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1.
Mol Pharm ; 20(9): 4559-4573, 2023 09 04.
Artículo en Inglés | MEDLINE | ID: mdl-37555521

RESUMEN

The enzyme PACE4 has been validated as a promising therapeutic target to expand the range of prostate cancer (PCa) treatments. In recent years, we have developed a potent peptidomimetic inhibitor, namely, compound C23 (Ac-(DLeu)LLLRVK-4-amidinobenzylamide). Like many peptides, C23 suffers from an unfavorable drug-like profile which, despite our efforts, has not yet benefited from the usual SAR studies. Hence, we turned our attention toward a novel formulation strategy, i.e., the use of cyclodextrins (CDs). CDs can benefit compounds through the formation of "host-guest" complexes, shielding the guest from degradation and enhancing biological survival. In this study, a series of ßCD-C23 complexes have been generated and their properties evaluated, including potency toward the enzyme in vitro, a cell-based proliferation assay, and stability in plasma. As a result, a new ßCD-formulated lead compound has been identified, which, in addition to being more soluble and more potent, also showed an improved stability profile.


Asunto(s)
Ciclodextrinas , beta-Ciclodextrinas , Masculino , Humanos , Péptidos/farmacología , beta-Ciclodextrinas/farmacología , Ciclodextrinas/farmacología , Ciclodextrinas/química
2.
Int J Psychol ; 58(2): 103-115, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36606293

RESUMEN

Ecological degradation threatens human survival, increasing the need to understand factors related to pro-environmental attitudes and worldviews. In a globalising world, new paradigms arise as central to social sciences, including the New Ecological Paradigm (NEP) and the multicultural identities of individuals raised between the cultures, third culture kids (TCKs). NEP is an ecocentric perspective that stresses the interdependence between nature and humans, opposite to anthropocentrism. TCKs' exposure to cultural diversity during developmental years might support global issues engagement and ecocentric worldviews. The present study focused on non-Western TCKs (N = 399; mean age 21 years), aiming to explore whether multicultural identity configurations (integration, categorisation, compartmentalisation), values dimensions (self-transcendence, openness and conservation) and global mindset predicted ecocentric and anthropocentric worldviews. The results demonstrated that TCKs were ecocentrically inclined. The path model revealed that ecocentrism could be directly positively predicted by integrated multicultural identity, self-transcendence and a global mindset. Anthropocentrism was predicted by multicultural identity categorisation and conservation values. Also, values of self-transcendence and openness buffered the impact of compartmentalisation and categorisation on ecocentrism and anthropocentrism. This study set innovative directions in multiculturism and environmentalism discourse through understanding a multicultural identity's relationships with pro-environmental attitudes.


Asunto(s)
Actitud , Diversidad Cultural , Humanos , Adulto Joven , Adulto , Encuestas y Cuestionarios
3.
Int J Mol Sci ; 23(7)2022 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-35408793

RESUMEN

The spurious acquisition and optimization of a furin cleavage site in the SARS-CoV-2 spike protein is associated with increased viral transmission and disease, and has generated intense interest in the development and application of therapeutic furin inhibitors to thwart the COVID-19 pandemic. This review summarizes the seminal studies that informed current efforts to inhibit furin. These include the convergent efforts of endocrinologists, virologists, and yeast geneticists that, together, culminated in the discovery of furin. We describe the pioneering biochemical studies which led to the first furin inhibitors that were able to block the disease pathways which are broadly critical for pathogen virulence, tumor invasiveness, and atherosclerosis. We then summarize how these studies subsequently informed current strategies leading to the development of small-molecule furin inhibitors as potential therapies to combat SARS-CoV-2 and other diseases that rely on furin for their pathogenicity and progression.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , Furina , Furina/metabolismo , Humanos , Pandemias , Feromonas , SARS-CoV-2 , Saccharomyces cerevisiae/metabolismo , Glicoproteína de la Espiga del Coronavirus
4.
Pers Individ Dif ; 171: 110540, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33223590

RESUMEN

Reports to date have shown that the SARS-CoV-2 pandemic may have a negative impact on individuals' mental health. The purpose of this study was to assess the relation between ego-resiliency, social support, coronavirus anxiety and trauma effects. The study employed the Polish adaptation of the Coronavirus Anxiety Scale (CAS). It involved 515 individuals aged 18-78. The Polish version of CAS revealed satisfactory internal consistency (α = 0.86). Structural equation modeling indicated that ego-resiliency (the Ego-Resiliency Scale) and social support (the Multidimensional Scale of Perceived Social Support) were correlated and negatively predicted the severity of the novel coronavirus anxiety (CAS). Moreover, the level of anxiety showed positive correlation with negative trauma effects (the short form of the Changes in Outlook Questionnaire). The scores indicate the need for practitioners to focus on interventions which elevate ego-resiliency and perceived social support to improve mental health during the SARS-CoV-2 pandemic.

5.
Molecules ; 25(15)2020 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-32722067

RESUMEN

2,3,4-Tri-O-benzyl-D-xylopyranose was used as a starting material in the preparation of the corresponding triene, which underwent smooth cyclization to a polyhydroxylated hydrindane, as a single diastereoisomer. The analogous triene prepared from D-glucose did not undergo any cyclization even under high pressure.


Asunto(s)
Carba-azúcares/síntesis química , Xilosa/análogos & derivados , Mimetismo Biológico , Carba-azúcares/química , Ciclización , Estructura Molecular , Estereoisomerismo , Xilosa/química
6.
Medicina (Kaunas) ; 55(4)2019 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-31003557

RESUMEN

BACKGROUND AND OBJECTIVES: Laparoscopic splenectomy (LS) has become the gold standard for patients with immune thrombocytopenic purpura (ITP). The total remission rate after splenectomy is 70%-90%, of which 66% is long-term. Despite this high response rate, some patients do not benefit from surgery. It is therefore important to try to identify risk factors for an unsatisfactory clinical response. The aim of this study was to assess long-term outcomes of LS for ITP and identify factors associated with increased disease remission rates. MATERIALS AND METHODS: We retrospectively studied consecutive patients with ITP undergoing LS in a tertiary referral surgical center prospectively recorded in a database. Inclusion criteria were: Elective, laparoscopic splenectomy for diagnosed ITP, and complete follow-up. The cohort was divided into two groups-Group 1 (G1) patients with ITP remission after splenectomy and Group 2 (G2) patients without remission. There were 113 G1 patients and 52 G2 patients. Median follow-up was 9.5 (IQR: 5-15) years. RESULTS: In univariate analysis, patient's age, body mass index (BMI), preoperative platelet count, the need for platelet transfusions, and presence of hemorrhagic diathesis were shown to be statistically significant factors. Next, we built a multivariate logistic regression model using factors significant in univariate analysis. Age <41 years (odds ratio (OR) 4.49; 95% CI: 1.66-12.09), BMI <24.3 kg/m2 (OR: 4.67; 95% CI: 1.44-15.16), and preoperative platelet count ≥97 × 103/mm3 (OR: 3.50; 95% CI: 1.30-9.47) were shown to be independent prognostic factors for ITP remission after LS. CONCLUSION: The independent prognostic factors for ITP remission after LS revealed in our study are: age <41 years, BMI <24.3 kg/m2, and preoperative platelet count ≥97 × 103/mm3. Duration of the ITP and the time of treatment are not related to remission after LS.


Asunto(s)
Laparoscopía/métodos , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/cirugía , Esplenectomía/métodos , Adulto , Factores de Edad , Índice de Masa Corporal , Femenino , Estudios de Seguimiento , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Recuento de Plaquetas , Pronóstico , Estudios Retrospectivos , Estadísticas no Paramétricas , Centros de Atención Terciaria , Resultado del Tratamiento , Adulto Joven
7.
Genesis ; 56(2)2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29282851

RESUMEN

ESET protein (also known as SETDB1) catalyzes methylation of histone H3 at lysine 9 (H3-K9). In addition to the full-length transcript, mouse ESET gene also gives rise to alternative spicing variants encoding truncated proteins capable of retaining interaction with other epigenetic enzymes. To completely eliminate full-length ESET and its splicing variants, we have generated a conditional ESET allele with exon 4 flanked by two loxP sites for Cre-mediated DNA deletion and downstream frame-shift mutation of the entire coding region. Mating with Prx1-Cre mice and analysis of the resultant embryos revealed that mesenchyme-specific knockout of exon 4 completely eliminates full-length ESET and its truncated protein products, leading to profound defects in both the flat bones and long bones, ectopic hypertrophy of growth plate chondrocytes and downregulation of Indian hedgehog protein. In addition, exon 4 deletion results in reduced thickness of articular cartilage in E17.5 embryos, whereas deletion of exons 15-16 fails to do so. These findings offer us a useful tool to further study epigenetic regulation in a truly ESET-null background, and demonstrate that ESET plays a critical role in the control of chondrocyte hypertrophy and skeletal development.


Asunto(s)
Eliminación de Gen , Expresión Génica , N-Metiltransferasa de Histona-Lisina/genética , Mesodermo/metabolismo , Ratones Noqueados , Animales , Orden Génico , Marcación de Gen , Sitios Genéticos , Genotipo , Edad Gestacional , N-Metiltransferasa de Histona-Lisina/metabolismo , Inmunohistoquímica , Mesodermo/embriología , Ratones , Especificidad de Órganos , Fenotipo
8.
Beilstein J Org Chem ; 13: 2146-2152, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29114320

RESUMEN

The C12-aminoalditol H2NCH2-(CHOBn)10-CH2OH was prepared from two simple monosaccharide building blocks. The synthesis was realized by a regioselective introduction of the azide group and subsequent protection-deprotection transformations. The chemical reactivity of the aminoalditol was tested in the reductive amination reaction with a selectively protected sucrose monoaldehyde.

9.
Dev Biol ; 380(1): 99-110, 2013 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-23652029

RESUMEN

The ESET (also called SETDB1) protein contains an N-terminal tudor domain that mediates protein-protein interactions and a C-terminal SET domain that catalyzes methylation of histone H3 at lysine 9. We report here that ESET protein is transiently upregulated in prehypertrophic chondrocytes in newborn mice. To investigate the in vivo effects of ESET on chondrocyte differentiation, we generated conditional knockout mice to specifically eliminate the catalytic SET domain of ESET protein only in mesenchymal cells. Such deletion of the ESET gene caused acceleration of chondrocyte hypertrophy in both embryos and young animals, depleting chondrocytes that are otherwise available to form epiphyseal plates for endochondral bone growth. ESET-deficient mice are thus characterized by defective long bone growth and trabecular bone formation. To understand the underlying mechanism for ESET regulation of chondrocytes, we carried out co-expression experiments and found that ESET associates with histone deacetylase 4 to bind and inhibit the activity of Runx2, a hypertrophy-promoting transcription factor. Repression of Runx2-mediated gene transactivation by ESET is dependent on its H3-K9 methyltransferase activity as well as its associated histone deacetylase activity. In addition, knockout of ESET is associated with repression of Indian hedgehog gene in pre- and early hypertrophic chondrocytes. Together, these results provide clear evidence that ESET controls hypertrophic differentiation of growth plate chondrocytes and endochondral ossification during embryogenesis and postnatal development.


Asunto(s)
Condrocitos/citología , Regulación del Desarrollo de la Expresión Génica , Placa de Crecimiento/metabolismo , N-Metiltransferasa de Histona-Lisina/fisiología , Alelos , Animales , Huesos/embriología , Huesos/metabolismo , Cartílago/embriología , Diferenciación Celular , Epigénesis Genética , Proteínas Hedgehog/metabolismo , Histona Desacetilasas/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Mesodermo/citología , Ratones , Ratones Noqueados , Estructura Terciaria de Proteína
10.
J Biol Chem ; 288(45): 32119-32125, 2013 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-24056368

RESUMEN

The exact molecular mechanisms governing articular chondrocytes remain unknown in skeletal biology. In this study, we have found that ESET (an ERG-associated protein with a SET domain, also called SETDB1) histone methyltransferase is expressed in articular cartilage. To test whether ESET regulates articular chondrocytes, we carried out mesenchyme-specific deletion of the ESET gene in mice. ESET knock-out did not affect generation of articular chondrocytes during embryonic development. Two weeks after birth, there was minimal qualitative difference at the knee joints between wild-type and ESET knock-out animals. At 1 month, ectopic hypertrophy, proliferation, and apoptosis of articular chondrocytes were seen in the articular cartilage of ESET-null animals. At 3 months, additional signs of terminal differentiation such as increased alkaline phosphatase activity and an elevated level of matrix metalloproteinase (MMP)-13 were found in ESET-null cartilage. Staining for type II collagen and proteoglycan revealed that cartilage degeneration became progressively worse from 2 weeks to 12 months at the knee joints of ESET knock-out mutants. Analysis of over 14 pairs of age- and sex-matched wild-type and knock-out mice indicated that the articular chondrocyte phenotype in ESET-null mutants is 100% penetrant. Our results demonstrate that expression of ESET plays an essential role in the maintenance of articular cartilage by preventing articular chondrocytes from terminal differentiation and may have implications in joint diseases such as osteoarthritis.


Asunto(s)
Cartílago Articular/enzimología , Diferenciación Celular , Condrocitos/enzimología , N-Metiltransferasa de Histona-Lisina/metabolismo , Articulación de la Rodilla/enzimología , Osteoartritis de la Rodilla/enzimología , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Animales , Cartílago Articular/patología , Condrocitos/patología , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Hipertrofia/enzimología , Hipertrofia/genética , Hipertrofia/patología , Articulación de la Rodilla/patología , Metaloproteinasa 13 de la Matriz/genética , Metaloproteinasa 13 de la Matriz/metabolismo , Ratones , Ratones Noqueados , Especificidad de Órganos/genética , Osteoartritis de la Rodilla/genética , Osteoartritis de la Rodilla/patología
11.
Pol Przegl Chir ; 96(3): 1-8, 2024 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-38940246

RESUMEN

<b>Introduction:</b> Hemorrhoidal disease is the most common disease treated in proctology ambulatories. Conservative treatment is the basic form of treatment for this disease. One of the elements of treatment may be preparations with myoand phlebotropic effects.<b>Aim:</b> To assess the effect of a multi-ingredient myophlebotropic dietary supplement used as an adjunct on the rate and effectiveness of symptom relief in patients with stage II and III hemorrhoidal disease.<b>Material and method:</b> Patients with stage II and III hemorrhoidal disease with clinical symptoms such as pain, burning, itching and bleeding were qualified for the study. The patients were divided into two groups. The control group (Group I) of 29 patients receiving standard local treatment plus placebo and the study group (Group II) of 32 patients receiving the same local treatment and a six-component myophlebotropic product. Symptoms were analyzed at the time of inclusion in the study (day 0), after 4 and 10 days of therapy. The severity of hemorrhoidal disease and the feeling of relief were assessed on the day of inclusion (W0) and after 30 days of therapy.<b>Results:</b> There were no statistical differences between the groups in terms of disease advancement, age, gender, and duration of symptoms. Compared to the moment of inclusion in the study (W0), after 4 days (W1), after 10 days (W2) of taking the multi- -component product, there was a statistically significant improvement in the VAS scale: spontaneous pain and pain during defecation. In the qualitative assessment (yes/no), there were statistically significantly fewer cases of burning in the anus and itching. The treatment did not affect the rate of spontaneous bleeding, which was low at the beginning of the study, but significantly reduced the rate of bleeding during defecation. After 30 days of observation, it was found that the improvement in the severity of hemorrhoidal disease symptoms was significantly higher in the group using the tested preparation. Relief after a month of the study (one-question method) was noted in the group of patients receiving the tested product.<b>Conclusions:</b> The tested six-component myophlebotropic product proved to be effective in reducing the severity of symptoms such as spontaneous pain, pain during defecation, burning/burning in the anus and bleeding during defecation. Statistical significance was demonstrated in the symptom's relief and reduction in the severity of hemorrhoidal disease.


Asunto(s)
Hemorroides , Humanos , Hemorroides/terapia , Femenino , Masculino , Persona de Mediana Edad , Adulto , Resultado del Tratamiento , Suplementos Dietéticos , Anciano
12.
Perspect Psychol Sci ; : 17456916231208367, 2024 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-38350096

RESUMEN

Psychological science tends to treat subjective well-being and happiness synonymously. We start from the assumption that subjective well-being is more than being happy to ask the fundamental question: What is the ideal level of happiness? From a cross-cultural perspective, we propose that the idealization of attaining maximum levels of happiness may be especially characteristic of Western, educated, industrial, rich, and democratic (WEIRD) societies but less so for others. Searching for an explanation for why "happiness maximization" might have emerged in these societies, we turn to studies linking cultures to their eco-environmental habitat. We discuss the premise that WEIRD cultures emerged in an exceptionally benign ecological habitat (i.e., faced relatively light existential pressures compared with other regions). We review the influence of the Gulf Stream on the Northwestern European climate as a source of these comparatively benign geographical conditions. We propose that the ecological conditions in which WEIRD societies emerged afforded them a basis to endorse happiness as a value and to idealize attaining its maximum level. To provide a nomological network for happiness maximization, we also studied some of its potential side effects, namely alcohol and drug consumption and abuse and the prevalence of mania. To evaluate our hypothesis, we reanalyze data from two large-scale studies on ideal levels of personal life satisfaction-the most common operationalization of happiness in psychology-involving respondents from 61 countries. We conclude that societies whose members seek to maximize happiness tend to be characterized as WEIRD, and generalizing this across societies can prove problematic if adopted at the ideological and policy level.

13.
Biochim Biophys Acta ; 1818(12): 2982-93, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22824299

RESUMEN

In this work, the behavior of the neurohypophyseal hormones and their selected analogs was studied in the presence of membrane models in an attempt to correlate their activities with a distinct behavior at a level of peptide-lipid interactions. The influence of the peptides studied on the lipid acyl chain order was determined using FTIR spectroscopy. Conformational changes in the peptides upon binding to liposomes were examined using CD spectra. Attempts were also made to determine the binding parameters of the peptides to lipids using isothermal titration calorimetry (ITC). The results show unambiguously that the neurohyphophyseal hormone-like peptides interact with lipids, being a model of a eukaryotic cell membrane. Moreover, hydrophobic interactions between the peptides and liposomes are likely to determine the overall conformation of the peptide, especially below the temperature of the main phase transition (T(m)). Thus, the bulky and hydrophobic nature of the residues incorporated into the N-terminal part of neurohyphophyseal hormones is an important factor for both restriction of peptide mobility and the interaction of the analog with biomembrane. In turn, above T(m), the electrostatic interactions become also relevant for the conformation of the acyclic tail of the AVP-like peptides.


Asunto(s)
Membrana Celular/química , Membrana Celular/metabolismo , Membrana Dobles de Lípidos/metabolismo , Hormonas Peptídicas/metabolismo , Hormonas Neurohipofisarias/metabolismo , Rastreo Diferencial de Calorimetría , Membrana Celular/ultraestructura , Estructuras de la Membrana Celular , Interacciones Hidrofóbicas e Hidrofílicas , Membrana Dobles de Lípidos/química , Liposomas/química , Liposomas/metabolismo , Hormonas Peptídicas/química , Hormonas Neurohipofisarias/química , Unión Proteica , Conformación Proteica , Estructura Secundaria de Proteína
14.
Neurochem Res ; 38(7): 1490-5, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23619559

RESUMEN

Oxidative injury in schizophrenia can be caused by the disease itself and probably by antipsychotics treatment. The aim of the study was to establish whether there is a difference between ziprasidone, clozapine and haloperidol effect on lipid peroxidation in human plasma, measured by the level of thiobarbituric acid reactive substances (TBARS). The samples of plasma from healthy subjects were incubated with the drugs (1 and 24 h) and compared with control samples. The levels of TBARS were measured spectrophotometrically, according to the Rice-Evans method. The multifactorial variance analysis ANOVA II test showed that the differences in TBARS levels significantly depended on the studied drugs (ziprasidone 40 ng/ml, haloperidol 4 ng/ml and clozapine 350 ng/ml) (F = 3.248 p = 0.047) and (ziprasidone 139 ng/ml, haloperidol 20 ng/ml and clozapine 420 ng/ml) (F = 2.248, p = 2.9 × 10(-5)). Statistically increased levels of TBARS after 24 h incubation of plasma with ziprasidone 139 ng/ml and haloperidol 20 ng/ml (p < 0.001, p < 0.05 respectively) in comparison with control samples were observed. Clozapine did not significantly (p > 0.05) increase TBARS level in plasma in comparison with control samples. The results obtained in the study showed that ziprasidone and haloperidol contrary to clozapine induced a significant increase in plasma lipid peroxidation.


Asunto(s)
Antipsicóticos/farmacología , Clozapina/farmacología , Haloperidol/farmacología , Peroxidación de Lípido/efectos de los fármacos , Piperazinas/farmacología , Tiazoles/farmacología , Adulto , Femenino , Humanos , Técnicas In Vitro , Masculino , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo
15.
Artículo en Inglés | MEDLINE | ID: mdl-36900890

RESUMEN

Globalization has resulted in an exponential increase in the number of Third Culture Kids (TCKs), defined as being raised in a culture other than that of their parents (or the passport country) and meaningfully interacting with different cultures. Inconsistencies regarding the effect of multicultural and transient experiences on well-being exist in the psychological literature. We aimed to reveal associations between multicultural identity configurations (integration, categorization, compartmentalization) and well-being with the mediating role of self-concept consistency and self-efficacy. Participants (n = 399, M = 21.2 years) were students at an international university in the United Arab Emirates. We used the Multicultural Identity Integration Scale, the Berne Questionnaire of Subjective Well-Being, the General Self-Efficacy Scale, and the Self-Consistency Subscale from the Self-Construal Scale. The findings suggest that not merely exposure to diversity but also internal integration versus identity compartmentalization moderate the well-being of TCKs. We explained such mechanisms via partial mediation of self-consistency and self-efficacy. Our study contributed to a better understanding of the TCKs' identity paradigm and pointed to multicultural identity integration as vital to TCKs' well-being via its effect on self-consistency and self-efficacy. Conversely, identity compartmentalization decreased well-being via a reduction in the sense of self-consistency.


Asunto(s)
Autoimagen , Autoeficacia , Humanos , Diversidad Cultural , Encuestas y Cuestionarios , Estudiantes
16.
PLoS One ; 18(7): e0288622, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37463144

RESUMEN

Phosphatase and tensin homolog (PTEN) mutation is common in prostate cancer during progression to metastatic and castration resistant forms. We previously reported that loss of PTEN function in prostate cancer leads to increased expression and secretion of the Prorenin Receptor (PRR) and its soluble processed form, the soluble Prorenin Receptor (sPRR). PRR is an essential factor required for proper assembly and activity of the vacuolar-ATPase (V-ATPase). The V-ATPase is a rotary proton pump required for the acidification of intracellular vesicles including endosomes and lysosomes. Acidic vesicles are involved in a wide range of cancer related pathways such as receptor mediated endocytosis, autophagy, and cell signalling. Full-length PRR is cleaved at a conserved consensus motif (R-X-X-R↓) by a member of the proprotein convertase family to generate sPRR, and a smaller C-terminal fragment, designated M8.9. It is unclear which convertase processes PRR in prostate cancer cells and how processing affects V-ATPase activity. In the current study we show that PRR is predominantly cleaved by PACE4, a proprotein convertase that has been previously implicated in prostate cancer. We further demonstrate that PTEN controls PRR processing in mouse tissue and controls PACE4 expression in prostate cancer cells. Furthermore, we demonstrate that PACE4 cleavage of PRR is needed for efficient V-ATPase activity and prostate cancer cell growth. Overall, our data highlight the importance of PACE4-mediated PRR processing in normal physiology and prostate cancer tumorigenesis.


Asunto(s)
Neoplasias de la Próstata , ATPasas de Translocación de Protón Vacuolares , Animales , Humanos , Masculino , Ratones , Proproteína Convertasas/metabolismo , Receptor de Prorenina , Neoplasias de la Próstata/genética , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , ATPasas de Translocación de Protón Vacuolares/genética , ATPasas de Translocación de Protón Vacuolares/metabolismo
17.
Amino Acids ; 43(2): 617-27, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22038179

RESUMEN

In this study we present the synthesis and some pharmacological properties of fourteen new analogues of neurohypophyseal hormones conformationally restricted in the N-terminal part of the molecule. All new peptides were substituted at position 2 with cis-1-amino-4-phenylcyclohexane-1-carboxylic acid (cis-Apc). Moreover, one of the new analogues: [cis-Apc(2), Val(4)]AVP was also prepared in N-acylated forms with various bulky acyl groups. All the peptides were tested for pressor, antidiuretic, and in vitro uterotonic activities. We also determined the binding affinity of the selected compounds to human OT receptor. Our results showed that introduction of cis -Apc(2) in position 2 of either AVP or OT resulted in analogues with high antioxytocin potency. Two of the new compounds, [Mpa(1),cis-Apc(2)]AVP and [Mpa(1),cis-Apc(2),Val(4)]AVP, were exceptionally potent antiuterotonic agents (pA(2) = 8.46 and 8.40, respectively) and exhibited higher affinities for the human OT receptor than Atosiban (K (i) values 5.4 and 9.1 nM). Moreover, we have demonstrated for the first time that N -terminal acylation of AVP analogue can improve its selectivity. Using this approach, we obtained compound Aba[cis-Apc(2),Val(4)]AVP (XI) which turned out to be a moderately potent and exceptionally selective OT antagonist (pA(2) = 7.26).


Asunto(s)
Arginina Vasopresina/análogos & derivados , Arginina Vasopresina/farmacología , Oxitocina/análogos & derivados , Oxitocina/farmacología , Receptores de Oxitocina/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Fármacos Antidiuréticos , Arginina Vasopresina/síntesis química , Ácidos Carboxílicos/química , Ciclohexanos/química , Diseño de Fármacos , Femenino , Células HEK293 , Humanos , Técnicas In Vitro , Masculino , Oxitocina/síntesis química , Unión Proteica , Estructura Secundaria de Proteína , Ratas , Ratas Wistar , Receptores de Oxitocina/metabolismo , Vasoconstrictores
18.
Carbohydr Res ; 518: 108584, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35643050

RESUMEN

d-Glucose was converted into the orthogonally protected open-chain derivative having different blocks at both terminal positions: C1 and C6. Selective deprotection of the C1-position opened a route to intermediate with the D-gluco-configuration, while deprotection at the C6-position gave the L-gulo isomer. In both derivatives, the oxime functionality was installed at the proper terminal position, which produced the corresponding precursors of a family of 7-membered ring iminosugars. One of these oximes was converted into the direct precursor: 6,1-bromonitrile.


Asunto(s)
Glucosa , Oximas , Isomerismo
19.
Sci Rep ; 12(1): 17489, 2022 10 19.
Artículo en Inglés | MEDLINE | ID: mdl-36261691

RESUMEN

Prostate cancer (PCa) is a complex disease progressing from in situ to invasive or metastatic tumors while also being capable of modulating its androgen dependence. Understanding how novel therapies are working across the different stages of the disease is critical for their proper positioning in the spectrum of PCa treatments. The targeting of proprotein convertase PACE4 (Paired basic Amino Acid-Cleaving Enzyme 4) has been proposed as a novel approach to treat PCa. Animal studies performed on LNCaP xenografts, an androgen-dependent model, already yielded positive results. In this study, we tested PACE4 inhibition on JHU-LNCaP-SM, a newly described androgen-independent model, in cell-based and xenograft assays. Like LNCaP, JHU-LNCaP-SM cells express PACE4 and its oncogenic isoform PACE4-altCT. Using isoform-specific siRNAs, downregulation of PACE4-altCT resulted in JHU-LNCaP-SM growth inhibition. Furthermore, JHU-LNCaP-SM responded to the PACE4 pharmacological inhibitor known as C23 in cell-based assays as well as in athymic nude mice xenografts. These data support the efficacy of PACE4 inhibitors against androgen independent PCa thereby demonstrating that PACE4 is a key target in PCa. The JHU-LNCaP-SM cell line represents a model featuring important aspects of androgen-independent PCa, but it also represents a very convenient model as opposed to LNCaP cells for in vivo studies, as it allows rapid screening due to its high implantation rate and growth characteristics as xenografts.


Asunto(s)
Andrógenos , Neoplasias de la Próstata , Ratones , Animales , Masculino , Humanos , Andrógenos/metabolismo , Ratones Desnudos , Línea Celular Tumoral , Neoplasias de la Próstata/patología , Proproteína Convertasas/metabolismo , Isoformas de Proteínas , Aminoácidos Básicos , Proliferación Celular , Receptores Androgénicos
20.
Artículo en Inglés | MEDLINE | ID: mdl-36293819

RESUMEN

According to past research, religious attitudes can strongly influence individuals' beliefs and behaviors. The purpose of this study was to assess the relationships between spirituality (the Scale of Spirituality; dimensions include religious spirituality, expanding consciousness, searching for meaning, sensitivity to art, doing good, and sensitivity to inner beauty), religious fundamentalism (the Religious Fundamentalism Scale), support for right-wing authoritarianism (the Right-Wing Authoritarianism Scale), climate concerns (the Environmental Concern Scale), and pro-environmental behavior (the Pro-Environmental Behavior Scale). The cross-sectional study involved 512 Poles aged 18-63 (M = 34.63, SD = 5.96; Mdn = 33), including 51% females. Multiple regression analysis revealed that two dimensions of spirituality (sensitivity to art and doing good) and religious fundamentalism are significant and opposite predictors of climate concern and pro-environmental behavior. Spirituality appeared to foster increased climate concern and caring behavior, while religious fundamentalism negatively predicted the same variables. Mediation analysis revealed that the relationship between religion and environmentalism could be explained in part by differences in support for right-wing authoritarianism (authoritarianism itself was negatively related to environmental outcomes). In addition, analysis of variance revealed that believers (70% of participants in the study were Catholic) showed significantly lower scores regarding climate concerns and pro-environmental behavior than non-believers, yet the inclusion of support for right-wing authoritarianism as a covariate in the equation reduced intergroup differences to statistical insignificance. The data obtained suggest that religious attitudes and socio-political views may play important roles in solving environmental problems.


Asunto(s)
Autoritarismo , Espiritualidad , Femenino , Humanos , Masculino , Estudios Transversales , Ambientalismo , Religión
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