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Biomedical subjects

V M González

Publications and source records attributed to V M González.

At least 19 recordsLinked to original sources
PubMed2006

Heat-induced programmed cell death in Leishmania infantum is reverted by Bcl-X(L) expression.

An increasing number of reports indicate that single-celled organisms are able to die following what seems to be an ordered program of cell death with strong similarities to apoptosis from higher eukaryotes. DNA degradation and several other apoptotic-like processes have also been described in the parasitic protozoa Leishmania. However, the existence of an apoptotic death in this parasite is still a matter of controversy. Our results indicate that most of the processes of macromolecular degradation and organelle dysfunction observed in mammalian cells during apoptosis can also be reproduced in promastigotes of the genus Leishmania when incubated at temperatures above 38 degrees C. These processes can be partially reversed by the expression of the anti-apoptotic mammalian gene Bcl-X(L), which suggests that this family of apoptosis-regulating proteins was present very early in the evolution of eukaryotic cells.

Animals↗
PubMed2001

A kinetic model for the B-Z transition of poly[d(G-C)].poly[d(G-C)] and poly[d(G-m5C)].poly[d(G-m5C)].

The analysis of the kinetic data of the B-Z conformational changes induced by salt in sized double-stranded poly[d(G-C)].poly[d(G-C)] and poly[d(G-m5C)].poly[d(G-m5C)] polymers indicated that there exists a salt threshold which reveals some largely, as yet, unrecognised characteristics of the transition. It was observed that there is a direct correlation between the length of the polymer and the rate of the B-Z transition when the salt concentration in the polymer solution is lower than the salt threshold. The correlation is inverse when the salt concentration is higher than the salt threshold. Thus, the molecular mechanism of the B- to Z-DNA transition varies depending on whether the salt concentration is higher or lower than the threshold. In this context, we have found that the contrasting results reported in the literature describing the rate of the B-Z transition are not contradictory but complementary. The finding of a salt threshold leads to the establishment of a relationship between the cooperativity index of the B-Z transition and the polymer chain length. That relationship is dependent on the chemical structure of the polymer but is temperature independent.

DNA↗
PubMed2000

Induction of apoptosis by the bis-Pt(III) complex [Pt(2)(2-mercaptopyrimidine)(4)Cl(2)].

We analyzed both the cytotoxicity and the type of cell death produced by the novel binuclear Pt(III) compound Pt-Spym ([Pt(2)(2-mercaptopyrimidine)(4)Cl(2)]) in kidney human fibroblasts and in human tumor cell lines (HeLa, CH1, CH1cisR and HL-60). The data showed that Pt-Spym displayed higher cytotoxicity against these tumor cells than cisplatin. In contrast, Pt-Spym had low toxicity against normal human fibroblasts. Interestingly, Pt-Spym circumvented cisplatin resistance in CH1cisR cells. We also observed that Pt-Spym induced the characteristic changes attributed to apoptosis in cells with normal levels of p53 protein (CH1 and CH1cisR) and with low levels of p53 protein (HeLa), but not in cells lacking p53 (HL-60). Interestingly, Western blot data indicated that apoptosis induction by Pt-Spym in HeLa, CH1, and CH1cisR cells was not associated with drastic changes in p53 levels. However, cis-DDP strongly decreased p53 levels in CH1 and CH1cisR cells and abolish p53 protein in HeLa cells. Altogether, these results suggest that induction of apoptosis by Pt-Spym requires the presence of p53 protein.

Annexins↗
PubMed1999

Regulation of the forkhead transcription factor FKHR, but not the PAX3-FKHR fusion protein, by the serine/threonine kinase Akt.

Akt, a proto-oncogene that encodes a cytosolic serine/threonine kinase, can phosphorylate and modulate the activity of several proteins involved in cellular metabolism and survival. Recently, two mammalian highly related forkhead transcription factors FKHRL1 and AFX and their nematode homologue Daf-16 have been found to be targets of this kinase. Here we show that Akt, but not inactive Akt, represses the transcriptional activity of FKHR, another member of the forkhead family. FKHR mutants with alanine substitutions at three Akt phosphorylation consensus sites (T24, S256 and S319) were inhibited by Akt, but mutation of all three sites rendered FKHR resistant to suppression. By contrast, the transcriptional activity of the oncogenic PAX3-FKHR fusion protein, containing two consensus phosphorylation sites, was not inhibited by Akt. Importantly, Akt inhibited the translocation of FKHR to the nucleus, providing a mechanism by which Akt might regulate the transcriptional activity of FKHR. Consistent with this model, the localization of the PAX3-FKHR fusion protein was nuclear and was not altered by Akt. These results provide evidence that Akt inhibits the transcriptional activity of FKHR by controlling its trafficking into the nucleus and that oncogenic PAX3-FKHR can escape this negative regulation by Akt.

3T3 Cells↗
PubMed1999

Empirical validation of a two-state kinetic model for the B-Z transition of double-stranded poly[d(G-m5C)].

A formula based on a first-order kinetic equation is derived to evaluate the rate constant of the B-Z transition of a synthetic double-stranded poly[d(G-m5C)] in terms of the salt concentration, the absolute temperature, and the cooperativity index. The validity of the formula was tested using circular dichroism spectroscopy after variation of the type of salt (NaCl, MgCl2), the salt concentration, and the temperature of the polynucleotide solution. A consequence of the proposed function is that in conditions of high salt there is a predictable salt threshold which determines the particular molecular mechanism of the B-Z transition. The paper also describes the way in which this threshold level is temperature dependent. A detailed comparison of our data with the experimental data found by other authors is given. The function agrees quantitatively with the experiments and explains the contrasting results found in the literature about the influence in the B-Z transition of both the temperature and the polymer size.

Circular Dichroism↗
PubMed1999

The formation of DNA interstrand cross-links by a novel bis-[Pt2Cl4(diminazene aceturate)2]Cl4.4H2O complex inhibits the B to Z transition.

We present data demonstrating that the cytotoxic compound [Pt2Cl4(diminazene aceturate)2]Cl4.4H2O (Pt-berenil) circumvents cisplatin resistance in ovarian carcinoma cells. The analysis of the interaction of Pt-berenil with linear and supercoiled DNA indicates that this compound induces the formation of a large number of covalent interstrand cross-links on DNA and that this number is significantly higher than that produced by cis-diamminedichloroplatinum(II) (cis-DDP). Renaturation experiments, interstrand cross-link assays, and electron microscopy indicate that the kinetics of DNA interstrand cross-link formation caused by Pt-berenil binding is faster than that caused by cis-DDP at similar levels of platinum bound to DNA. Furthermore, the number of DNA interstrand cross-links in Pt-berenil-DNA complexes is influenced by supercoiling. Circular dichroism experiments show that Pt-berenil strongly inhibits the B-DNA-to-Z-DNA transition of poly(dG-m5 dC). poly(dG-m5dC) at salt concentrations (3 mM MgCl2) at which the native methylated polynucleotide readily adopts the Z-DNA conformation, which suggests that the induction of interstrand cross-links by Pt-berenil inhibits the Z-DNA transition. On the basis of these results, we propose that bis(platinum) compounds with structure similar to Pt-berenil may act as blockers of DNA conformational changes and may also display activity in cisplatin-resistant cells.

Animals↗
PubMed1998

Caenorhabditis elegans EGL-1 disrupts the interaction of CED-9 with CED-4 and promotes CED-3 activation.

In the nematode Caenorhabditis elegans, programmed cell death is implemented by the protease CED-3 whose activity is inhibited by CED-9 through physical associations with the regulator CED-4. The product of a recently described gene, egl-1, binds to and inhibits CED-9. In the present studies, we have addressed the molecular mechanism by which EGL-1 regulates CED-9 function and promotes cell death. Expression of CED-4 and CED-3 resulted in decreased survival and apoptosis of mammalian cells, activities that could be inhibited by CED-9. Importantly, this protective effect of CED-9 was antagonized by EGL-1. Immunoprecipitation analysis showed that EGL-1 binding to CED-9 disrupts the association between CED-4 and CED-9, an activity that required the BH3 motif of EGL-1. Consistent with these results, expression of EGL-1 promoted CED-4-dependent processing of CED-3, and this activity of EGL-1 was mediated through inhibition of CED-9. In mammalian cells, CED-9 is known to target the subcellular localization of CED-4 from the cytosol to intracellular membranes. Expression of EGL-1 resulted in redistribution of CED-4 from intracellular membranes, where it co-localized with CED-9, to the cytoplasm, providing further evidence that EGL-1 regulates CED-4 through CED-9. Finally, the levels of EGL-1 were greatly enhanced by co-expression of CED-9 in both mammalian cells and in a cell-free system, suggesting a role for CED-9 in the expression and/or stabilization of EGL-1. These studies provide a mechanism for how EGL-1 functions to antagonize pro-survival of CED-9 and to promote CED-3 activation and programmed cell death.

Animals↗
PubMed1998

A randomized trial of a lay person-led self-management group intervention for back pain patients in primary care.

STUDY DESIGN: Randomized, controlled trial. OBJECTIVE: To evaluate a four-session self-management group intervention for patients with pain in primary care, led by trained lay persons with back pain. The intervention was designed to reduce patient worries, encourage self-care, and reduce activity limitations. BACKGROUND DATA: Randomized trials of educational interventions suggest that activating interventions may improve back pain outcomes. Expert opinion increasingly regards effective self-management of back pain as important in achieving good outcomes. In this study, an educational intervention designed to activate patients and support effective self-management was evaluated. METHODS: Six to 8 weeks after a primary care visit for back pain, patients were invited to participate in an educational program to improve back pain self-management. Those showing interest by returning a brief questionnaire became eligible for the study. Participants (n = 255) randomly were assigned to either a self-management group intervention or to a usual care control group. The effect of the intervention, relative to usual care, was assessed 3, 6, and 12 months after randomization, controlling for baseline values. The intervention consisted of a four-session group applying problem-solving techniques to back pain self-management, supplemented by educational materials (book and videos) supporting active management of back pain. The groups were led by lay persons trained to implement a fully structured group protocol. The control group received usual care, supplemented by a book on back pain care. RESULTS: Participants randomly assigned to the self-management groups reported significantly less worry about back pain and expressed more confidence in self-care. Roland Disability Questionnaire Scores were significantly lower among participants in the self-management groups relative to the usual care controls at 6 months (P = 0.007), and this difference was sustained at 12 months at borderline significance levels (P = 0.09). Among self-management group participants, 48% showed a 50% or greater reduction in Roland Disability Questionnaire Score at 6 months, compared with 33% among the usual care controls. CONCLUSIONS: Self-management groups led by trained lay persons following a structured protocol were more effective than usual care in reducing worries, producing positive attitudes toward self-care, and reducing activity limitations among patients with back pain in primary care.

Activities of Daily Living↗
PubMed1998

Arthritis self-management program variations: three studies.

OBJECTIVES: 1) Determine strengths and weaknesses of the Arthritis Self-Management Program (ASMP). 2) Compare 3- and 6-week ASMP. 3) Evaluate 1.5-hour arthritis program. METHODS: Study 1: Qualitative methods incorporating incomplete block design. Study 2: Comparison of 3- and 6-week outcomes. Study 3: Pretest/posttest comparison. RESULTS: Study 1: Pain management, exercise, and sharing ranked as the most useful aspects of the ASMP. Nutrition, medications, and making decisions about nontraditional treatments ranked least useful. Study 2: Six-week ASMP subjects improved pain, health distress, illness impact, exercise, cognitive pain management, self-efficacy, and reduced visits to physicians (P < 0.05). Three-week subjects improved health distress, cognitive pain management, and self-efficacy (P < 0.05). Study 3: Improved knowledge, self-efficacy, and pain (P < 0.05). CONCLUSIONS: The traditional 6-week ASMP is more effective than a 3-week version. A 1.5-hour community program is effective in increasing knowledge, self-efficacy, and contact with the Arthritis Foundation.

Adult↗
PubMed1997

Cultural diversity issues in the development of valid and reliable measures of health status.

The development of instruments for use in culturally diverse settings and populations really involves much more than mere translation. Measurements must be tested for content validity and appropriate meaning among members of the group to be studied. Attention to issues of validity, reliability, and cross-cultural differences will lead to effective assessment, culturally competent health care, and the enhancement of the client/provider relationship. The concerns surrounding the use of quantitative measurement in diverse cultural groups are substantial. While the refinement of scales to meet the needs of various groups is a challenging task, such effort is essential to the diagnosis of disease, determination of health status, and the measurement of health outcomes in the diverse subgroups of this country's population.

Cross-Cultural Comparison↗
PubMed1997

The berenil ligand directs the DNA binding of the cytotoxic drug Pt-berenil.

To determine the affinity towards DNA sequences of novel antitumor drugs in comparison with their parental compounds may lead to the design of new analogous drugs with improved antitumor activity. Thus, the affinities of Pt-berenil towards different DNA sites relative to cis-DDP and berenil drugs were analysed using DNase I footprinting and restriction endonuclease analysis. The data show that the Pt-berenil drug inhibits the cutting activity of Hind III enzyme to the same extent as the berenil ligand. In contrast, inhibition by Pt-berenil of the cutting activity of Bam HI enzyme is significantly lower than that of cis-DDP. These results indicate that although the cis-Pt(II) centres of Pt-berenil maintain certain affinity toward G + C regions, which are the main binding sequences of cis-DDP, however, the berenil ligand seems to direct the Pt-berenil molecule towards A + T regions, which are the binding sequences preferred by berenil. In fact, 1H- and 195Pt-NMR spectra of Pt-berenil:nucleoside complexes show that Pt-berenil not only covalently binds to N7 of guanosine but also to N1/N7 of adenosine.

Adenosine↗
PubMed1996

Modification of the recognition of restriction sites of plasmid DNA by the antitumor drug Pt-pentamidine.

The rate of binding of the antineoplastic drugs Pt-pentamidine [(cis-PtCl2)3(pentamidine)3][PtCl4]2 and cis-DDP [cis-diamminedichloroplatimum(II)] to pUC8 DNA, as well as the effect of the binding of these platinum compounds on the cutting effectiveness of Bam HI, Hind III, and Sal I restriction endonucleases, were determined by flameless atomic absorption spectroscopy and gel electrophoresis, respectively. The results show that covalent DNA platination is 12% to 22% lower in DNA: Pt-pentamidine complexes than in DNA: cis-DDP at the same molar rate of platinum/nucleotide, and the number of Pt-pentamidine molecules bound to DNA is significantly lower in Pt-pentamidine: DNA complexes than in cis-DDP: DNA complexes. Although both compounds inhibit Bam HI cleavage of pUC8 DNA, Pt-pentamidine does not prevent the cutting activity of Hind III, in contrast with cis-DDP. Neither cis-DDP nor Pt-pentamidine inhibits the cutting activity of Sal I, whose recognition sequence neighbors the Bam HI and Hind III sites.

DNA↗
PubMed1996

Cis-Dichloro(diaminosuccinate diethyl ester)palladium (II) as Pd(II)/Pt(II) model compound for DNA-binding and antitumor properties: solution equilibria of their aqua-, hydroxo-, and/or chloro-species.

Cis-Dichloro(diaminosuccinic acid)palladium(II), cis-[Pd(H2dasa)Cl2] (I), or cis-dichloro(diaminosuccinate diethyl ester)palladium(II), cis-[Pd(Et2dasa)Cl2] (II) reacts with two equivalents of AgClO4 to give insoluble Pd(dasa) or an aqueous solution of [Pd(Et2dasa) (H2O)2](ClO4)2, respectively. Three solutions of this salt were titrated with NaOH (I = NaClO4 (0.15M),37 degrees C), and 133 E(H+) data (3.5 < or = pH < or = 7) were treated by SUPERQUAD to fit log beta pqr of cis-aquahydroxo-(pqr = 10-1, -5.25(3)) and di-mu-hydroxo-species (20-2, -6.55(1)). At pH > 7 the ester hydrolysis prevents the calculation of log beta 10-2 for the cis-dihydroxo-complex. Another three solutions of such salt were titrated (I = 0.15M (NaClO4), 37 degrees C) with NaOH and NaCl simultaneously using two potentiometric systems (which measure H+ or Cl-). From 147 E(H+) and E(Cl-) data pairs and the above fixed log beta pqr, SUPERQUAD calculations yield log beta pqr for cis-chloro-aqua (pqr = 110, 3.65(1)), cis-chloro-hydroxo (11-1, -2.68 (4)), and cis-dichloro-species (120, 5.86(3)). Simulated and experimental titrations are in good agreement. Circular dichroism spectra of native DNA and drug:DNA complexes suggest that cis-Pd(H2dasa) and cis-Pd(Et2dasa) chelate moieties induce an opening and rotation of the stacked bases in the double helix. This finding is explained by the abundance of each one and of the total neutral and charged species of II in the tested CD solution.

Amino Acids, Diamino↗
PubMed1996

Synthesis, characterization, and DNA modification induced by a novel Pt-berenil compound with cytotoxic activity.

In the present paper, we show that the reaction of the antipyranosomatid berenil drug with K2PtCl4 resulted in the synthesis of a covalent (Pt(II)-berenil compound of formula [Pt2Cl4(berenil)2]Cl4.4H2O as shown by IR, 1H, 13C, and 195Pt-NMR. The Pt-berenil compound was tested for in vitro antitumor activity against HL-60 and U-937 human leukemic cells. The results show that the LC70 values of the Pt-berenil are about two-fold lower than those of cis-DDP in both HL-60 and U-937 cell lines. Melting data of Pt-berenil:DNA and berenil:DNA complexes indicate that the platinated compound produces on a DNA secondary structure higher compaction than the berenil ligand. The mobility in agarose gels and the circular dichroism spectra of the compounds:DNA complexes revealed, moreover, that both induce drastic changes on a DNA secondary and tertiary structure. The total reflection X-ray fluorescence data showed, in additIon that DNA platination in Pt-berenil:DNA complexes occurs within minutes after addition of the drug, in contrast to what that observed in cis-DDP:DNA complexes. On the basis of these results, we propose that in Pt-berenil, the berenil ligand acts as a carrier of the active cis-P(II) centers towards DNA.

Antineoplastic Agents↗
PubMed1996

Cytotoxicity, DNA binding, and reactivity against nucleosides of platinum (II) and (IV) spermine compounds.

We describe the synthesis and characterization of a [sperH4][PtCl4]2 salt and of five binuclear platinum (II) and (IV)-spermine compounds of formula [(PtCl2)2(sper)], cis-[(Pt(CH2(COO)2)2(sper)], cis-[(PtCBDCA)2(sper)], (CBDCA = 1,1'-cyclobutanedicarboxylate), cis-trans-cis[(PtCl2(OH)2)2(sper)], and cis-[(PtCl4)2(sper)], respectively. The 1H and 195Pt-NMR analysis of the complexes formed between these compounds and nucleosides indicated that the Pt centers show preferential binding to the N(7) of guanosine and adenosine residues, also being capable of forming bridged structures through the N(7) and N(1). The synthesized Pt-spermine compounds do not form complexes with cytidine residues at 37 degrees C. The circular dichroism, melting, and electrophoretic data of the compounds-DNA complexes show that the Pt(IV)-spermine complexes induce lower DNA conformational changes than their Pt(II) analogs. These results correlate with the IC50 values obtained against MDA-MB 468 and HL-60 human cancer cells which are higher than those of cis-DDP. The [sperH4][PtCl4]2 salt produces a high level of DNA modification and exhibits IC50 values lower than those of cis-DDP.

Antineoplastic Agents↗
PubMed1995

Translation and validation of arthritis outcome measures into Spanish.

OBJECTIVE: To produce Spanish versions of common arthritis outcome measures: the Health Assessment Questionnaire (HAQ) Disability Scale, the Center for Epidemiologic Studies Depression Scale (CES-D), the Medical Outcomes Study (MOS) Pain Severity Scale, the Arthritis Self-Efficacy Scale for Pain and Other Symptoms (with the addition of 2 new items), the Visual Analogue Pain Scale, the MOS Self-Rated Health Item, and a Physical Activities Scale that would be usable by most Hispanics living in the US. We tested these translated measures for reliability and, where appropriate, validity. METHODS: Instruments were translated and back translated by bilingual persons from 5 different countries of origin. Translators met to resolve variations in translation. The instruments were then administered to Hispanic arthritis patients in 6 geographic locations (5 in the United States and 1 in Latin America). All instruments underwent standard psychometric testing. As appropriate, the sample was stratified by level of acculturation, nation of origin, and geographic location. RESULTS: The translated instruments, with slight modification, met acceptable levels of reliability and validity. They are understood and easily usable by diverse Spanish-speaking populations. CONCLUSION: The availability of these translated outcome measures should enable investigators to include monolingual Spanish-speakers into their studies, and should facilitate study of cross-cultural differences with respect to these specific outcomes.

Activities of Daily Living↗
PubMed1994

Platinum (II) and (IV) spermidine complexes. Synthesis, characterization, and biological studies.

By reaction of K2PtCl4 with spermidine we have synthesized two tris-platinum covalent compounds of formula (PtI2)3(sper)2 and (PtCl2)3(sper)2, one ionic compound of formula (sperH3)2(PtCl4)3, and another one of a covalent nature of formula (PtCl2sperH)2 (PtCl4) having a partially protonated spermidine residue. Treatment of the tris-platinum compounds with hydrogen peroxide and hydrochloric acid led to the production of two compounds of formula cis-trans-cis-(PtIVCl2(OH)2)3(sper)2 and cis-(PtIVCl4)3(sper)2, respectively. All of them have been characterized by IR and 1H MNR spectroscopy and tested for their ability to interact with pUC8 plasmid DNA by the use of UV, CD, and electrophoretic techniques. The results suggest that all of these compounds modify the secondary structure of the double helix. We observed that the alteration in electrophoretic mobility of nicked and closed circular forms of DNA induced by the Pt(II) complexes is higher than that induced by the Pt(IV) complexes. The synthesized compounds were also assayed for antitumor activity in vitro against breast (MDA-MB468) and leukemia (HL-60) tumor cells. Only three of these complexes may be regarded as potential antitumor agents, since their ID50 values are lower than 10 micrograms/ml.

Antineoplastic Agents↗