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1.
Cell ; 184(8): 2167-2182.e22, 2021 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-33811809

RESUMEN

Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1ß, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.


Asunto(s)
COVID-19/complicaciones , Cardiotónicos/uso terapéutico , Proteínas de Ciclo Celular/antagonistas & inhibidores , Cardiopatías/tratamiento farmacológico , Quinazolinonas/uso terapéutico , Factores de Transcripción/antagonistas & inhibidores , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Proteínas de Ciclo Celular/metabolismo , Línea Celular , Citocinas/metabolismo , Femenino , Cardiopatías/etiología , Células Madre Embrionarias Humanas , Humanos , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción/metabolismo , Tratamiento Farmacológico de COVID-19
2.
Med Res Rev ; 41(1): 223-245, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32926459

RESUMEN

Clinical development of bromodomain and extra-terminal (BET) protein inhibitors differs from the traditional course of drug development. These drugs are simultaneously being evaluated for treating a wide spectrum of human diseases due to their novel mechanism of action. BET proteins are epigenetic "readers," which play a primary role in transcription. Here, we briefly describe the BET family of proteins, of which BRD4 has been studied most extensively. We discuss BRD4 activity at latent enhancers as an example of BET protein function. We examine BRD4 redistribution and enhancer reprogramming in embryonic development, cancer, cardiovascular, autoimmune, and metabolic diseases, presenting hallmark studies that highlight BET proteins as attractive targets for therapeutic intervention. We review the currently available approaches to targeting BET proteins, methods of selectively targeting individual bromodomains, and review studies that compare the effects of selective BET inhibition to those of pan-BET inhibition. Lastly, we examine the current clinical landscape of BET inhibitor development.


Asunto(s)
Neoplasias , Proteínas Nucleares , Proteínas de Ciclo Celular , Humanos , Neoplasias/tratamiento farmacológico , Dominios Proteicos , Factores de Transcripción
3.
Cardiovasc Diabetol ; 20(1): 125, 2021 06 22.
Artículo en Inglés | MEDLINE | ID: mdl-34158057

RESUMEN

BACKGROUND: In stable patients with type 2 diabetes (T2D), insulin treatment is associated with elevated risk for major adverse cardiovascular events (MACE). Patients with acute coronary syndrome (ACS) and T2D are at particularly high risk for recurrent MACE despite evidence-based therapies. It is uncertain to what extent this risk is further magnified in patients with recent ACS who are treated with insulin. We examined the relationship of insulin use to risk of MACE and modification of that risk by apabetalone, a bromodomain and extra-terminal (BET) protein inhibitor. METHODS: The analysis utilized data from the BETonMACE phase 3 trial that compared apabetalone to placebo in patients with T2D, low HDL cholesterol, andACS. The primary MACE outcome (cardiovascular death, myocardial infarction, or stroke) was examined according to insulin treatment and assigned study treatment. Multivariable Cox regression was used to determine whether insulin use was independently associated with the risk of MACE. RESULTS: Among 2418 patients followed for median 26.5 months, 829 (34.2%) were treated with insulin. Despite high utilization of evidence-based treatments including coronary revascularization, intensive statin treatment, and dual antiplatelet therapy, the 3-year incidence of MACE in the placebo group was elevated among insulin-treated patients (20.4%) compared to those not-treated with insulin (12.8%, P = 0.0001). Insulin treatment remained strongly associated with the risk of MACE (HR 2.10, 95% CI 1.42-3.10, P = 0.0002) after adjustment for demographic, clinical, and treatment variables. Apabetalone had a consistent, favorable effect on MACE in insulin-treated and not insulin-treated patients. CONCLUSION: Insulin-treated patients with T2D, low HDL cholesterol, and ACS are at high risk for recurrent MACE despite the use of evidence-based, contemporary therapies. A strong association of insulin treatment with risk of MACE persists after adjustment for other characteristics associated with MACE. There is unmet need for additional treatments to mitigate this risk. Trial registration ClinicalTrials.gov NCT02586155, registered October 26, 2015.


Asunto(s)
Síndrome Coronario Agudo/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Quinazolinonas/uso terapéutico , Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/mortalidad , Anciano , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidad , Femenino , Humanos , Hipoglucemiantes/efectos adversos , Insulina/efectos adversos , Masculino , Persona de Mediana Edad , Quinazolinonas/efectos adversos , Recurrencia , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento
4.
Cardiovasc Diabetol ; 20(1): 13, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33413345

RESUMEN

BACKGROUND: Patients with diabetes and acute coronary syndrome (ACS) are at high risk for subsequent heart failure. Apabetalone is a selective inhibitor of bromodomain and extra-terminal (BET) proteins, epigenetic regulators of gene expression. Preclinical data suggest that apabetalone exerts favorable effects on pathways related to myocardial structure and function and therefore could impact subsequent heart failure events. The effect of apabetalone on heart failure events after an ACS is not currently known. METHODS: The phase 3 BETonMACE trial was a double-blind, randomized comparison of apabetalone versus placebo on the incidence of major adverse cardiovascular events (MACE) in 2425 patients with a recent ACS and diabetes. This prespecified secondary analysis investigated the impact of apabetalone on hospitalization for congestive heart failure, not previously studied. RESULTS: Patients (age 62 years, 74.4% males, 90% high-intensity statin use, LDL-C 70.3 mg/dL, HDL-C 33.3 mg/dL and HbA1c 7.3%) were followed for an average 26 months. Apabetalone treated patients experienced the nominal finding of a lower rate of first hospitalization for heart failure (2.4% vs. 4.0%, HR 0.59 [95%CI 0.38-0.94], P = 0.03), total number of hospitalizations for heart failure (35 vs. 70, HR 0.47 [95%CI 0.27-0.83], P = 0.01) and the combination of cardiovascular death or hospitalization for heart failure (5.7% vs. 7.8%, HR 0.72 [95%CI 0.53-0.98], P = 0.04). CONCLUSION: Apabetalone treatment was associated with fewer hospitalizations for heart failure in patients with type 2 diabetes and recent ACS. Future studies are warranted to define the potential for BET inhibition with apabetalone to prevent heart failure in patients with diabetes and ACS.


Asunto(s)
Síndrome Coronario Agudo/tratamiento farmacológico , Fármacos Cardiovasculares/uso terapéutico , Diabetes Mellitus Tipo 2/epidemiología , Insuficiencia Cardíaca/prevención & control , Admisión del Paciente , Quinazolinonas/uso terapéutico , Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/epidemiología , Síndrome Coronario Agudo/fisiopatología , Anciano , Fármacos Cardiovasculares/efectos adversos , Diabetes Mellitus Tipo 2/diagnóstico , Método Doble Ciego , Femenino , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Readmisión del Paciente , Quinazolinonas/efectos adversos , Factores de Tiempo , Resultado del Tratamiento
5.
Health Commun ; 36(6): 703-713, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-31931623

RESUMEN

This experiment explores the effects of agency assignment and self-construal on responses to tornado preparedness messages. Participants (N = 276) were randomly assigned to one of four conditions crossing agency assignment and self-construal. Results found threat agency associated with greater perceived susceptibility and tornado threat, whereas self-construal was primarily associated with perceived threat severity, such that those primed with interdependent self-construal showed marginally increased perceptions of tornado severity relative to those primed with independent self-construal. Self-construal did not appear to moderate the effects of agency assignment on attitudes or behavioral intentions. Results are discussed in light of potential psychological reactance, suggesting human agency assignment should be used cautiously, since it may pose an increased threat to perceived freedoms in certain instances. Moreover, combining human agency and independent self-construal may trigger negative cognitions directed toward the message and/or its source. It is concluded that cautious, strategic use of agency assignment can improve message acceptance and facilitate adaptive, preparedness actions.


Asunto(s)
Tornados , Actitud , Libertad , Humanos
6.
JAMA ; 323(16): 1565-1573, 2020 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-32219359

RESUMEN

Importance: Bromodomain and extraterminal proteins are epigenetic regulators of gene transcription. Apabetalone is a selective bromodomain and extraterminal protein inhibitor targeting bromodomain 2 and is hypothesized to have potentially favorable effects on pathways related to atherothrombosis. Pooled phase 2 data suggest favorable effects on clinical outcomes. Objective: To test whether apabetalone significantly reduces major adverse cardiovascular events. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled trial, conducted at 190 sites in 13 countries. Patients with an acute coronary syndrome in the preceding 7 to 90 days, type 2 diabetes, and low high-density lipoprotein cholesterol levels were eligible for enrollment, which started November 11, 2015, and ended July 4, 2018, with end of follow-up on July 3, 2019. Interventions: Patients were randomized (1:1) to receive apabetalone, 100 mg orally twice daily (n = 1215), or matching placebo (n = 1210) in addition to standard care. Main Outcomes and Measures: The primary outcome was a composite of time to the first occurrence of cardiovascular death, nonfatal myocardial infarction, or stroke. Results: Among 2425 patients who were randomized (mean age, 62 years; 618 women [25.6%]), 2320 (95.7%) had full ascertainment of the primary outcome. During a median follow-up of 26.5 months, 274 primary end points occurred: 125 (10.3%) in apabetalone-treated patients and 149 (12.4%) in placebo-treated patients (hazard ratio, 0.82 [95% CI, 0.65-1.04]; P = .11). More patients allocated to apabetalone than placebo discontinued study drug (114 [9.4%] vs 69 [5.7%]) for reasons including elevations of liver enzyme levels (35 [2.9%] vs 11 [0.9%]). Conclusions and Relevance: Among patients with recent acute coronary syndrome, type 2 diabetes, and low high-density lipoprotein cholesterol levels, the selective bromodomain and extraterminal protein inhibitor apabetalone added to standard therapy did not significantly reduce the risk of major adverse cardiovascular events. Trial Registration: ClinicalTrials.gov Identifier: NCT02586155.


Asunto(s)
Síndrome Coronario Agudo/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Proteínas/antagonistas & inhibidores , Quinazolinonas/uso terapéutico , Síndrome Coronario Agudo/complicaciones , Análisis Químico de la Sangre , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/prevención & control , HDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/complicaciones , Método Doble Ciego , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Infarto del Miocardio/etiología , Quinazolinonas/efectos adversos , Accidente Cerebrovascular/etiología
7.
Am Heart J ; 217: 72-83, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31520897

RESUMEN

After an acute coronary syndrome (ACS), patients with diabetes remain at high risk for additional cardiovascular events despite use of current therapies. Bromodomain and extra-terminal (BET) proteins are epigenetic modulators of inflammation, thrombogenesis, and lipoprotein metabolism implicated in atherothrombosis. The BETonMACE trial tests the hypothesis that treatment with apabetalone, a selective BET protein inhibitor, will improve cardiovascular outcomes in patients with diabetes after an ACS. DESIGN: Patients (n = 2425) with ACS in the preceding 7 to 90 days, with type 2 diabetes and low HDL cholesterol (≤40 mg/dl for men, ≤45 mg/dl for women), receiving intensive or maximum-tolerated therapy with atorvastatin or rosuvastatin, were assigned in double-blind fashion to receive apabetalone 100 mg orally twice daily or matching placebo. Baseline characteristics include female sex (25%), myocardial infarction as index ACS event (74%), coronary revascularization for index ACS (80%), treatment with dual anti-platelet therapy (87%) and renin-angiotensin system inhibitors (91%), median LDL cholesterol 65 mg per deciliter, and median HbA1c 7.3%. The primary efficacy measure is time to first occurrence of cardiovascular death, non-fatal myocardial infarction, or stroke. Assumptions include a primary event rate of 7% per annum in the placebo group and median follow-up of 1.5 years. Patients will be followed until at least 250 primary endpoint events have occurred, providing 80% power to detect a 30% reduction in the primary endpoint with apabetalone. SUMMARY: BETonMACE will determine whether the addition of the selective BET protein inhibitor apabetalone to contemporary standard of care for ACS reduces cardiovascular morbidity and mortality in patients with type 2 diabetes. Results are expected in 2019.


Asunto(s)
Síndrome Coronario Agudo/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Angiopatías Diabéticas/tratamiento farmacológico , Proteínas/antagonistas & inhibidores , Quinazolinonas/farmacología , Síndrome Coronario Agudo/sangre , Síndrome Coronario Agudo/mortalidad , Anciano , Atorvastatina/administración & dosificación , Atorvastatina/uso terapéutico , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/sangre , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Masculino , Infarto del Miocardio/etiología , Intervención Coronaria Percutánea , Inhibidores de Agregación Plaquetaria/uso terapéutico , Quinazolinonas/administración & dosificación , Quinazolinonas/metabolismo , Insuficiencia Renal Crónica/complicaciones , Sistema Renina-Angiotensina/efectos de los fármacos , Rosuvastatina Cálcica/administración & dosificación , Rosuvastatina Cálcica/uso terapéutico , Accidente Cerebrovascular/etiología , Resultado del Tratamiento
8.
J Am Chem Soc ; 140(3): 1077-1082, 2018 01 24.
Artículo en Inglés | MEDLINE | ID: mdl-29272575

RESUMEN

Two complementary design strategies, isomorphous ligand replacement and heterocycle doping, have been applied to iteratively enhance the proton conductivity of a metal-organic framework, ß-PCMOF2. The resulting materials, PCMOF21/2(Pz) and PCMOF21/2(Tz) (Pz = 1H-pyrazole, Tz = 1H-1,2,4-triazole), have their proton conduction raised almost 2 orders of magnitude compared to ß-PCMOF2. The bulk conductivities of these materials are over 10-1 S cm-1 at 85 °C and 90% relative humidity (RH), while maintaining the parent MOF structure. A solid state synthetic route for doping 1-D channels is also presented.

9.
Kidney Blood Press Res ; 43(2): 449-457, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29566379

RESUMEN

BACKGROUND/AIMS: The association between serum alkaline phosphatase (ALP) with adverse cardiovascular outcomes, in Chronic Kidney Disease (CKD) patients has previously been reported and may be a result of increased vascular calcification and inflammation. Here we report, for the first time, the effects of pharmacologic epigenetic modulation on levels of ALP and kidney function via a novel oral small molecule BET inhibitor, apabetalone, in CKD patients. METHODS: A post-hoc analysis evaluated patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2, who participated in the apabetalone phase 2 randomized controlled trials (SUSTAIN and ASSURE). 48 CKD subjects with a history of cardiovascular disease (CVD) were treated with 100mg twice-daily of 24 and 26 weeks of apabetalone or placebo. ALP and eGFR were measured prior to randomization and at final visits. RESULTS: Patients who received apabetalone (n=35) versus placebo (n=13) over 6 months showed significantly (p=0.02) lowered serum ALP -14.0% (p<0.0001 versus baseline) versus -6.3% (p=0.9 versus baseline). The eGFR in the apabetalone group increased by 3.4% (1.7 mL/min/1.73 m2) (p=0.04 versus baseline) and decreased by 5.8% (2.9 mL/min/1.73 m2) (p=0.6 versus baseline) in the placebo group. Apabetalone was well tolerated. CONCLUSION: A post-hoc analysis of CKD subjects from the SUSTAIN and ASSURE randomized controlled trials demonstrated favorable effects of apabetalone on ALP and eGFR, and generated the hypothesis that epigenetic modulation by BET inhibition may potentially offer a novel therapeutic strategy to treat CVD and progressive kidney function loss in CKD patients. This is being examined in the phase III trial BETonMACE.


Asunto(s)
Fosfatasa Alcalina/sangre , Epigénesis Genética/efectos de los fármacos , Quinazolinonas/farmacología , Insuficiencia Renal Crónica/tratamiento farmacológico , Adulto , Anciano , Fosfatasa Alcalina/genética , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/etiología , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Proteínas , Quinazolinonas/uso terapéutico , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/fisiopatología
10.
Mol Pharmacol ; 92(6): 694-706, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28974538

RESUMEN

Bromodomain (BD) and extra-terminal domain containing proteins (BET) are chromatin adapters that bind acetylated histone marks via two tandem BDs, BD1 and BD2, to regulate gene transcription. BET proteins are involved in transcriptional reprogramming in response to inflammatory stimuli. BET BD inhibitors (BETis) that are nonselective for BD1 or BD2 have recognized anti-inflammatory properties in vitro and counter pathology in models of inflammation or autoimmune disease. Although both BD1 and BD2 bind acetylated histone residues, they may independently regulate the expression of BET-sensitive genes. Here we characterized the ability of RVX-297, a novel orally active BETi with selectivity for BD2, to modulate inflammatory processes in vitro, in vivo, and ex vivo. RVX-297 suppressed inflammatory gene expression in multiple immune cell types in culture. Mechanistically, RVX-297 displaced BET proteins from the promoters of sensitive genes and disrupted recruitment of active RNA polymerase II, a property shared with pan-BETis that nonselectively bind BET BDs. In the lipopolysaccharide model of inflammation, RVX-297 reduced proinflammatory mediators assessed in splenic gene expression and serum proteins. RVX-297 also countered pathology in three rodent models of polyarthritis: rat and mouse collagen-induced arthritis, and mouse collagen antibody-induced arthritis. Further, RVX-297 prevented murine experimental autoimmune encephalomyelitis (a model of human multiple sclerosis) disease development when administered prophylactically and reduced hallmarks of pathology when administered therapeutically. We show for the first time that a BD2-selective BETi maintains anti-inflammatory properties and is effective in preclinical models of acute inflammation and autoimmunity.


Asunto(s)
Antiinflamatorios/farmacología , Artritis/tratamiento farmacológico , Enfermedades Autoinmunes/tratamiento farmacológico , Proteínas/antagonistas & inhibidores , Quinazolinonas/uso terapéutico , Enfermedad Aguda , Animales , Antiinflamatorios/uso terapéutico , Anticuerpos/inmunología , Artritis/inducido químicamente , Artritis/inmunología , Artritis/patología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Células Cultivadas , Colágeno/inmunología , Citocinas/biosíntesis , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Masculino , Ratones Endogámicos C57BL , Ratas Endogámicas Lew , Bazo/efectos de los fármacos , Bazo/metabolismo , Bazo/patología , Células U937
11.
J Am Chem Soc ; 139(41): 14676-14683, 2017 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-28953403

RESUMEN

Seven isomorphous lanthanide metal-organic frameworks in the PCMOF-5 family, [Ln(H5L)(H2O)n](H2O) (L = 1,2,4,5-tetrakis(phosphonomethyl)benzene, Ln = La, Ce, Pr, Nd, Sm, Eu, Gd) have been synthesized and characterized. This family contains 1-D water-filled channels lined with free hydrogen phosphonate groups and gives a very low activation energy pathway for proton transfer. The lanthanide contraction was employed to systematically vary the unit cell dimensions and tune the proton conducting pathways. LeBail fitting of the crystalline series shows that the crystallographic a-axis, along the channel, can be varied in increments less than 0.02 Å correspondingly shortening the proton transfer pathway. The proton conductivities for the La and Pr complexes were roughly an order of magnitude higher than other members of the series (10-3 S cm-1 versus 10-4 S cm-1). Single crystal structures of the high and low conducting members of the series (La, Pr for high and Ce for low) affirm the structural similarities extend beyond the unit cell parameters to positions of free acid groups and included water molecules. Scanning electron microscopy reveals marked differences in particle size of the different members of the Ln series owing to lattice strain effects induced by changing the lanthanide. Notably, the high conducting La and Pr complexes have the largest particle sizes. This result contradicts any notion that degradation of the MOF at grain boundaries is enabling the observed conductivity as proton conduction dominated by extrinsic pathways would be enabled by small particles (i.e., the La and Pr complexes would be the worst conductors). Proton conductivity measurements of a ball milled sample of the La complex corroborate this result.

12.
Health Commun ; 32(4): 451-460, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-27314311

RESUMEN

This study utilizes Terror Management Theory (TMT) to examine differences between eliciting social death and physical death anxiety related to smoking, smoking attitudes, and quitting intent among college students. Moreover, an important TMT variable-self-esteem-was used as a moderator. A 2 × 3 between-subjects factorial design crossed smoking-based self-esteem (low, high) with mortality salience manipulation (health-focused, social-focused, control). Results suggest while both making health-focused salient and making social-focused mortality salient were effective at getting smokers to quit, there was less effect for health-focused mortality salience on those whose self-esteem is strongly tied to smoking. Effect of social-focused mortality salience was more pronounced among participants who highly linked self-esteem with smoking. For smokers with low smoking-based self-esteem, both health-focused and social-focused mortality salience were effective at motivating attitude change toward smoking and quitting intentions. Implications for smoking cessation ad design and TMT are discussed.


Asunto(s)
Conocimientos, Actitudes y Práctica en Salud , Autoimagen , Fumadores/psicología , Cese del Hábito de Fumar/psicología , Prevención del Hábito de Fumar/métodos , Fumar/psicología , Adulto , Análisis de Varianza , Ira , Actitud Frente a la Muerte , Femenino , Promoción de la Salud/métodos , Humanos , Masculino , Medio Oeste de Estados Unidos , Mortalidad , Comunicación Persuasiva , Avisos de Utilidad Pública como Asunto , Estudiantes , Encuestas y Cuestionarios , Universidades , Adulto Joven
13.
J Am Chem Soc ; 137(24): 7640-3, 2015 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-26053659

RESUMEN

From the outset of the study of MOFs as proton conductors, both conductivity and hydrolytic robustness of the materials have needed to be improved. Here, we report a layered magnesium carboxyphosphonate framework, PCMOF10, that shows an extremely high proton conductivity value of 3.55 × 10(-2) S·cm(-1) at 70 °C and 95% RH. Moreover, PCMOF10 is water stable owing to strong Mg phosphonate bonding. The 2,5-dicarboxy-1,4-benzenediphosphonic acid (H6L) linker anchors a robust backbone and has hydrogen phosphonate groups that interact with the lattice water to form an efficient proton transfer pathway.

14.
Chem Soc Rev ; 43(16): 5913-32, 2014 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-24733639

RESUMEN

Proton conducting materials have garnered immense attention for their role as electrolytes in fuel cells. Metal Organic Frameworks (MOFs) and coordination polymers have recently been investigated as possible candidates for proton-conducting applications. Their crystallinity, chemically functionalizable pores and options for systematic structural variation are some of the factors that allow for the targeted design of better proton conductors operating over a wide variety of temperatures and/or humidity conditions. This review will examine selected examples from this nascent field, and will focus on the design and synthesis of proton conducting MOFs, their properties and conditions under which they operate.

15.
J Cell Biochem ; 115(2): 253-60, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24038215

RESUMEN

Tumor necrosis factor alpha (TNF α) signals in part through the mitogen activated protein (MAP) kinase c-jun-N-terminal kinase (JNK). Activation of JNK has been shown to promote insulin resistance and dyslipidemia, including reductions in plasma high-density lipoprotein (HDL) and apolipoprotein A-I (apo A-I). To examine how TNF α-mediated JNK activation inhibits hepatic apo A-I production, the effects of c-jun activation on apo A-I gene expression were examined in HepG2 cells. Apo A-I gene expression and promoter activity were measured by Northern and Western blotting and transient transfection. Transient transfection and siRNA were used to specifically over-express or knockout c-jun, c-jun-N-terminal kinase-1 and -2 (JNK1 and JNK2, respectively) and mitogen-activated protein kinase-4 (MKK4). TNF α-treatment of HepG2 cells induced rapid phosphorylation of c-jun on serine 63. In cells treated with phorbol-12-myristate-13-acetate (PMA), apo A-I gene promoter activity was inhibited and apo A-I mRNA content and apo A-I protein secretion decreased. Likewise, over-expression of JNK1 and JNK2 inhibited apo A-I promoter activity. Over-expression of constitutively active MKK4, an upstream protein kinase that directly activates JNK, also inhibited apo A-I promoter activity, while over-expression of a dominant-negative MKK4 de-repressed apo A-I promoter activity in TNF α-treated cells. Inhibition of c-jun synthesis using siRNA but not a control siRNA prevented TNF α-mediated inhibition of apo A-I. These results suggest that the MKK4/JNK/c-jun signaling pathway mediates TNF α-dependent inhibition of apo A-I synthesis.


Asunto(s)
Apolipoproteína A-I/biosíntesis , Proteína Quinasa 8 Activada por Mitógenos/biosíntesis , Proteína Quinasa 9 Activada por Mitógenos/genética , Factor de Necrosis Tumoral alfa/biosíntesis , Apolipoproteína A-I/antagonistas & inhibidores , Dislipidemias/genética , Regulación Neoplásica de la Expresión Génica , Técnicas de Inactivación de Genes , Células Hep G2 , Humanos , Proteína Quinasa 9 Activada por Mitógenos/biosíntesis , ARN Interferente Pequeño , Transducción de Señal/genética , Factor de Necrosis Tumoral alfa/genética
16.
Pharm Biol ; 52(9): 1119-27, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24635344

RESUMEN

CONTEXT: Black seed [Nigella sativa L. (Ranunculaceae)] has been shown in animal models to lower serum cholesterol levels. OBJECTIVES: In order to determine if extracts from black seed have any effects on high-density lipoprotein (HDL), we characterized the effects of black seed extract on apolipoprotein A-I (apo A-I) gene expression, the primary protein component of HDL. MATERIALS AND METHODS: Hepatocytes (HepG2) and intestinal cells (Caco-2) were treated with black seed extracts, and Apo A-I, peroxisome proliferator-activated receptor α (PPARα), and retinoid-x-receptor α (RXRα) were measured by Western blot analysis. Apo A-I mRNA levels were measured by quantitative real-time polymerase chain reaction and apo A-I gene transcription was measured by transient transfection of apo A-I reporter plasmids. RESULTS: Extracts from black seeds significantly increased hepatic and intestinal apo A-I secretion, as well as apo A-I mRNA and gene promoter activity. This effect required a PPARα binding site in the apo A-I gene promoter. Treatment of the extract with either heat or trypsin had no effect on its ability to induce apo A-I secretion. Treatment with black seed extract induced PPARα expression 9-fold and RXRα expression 2.5-fold. Furthermore, the addition of PPARα siRNA but not a control siRNA prevented some but not all the positive effects of black seed on apo A-I secretion. DISCUSSION: Black seed extract is a potent inducer of apo A-I gene expression, presumably by enhancing PPARα/RXRα expression. CONCLUSIONS: We conclude that black seed may have beneficial effects in treating dyslipidemia and coronary heart disease.


Asunto(s)
Apolipoproteína A-I/genética , Lipoproteínas HDL/efectos de los fármacos , Nigella sativa/química , Extractos Vegetales/farmacología , Células CACO-2 , Regulación de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Lipoproteínas HDL/metabolismo , PPAR alfa/genética , Regiones Promotoras Genéticas/efectos de los fármacos , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor alfa X Retinoide/genética , Semillas
17.
Health Psychol ; 43(8): 615-625, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38635189

RESUMEN

OBJECTIVE: This study investigates the interaction between message framing and point-of-reference (self vs. others) for vaccine benefits on young adults' COVID-19 vaccine confidence and intentions. It also examines how COVID-19-related health beliefs-such as perceived severity of COVID-19 and perceived benefits of obtaining the vaccine to protect others-mediate these interactions. METHOD: In a 2 (framing: gain vs. loss) × 3 (reference point: self, others, university community) between-subjects experiment (Fall 2021), 202 participants ages 18-23 were shown animated messages with embedded manipulations to convey vaccine information. Moderated mediation models tested the conditional indirect effects of framing on vaccine confidence and intentions. RESULTS: Reference point significantly moderated the effect of framing on the perceived severity of COVID-19. More specifically, and somewhat contrary to previous literature, perceived severity was highest when messages emphasized gains for others. In turn, perceived severity correlated positively with vaccine confidence and intentions, resulting in a significant conditional indirect effect. Despite its positive relationship with COVID-19 vaccine confidence and intentions, perceived benefit to others was not a significant mediator. CONCLUSION: This study provides evidence for the role of reference point in moderating the effect of gain-loss message framing on COVID-19 vaccine attitudes and intentions. However, the findings differ from past research, suggesting other-gain messages may be an optimal strategy for promoting these vaccine outcomes for young adults. Overall, findings have implications for developing tailored messaging strategies that account for the nature of targeted populations and the evolving perceptions of the disease and its associated messaging campaigns. (PsycInfo Database Record (c) 2024 APA, all rights reserved).


Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Intención , Humanos , Adulto Joven , Masculino , Femenino , COVID-19/prevención & control , COVID-19/psicología , Adolescente , Conocimientos, Actitudes y Práctica en Salud , Comunicación en Salud/métodos , SARS-CoV-2/inmunología , Adulto
18.
J Am Heart Assoc ; 13(3): e031586, 2024 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-38240199

RESUMEN

BACKGROUND: This study evaluated the effects of canagliflozin in patients with type 2 diabetes with and without prevalent cardiovascular disease (secondary and primary prevention). METHODS AND RESULTS: This was a pooled participant-level analysis of the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program and CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial. The CANVAS Program included participants with type 2 diabetes at elevated cardiovascular risk, whereas the CREDENCE trial included participants with type 2 diabetes and albuminuric chronic kidney disease. Hazard ratios (HRs) with interaction terms were obtained from Cox regression models to estimate relative risk reduction with canagliflozin versus placebo across the primary and secondary prevention groups. We analyzed 5616 (38.9%) and 8804 (61.1%) individuals in the primary and secondary prevention subgroups, respectively. Primary versus secondary prevention participants were on average younger (62.2 versus 63.8 years of age) and more often women (42% versus 31%). Canagliflozin reduced the risk of major adverse cardiovascular events (HR, 0.84 [95% CI, 0.76-0.94]) consistently across primary and secondary prevention subgroups (Pinteraction=0.86). Similarly, no treatment effect heterogeneity was observed with canagliflozin for hospitalization for heart failure, cardiovascular death, end-stage kidney disease, or all-cause mortality (all Pinteraction>0.5). CONCLUSIONS: Canagliflozin reduced cardiovascular and kidney outcomes with no statistical evidence of heterogeneity for the treatment effect across the primary and secondary prevention subgroups in the CANVAS Program and CREDENCE trial. Although studies on the optimal implementation of canagliflozin within these populations are warranted, these results reinforce canagliflozin's role in cardiorenal prevention and treatment in individuals with type 2 diabetes. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01032629, NCT01989754, NCT02065791.


Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Insuficiencia Renal Crónica , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Femenino , Canagliflozina/uso terapéutico , Canagliflozina/farmacología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Resultado del Tratamiento , Riñón , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/tratamiento farmacológico , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/epidemiología
19.
J Health Commun ; 18(12): 1402-21, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24015773

RESUMEN

This study examined nonsmokers' emotional responses and intentions to promote smoking cessation after exposure to a gain- or loss-framed antismoking public service announcement (PSA). Participants were 183 nonsmokers, and results reveal that gain- and loss-framed antismoking PSAs elicited different types and levels of affect as a function of the message theme for the antismoking PSA. Although secondhand smoke PSAs elicited higher levels of anger toward smokers and fear of secondhand smoke, smoking addiction PSAs tended to elicit more guilt among nonsmokers. Elicited emotions were significant predictors of intentions, and overall, loss-framed appeals worked better than gain-framed appeals at increasing nonsmokers' intentions to talk to friends who smoke about quitting.


Asunto(s)
Actitud Frente a la Salud , Comunicación en Salud/métodos , Cese del Hábito de Fumar/métodos , Prevención del Hábito de Fumar , Fumar/psicología , Adolescente , Emociones , Femenino , Humanos , Intención , Masculino , Cese del Hábito de Fumar/psicología , Contaminación por Humo de Tabaco , Adulto Joven
20.
Atherosclerosis ; 364: 10-19, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36455344

RESUMEN

BACKGROUND AND AIMS: Obese patients are at risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). A lipid-rich diet promotes arterial changes by inducing hypertension, oxidative stress, and inflammation. Bromodomain and extraterminal (BET) proteins contribute to endothelial and immune cell activation in vitro and in atherosclerosis mouse models. We aim to determine if BET inhibition can reduce lipid-rich diet-induced vascular inflammation in mice. METHODS: Body weight, serum glucose and lipid levels were measured in mice fed a high-fat diet (HFD) or low-fat diet (LFD) for 6 weeks and at study termination. BET inhibitors apabetalone and JQ1 were co-administered with the HFD for additional 16 weeks. Aortic gene expression was analyzed post necropsy by PCR, Nanostring nCounter® Inflammation Panel and bioinformatics pathway analysis. Transcription changes and BRD4 chromatin occupancy were analyzed in primary human endothelial cells in response to TNFα and apabetalone. RESULTS: HFD induced weight gain, visceral obesity, high fasting blood glucose, glucose intolerance and insulin resistance compared to LFD controls. HFD upregulated the aortic expression of 47 genes involved in inflammation, innate immunity, cytoskeleton and complement pathways. Apabetalone and JQ1 treatment reduced HFD-induced aortic expression of proinflammatory genes. Congruently, bioinformatics predicted enhanced signaling by TNFα in the HFD versus LFD aorta, which was countered by BETi treatment. TNFα-stimulated human endothelial cells had increased expression of HFD-sensitive genes and higher BRD4 chromatin occupancy, which was countered by apabetalone treatment. CONCLUSIONS: HFD induces vascular inflammation in mice through TNFα signaling. Apabetalone treatment reduces this proinflammatory phenotype, providing mechanistic insight into how BET inhibitors may reduce CVD risk in obese patients.


Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Inflamación , Obesidad , Animales , Humanos , Ratones , Aorta/metabolismo , Enfermedades Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Dieta Alta en Grasa/efectos adversos , Células Endoteliales/metabolismo , Epigénesis Genética , Expresión Génica/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/genética , Lípidos , Ratones Endogámicos C57BL , Proteínas Nucleares/genética , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Obesidad/genética , Factores de Transcripción/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas del Tejido Nervioso/genética , Receptores de Superficie Celular/genética , Ratones Obesos
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