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1.
Artif Organs ; 47(1): 88-104, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-35962603

RESUMEN

BACKGROUND: The centrifugal blood pump volute has a significant impact on its hemodynamic performance hemocompatibility. Previous studies about the effect of volute design features on the performance of blood pumps are relatively few. METHODS: In the present study, the computational fluid dynamics (CFD) method was utilized to evaluate the impact of volute design factors, including spiral start position, volute tongue radius, inlet height, size, shape and diffuser pipe angle on the hemolysis index and thrombogenic potential of the centrifugal blood pump. RESULTS: Correlation analysis shows that flow losses affect the hemocompatibility of the blood pump by influencing shear stress and residence time. The closer the spiral start position of the volute, the better the hydraulic performance and hemocompatibility of the blood pump. Too large or too small volute inlet heights can worsen hydraulic performance and hemolysis, and higher volute inlet height can increase the thrombogenic potential. Small volute sizes exacerbate hemolysis and large volute sizes increase the thrombogenic risk, but volute size does not affect hydraulic performance. When the diffuser pipe is tangent to the base circle of the volute, the best hydraulic performance and hemolysis performance of the blood pump is achieved, but the thrombogenic potential is increased. The trapezoid volute has poor hydraulic performance and hemocompatibility. The round volute has the best hydraulic and hemolysis performance, but the thrombogenic potential is higher than that of the rectangle volute. CONCLUSION: This study found that the hemolysis index shows a significant correlation with spiral start position, volute size, and diffuser pipe angle. Thrombogenic potential exhibits a good correlation with all the studied volute design features. The flow losses affect the hemocompatibility of the blood pump by influencing shear stress and residence time. The finding of this study can be used to guide the optimization of blood pump for improving the hemodynamic performance and hemocompatibility.


Asunto(s)
Oxigenación por Membrana Extracorpórea , Corazón Auxiliar , Humanos , Corazón Auxiliar/efectos adversos , Hemólisis , Hemodinámica , Estrés Mecánico , Diseño de Equipo
2.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 40(2): 244-248, 2023 Apr 25.
Artículo en Zh | MEDLINE | ID: mdl-37139754

RESUMEN

Cardiovascular disease is the leading cause of death worldwide, accounting for 48.0% of all deaths in Europe and 34.3% in the United States. Studies have shown that arterial stiffness takes precedence over vascular structural changes and is therefore considered to be an independent predictor of many cardiovascular diseases. At the same time, the characteristics of Korotkoff signal is related to vascular compliance. The purpose of this study is to explore the feasibility of detecting vascular stiffness based on the characteristics of Korotkoff signal. First, the Korotkoff signals of normal and stiff vessels were collected and preprocessed. Then the scattering features of Korotkoff signal were extracted by wavelet scattering network. Next, the long short-term memory (LSTM) network was established as a classification model to classify the normal and stiff vessels according to the scattering features. Finally, the performance of the classification model was evaluated by some parameters, such as accuracy, sensitivity, and specificity. In this study, 97 cases of Korotkoff signal were collected, including 47 cases from normal vessels and 50 cases from stiff vessels, which were divided into training set and test set according to the ratio of 8 : 2. The accuracy, sensitivity and specificity of the final classification model was 86.4%, 92.3% and 77.8%, respectively. At present, non-invasive screening method for vascular stiffness is very limited. The results of this study show that the characteristics of Korotkoff signal are affected by vascular compliance, and it is feasible to use the characteristics of Korotkoff signal to detect vascular stiffness. This study might be providing a new idea for non-invasive detection of vascular stiffness.


Asunto(s)
Enfermedades Cardiovasculares , Rigidez Vascular , Humanos , Redes Neurales de la Computación , Enfermedades Cardiovasculares/diagnóstico , Sensibilidad y Especificidad
3.
J Endovasc Ther ; : 15266028221119309, 2022 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-36052406

RESUMEN

CLINICAL IMPACT: Studies have shown that the biomechanical indicators based on multi-scale models are more effective in accurately assessing the rupture risk of AAA. To meet the need for clinical monitoring and rapid decision making, the typical morphological parameters associated with AAA rupture and their relationships with the mechanical environment have been summarized, which provide a reference for clinical preoperative risk assessment of AAA.

4.
Am J Physiol Heart Circ Physiol ; 320(4): H1724-H1737, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33710913

RESUMEN

The surface of vascular endothelial cells (ECs) is covered by a protective negatively charged layer known as the endothelial glycocalyx. Herein, we hypothesized its transport barrier and mechanosensory role in transmural water flux and low-density lipoprotein (LDL) transport in an isolated rat abdominal aorta perfused under 85 mmHg and 20 dyn/cm2 ex vivo. The endothelial glycocalyx was digested by hyaluronidase (HAase) from bovine tests. Water infiltration velocity (Vw) was measured by a graduated pipette. LDL coverage and mean maximum infiltration distance (MMID) in the vessel wall were quantified by confocal laser scanning microscopy. EC apoptosis was determined by the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) technique, and leaky junction rates were evaluated by electron microscopy. The results showed that a 42% degradation of the endothelial glycocalyx by HAase treatment increased Vw, LDL coverage, and MMID. Shear stress increased Vw, which cannot be inhibited by HAase treatment. Four hour-shear application increased about fourfolds of LDL coverage, whereas exerted no significant effects on its MMID, EC apoptosis, and the leaky junctions. On the contrary, 24-h shear exposure has no significant effects on LDL coverage, whereas increased 2.74-folds of MMID and about 53% of EC apoptotic rates that could be inhibited by HAase treatment. These results suggest endothelial glycocalyx acts as a transport barrier by decreasing water and LDL transport, as well as a mechanosensor of shear to regulate EC apoptosis, thus affecting leaky junctions and regulating LDL transport into the vessel wall.NEW & NOTEWORTHY A 42% degradation of the endothelial glycocalyx by hyaluronidase of the isolated rat abdominal aorta facilitated water and LDL transport across the vessel wall, suggesting endothelial glycocalyx as a transport barrier. A 24-h shear exposure increased LDL mean maximum infiltration distance, and enhanced EC apoptosis, which could be both inhibited by hyaluronidase treatment, suggesting endothelial glycocalyx may also act as a mechanosensor of shear to regulate EC apoptosis, thus affecting leaky junctions and regulating LDL transport.


Asunto(s)
Aorta Abdominal/metabolismo , Células Endoteliales/metabolismo , Glicocálix/metabolismo , Lipoproteínas LDL/metabolismo , Agua/metabolismo , Animales , Aorta Abdominal/ultraestructura , Apoptosis , Transporte Biológico , Células Endoteliales/ultraestructura , Glicocálix/ultraestructura , Hialuronoglucosaminidasa/metabolismo , Técnicas In Vitro , Masculino , Mecanotransducción Celular , Permeabilidad , Ratas Sprague-Dawley , Flujo Sanguíneo Regional , Estrés Mecánico
5.
Am J Physiol Heart Circ Physiol ; 319(4): H814-H823, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32822214

RESUMEN

Hypercholesterolemia- and atherosclerosis-caused vasomotor property dysfunction may be involved in many clinic manifestations of atherosclerosis, including angina, acute myocardial infarction, and sudden cardiac death. However, its underlying mechanism is not clear. The endothelial glycocalyx is a protective surface layer on the endothelial cells, serving as a molecular sieve, cell adhesion modulator, and mechanosensor for blood flow. In the present study, we demonstrated by confocal microscopy in Sprague-Dawley (SD) male rats fed a 12-wk high-cholesterol diet (HC) compared with the normal diet (NC) that the dimension of the endothelial glycocalyx reduced significantly in both the common carotid artery (2.89 ± 0.41 µm and 3.25 ± 0.44 µm, respectively) and the internal sinus region (2.35 ± 0.07 µm and 3.46 ± 0.86 µm, respectively). Furthermore, we showed by real-time PCR that this dimension modification of endothelial glycocalyx may be attributed to a significant downregulation of heparan sulfate proteoglycan (HSPG)-related genes, including syndecan-3, glypican-1, and EXT1, not resulting from an enhanced shedding of sulfated glycosaminoglycans (sGAGs) from the vessel wall to the plasma. Meanwhile, the mean contraction and relaxation forces of the common carotid artery with responses to norepinephrine (NE) and acetylcholine (ACh) decreased ~0.34- and 0.13-fold, respectively, accompanied by a lower level of nitric oxide (NO) release. These findings suggest that the atherogenic high cholesterol diet diminished endothelial glycocalyx and disturbed the local NO release, thus contributing to the impaired vasomotor properties of the vessel.NEW & NOTEWORTHY Twelve-week high-cholesterol (HC) diet reduces the thickness of the endothelial glycocalyx in Sprague-Dawley (SD) male rats, which is mainly attributed to a downregulation of heparan sulfate proteoglycan-related genes (syndecan-3, glypican-1, EXT1), not resulting from an enhanced shedding of sulfated glycosaminoglycans (sGAGs) into the plasma. HC-diminished glycocalyx may disturb its mechanotransduction of local shear stress, lower nitric oxide (NO) release, and impair vasomotor responses to norepinephrine (NE) and acetylcholine (ACh).


Asunto(s)
Arterias Carótidas/patología , Enfermedades de las Arterias Carótidas/patología , Dieta Aterogénica , Células Endoteliales/patología , Glicocálix/patología , Vasoconstricción , Vasodilatación , Animales , Arterias Carótidas/metabolismo , Arterias Carótidas/fisiopatología , Enfermedades de las Arterias Carótidas/genética , Enfermedades de las Arterias Carótidas/metabolismo , Enfermedades de las Arterias Carótidas/fisiopatología , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Regulación de la Expresión Génica , Glicocálix/metabolismo , Glicosaminoglicanos/metabolismo , Masculino , Óxido Nítrico/metabolismo , Ratas Sprague-Dawley , Transducción de Señal
6.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 37(6): 967-973, 2020 Dec 25.
Artículo en Zh | MEDLINE | ID: mdl-33369335

RESUMEN

Biodegradable stents (BDSs) are the milestone in percutaneous coronary intervention(PCI). Biodegradable polymeric stents have received widespread attention due to their good biocompatibility, moderate degradation rate and degradation products without toxicity or side effects. However, due to the defects in mechanical properties of polymer materials, the clinical application of polymeric BDS has been affected. In this paper, the BDS geometric configuration design was analyzed to improve the radial strength, flexibility and reduce the shrinkage rate of biodegradable polymeric stents. And from the aspects of numerical simulation, in vitro experiment and animal experiment, the configuration design and mechanical properties of biodegradable polymeric stents were introduced in detail in order to provide further references for the development of biodegradable polymeric stents.


Asunto(s)
Stents , Implantes Absorbibles , Animales , Intervención Coronaria Percutánea , Polímeros , Diseño de Prótesis
7.
Biochem Biophys Res Commun ; 512(3): 498-504, 2019 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-30904162

RESUMEN

Thoracic aortic aneurysm (TAA) is fatal diseases, which leads to aortic rupture and sudden death. Blood pressure-lowering drugs are ineffective for most of the patients. Our previous study demonstrated the inhibition of endothelial secreted miR-126-3p by rapamycin ameliorate the aneurysmal phenotype of smooth muscle cells (SMCs) in vitro. Hence, this study aimed to evaluate the modulation and mechanism of miR-126-3p in a murine model of TAA (Fbn1C1039G/+). Our results showed that noticeable disturbed flow (DF) was observed in the aorta of Fbn1C1039G/+ mice, and the expression of miR-126-3p was significantly increased under the DF in the cell chamber. This finding was also confirmed by tests in the corresponding DF area of the human aortic aneurysm tissue. Constant rapamycin administration significantly ameliorates the incidence and severity of Fbn1C1039G/+ mice characterized by decreased aortic media degradation, macrophage infiltration and MMP2/9 expression in the aortic wall. Mechanistic studies showed that rapamycin attenuates TAA progression by inhibiting miR-126-3p through ERK1/2 inactivation.


Asunto(s)
Antibacterianos/uso terapéutico , Aneurisma de la Aorta Torácica/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , MicroARNs/genética , Sirolimus/uso terapéutico , Animales , Aneurisma de la Aorta Torácica/genética , Aneurisma de la Aorta Torácica/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Humanos , Ratones , Ratones Endogámicos C57BL
8.
Biomed Eng Online ; 18(1): 50, 2019 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-31023303

RESUMEN

BACKGROUND: Blood flow condition may have influence upon the hydraulic conductivity of venous graft (Lp,vein) in an arterial bypass, then affecting the accumulation of low-density lipoproteins (LDLs) within the graft wall. To probe this possibility, we first measured in vitro the filtration rates of swine lateral saphenous vein segments under different flow rates, and the correlation of Lp,vein with wall shear stress (WSS) was then obtained. RESULTS: The experimental results showed that when WSS was very low, Lp,vein would increase drastically with WSS from 1.16 ± 0.15 × 10-11 m/s Pa at 0 dyn/cm2 to 2.17 ± 0.20 × 10-11 m/s Pa at 0.7 dyn/cm2, then became constant of approximately 2.33 × 10-11 m/s Pa as the WSS increased further. Based on the experimental results, we assumed three different cases of Lp,vein and numerically simulated the LDLs transport in an arterial bypass model with venous graft. Case A: Lp,vein = 2.33 × 10-11 m/s Pa; Case B: Lp,vein = 1.16 × 10-11 m/s Pa (static condition with WSS of 0); Case C: Lp,vein was shear dependent. The simulation showed that the deposition/accumulation of LDLs within the venous graft wall in Case A was greatly enhanced when compared with that in Case B. However, the LDL accumulation in the graft wall was similar for Case A and Case C. CONCLUSIONS: Our study, therefore, indicates that when the venous graft was implanted as a bypass graft, the Lp,vein might remain nearly constant along its whole length except for very few areas where the value of WSS was extremely low (less than 0.7 dyn/cm2) and the effects of Lp,vein modulated by blood flow on LDL transport may be neglected.


Asunto(s)
Arterias/cirugía , Hidrodinámica , Lipoproteínas LDL/metabolismo , Injerto Vascular , Venas/cirugía , Animales , Modelos Biológicos , Transporte de Proteínas , Estrés Mecánico , Porcinos
9.
Clin Exp Pharmacol Physiol ; 46(11): 1013-1021, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31175664

RESUMEN

The importance of vascular cell glycocalyx in mechanotransduction has been demonstrated by many studies. The simulated microgravity induced a region-dependent adaptation of arterial glycocalyx including its thickness, coverage, and gene expression in conduit arteries of tail-suspended rats has been reported in our previous studies. Herein, we extended this line of research by quantifying the mRNA levels of three nitric oxide synthase (NOSI, NOSII, and NOSIII) and evaluating the apoptotic rates of endothelial cells (ECs) and smooth muscle cells (SMCs) in the common carotid artery, abdominal aorta, and femoral artery of 3 week tail-suspended rats. Results indicated that the tail suspension of rats induced about 0.36, 0.22, and 0.33 fold down-regulation of NOSI, NOSII, and NOSIII in the abdominal aorta, while 3.21, and 3.48 fold up-regulation of NOSII and NOSIII in the carotid artery and no significant effects on three NOS isoforms in the femoral artery. Moreover, the apoptosis of ECs and SMCs were significantly inhibited in both carotid artery and abdominal aorta, while enhanced in the femoral artery of the tail-suspended rats. A linear positive correlation exists between the normalized coverage of the glycocalyx and the normalized NOSI and NOSIII mRNA levels. These results indicated that the redistribution of haemodynamics in the conduit arteries of 3 week tail-suspended rats regulated the glycocalyx, NOS expression, and vascular cell apoptosis in a region-dependent manner, contributing to the final vascular remodelling under simulated microgravity condition.


Asunto(s)
Adaptación Fisiológica , Apoptosis , Arterias/metabolismo , Regulación Enzimológica de la Expresión Génica , Glicocálix/metabolismo , Suspensión Trasera/efectos adversos , Óxido Nítrico Sintasa/genética , Animales , Arterias/fisiología , Elasticidad , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/metabolismo , ARN Mensajero/genética , Ratas
10.
Biomed Eng Online ; 17(1): 85, 2018 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-29921281

RESUMEN

BACKGROUND AND AIMS: The crossed limbs stent graft technique is regularly employed to treat abdominal aortic aneurysm patients with unfavorable aneurysm necks or widely splayed common iliac arteries. This article numerically evaluates the hemodynamic performance of the crossed limbs strategy by analyzing numerical simulations and conducting experiments using two series of idealized bifurcated stent grafts with different cross angles and cross positions. RESULTS: Results demonstrated that the absolute helicity at outlets decreased with increased cross angles and increased with decreased cross positions. The time-averaged wall shear stress remained approximately unchanged, whereas the oscillating shear index and relative resident time decreased slightly when the cross angle increased and cross position decreased in iliac grafts. Additionally, both numerical and in vitro experimental results indicate the displacement force acting on the stent graft gradually increased as cross angles increased and cross positions decreased. Results further indicated that strip areas with a high oscillating shear index and high relative resident time, which may be vulnerable to thrombosis formation, exist along the outer surface of the iliac artery grafts. CONCLUSION: Given this information, the optimal crossed limbs configuration may contain a small cross angle and low cross position; however, low cross positions may increase the risk of migration.


Asunto(s)
Simulación por Computador , Hemodinámica , Stents , Aneurisma de la Aorta Abdominal/fisiopatología , Aneurisma de la Aorta Abdominal/terapia , Arteria Ilíaca/fisiología , Resistencia al Corte , Estrés Mecánico
11.
Int J Mol Sci ; 19(9)2018 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-30135409

RESUMEN

Cancer is a malignant tumor that threatens the health of human beings, and has become the leading cause of death in urban and rural residents in China. The glycocalyx is a layer of multifunctional glycans that covers the surfaces of a variety of cells, including vascular endothelial cells, smooth muscle cells, stem cells, epithelial, osteocytes, as well as cancer cells. The glycosylation and syndecan of cancer cell glycocalyx are unique. However, heparan sulfate (HS), hyaluronic acid (HA), and syndecan are all closely associated with the processes of cancer progression, including cell migration and metastasis, tumor cell adhesion, tumorigenesis, and tumor growth. The possible underlying mechanisms may be the interruption of its barrier function, its radical role in growth factor storage, signaling, and mechanotransduction. In the later sections, we discuss glycocalyx targeting therapeutic approaches reported in animal and clinical experiments. The study concludes that cancer cells' glycocalyx and its role in cancer progression are beginning to be known by more groups, and future studies should pay more attention to its mechanotransduction of interstitial flow-induced shear stress, seeking promising therapeutic targets with less toxicity but more specificity.


Asunto(s)
Glicocálix/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Animales , Biomarcadores de Tumor , Movimiento Celular , Progresión de la Enfermedad , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Mecanotransducción Celular , Terapia Molecular Dirigida , Metástasis de la Neoplasia , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Estrés Mecánico , Sindecanos/genética
12.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 35(6): 959-963, 2018 12 25.
Artículo en Zh | MEDLINE | ID: mdl-30583323

RESUMEN

The phenomenon of sex differences exists in patients who have abdominal aortic aneurysms (AAA). The occurrence rate of AAA is higher in male, while the rates of rupture and postoperative mortality are higher for female. This phenomenon of sex differences would affect the diagnosis, treatment and postoperative rehabilitation for AAA patients. This article reviewed the recent research status of sex differences on AAA, and explored the phenomenon of sex differences from the aspects of threshold determination, biomechanics and mechanobiology. This review points out that the sex differences on AAA could ascribe to the differences of biomechanical environment and biological properties induced by the vascular size, anatomy structure and structure components of abdominal aortic artery. The comprehensive investigations of the sex differences on AAA could help to optimize the diagnosis, treatment and device design, patient care and rehabilitation strategy of AAA based on sex differences phenomenon.

13.
Biomed Eng Online ; 15(Suppl 2): 135, 2016 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-28155691

RESUMEN

BACKGROUND: Abdominal aortic aneurysm (AAA) is a kind of dangerous aortic vascular disease, which is characterized by abdominal aorta partial enlargement. At present, endovascular aneurysm repair (EVAR) is one of the main treatments of abdominal aortic aneurysm. However for some patients after EVAR the aneurysm re-expanded and even ruptured, leading to poor postoperative effect. The stent-graft endoleak after EVAR was realized to influence the AAA in-sac pressure and contribute to the aneurysm re-enlargement. METHODS: In order to analyze the influence of endoleaks positions on the pressure shielding ability of stent-graft after EVAR, type I and type III endoleak models were reconstructed based on computed tomography (CT) scan images, and the hemodynamic environment in AAA was numerically simulated. RESULTS: When the endoleak was at the proximal position the pressure shielding ability will be obviously weakened. While, the pressure shielding ability was higher in the systole phase than that in diastole phase when the endoleak located at the middle or distal positions. Unfortunately, when the endoleak located at the proximal position, the pressure shielding ability would be relatively weak in the whole cardiac cycle. CONCLUSIONS: The results revealed that the influence of endoleaks on pressure shielding ability of stent-graft was both location and time specific.


Asunto(s)
Aneurisma de la Aorta Abdominal/fisiopatología , Aneurisma de la Aorta Abdominal/cirugía , Endofuga , Procedimientos Endovasculares/métodos , Stents , Aneurisma de la Aorta Abdominal/diagnóstico por imagen , Aortografía , Simulación por Computador , Hemodinámica , Humanos , Procesamiento de Imagen Asistido por Computador , Modelos Cardiovasculares , Presión , Tomografía Computarizada por Rayos X
14.
Artif Organs ; 40(7): 669-77, 2016 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26581476

RESUMEN

Local flow disturbance by arterial stent struts has been shown to play an important role in stent thrombosis. To reduce the local flow disturbance near a stent strut, we proposed a new concept of stent design with small holes in the stent struts. The present study evaluated the new design numerically by comparing it with the traditional stent in terms of local hemodynamic parameters such as flow velocity, flow recirculation area, time-averaged wall shear stress (TAWSS), oscillating shear index (OSI), and relative residence time (RRT). The results demonstrated that when compared with the traditional strut, the new design could significantly enhance flow velocity and reduce the flow recirculation zone in the vicinity of the strut. Moreover, the new design would significantly elevate TAWSS and remarkably reduce OSI and RRT along the host arterial wall. In conclusion, the new design of stent struts with punched holes is advantageous over the traditional one in the aspect of improving local hemodynamics, which may reduce thrombosis formation and promote re-endothelialization after stenting.


Asunto(s)
Hemodinámica , Stents/efectos adversos , Trombosis/etiología , Velocidad del Flujo Sanguíneo , Vasos Sanguíneos/patología , Vasos Sanguíneos/fisiología , Simulación por Computador , Diseño de Equipo , Humanos , Hidrodinámica , Modelos Cardiovasculares , Estrés Mecánico , Trombosis/patología
15.
J Biol Chem ; 288(19): 13850-62, 2013 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-23546875

RESUMEN

BACKGROUND: Small ubiquitin-like modifiers (SUMO) are covalently conjugated to other proteins including nuclear receptors leading to modification of various cellular processes. RESULTS: Ligand-dependent SUMOylation of farnesoid X receptor (FXR) negatively regulates the expression of its target genes. CONCLUSION: SUMO modification attenuates the capacity of FXR to function as a transcriptional activator. SIGNIFICANCE: Defining post-translation modification of FXR bySUMOis important to understanding how this nuclear receptor functions in health and disease. The farnesoid X receptor (FXR) belongs to a family of ligand-activated transcription factors that regulate many aspects of metabolism including bile acid homeostasis. Here we show that FXR is covalently modified by the small ubiquitin-like modifier (Sumo1), an important regulator of cell signaling and transcription. Well conserved consensus sites at lysine 122 and 275 in the AF-1 and ligand binding domains, respectively, of FXR were subject to SUMOylation in vitro and in vivo. Chromatin immunoprecipitation (ChIP) analysis showed that Sumo1 was recruited to the bile salt export pump (BSEP), the small heterodimer partner (SHP), and the OSTα-OSTß organic solute transporter loci in a ligand-dependent fashion. Sequential chromatin immunoprecipitation (ChIP-ReChIP) verified the concurrent binding of FXR and Sumo1 to the BSEP and SHP promoters. Overexpression of Sumo1 markedly decreased binding and/or recruitment of FXR to the BSEP and SHP promoters on ChIP-ReChIP. SUMOylation did not have an apparent effect on nuclear localization of FXR. Expression of Sumo1 markedly inhibited the ligand-dependent, transactivation of BSEP and SHP promoters by FXR/retinoid X receptor α (RXRα) in HepG2 cells. In contrast, mutations that abolished SUMOylation of FXR or siRNA knockdown of Sumo1 expression augmented the transactivation of BSEP and SHP promoters by FXR. Pathways for SUMOylation were significantly altered during obstructive cholestasis with differential Sumo1 recruitment to the promoters of FXR target genes. In conclusion, FXR is subject to SUMOylation that regulates its capacity to transactivate its target genes in normal liver and during obstructive cholestasis.


Asunto(s)
Regulación de la Expresión Génica , Receptores Citoplasmáticos y Nucleares/metabolismo , Sumoilación , Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP , Transportadoras de Casetes de Unión a ATP/genética , Secuencias de Aminoácidos , Sustitución de Aminoácidos , Animales , Colestasis/metabolismo , Cromatina/metabolismo , Secuencia de Consenso , Técnicas de Silenciamiento del Gen , Células Hep G2 , Humanos , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Mutagénesis Sitio-Dirigida , Regiones Promotoras Genéticas , Unión Proteica , Procesamiento Proteico-Postraduccional , Transporte de Proteínas , ARN Interferente Pequeño/genética , Receptores Citoplasmáticos y Nucleares/química , Receptores Citoplasmáticos y Nucleares/genética , Proteína SUMO-1/genética , Proteína SUMO-1/metabolismo , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/genética , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/metabolismo , Transcripción Genética
16.
Am J Physiol Gastrointest Liver Physiol ; 306(2): G154-62, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24264050

RESUMEN

The organic solute transporter-α/ß (OSTα/ß) is a heteromeric transporter that is essential for bile acid and sterol disposition and for the enterohepatic circulation. To better understand the mechanism underlying OST gene regulation, the effects of retinoic acid (RA) on OSTα/ß gene expression were investigated. The results show a dose-dependent induction of OSTß but not OSTα expression in both Huh7 and HepG2 cells by RA treatment. A novel functional RA receptor response element (RARE; so-called DR5) in the promoter of OSTß gene was identified. The interaction of RARα/RXRα with the RARE was verified by electrophoretic mobility shift and chromatin immunoprecipitation assays and its functional importance by hOSTß promoter activation in luciferase reporter assays. The studies demonstrated that the RARE is also a constitutive androstane receptor (CAR) binding site for OSTß gene regulation. These results suggest that OSTß is a target of both FXR-mediated (by binding to IR-1 element) and RARα- and CAR-mediated (by binding to DR5 element) gene regulation pathways. In summary, this study has uncovered a novel RARE (DR5) element in the promoter of OSTß that binds RARα or CAR heterodimerized with RXRα and appears to function synergistically with the IR-1 element to provide maximal induction of OSTß in response to RA. These findings demonstrate a role for RARα and CAR in controlling OSTß expression levels.


Asunto(s)
Proteínas de Transporte de Membrana/biosíntesis , Receptores de Ácido Retinoico/fisiología , Secuencia de Bases , Western Blotting , Línea Celular Tumoral , Colestasis/metabolismo , Colesterol/metabolismo , Inmunoprecipitación de Cromatina , Ensayo de Cambio de Movilidad Electroforética , Genes Reporteros , Humanos , Proteínas de Transporte de Membrana/genética , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , ARN/biosíntesis , ARN/genética , ARN Interferente Pequeño/farmacología , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/fisiología , Elementos de Respuesta/fisiología , Receptor alfa de Ácido Retinoico , Receptor alfa X Retinoide/metabolismo , Transfección , Tretinoina/farmacología , Xenobióticos/metabolismo
18.
ScientificWorldJournal ; 2014: 803276, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25692178

RESUMEN

One assumption of DSC-MRI is that the injected contrast agent is kept totally intravascular and the arterial wall is impermeable to contrast agent. The assumption is unreal for such small contrast agent as Gd-DTPA can leak into the arterial wall. To investigate whether the unreal assumption is valid for the estimation of the delay and dispersion of the contrast agent bolus, we simulated flow and Gd-DTPA transport in a model with multilayer arterial wall and analyzed the bolus delay and dispersion qualified by mean vascular transit time (MVTT) and the variance of the vascular transport function. Factors that may affect Gd-DTPA transport hence the delay and dispersion were further investigated, such as integrity of endothelium and disturbed flow. The results revealed that arterial transmural transport would slightly affect MVTT and moderately increase the variance. In addition, although the integrity of endothelium can significantly affect the accumulation of contrast agent in the arterial wall, it had small effects on the bolus delay and dispersion. However, the disturbed flow would significantly increase both MVTT and the variance. In conclusion, arterial transmural transport may have a small effect on the bolus delay and dispersion when compared to the flow pattern in the artery.


Asunto(s)
Arterias/fisiología , Permeabilidad Capilar , Medios de Contraste/farmacocinética , Gadolinio DTPA/farmacocinética , Modelos Cardiovasculares , Arterias/efectos de los fármacos , Humanos , Imagen por Resonancia Magnética
19.
ASAIO J ; 70(4): 280-292, 2024 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-38215762

RESUMEN

To investigate the effects of blood pumps operated in different modes on nonphysiologic flow patterns, cell and protein function, and the risk of bleeding, thrombosis, and hemolysis, an extracorporeal blood pump (CentriMag) was operated in three clinical modalities including heart failure (HF), venous-venous (V-V) extracorporeal membrane oxygenation (ECMO), and venous-arterial (V-A) ECMO. Computational fluid dynamics (CFD) methods and coupled hemolysis models as well as recently developed bleeding and thrombosis models associated with changes in platelet and von Willebrand factor (vWF) function were used to predict hydraulic performance and hemocompatibility. The V-A ECMO mode had the highest flow losses and shear stress levels, the V-V ECMO mode was intermediate, and the HF mode was the lowest. Different nonphysiologic flow patterns altered cell/protein morphology and function. The V-A ECMO mode resulted in the highest levels of platelet activation, receptor shedding, vWF unfolding, and high molecular weight multimers vWF (HMWM-vWF) degradation, leading to the lowest platelet adhesion and the highest vWF binding capacity, intermediate in the V-V ECMO mode, and opposite in the HF mode. The V-A ECMO mode resulted in the highest risk of bleeding, thrombosis, and hemolysis, with the V-V ECMO mode intermediate and the HF mode lowest. These findings are supported by published experimental or clinical statistics. Further studies found that secondary blood flow passages resulted in the highest risk of blood damage. Nonphysiologic blood flow patterns were strongly associated with cell and protein function changing, blood damage, and complications.


Asunto(s)
Insuficiencia Cardíaca , Trombosis , Humanos , Factor de von Willebrand/metabolismo , Hemólisis , Hemorragia/etiología , Activación Plaquetaria , Insuficiencia Cardíaca/complicaciones
20.
Food Res Int ; 176: 113815, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38163719

RESUMEN

Gastrojejunostomy is a prominent approach in managing distal gastric cancer that is unresectable due to gastric outlet obstruction (GOO). Research has demonstrated that stomach-partitioning gastrojejunostomy (SPGJ) exhibits superior clinical efficacy compared to conventional gastrojejunostomy (CGJ), however, the underlying mechanism of this phenomenon remains elusive. This study constructed 3D models of the SPGJ and CGJ based on the computed tomography (CT) images obtained from a patient diagnosed with distal gastric cancer. The biomechanical patterns of these procedures in the digestive system were subsequently compared through numerical simulations and in vitro experiments. The results of the numerical simulation demonstrated that the model following SPGJ promoted the discharge of food through the anastomotic orifice and into the lower jejunum. Furthermore, a decrease in passage size after partitioning, the low-level velocity of esophageal, and an increase in contents viscosity effectively inhibited the flow through the passage to the pylorus, ultimately reducing stimulation to tumor. The study also revealed that favorable gastric emptying is associated with a smaller passage and faster inlet velocity, and that lower contents viscosity. ​The experimental findings conducted in vitro demonstrated that SPGJ exhibited superior efficacy in obstructing the flow near the pylorus in comparison to CGJ. Moreover, a decrease in passage size correlates with a reduction in fluid flow towards the pylorus. These results provide the foundation of theory and practice for the surgical management of patients with GOO resulting from unresectable distal gastric cancer, and have potential implications for clinical interventions.


Asunto(s)
Derivación Gástrica , Obstrucción de la Salida Gástrica , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/complicaciones , Derivación Gástrica/métodos , Vaciamiento Gástrico , Resultado del Tratamiento , Obstrucción de la Salida Gástrica/complicaciones , Obstrucción de la Salida Gástrica/cirugía
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