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1.
J Biomol Struct Dyn ; : 1-21, 2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38285669

RESUMO

Chronic pain is a common and debilitating condition with a huge social and economic burden worldwide. Currently, available drugs in clinics are not adequately effective and possess a variety of severe side effects leading to treatment withdrawal and poor quality of life. Recent findings highlight the potential role of autotaxin (ATX) as a promising novel target for chronic pain management, extending beyond its previously established involvement in arthritis and other neurological disorders, such as Alzheimer's disease. In the present study, we used a virtual screening strategy by targeting ATX against commercially available natural compounds (enamine- phenotypic screening library) to identify the potential inhibitors for the treatment of chronic pain. After initial identification using molecular docking based virtual screening, molecular mechanics (MM/GBSA), ADMET profiling and molecular dynamics simulation were performed to verify top hits. The computational screening resulted in the identification of fifteen top scoring structurally diverse hits that have free energy of binding (ΔG) values in the range of -25.792 (for compound Enamine_1850) to -74.722 Kcal/mol (for compound Enamine_1687). Moreover, the top-scoring hits have favourable ADME properties as calculated using in-silico algorithms. Additionally, the molecular dynamics simulation revealed the stable nature of protein-ligand interaction and provided information about amino acid residues involved in binding. This study led to the identification of potential autotaxin inhibitors with favourable pharmacokinetic properties. Identified hits may further be investigated for their safety and efficacy potential using in-vitro and in-vivo models of chronic pain.Communicated by Ramaswamy H. Sarma.

2.
Nanoscale ; 13(26): 11544-11551, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34184025

RESUMO

In this contribution, the excited state charge-transfer interactions between single-walled carbon nanotubes (SWCNTs) and a variety of phenyl, 4-bromophenyl, and thiophene substituted diketopyrrolopyrroles (DPPs), is described. Atomic force microscopy (AFM) and aberration corrected high resolution transmission electron microscopy (AC-HRTEM) corroborated the successful formation of DPP/SWCNTs. Steady-state absorption, fluorescence, and Raman spectroscopies all gave insights into the impact on their ground and excited states as well as on the nature of their electronic communication/interaction. Of great value was time-resolved transient absorption spectroscopy on the femto- and nanosecond time-scales; it assisted in deciphering the charge-transfer mechanism from the DPPs to the SWCNT and in analyzing the dynamics thereof with transfer efficiencies of up to 81%. Important confirmation for the one-electron oxidized DPPs came from pulse radiolysis assays with focus on establishing their spectral fingerprints. Our full-fledged work demonstrates that the successful preparation of stable DPP/SWCNTs represents an important step towards establishing them as a viable alternative to porphyrin-based systems in emerging applications such as solar energy conversion.

3.
Curr Probl Cancer ; 45(6): 100710, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33622518

RESUMO

Ipilimumab, a monoclonal antibody against CTLA-4, is used in the treatment of melanoma and renal cell cancer. Hypophysitis is one of the more common adverse events, usually presenting with headache, pituitary enlargement and hypopituitarism, mostly ACTH deficiency, which is usually permanent. We describe a series of 3 cases developing pituitary enlargement in keeping with hypophysitis after ipilimumab without any long-term pituitary hormone deficiencies. This illustrates that a comprehensive endocrine assessment is required even when pituitary enlargement is present.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Hipofisite/induzido quimicamente , Ipilimumab/efeitos adversos , Ipilimumab/uso terapêutico , Melanoma/tratamento farmacológico , Adulto , Anticorpos Monoclonais/efeitos adversos , Feminino , Glucocorticoides/uso terapêutico , Humanos , Hipofisite/tratamento farmacológico , Masculino , Melanoma/diagnóstico por imagem , Pessoa de Meia-Idade , Doenças da Hipófise/induzido quimicamente , Prednisolona/uso terapêutico
4.
Small ; 17(48): e2005648, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33458948

RESUMO

Herein, the microscopic and spectroscopic characterization of a novel non-covalent electron donor-acceptor system, in which three different metalloporphyrins (1, 2, and 3) play the dual role of light harvester and electron donor with SWCNTs as electron acceptor, is described. To this end, microscopy, that is, atomic force microscopy (AFM) and transmission electron microscopy (TEM) corroborate the formation of 1-SWCNT, 2-SWCNT, and 3-SWCNT. Spectroscopy by means of Raman, fluorescence, and transient absorption spectroscopy confirmed efficient charge-transfer interaction from photoexcited metalloporphyrins to SWCNTs in the ground and excited state of 1-SWCNT, 2-SWCNT, and 3-SWCNT. The complementary use of spectroelectrochemical and transient absorption measurements substantiates the formation of one-electron oxidized metalloporphyrins after photoexcitation. Multiwavelength global analysis provides insights into the charge-separation and recombination processes in 1-SWCNT, 2-SWCNT, and 3-SWCNT upon photoexcitation. Notably, both the charge-separation and recombination dynamics are fastest in 2-SWCNT. Importantly, the strongest interactions in the steady-state experiments are associated with the fastest excited state decay in the time-resolved measurements.


Assuntos
Metaloporfirinas , Nanotubos de Carbono , Microscopia de Força Atômica , Análise Espectral
5.
Angew Chem Int Ed Engl ; 59(42): 18774-18785, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-32544289

RESUMO

The formation of discrete macrocycles wrapped around single-walled carbon nanotubes (SWCNTs) has recently emerged as an appealing strategy to functionalize these carbon nanomaterials and modify their properties. Here, we demonstrate that the reversible disulfide exchange reaction, which proceeds under mild conditions, can install relatively large amounts of mechanically interlocked disulfide macrocycles on the one-dimensional nanotubes. Size-selective functionalization of a mixture of SWCNTs of different diameters were observed, presumably arising from error correction and the presence of relatively rigid, curved π-systems in the key building blocks. A combination of UV/Vis/NIR, Raman, photoluminescence excitation, and transient absorption spectroscopy indicated that the small (6,4)-SWCNTs were predominantly functionalized by the small macrocycles 12 , whereas the larger (6,5)-SWCNTs were an ideal match for the larger macrocycles 22 . This size selectivity, which was rationalized computationally, could prove useful for the purification of nanotube mixtures, since the disulfide macrocycles can be removed quantitatively under mild reductive conditions.

6.
ACS Nano ; 14(7): 8875-8886, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32543172

RESUMO

In this contribution, we focused on integrating a phenylene-bridged dibenzodiazahexacene dimer (o-DAD), which is singlet fission (SF) active, onto single-walled carbon nanotubes (SWCNTs) as a low-energy sink for energetically low lying excited states that stem from SF. Spectroscopic and microscopic assays assisted in documenting that SWCNT/o-DAD feature high stability in THF as a result of electronic interactions between the individual constituents. For example, statistical Raman analysis underlined n-doping of SWCNTs in the presence of o-DAD. Fluorescence spectroscopy prompted an energy transfer between the individual constituents, a conclusion that was exclusively derived from the quenching of the o-DAD-centered fluorescence. Excitation spectroscopy with a focus on the SWCNT fluorescence confirmed independently this conclusion by showing o-DAD-centered features. Our work was rounded off by time-resolved transient absorption measurements with SWCNT/o-DAD, in which evidence was gathered for the sequential o-DAD-centered SF with an efficiency of 112% followed by a unidirectional energy transfer from o-DAD to SWCNT and a rapid deactivation. The energy transfer efficiency from SF products such as (S1S0)CT and 1(T1T1) exceeded the 100% threshold with values of 115%, which is conventionally found in energy transfer schemes.

7.
Small ; 16(8): e1906745, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32003927

RESUMO

Here, the ability of a novel near-infrared dye to noncovalently self-assemble onto the surface of single-walled carbon nanotubes (SWCNTs) driven by charge-transfer interactions is demonstrated. Steady-state, Raman, and transient absorption spectroscopies corroborate the electron donating character of the near-infrared dye when combined with SWCNTs, in the form of fluorescence quenching of the excited state of the dye, n-doping of SWCNTs, and reversible charge transfer, respectively. Formation of the one-electron oxidized dye as a result of interactions with SWCNTs is supported by spectroelectrochemical measurements. The ultrafast electronic process in the near-infrared dye, once immobilized onto SWCNTs, starts with the formation of excited states, which decay to the ground state via the intermediate population of a fully charge-separated state, with characteristic time constants for the charge separation of 1.5 ps and charge recombination of 25 ps, as derived from the multiwavelength global analysis. Of great relevance is the fact that charge-transfer occurs from the hot excited state of the near-infrared dye to SWCNTs.

8.
Diabetes Obes Metab ; 21(11): 2384-2393, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31264346

RESUMO

AIM: To compare the second-generation basal insulin glargine 300 units/mL (Gla-300) and first-generation basal insulins on glycaemic control and hypoglycaemia risk in older adults with type 2 diabetes (T2D). MATERIALS AND METHODS: DELIVER 3 was a retrospective observational cohort study of electronic medical records. A total of 1176 older adults (aged ≥ 65 years) with T2D and ≥1 HbA1c value during 6 month baseline and 3 to 6 month follow-up who switched from basal insulin to Gla-300 were propensity score-matched to 1176 older adults who switched to a first-generation basal insulin [insulin detemir (IDet) or insulin glargine 100 units/mL (Gla-100)]. Outcomes were follow-up HbA1c, achievement of HbA1c <7% and <8%, hypoglycaemia incidence and event rates, and healthcare resource utilization. RESULTS: Following basal insulin switching, HbA1c reductions were greater/similar with Gla-300 versus IDet/Gla-100 (variable follow-up: -0.45% ± 1.40% vs. -0.29% ± 1.57%; P = .021; fixed follow-up: -0.48% ± 1.49% vs. -0.38% ± 1.59%; P = .114), while HbA1c goal attainment was similar in both cohorts. Gla-300 was associated with less hypoglycaemia [event rate: adjusted rate ratio (aRR): 0.63, 95% CI: 0.53-0.75; P < .001] and inpatient/emergency department-associated hypoglycaemia (adjusted hazard ratio: 0.58, 95% CI: 0.37-0.90; P = .016; aRR: 0.43, 95% CI: 0.31-0.60; P < .001) by variable follow-up. By fixed follow-up, hypoglycaemia results significantly or numerically favoured Gla-300. CONCLUSION: Among older adults with T2D, switching to Gla-300 versus Gla-100/IDet was associated with greater/similar improvements in glycaemic control, and generally less hypoglycaemia.


Assuntos
Diabetes Mellitus Tipo 2 , Insulina Glargina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Hemoglobinas Glicadas/análise , Hospitalização/estatística & dados numéricos , Humanos , Hipoglicemia , Insulina Glargina/administração & dosagem , Masculino , Estudos Retrospectivos
9.
Diabetes Obes Metab ; 21(9): 2123-2132, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31144445

RESUMO

AIM: To compare glycaemic control, hypoglycaemia and treatment discontinuation of insulin glargine 300 units/mL (Gla-300) and insulin degludec (IDeg) in a real-world study of insulin-naïve adults with type 2 diabetes (T2D). MATERIALS AND METHODS: DELIVER Naive D was a retrospective observational study that used electronic medical record data from the IBM Watson Health Explorys database. Insulin-naïve adults with T2D who started Gla-300 or IDeg between March 2015 and September 2017 were identified. Patients were active in the system for ≥12 months before and ≥6 months after starting Gla-300 or IDeg and had HbA1c measurements during 6-month baseline and 3- to 6-month follow-up. Outcomes were compared among 1:1 propensity score-matched cohorts. RESULTS: In the matched cohorts (n = 638 each), the mean age was 59 years, approximately 53% were male, and mean HbA1c was 9.67% (82 mmol/mol). Mean (SD) HbA1c decreases were comparable in the Gla-300 and IDeg cohorts (-1.67% [2.22] and -1.58% [2.20]; P = 0.51), as were HbA1c target attainment [<7% (53 mmol/mol): 23.8% and 27.4%; P = 0.20; <8% (64 mmol/mol): 55.0% and 57.1%; P = 0.63] and treatment discontinuation (29.2% and 32.6%; P = 0.14). Overall and inpatient/emergency department-associated hypoglycaemia incidences and event rates were similar in both cohorts using fixed 6-month or variable on-treatment follow-up. CONCLUSIONS: Among real-world insulin-naïve adults with T2D, initiation of Gla-300 or IDeg resulted in comparable improvements in glycaemic control and similar rates of hypoglycaemia. These real-world data complement and confirm a randomized trial and other real-world studies.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemia/epidemiologia , Hipoglicemiantes/uso terapêutico , Insulina Glargina/uso terapêutico , Insulina de Ação Prolongada/uso terapêutico , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Hemoglobinas Glicadas/efeitos dos fármacos , Humanos , Hipoglicemia/etiologia , Incidência , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Estudos Retrospectivos , Resultado do Tratamento
10.
Pharmacy (Basel) ; 6(2)2018 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-29867012

RESUMO

The use of community pharmacies across Europe has potential to alleviate the burden on overstretched healthcare providers. Children and young people (0⁻18 years) account for a large number of primary care attendances. This narrative literature review between January 2000 and December 2017 examines the use of community pharmacy by paediatric patients in Europe. The results report both positive and negative perceptions of community pharmacy by parents and children, opportunities for an extended role in Europe, as well as the need for further training. The main limitations were the inclusion of English language papers only and an initial review of the literature carried out by a single researcher. It remains to be seen whether a 'new-look' role of the community pharmacist is practical and in alignment with specific European Commission and national policies.

13.
Cell Mol Gastroenterol Hepatol ; 4(3): 405-417, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28936471

RESUMO

BACKGROUND & AIMS: Hepatitis C virus (HCV) is a leading cause of chronic liver diseases and the most common indication for liver transplantation in the United States. HCV particles in the blood of infected patients are characterized by heterogeneous buoyant densities, likely owing to HCV association with lipoproteins. However, clinical isolates are not infectious in vitro and the relative infectivity of the particles with respect to their buoyant density therefore cannot be determined, pointing to the need for better in vivo model systems. METHODS: To analyze the evolution of the buoyant density of in vivo-derived infectious HCV particles over time, we infected immunodeficient human liver chimeric fumaryl acetoacetate hydrolase-/- mice with J6/JFH1 and performed ultracentrifugation of infectious mouse sera on isopicnic iodixanol gradients. We also evaluated the impact of a high sucrose diet, which has been shown to increase very-low-density lipoprotein secretion by the liver in rodents, on lipoprotein and HCV particle characteristics. RESULTS: Similar to the severe combined immunodeficiency disease/Albumin-urokinase plasminogen activator human liver chimeric mouse model, density fractionation of infectious mouse serum showed higher infectivity in the low-density fractions early after infection. However, over the course of the infection, viral particle heterogeneity increased and the overall in vitro infectivity diminished without loss of the human liver graft over time. In mice provided with a sucrose-rich diet we observed a minor shift in HCV infectivity toward lower density that correlated with a redistribution of triglycerides and cholesterol among lipoproteins. CONCLUSIONS: Our work indicates that the heterogeneity in buoyant density of infectious HCV particles evolves over the course of infection and can be influenced by diet.

14.
Adv Healthc Mater ; 6(20)2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28730752

RESUMO

The pharmacological manipulation of liver X receptors (LXRs) has been an attractive therapeutic strategy for atherosclerosis treatment as they control reverse cholesterol transport and inflammatory response. This study presents the development and efficacy of nanoparticles (NPs) incorporating the synthetic LXR agonist GW3965 (GW) in targeting atherosclerotic lesions. Collagen IV (Col IV) targeting ligands are employed to functionalize the NPs to improve targeting to the atherosclerotic plaque, and formulation parameters such as the length of the polyethylene glycol (PEG) coating molecules are systematically optimized. In vitro studies indicate that the GW-encapsulated NPs upregulate the LXR target genes and downregulate proinflammatory mediator in macrophages. The Col IV-targeted NPs encapsulating GW (Col IV-GW-NPs) successfully reaches atherosclerotic lesions when administered for 5 weeks to mice with preexisting lesions, substantially reducing macrophage content (≈30%) compared to the PBS group, which is with greater efficacy versus nontargeting NPs encapsulating GW (GW-NPs) (≈18%). In addition, mice administered the Col IV-GW-NPs do not demonstrate increased hepatic lipid biosynthesis or hyperlipidemia during the treatment period, unlike mice injected with the free GW. These findings suggest a new form of LXR-based therapeutics capable of enhanced delivery of the LXR agonist to atherosclerotic lesions without altering hepatic lipid metabolism.


Assuntos
Benzoatos/farmacologia , Benzilaminas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Receptores X do Fígado/agonistas , Nanomedicina , Receptores de LDL/genética , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Aterosclerose/patologia , Benzoatos/química , Benzoatos/uso terapêutico , Benzilaminas/química , Benzilaminas/uso terapêutico , Células Cultivadas , Colesterol/sangue , Colágeno Tipo IV/química , Colágeno Tipo IV/metabolismo , Modelos Animais de Doenças , Portadores de Fármacos/química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nanopartículas/química , Nanopartículas/metabolismo , Polietilenoglicóis/química , Receptores de LDL/deficiência , Triglicerídeos/sangue
15.
Proc Natl Acad Sci U S A ; 113(44): E6731-E6740, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27791119

RESUMO

Immunological complexity in atherosclerosis warrants targeted treatment of specific inflammatory cells that aggravate the disease. With the initiation of large phase III trials investigating immunomodulatory drugs for atherosclerosis, cardiovascular disease treatment enters a new era. We here propose a radically different approach: implementing and evaluating in vivo a combinatorial library of nanoparticles with distinct physiochemical properties and differential immune cell specificities. The library's nanoparticles are based on endogenous high-density lipoprotein, which can preferentially deliver therapeutic compounds to pathological macrophages in atherosclerosis. Using the apolipoprotein E-deficient (Apoe-/-) mouse model of atherosclerosis, we quantitatively evaluated the library's immune cell specificity by combining immunological techniques and in vivo positron emission tomography imaging. Based on this screen, we formulated a liver X receptor agonist (GW3965) and abolished its liver toxicity while still preserving its therapeutic function. Screening the immune cell specificity of nanoparticles can be used to develop tailored therapies for atherosclerosis and other inflammatory diseases.


Assuntos
Aterosclerose/tratamento farmacológico , Aterosclerose/imunologia , Imunoterapia , Nanopartículas/química , Animais , Anti-Inflamatórios , Apolipoproteínas E/deficiência , Aterosclerose/patologia , Autorradiografia , Benzoatos/agonistas , Benzoatos/química , Benzilaminas/agonistas , Benzilaminas/química , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/métodos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Lipoproteínas HDL/química , Lipoproteínas HDL/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Imagem Molecular , Nanomedicina , Nanopartículas/metabolismo , Tomografia por Emissão de Pósitrons/métodos , RNA Mensageiro/metabolismo
16.
PLoS One ; 11(7): e0159679, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27442505

RESUMO

Atherosclerosis, caused in part by monocytes in plaques, continues to be a disease that afflicts the modern world. Whilst significant steps have been made in treating this chronic inflammatory disease, questions remain on how to prevent monocyte and macrophage accumulation in atherosclerotic plaques. Junctional Adhesion Molecule C (JAM-C) expressed by vascular endothelium directs monocyte transendothelial migration in a unidirectional manner leading to increased inflammation. Here we show that interfering with JAM-C allows reverse-transendothelial migration of monocyte-derived cells, opening the way back out of the inflamed environment. To study the role of JAM-C in plaque regression we used a mouse model of atherosclerosis, and tested the impact of vascular JAM-C expression levels on monocyte reverse transendothelial migration using human cells. Studies in-vitro under inflammatory conditions revealed that overexpression or gene silencing of JAM-C in human endothelium exposed to flow resulted in higher rates of monocyte reverse-transendothelial migration, similar to antibody blockade. We then transplanted atherosclerotic, plaque-containing aortic arches from hyperlipidemic ApoE-/- mice into wild-type normolipidemic recipient mice. JAM-C blockade in the recipients induced greater emigration of monocyte-derived cells and further diminished the size of atherosclerotic plaques. Our findings have shown that JAM-C forms a one-way vascular barrier for leukocyte transendothelial migration only when present at homeostatic copy numbers. We have also shown that blocking JAM-C can reduce the number of atherogenic monocytes/macrophages in plaques by emigration, providing a novel therapeutic strategy for chronic inflammatory pathologies.


Assuntos
Movimento Celular , Molécula C de Adesão Juncional/metabolismo , Monócitos/patologia , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Animais , Anticorpos/farmacologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/metabolismo , Artérias Carótidas/patologia , Movimento Celular/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Citometria de Fluxo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/patologia , Junções Intercelulares/efeitos dos fármacos , Junções Intercelulares/metabolismo , Leucócitos/efeitos dos fármacos , Leucócitos/patologia , Lipídeos/sangue , Camundongos Endogâmicos C57BL , Modelos Biológicos , Monócitos/efeitos dos fármacos , Placa Aterosclerótica/sangue
17.
Am J Physiol Heart Circ Physiol ; 303(11): H1304-18, 2012 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-23023871

RESUMO

Coarctation of the aorta (CoA) is associated with substantial morbidity despite treatment. Mechanically induced structural and functional vascular changes are implicated; however, their relationship with smooth muscle (SM) phenotypic expression is not fully understood. Using a clinically representative rabbit model of CoA and correction, we quantified mechanical alterations from a 20-mmHg blood pressure (BP) gradient in the thoracic aorta and related the expression of key SM contractile and focal adhesion proteins with remodeling, relaxation, and stiffness. Systolic and mean BP were elevated for CoA rabbits compared with controls leading to remodeling, stiffening, an altered force response, and endothelial dysfunction both proximally and distally. The proximal changes persisted for corrected rabbits despite >12 wk of normal BP (~4 human years). Computational fluid dynamic simulations revealed reduced wall shear stress (WSS) proximally in CoA compared with control and corrected rabbits. Distally, WSS was markedly increased in CoA rabbits due to a stenotic velocity jet, which has persistent effects as WSS was significantly reduced in corrected rabbits. Immunohistochemistry revealed significantly increased nonmuscle myosin and reduced SM myosin heavy chain expression in the proximal arteries of CoA and corrected rabbits but no differences in SM α-actin, talin, or fibronectin. These findings indicate that CoA can cause alterations in the SM phenotype contributing to structural and functional changes in the proximal arteries that accompany the mechanical stimuli of elevated BP and altered WSS. Importantly, these changes are not reversed upon BP correction and may serve as markers of disease severity, which explains the persistent morbidity observed in CoA patients.


Assuntos
Coartação Aórtica/metabolismo , Coartação Aórtica/fisiopatologia , Procedimentos Cirúrgicos Cardiovasculares , Proteínas Contráteis/metabolismo , Endotélio Vascular/fisiopatologia , Hemodinâmica/fisiologia , Actinas/metabolismo , Animais , Coartação Aórtica/cirurgia , Pressão Sanguínea/fisiologia , Fibronectinas/metabolismo , Masculino , Modelos Animais , Cadeias Pesadas de Miosina/metabolismo , Coelhos , Resistência ao Cisalhamento/fisiologia , Estresse Mecânico , Talina/metabolismo
18.
J Pharmacol Toxicol Methods ; 65(1): 18-28, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22079597

RESUMO

INTRODUCTION: Coarctation of the aorta (CoA) is associated with morbidity despite treatment. Although mechanisms remain elusive, abnormal hemodynamics and vascular biomechanics are implicated. We present a novel approach that facilitates quantification of coarctation-induced mechanical alterations and their impact on vascular structure and function, without genetic or confounding factors. METHODS: Rabbits underwent thoracic CoA at 10weeks of age (~9 human years) to induce a 20mmHg blood pressure (BP) gradient using permanent or dissolvable suture thereby replicating untreated and corrected CoA. Computational fluid dynamics (CFD) was performed using imaging and BP data at 32weeks to quantify velocity, strain and wall shear stress (WSS) for comparison to vascular structure and function as revealed by histology and myograph results. RESULTS: Systolic and mean BP was elevated in CoA compared to corrected and control rabbits leading to vascular thickening, disorganization and endothelial dysfunction proximally and distally. Corrected rabbits had less severe medial thickening, endothelial dysfunction, and stiffening limited to the proximal region despite 12weeks of normal BP (~4 human years) after the suture dissolved. WSS was elevated distally for CoA rabbits, but reduced for corrected rabbits. DISCUSSION: These findings are consistent with alterations in humans. We are now poised to investigate mechanical contributions to mechanisms of morbidity in CoA using these methods.


Assuntos
Aorta Torácica/fisiopatologia , Coartação Aórtica/fisiopatologia , Pressão Sanguínea , Animais , Simulação por Computador , Modelos Animais de Doenças , Endotélio Vascular/patologia , Hemodinâmica , Hidrodinâmica , Masculino , Miografia , Coelhos , Fatores de Tempo
19.
Ann Biomed Eng ; 36(1): 86-101, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17943447

RESUMO

Restenosis in peripheral arteries is a major health care problem in the United States. Typically, 30-40% of angioplasties result in restenosis and hence alternative treatment techniques are being actively investigated. Cryoplasty, a novel technique involving simultaneous stretching and freezing of the peripheral arteries (e.g., femoral, iliac, popliteal) using a cryogen-filled balloon catheter, has shown the potential to combat restenosis. However, evaluation of the thermal and biophysical mechanisms that affect cellular survival during cryoplasty is lacking. To achieve this, the thermal history in arteries was predicted for different balloon temperatures using a thermal model. Cellular biophysical responses (water transport (WT) and intracellular ice formation (IIF)) were then characterized, using in vitro model systems, based on the thermal model predictions. The thermal and biophysical effects on cell survival were eventually determined. For this study, smooth muscle cells (SMC) isolated from porcine femoral arteries were used in suspensions and attached in vitro systems (monolayer and fibrin gel). Results showed that for different balloon temperatures, the thermal model predicted cooling rates from 2200 to 5 degrees C/min in the artery. Biophysical parameters (WT & IIF) were higher for SMCs in attached systems as compared to suspensions. The "combined" fit WT parameters for SMCs in suspension (at 5, 10, and 25 degrees C/min) are L (pg) = 0.12 microm/(min atm) and E (Lp) = 24.1 kcal/mol. Individual WT parameters for SMCs in attached cell systems at higher cooling rates are approximately an order of magnitude higher compared to suspensions (e.g., at 130 degrees C/min, WT parameters in monolayer and fibrin TE systems are L (pg) = 18.6, 19.4 microm/(min atm) and E (Lp) = 112, 127 kcal/mol, respectively). Similarly, IIF parameters assessed at 130 degrees C/min are higher for SMCs in attached systems than suspensions (Omega 0 = 1.1, 354, 378 (x 10(8) (1/m(2) s)) and kappa(o) = 1.6, 1.8, 2.1 (x 10(9) K(5)) for suspensions, monolayer, and fibrin TE, respectively). One possible reason for the differences in IIF kinetics was verified to be the presence of gap junctions, which facilitate cell-cell connections through which ice can propagate. This is reflected by the change in the predicted IIF parameters when a gap junction inhibitor was added and tested in monolayer (Omega 0 (1/m(2) s)); kappa(o) = 2.1 x 10(9) K(5)). SMC viability was affected by the model system (lower viability in attached systems), the thermal conditions and the biophysics. For e.g., IIF is lethal to cells and SMC viability was verified to be the least in fibrin TE (most % IIF) and the most in suspensions (least % IIF) at all cooling rates. Using the results from the fibrin TE (suggested as the best in vitro system to mimic a restenosis environment), conservative estimates of injury regimes in the artery during cryoplasty is predicted. The results can be used to suggest future optimizations and modifications during cryoplasty and also to design future in vivo studies.


Assuntos
Queimaduras/etiologia , Queimaduras/fisiopatologia , Criocirurgia/efeitos adversos , Modelos Cardiovasculares , Músculo Liso Vascular/lesões , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/patologia , Animais , Apoptose , Queimaduras/patologia , Sobrevivência Celular , Células Cultivadas , Simulação por Computador , Músculo Liso Vascular/patologia , Músculo Liso Vascular/cirurgia , Suínos
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