Conformationally Restricted Glycoconjugates Derived from Arylsulfonamides and Coumarins: New Families of Tumour-Associated Carbonic Anhydrase Inhibitors.

The involvement of carbonic anhydrases (CAs) in a myriad of biological events makes the development of new inhibitors of these metalloenzymes a hot topic in current Medicinal Chemistry. In particular, CA IX and XII are membrane-bound enzymes, responsible for tumour survival and chemoresistance. Herein, a bicyclic carbohydrate-based hydrophilic tail (imidazolidine-2-thione) has been appended to a CA-targeting pharmacophore (arylsulfonamide, coumarin) with the aim of studying the influence of the conformational restriction of the tail on the CA inhibition. For this purpose, the coupling of sulfonamido- or coumarin-based isothiocyanates with reducing 2-aminosugars, followed by the sequential acid-promoted intramolecular cyclization of the corresponding thiourea and dehydration reactions, afforded the corresponding bicyclic imidazoline-2-thiones in good overall yield. The effects of the carbohydrate configuration, the position of the sulfonamido motif on the aryl fragment, and the tether length and substitution pattern on the coumarin were analysed in the in vitro inhibition of human CAs. Regarding sulfonamido-based inhibitors, the best template turned out to be a d-galacto-configured carbohydrate residue, meta-substitution on the aryl moiety (9b), with Ki against CA XII within the low nM range (5.1 nM), and remarkable selectivity indexes (1531 for CA I and 181.9 for CA II); this provided an enhanced profile in terms of potency and selectivity compared to more flexible linear thioureas 1-4 and the drug acetazolamide (AAZ), used herein as a reference compound. For coumarins, the strongest activities were found for substituents devoid of steric hindrance (Me, Cl), and short linkages; derivatives 24h and 24a were found to be the most potent inhibitors against CA IX and XII, respectively (Ki = 6.8, 10.1 nM), and also endowed with outstanding selectivity (Ki > 100 µM against CA I, II, as off-target enzymes). Docking simulations were conducted on 9b and 24h to gain more insight into the key inhibitor-enzyme interactions.

Thio- and selenosemicarbazones as antiprotozoal agents against Trypanosoma cruzi and Trichomonas vaginalis.

Herein, we report the preparation of a panel of Schiff bases analogues as antiprotozoal agents by modification of the stereoelectronic effects of the substituents on N-1 and N-4 and the nature of the chalcogen atom (S, Se). These compounds were evaluated towards Trypanosoma cruzi and Trichomonas vaginalis. Thiosemicarbazide 31 showed the best trypanocidal profile (epimastigotes), similar to benznidazole (BZ): IC50 (31)=28.72 µM (CL-B5 strain) and 33.65 µM (Y strain), IC50 (BZ)=25.31 µM (CL-B5) and 22.73 µM (Y); it lacked toxicity over mammalian cells (CC50 > 256 µM). Thiosemicarbazones 49, 51 and 63 showed remarkable trichomonacidal effects (IC50 =16.39, 14.84 and 14.89 µM) and no unspecific cytotoxicity towards Vero cells (CC50 ≥ 275 µM). Selenoisosters 74 and 75 presented a slightly enhanced activity (IC50=11.10 and 11.02 µM, respectively). Hydrogenosome membrane potential and structural changes were analysed to get more insight into the trichomonacidal mechanism.

Ultra-fast direct method for identifying microorganisms from BACTEC lytic/10 anaerobic/F flasks.

Background: Fast diagnosis of bloodstream infections remains the most important challenge for clinical microbiologists. The introduction of the mass-spectrometry represents a breakthrough, although several methods are already commonly used for the direct identification from positive blood cultures we present a faster method (ultra fast) for Lytic anaerobic flasks. Methods: We compare the ultra-fast (UF) method with the extensively employed differential centrifugation method (DC) and both to routine identification after 18-24 h of incubation. UF and DC method correlation rates to the gold standard were calculated, and statistical significance was proved with the Z test. Results: UF performed better overall than DC, with this difference being statistically significant. This tendency was observed in every subanalysis.

Effects of locally applied Insulin-like Growth Factor-I on osseointegration

Background: The aim of this study was to assess the effect of local application of IGF-I on osseointegration of dental implants placed in osteoporotic bones. Material and Methods: 16 rabbits were randomly distributed into two groups: eight animals were ovariectomized and fed a low-calcium diet for six weeks, in order to induce experimental osteoporosis, and the others were sham-operated and fed a standard diet. A titanium implant was inserted into the tibiae in both groups. In half of the rabbits, 4 μg of IGF-I was applied into the ostectomy, prior to the implant insertion. A total of 32 implants were placed. Animals were sacrificed two weeks after surgery and decalcified samples were processed for Bone-To-Implant Contact (BIC) and Bone Area Density (BAD) measurements. Analysis of variance (ANOVA) was used for statistical evaluation. P < 0.05 was considered to be significant. Results: Ovariectomy induced statistically significant lower BAD values (p = 0.008) and a tendency towards lower BIC values when compared osteoporotic and healthy groups. The administration of 4 μg of IGF-I did not produce statistically significant differences neither on BIC nor on BAD values, neither in the osteoporotic animals nor in healthy. Conclusions: Within the limitations of this experimental study, local administration of 4 μg of IGF-I was not able to induce any changes in the osseointegration process two weeks after surgery, neither in healthy rabbits nor in the osteoporotic group

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Microbial and Natural Metabolites That Inhibit Splicing: A Powerful Alternative for Cancer Treatment.

In eukaryotes, genes are frequently interrupted with noncoding sequences named introns. Alternative splicing is a nuclear mechanism by which these introns are removed and flanking coding regions named exons are joined together to generate a message that will be translated in the cytoplasm. This mechanism is catalyzed by a complex machinery known as the spliceosome, which is conformed by more than 300 proteins and ribonucleoproteins that activate and regulate the precision of gene expression when assembled. It has been proposed that several genetic diseases are related to defects in the splicing process, including cancer. For this reason, natural products that show the ability to regulate splicing have attracted enormous attention due to its potential use for cancer treatment. Some microbial metabolites have shown the ability to inhibit gene splicing and the molecular mechanism responsible for this inhibition is being studied for future applications. Here, we summarize the main types of natural products that have been characterized as splicing inhibitors, the recent advances regarding molecular and cellular effects related to these molecules, and the applications reported so far in cancer therapeutics.

Evaluación de las necesidades de los pacientes respecto a la información y los cuidados médicos tras el diagnóstico de cáncer / Assessing the needs of patients about information and medical care after diagnosis of cancer

Objetivo: Estudiar las necesidades de los pacientes oncológicos sobre la información referida a su enfermedad y los cuidados al final de la vida. Métodos: 820 pacientes participaron de una encuesta sobre diagnóstico, pronóstico, eficacia y toxicidad de los tratamientos, así como también sobre cuidados paliativos, investigación clínica, apoyo psicológico, cuidados espirituales y deseos del final de la vida. Resultados: 695 pacientes conocen su diagnóstico, especialmente quienes tenían un mayor nivel educativo y un rango etario de 50-70 años. Seiscientos setenta y cuatro pacientes deseaban conocer su pronóstico, estando más predispuestos a conocerlo quienes tenían educación secundaria y superior. La mayoría (562 pacientes) deseaba conocer todo con respecto a la utilidad de los tratamientos, al igual que con respecto a la toxicidad (443) y valoraría contar con información sobre cuidados paliativos e investigación. Además consideraba la internación hospitalaria como el mejor lugar para morir (331). Las mujeres se mostraron más propensas a recibir ayuda psicológica y espiritual. Las condiciones más valoradas en el médico fueron: conocimiento (52,7%), Honestidad (45,5%) y Humanidad (44,3%). Un 82,3% de los pacientes valoraron positivamente la encuesta, mientras que el 58% la consideró útil. Sin embargo un 23,7% la recomendaría. Conclusiones: El estudio representa, en nuestro conocimiento, el primer intento en nuestro medio por identificar las necesidades y los deseos de los pacientes por conocer cuestiones vinculadas con su enfermedad. En este sentido hemos observado una búsqueda de participación activa en las decisiones vinculadas al manejo de la información y los tratamientos por parte de los pacientes

Objective: To study and understand the needs for informations of the patients in our environment, analyzing specifically the needs for information about their illness and care at the end of life after being diagnosed with cancer. Methods: 820 patients in a survey about diagnosis, prognosis, treatment efficacy and toxicity, as well as palliative care, clinical research, psychological support, spiritual care and wishes of the end of life. Results: Patients majority (695) was aware of their diagnosis, knowing more who had higher education and an age range of 50-70 years. Six hundred seventy-four patients wanted to know their prognosis, being more likely to know those who had secondary and higher education. The majority (562 patients) wanted to know everything about the treatment utility, as well as with respect to toxicity (443) and would value to have information on palliative care and research. Hospitalization also considered as the best place to die (331). omen were more likely to receive psychological and spiritual help. The most valued physician conditions were knowledge (52.7%), honesty (45.5%) and Humanities (44.3%). The 82.3% of patients appreciated the survey, while 58% considered it useful. However, 23.7 % would recommend it. Conclusions: This study represents, to our knowledge, the first attempt in our country to identify the needs and wishes of patients to know about issues related to their illness. We have observed a search for active participation in decisions related to information management and treatments by patients

Rapid conversion of spirostans into furostan skeletons at room temperature.

We report a facile protocol to obtain 22-substituted furostans and pseudosapogenins in high yields from (25R)- and (25S)-sapogenins. This method involves the treatment of the sapogenin with acetic-trifluoroacetic mixed anhydride and BF(3)·OEt(2) at room temperature, followed by the addition of a nucleophile (H(2)O, MeOH or KSeCN). In the case of 22-hydroxyfurostans, they can be transformed to pseudosapogenins by treatment with p-toluensulfonic acid.

Influencia de la ingesta de butirato de sodio en la carcinogénesis colónica murina / Influence of sodium butyrate intake on murine colonic carcinogenesis

El papel de los ácidos grasos de cadena corta (AGCC) en la carcinogénesis colónica murina (CCM) no fue aclarado. Evaluamos el efecto de la hemicolectomía derecha (HCD) (colon derecho, fuente de AGCC) y de la ingesta en agua de bebida de butirato de sodio (Buti.Na) al 2 por ciento a pH 7 o de cloruro de sodio (CINa) 4g/l, en la CCM. Formamos 7 grupos de 12 ratas Wistar macho de 150 g: HCD, Buti. Na, CINa, control (C). La mitad recibió dimetilhidrazina (DMH) 20 mg/Kg subucutánea semanal durante 12 semanas. La necropsia fue realizada a los 6 meses. Determinamos el contenido de AGCC en materia fecal por cromatografía gaseosa. El 70 por ciento de las ratas con DMH desarrolló tumor. El n§ de animales con tumor, por grupo fue: HCD 4/6, Buti.Na 4/6, CINa 3/5, C 6/6. El n§ de tumores promedio por animal, por grupo fue: HCD 1,17 ñ 0,48, Buti.Na 3/5, C 6/6. El n§ de tumores promedio por animal, por grupo fue: HCD 1,17 ñ 0,48, Buti.Na 1,50 ñ 0,76, ClNa 1,20 ñ 0,49, C 1,50 ñ 0,22. El grupo Buti.Na (DMH) presentó una concentración significativamente menor de butirato (p < 0,05) en relación a los demás grupos. En conclusión, el suplemento en agua de bebida de Buti.Na, CINa y la HCD redujeron en forma no significativa la CCM, con este número de animales

Influencia de la ingesta de butirato de sodio en la carcinogénesis colónica murina / Influence of sodium butyrate intake on murine colonic carcinogenesis

El papel de los ácidos grasos de cadena corta (AGCC) en la carcinogénesis colónica murina (CCM) no fue aclarado. Evaluamos el efecto de la hemicolectomía derecha (HCD) (colon derecho, fuente de AGCC) y de la ingesta en agua de bebida de butirato de sodio (Buti.Na) al 2 por ciento a pH 7 o de cloruro de sodio (CINa) 4g/l, en la CCM. Formamos 7 grupos de 12 ratas Wistar macho de 150 g: HCD, Buti. Na, CINa, control (C). La mitad recibió dimetilhidrazina (DMH) 20 mg/Kg subucutánea semanal durante 12 semanas. La necropsia fue realizada a los 6 meses. Determinamos el contenido de AGCC en materia fecal por cromatografía gaseosa. El 70 por ciento de las ratas con DMH desarrolló tumor. El nº de animales con tumor, por grupo fue: HCD 4/6, Buti.Na 4/6, CINa 3/5, C 6/6. El nº de tumores promedio por animal, por grupo fue: HCD 1,17 ñ 0,48, Buti.Na 3/5, C 6/6. El nº de tumores promedio por animal, por grupo fue: HCD 1,17 ñ 0,48, Buti.Na 1,50 ñ 0,76, ClNa 1,20 ñ 0,49, C 1,50 ñ 0,22. El grupo Buti.Na (DMH) presentó una concentración significativamente menor de butirato (p < 0,05) en relación a los demás grupos. En conclusión, el suplemento en agua de bebida de Buti.Na, CINa y la HCD redujeron en forma no significativa la CCM, con este número de animales (AU)