin and mucosa) 23 cases. The instrument used in 179 percutaneous exposures was needle lumen in 48%. The body fluid blood was involved in 73% of cases. The source was known in 65% of exposures. Antiretroviral prophylaxis post exposure was initially indicated in 52% of the TS. Adverse events occurred in 40 %, in 7 cases was cause for withdrawals. The monitoring was performed in 80%. A case of Human Immunodeficiency Virus occupational in which it ruled out other risk factors

PEST-domain-enriched tyrosine phosphatase and glucocorticoids as regulators of anaphylaxis in mice.

BACKGROUND: PEST-domain-enriched tyrosine phosphatase (PEP) is a protein tyrosine phosphatase exclusively expressed in hematopoietic cells. It is a potent negative regulator of T-cell receptor signalling that acts on receptor-coupled protein tyrosine kinases. PEST-domain-enriched tyrosine phosphatase is also expressed in mast cell and is positively regulated by glucocorticoids, but its function is unknown. In this communication, the function of PEP is analysed in mast cells. METHODS: Signal transduction cascades following IgE receptor cross-linking were compared in bone marrow-derived mast cells (BMMC) from PEP(-/-) and PEP(+/+) mice. Furthermore, antigen-induced passive systemic anaphylaxis (PSA) was analysed in PEP(+/+) and PEP(-/-) mice. RESULTS: Bone marrow-derived mast cells from PEP(-/-) mice showed impaired PLCγ1 phosphorylation and Ca(2+) mobilization. Additionally, mice deficient in PEP showed impaired mast cell degranulation and were less susceptible to PSA. Treatment of wild-type BMMC or mice with an Au(I)-phosphine complex that selectively inhibits PEP activity produced defects in Ca(2+) signalling pathway and reduced anaphylaxis similar to that caused by the deletion of the PEP gene. Glucocorticoid that negatively regulates a wide range of mast cell action increased PEP expression and only partially inhibited anaphylaxis. However, glucocorticoid potently inhibited anaphylaxis when combined with the PEP inhibitor. CONCLUSIONS: PEST-domain-enriched tyrosine phosphatase is an important positive regulator of anaphylaxis. Pharmacological inhibition of its activity together with glucocorticoid administration provide an effective rescue for PSA in mice.

Decomposition of alkyl-substituted urea molecules at a hydroxide-bridged dinickel center.

The interactions between N-methylurea, N,N'-dimethylurea, N,N-dimethylurea, tetramethylurea, and thiourea and the hydroxide-bridged dinickel complex [Ni(2)(mu-OH)(mu-H2O)(bdptz)(H2O2](OTs)(3) were investigated. Structural characterization of [Ni(2)(mu-OH)(mu-H2O)(bdptz)(Me-urea)(CH3CN)](ClO4)(3) (1) and [Ni(2)(mu-OH)(mu-H2O)(bdptz)(thiourea)(CH3CN)](ClO4)(3) (2) provided insight into the interactions of the substrates with the dinickel center. In 1, the methylurea molecule coordinates to the dinickel complex through its carbonyl oxygen atom. Complex 2 has a similar geometry, with the thiourea molecule bound to a nickel ion through its sulfur atom. When the urea substrates are heated in the presence of the hydroxide-bridged dinickel complex, N-methylurea and N,N-dimethylurea react to form methylammonium cyanate and dimethylammonium cyanate, respectively. After long reaction times, thiourea reacts similarly, producing ammonium thiocyanate. The other substrates are unreactive. These results indicate that the dinickel complex promotes the elimination of alkylamines from urea substrates to form cyanate but cannot effect the direct hydrolysis of such substrates.

The reactivity of well defined diiron(III) peroxo complexes toward substrates: addition to electrophiles and hydrocarbon oxidation.

The reactivity of previously reported peroxo adducts [Fe(mu-O2)(mu-L)(O2CPhCy)2(1-Bu-Im)2] (1), and [Fe(mu-O2)(mu-L)(O2CPhCy)2(py)2] (2), where L is a dinucleating ligand based on the m-xylylenediamine bis(Kemp's triacid imide), toward a variety of substrates is described. These studies were performed to probe the electronic properties of 1 and 2 and evaluate their potential as selective hydrocarbon oxidants. Compound 1 is nucleophilic at -77 degrees C, reacting with phenols and carboxylic acids to liberate hydrogen peroxide, whereas the less electron-rich pyridine analogue 2 is unreactive toward both reagents. By contrast, neither reacts at -77 degrees C with electrophilic reagents such as olefins or triphenylphosphine, or with weak hydrogen atom donors such as dimethylbenzylamine. When solutions of 1 are warmed to room temperature in solvents such as THF, toluene, and cyclopentane, mixtures of alcohol and ketone products derived from the solvent are formed. A detailed investigation of cyclopentane oxidation strongly points to a radical autoxidation pathway. These results are discussed in the context of the selective hydroxylation chemistry that occurs at the carboxylate-bridged diiron centers in soluble methane monooxygenase.