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Enrique Alvarez

Publications and source records attributed to Enrique Alvarez.

At least 19 recordsLinked to original sources
PubMed2025

Senescent-like microglia limit remyelination through the senescence associated secretory phenotype.

The capacity to regenerate myelin in the central nervous system diminishes with age. This decline is particularly evident in multiple sclerosis (MS), a chronic demyelinating disease. Whether cellular senescence, a hallmark of aging, contributes to remyelination impairment remains unknown. Here, we show that senescent cells accumulate within demyelinated lesions after injury, and treatments with senolytics enhances remyelination in young and middle-aged mice but not aged mice. In young mice, we observe the upregulation of senescence-associated transcripts, primarily in microglia and macrophages, after demyelination, followed by a reduction during remyelination. However, in aged mice, senescence-associated factors persist within lesions, correlating with inefficient remyelination. Proteomic analysis of the senescence-associated secretory phenotype (SASP) reveals elevated levels of CCL11/Eotaxin-1 in lesions of aged mice, which is found to inhibit oligodendrocyte maturation. These results suggest therapeutic targeting of SASP components, such as CCL11, may improve remyelination in aging and MS.

Animals↗
PubMed2006

A severe acute respiratory syndrome coronavirus that lacks the E gene is attenuated in vitro and in vivo.

A deletion mutant of severe acute respiratory syndrome coronavirus (SARS-CoV) has been engineered by deleting the structural E gene in an infectious cDNA clone that was constructed as a bacterial artificial chromosome (BAC). The recombinant virus lacking the E gene (rSARS-CoV-DeltaE) was rescued in Vero E6 cells. The recovered deletion mutant grew in Vero E6, Huh-7, and CaCo-2 cells to titers 20-, 200-, and 200-fold lower than the recombinant wild-type virus, respectively, indicating that although the E protein has an effect on growth, it is not essential for virus replication. No differences in virion stability under a wide range of pH and temperature were detected between the deletion mutant and recombinant wild-type viruses. Although both viruses showed the same morphology by electron microscopy, the process of morphogenesis seemed to be less efficient with the defective virus than with the recombinant wild-type one. The rSARS-CoV-DeltaE virus replicated to titers 100- to 1,000-fold lower than the recombinant wild-type virus in the upper and lower respiratory tract of hamsters, and the lower viral load was accompanied by less inflammation in the lungs of hamsters infected with rSARS-CoV-DeltaE virus than with the recombinant wild-type virus. Therefore, the SARS-CoV that lacks the E gene is attenuated in hamsters, might be a safer research tool, and may be a good candidate for the development of a live attenuated SARS-CoV vaccine.

Animals↗
PubMed2006

Differential cleavage of eIF4GI and eIF4GII in mammalian cells. Effects on translation.

Two isoforms of the translation initiation factor eIF4G, eIF4GI and eIF4GII, have been described in eukaryotic cells. The exact function of each isoform during the initiation of protein synthesis is still under investigation. We have developed an efficient and reliable method of expressing poliovirus 2Apro, which differentially proteolyzes eIF4GI and eIF4GII in a time- and dose-dependent manner. This system is based on the electroporation of an in vitro transcribed mRNA that contains the encephalomyocarditis virus internal ribosome entry site followed by the sequence of poliovirus 2Apro. In contrast to HeLa cells, expression of this protease in BHK-21 cells induces delayed hydrolysis kinetics of eIF4GI with respect to eIF4GII. Moreover, under these conditions the polyadenylate binding protein is not cleaved. Interestingly, translation of de novo synthesized luciferase mRNA is highly dependent on eIF4GI integrity, whereas ongoing translation is inhibited at the same time as eIF4GII cleavage. Moreover, reinitiation of a preexisting mRNA translation after polysome run-off is dependent on the integrity of eIF4GII. Notably, de novo translation of heat shock protein 70 mRNA depends little on eIF4GI integrity but is more susceptible to eIF4GII hydrolysis. Finally, translation of an mRNA containing encephalomyocarditis virus internal ribosome entry site when the two isoforms of eIF4G are differentially hydrolyzed has been examined.

Animals↗
PubMed2006

Construction of a severe acute respiratory syndrome coronavirus infectious cDNA clone and a replicon to study coronavirus RNA synthesis.

The engineering of a full-length infectious cDNA clone and a functional replicon of the severe acute respiratory syndrome coronavirus (SARS-CoV) Urbani strain as bacterial artificial chromosomes (BACs) is described in this study. In this system, the viral RNA was expressed in the cell nucleus under the control of the cytomegalovirus promoter and further amplified in the cytoplasm by the viral replicase. Both the infectious clone and the replicon were fully stable in Escherichia coli. Using the SARS-CoV replicon, we have shown that the recently described RNA-processing enzymes exoribonuclease, endoribonuclease, and 2'-O-ribose methyltransferase were essential for efficient coronavirus RNA synthesis. The SARS reverse genetic system developed as a BAC constitutes a useful tool for the study of fundamental viral processes and also for developing genetically defined vaccines.

Animals↗
PubMed2006

Improvement in social functioning in outpatients with schizophrenia with prominent negative symptoms treated with olanzapine or risperidone in a 1 year randomized, open-label trial.

UNLABELLED: GENERAL PURPOSE: To evaluate the social functioning of schizophrenic outpatients after switching to second-generation antipsychotics. METHODOLOGY: Multi-center, randomized, open-label, parallel, flexible-dose, 1-year study of schizophrenic outpatients with prominent negative symptoms (defined as a SANS Global score > or =10), previously treated with conventional antipsychotics. Patients were randomly assigned (1:1 ratio) to treatment with an initial dose of at least 10 mg/day olanzapine (N = 120) or at least 3 mg/day risperidone (N = 115). Dosage could be modified during the study according to clinical criteria. Social functioning was evaluated using the total and subscales scores of the Social Functioning Scale (SFS) (validated Spanish version). Other efficacy measures included the SANS, SAPS, and CGI-S scales. Response was defined in advance as a 30% improvement in the SANS Global score. RESULTS: The mean doses during the trial were 12.2 mg/day (S.D. = 5.8) of olanzapine and 4.9 mg/day (S.D. = 2) of risperidone. There were no significant baseline differences in SFS total scores or other relevant clinical variables. At 1 year, olanzapine-treated patients presented a mean improvement in SFS total scores (7.75) that were significantly higher (p = 0.0028) than for risperidone-treated patients (-0.92). Treatment with olanzapine resulted in a greater numerical improvement than risperidone in all SFS domains and reached statistical significance in such categories as social engagement or withdrawal (p = 0.01), independence (performance) (p = 0.0098), independence (competence) (p = 0.04), recreational activities (p = 0.0391), and occupation/employment (p = 0.0024) in which the greatest difference between the olanzapine and risperidone groups was found (0.86 vs. -3.06). Significantly more patients treated with olanzapine reached or surpassed the SFS typified total scores corresponding to a functional level that is representative of a sample of stabilized Spanish outpatients with schizophrenia without prominent negative symptoms (p = 0.0009). Associated factors were treatment with olanzapine and a 30% improvement or more in SANS global score or SAPS global score. CONCLUSIONS: Long-term treatment with olanzapine was associated with overall greater improvement in social functioning (as measured by SFS) compared to risperidone-treated patients.

Adolescent↗
PubMed2006

HIV protease cleaves poly(A)-binding protein.

The PABP [poly(A)-binding protein] is able to interact with the 3' poly(A) tail of eukaryotic mRNA, promoting its translation. Cleavage of PABP by viral proteases encoded by several picornaviruses and caliciviruses plays a role in the abrogation of cellular protein synthesis. We report that infection of MT-2 cells with HIV-1 leads to efficient proteolysis of PABP. Analysis of PABP integrity was carried out in BHK-21 (baby-hamster kidney) and COS-7 cells upon individual expression of the protease from several members of the Retroviridae family, e.g. MoMLV (Moloney murine leukaemia virus), MMTV (mouse mammary tumour virus), HTLV-I (human T-cell leukaemia virus type I), SIV (simian immunodeficiency virus), HIV-1 and HIV-2. Moreover, protease activity against PABP was tested in a HeLa-cell-free system. Only MMTV, HIV-1 and HIV-2 proteases were able to cleave PABP in the absence of other viral proteins. Purified HIV-1 and HIV-2 proteases cleave PABP1 directly at positions 237 and 477, separating the two first RNA-recognition motifs from the C-terminal domain of PABP. An additional cleavage site located at position 410 was detected for HIV-2 protease. These findings indicate that some retroviruses may share with picornaviruses and caliciviruses the capacity to proteolyse PABP.

Amino Acid Sequence↗
PubMed2006

Antagonism of PDGF-D by human antibody CR002 prevents renal scarring in experimental glomerulonephritis.

Glomerular mesangial cell proliferation and/or matrix accumulation characterizes many progressive renal diseases. PDGF-D was identified recently as a novel mediator of mesangial cell proliferation in vitro and in vivo. This study investigated the long-term consequences of PDGF-D inhibition in vivo. Rats with progressive mesangioproliferative glomerulonephritis (uninephrectomy plus anti-Thy-1.1 antibody) received the PDGF-D-neutralizing, fully human mAb CR002 on days 3, 10, and 17 after disease induction. Glomerular mesangioproliferative changes on day 10 were significantly reduced by anti-PDGF-D treatment as compared with control antibody. Eight weeks after disease induction, anti-PDGF-D therapy significantly ameliorated focal segmental glomerulosclerosis, podocyte damage (de novo desmin expression), tubulointerstitial damage, and fibrosis as well as the accumulation of renal interstitial matrix including type III collagen and fibronectin. Treatment with anti-PDGF-D also reduced the cortical infiltration of monocytes/macrophages on day 56, possibly related to lower renal cortical complement activation (C5b-9 deposition) and/or reduced epithelial-to-mesenchymal transition (preserved cortical expression of E-cadherin and reduced expression of vimentin and alpha-smooth muscle actin). In conclusion, these data provide evidence for a causal role of PDGF-D in the pathogenesis of renal scarring and point to a new therapeutic approach to progressive mesangioproliferative renal disease.

Animals↗
PubMed2006

A randomized, 1-year follow-up study of olanzapine and risperidone in the treatment of negative symptoms in outpatients with schizophrenia.

OBJECTIVE: To evaluate the efficacy of olanzapine compared with risperidone in negative symptoms, after 1 year of treatment, in schizophrenic outpatients with prominent negative symptoms. METHODS: This was a multicenter, randomized, monitored, open-label, parallel, dose-flexible, 1-year study of outpatients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) with prominent negative symptoms (Scale for the Assessment of Negative Symptoms [SANS] summary score > or =10) previously treated with conventional antipsychotics. Patients were randomly assigned to treatment with an initial dose of olanzapine 10 mg/d or more (n = 120) or risperidone 3 mg/d or more (n = 115). The primary efficacy measure was the SANS summary score. Secondary efficacy measures included Scale for the Assessment of Positive Symptoms, Clinical Global Impression of Severity Scale, Calgary Depression Scale, and Social Functioning Scale. The response rate was defined as 30% or more of improvement in the SANS summary score. RESULTS: The mean dose throughout the study was 12.2 mg/d (+/-5.8 mg/d) for olanzapine and 4.9 mg/d (+/-2.0 mg/d) for risperidone. At 1 year, olanzapine patients showed significantly higher improvement than risperidone patients on the SANS summary (P = 0.015) and on the affective flattening (P = 0.007) and avolition/apathy (P = 0.028) SANS subscales. There were also significant improvements in favor of olanzapine in the Scale for the Assessment of Positive Symptoms summary (P = 0.021), Clinical Global Impression of Severity (P = 0.008), and Social Functioning Scale total (P < 0.001) scores. The response rate was greater (P = 0.001) in the olanzapine cohort (69.2%) than in the risperidone cohort (48.7%). Olanzapine patients reported less extrapyramidal side effects but a higher incidence of clinically important body weight increase than risperidone patients. CONCLUSIONS: Long-term treatment with olanzapine was associated with significantly better improvement in negative symptoms as compared with risperidone-treated schizophrenic outpatients with prominent negative symptoms.

Adult↗
PubMed2005

Characterization of the Bex gene family in humans, mice, and rats.

To better understand the development of ventral mesencephalic dopamine neurons, we performed subtractive hybridization screens to find ventral mesencephalic genes expressed at rat embryonic day 10 when these neurons begin to differentiate. The most commonly identified genes in these screens were members of the Bex (Brain expressed X-linked) gene family, rat Bex1 (Rex3), and a novel gene, rat Bex4. After identifying these genes, we then sought to characterize the Bex gene family. Two additional novel Bex genes (human Bex5 and mouse Bex6) were discovered through genomic databases. Bex5 is present in humans and monkeys, but not rodents, while Bex6 exists in mice, but not humans. Bex4 and Bex5 are localized to the X chromosome, are expressed in brain, and are similar in sequence. Bex4 and Bex5 are 54% and 56% identical to human Bex3 (pHGR74, NADE). Mouse Bex6 is on chromosome 16 and is 67% identical to mouse Bex4. Human Bex gene expression was studied with tissue expression arrays probed with specific oligonucleotides. Human Bex1 and Bex2 have similar expression patterns in the central nervous system with high levels in pituitary, cerebellum, and temporal lobe, and Bex1 is widely expressed outside of the central nervous system with high expression in the liver. Human Bex4 is highly expressed in heart, skeletal muscle, and liver, while Bex3 and Bex5 are more widely expressed. The subcellular localization of the Bex proteins varies from nuclear (rat Bex1) to cytoplasmic (rat Bex3, human Bex5, and mouse Bex6) and to both nuclear and cytoplasmic (rat Bex2 and rat Bex4). Rat Bex3, rat Bex4, human Bex5, and mouse Bex6 are degraded by the proteasome, while rat Bex1 or Bex2 are not. Rat Bex3 protein can likely bind transition metals through a histidine-rich domain. Because this gene family was originally named Bex and because these genes are unified by sequence similarity and gene structure, we believe the Bex nomenclature should prevail over nomenclature based on function (NADE) that has not been extended to the other Bex genes. We conclude that the Bex gene family members are highly homologous but differ in their expression patterns, subcellular localization, and degradation by the proteasome.

Animals↗
PubMed2005

Recombinant semaphorin 6A-1 ectodomain inhibits in vivo growth factor and tumor cell line-induced angiogenesis.

The Semaphorins are a large family of transmembrane, GPI-anchored and secreted proteins that play an important role in neuronal and endothelial cell guidance. A human gene related to the class 6 Semaphorin family, Semaphorin 6A-1 (Sema 6A-1) was identified by homology-based genomic mining. Recent implication of Sema 3 family members in tumor angiogenesis and our expression analysis of Sema 6A-1 suggested that class 6 Semaphorin might effect tumor neovascularization. The mRNA expression of Sema 6A-1 was elevated in several renal tumor tissue samples relative to adjacent nontumor tissue samples from the same patient. Sema 6A-1 transcript was also expressed in the majority of renal clear cell carcinoma (RCC) cell lines and to a lesser extent in endothelial cells. To test the role of Sema 6A-1 in tumor angiogenesis, we engineered, expressed and purified the Sema 6A-1 soluble extracellular domain (Sema-ECD). The purified Sema-ECD was screened in a variety of endothelial cell-based assays both in vitro and in vivo. In vitro, Sema-ECD blocked VEGF-mediated endothelial cell migration. These effects were explained in part by our observation in endothelial cells that Sema-ECD inhibited VEGF-mediated Src, FAK and ERK phosphorylation. In vivo, mouse Matrigel assays demonstrated that the intraperitoneal administration of recombinant Sema-ECD inhibited both bFGF/VEGF and tumor cell line-induced neovascularization. These findings reveal a novel therapeutic utility for Sema 6A-1 (Sema-ECD) as an inhibitor of growth factor as well as tumor-induced angiogenesis.

Adenocarcinoma, Clear Cell↗
PubMed2005

Safety, effectiveness, and patterns of use of olanzapine in acute schizophrenia: a multivariate analysis of a large naturalistic study in the hospital setting.

BACKGROUND AND OBJECTIVE: This study assessed the safety and effectiveness of the atypical antipsychotic olanzapine for the treatment of inpatients with acute schizophrenia. Furthermore, we evaluated patterns of use of olanzapine and their relationship to safety and effectiveness. PATIENTS AND METHOD: This was a prospective, comparative, nonrandomized, open-label, observational study of 848 patients with schizophrenia (International Classification of Diseases, 10th edition) hospitalized due to an acute psychotic episode. Data were collected during patients' entire hospital stay. Safety of antipsychotic therapy was assessed with an extrapyramidal symptoms questionnaire (based on the Udvalg for Kliniske Undersøgelser scale) and the report of spontaneous adverse events. Clinical status was assessed with the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impressions-Severity of Illness (CGI-S). A multivariate statistical approach was employed. RESULTS: Patients treated with olanzapine in monotherapy had the lowest risk of developing extrapyramidal symptoms (11.2%), whereas patients treated with conventional antipsychotics had a higher risk (39.0%; p < 0.001). Patients treated with olanzapine in monotherapy (even patients with prominent positive symptoms) displayed a higher rate of response compared with conventional antipsychotics-treated patients (p = .007). CONCLUSIONS: Olanzapine is a safe and effective treatment for patients with acute schizophrenia in the hospital setting, even for patients with prominent positive or agitation symptoms.

Acute Disease↗
PubMed2005

Safety and effectiveness of olanzapine in monotherapy: a multivariate analysis of a naturalistic study.

BACKGROUND: This study investigated safety and effectiveness of olanzapine in monotherapy compared with conventional antipsychotics in treatment of acute inpatients with schizophrenia. METHOD: This was a prospective, comparative, nonrandomized, open-label, multisite, observational study of Spanish inpatients with an acute episode of schizophrenia. Data included safety assessments with an extrapyramidal symptoms (EPS) questionnaire and the report of spontaneous adverse events, plus clinical assessments with the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impressions-Severity of Illness (CGI-S). A multivariate methodology was used to more adequately determine which factors can influence safety and effectiveness of olanzapine in monotherapy. RESULTS: 339 patients treated with olanzapine in monotherapy (OGm) and 385 patients treated with conventional antipsychotics (CG) were included in the analysis. Treatment-emergent EPS were significantly higher in the CG (p<0.0001). Response rate was significantly higher in the OGm (p=0.005). Logistic regression analyses revealed that the only variable significantly correlated with treatment-emergent EPS and clinical response was treatment strategy, with patients in OGm having 1.5 times the probability of obtaining a clinical response and patients in CG having 5 times the risk of developing EPS. CONCLUSION: In this naturalistic study olanzapine in monotherapy was better-tolerated and at least as effective as conventional antipsychotics.

Adult↗
PubMed2005

Subcellular localization of the severe acute respiratory syndrome coronavirus nucleocapsid protein.

The coronavirus nucleocapsid (N) protein is a viral RNA-binding protein with multiple functions in terms of virus replication and modulating cell signalling pathways. N protein is composed of three distinct regions containing RNA-binding motif(s), and appropriate signals for modulating cell signalling. The subcellular localization of severe acute respiratory syndrome coronavirus (SARS-CoV) N protein was studied. In infected cells, SARS-CoV N protein localized exclusively to the cytoplasm. In contrast to the avian coronavirus N protein, overexpressed SARS-CoV N protein remained principally localized to the cytoplasm, with very few cells exhibiting nucleolar localization. Bioinformatic analysis and deletion mutagenesis coupled to confocal microscopy and live-cell imaging, revealed that SARS-CoV N protein regions I and III contained nuclear localization signals and region II contained a nucleolar retention signal. However, cytoplasmic localization was directed by region III and was the dominant localization signal in the protein.

Amino Acid Sequence↗
PubMed2005

Double-blind, placebo-controlled study of dialectical behavior therapy plus olanzapine for borderline personality disorder.

OBJECTIVE: The aim of this study was to determine the efficacy and safety of dialectical behavior therapy plus olanzapine compared with dialectical behavior therapy plus placebo in patients with borderline personality disorder. METHOD: Sixty patients with borderline personality disorder were included in a 12-week, double-blind, placebo-controlled study. All patients received dialectical behavior therapy and were randomly assigned to receive either olanzapine or placebo following a 1-month baseline period. RESULTS: Seventy percent of the patients completed the 4-month trial. Combined treatment showed an overall improvement in most symptoms studied in both groups. Olanzapine was associated with a statistically significant improvement over placebo in depression, anxiety, and impulsivity/aggressive behavior. The mean dose of olanzapine was 8.83 mg/day. CONCLUSIONS: A combined psychotherapeutic plus pharmacological approach appears to lower dropout rates and constitutes an effective treatment for borderline personality disorder.

Adult↗
PubMed2004

Acyl sulfonamide anti-proliferatives: benzene substituent structure-activity relationships for a novel class of antitumor agents.

Two closely related diaryl acylsulfonamides were recently reported as potent antitumor agents against a broad spectrum of human tumor xenografts (colon, lung, breast, ovary, and prostate) in nude mice. Especially intriguing was their activity against colorectal cancer xenografts. In this paper, rapid parallel synthesis along with traditional medicinal chemistry techniques were used to quickly delineate the structure-activity relationships of the substitution patterns in both phenyl rings of the acylsufonamide anti-proliferative scaffold. Although the molecular target of the compounds remains unclear, we determined that the vascular endothelial growth factor-dependent human umbilical vein endothelial cells assay in combination with a soft agar disk diffusion assay allowed for optimization of potency in the series. The pharmacokinetic properties and in vivo activity in an HCT116 xenograft model are reported for representative compounds.

Animals↗