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1.
J Innov Card Rhythm Manag ; 14(12): 5690-5696, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38155725

RESUMO

Pulmonary vein isolation via cryoballoon (CB) ablation is the cornerstone ablation strategy for the treatment of atrial fibrillation (AF). Acute intraprocedural hypotensive and/or bradycardic responses have been reported in patients undergoing CB ablation for AF. However, it remains unclear as to whether these are due to a true vagal response (VR), which can be used to predict long-term outcomes of CB ablation. We analyzed 139 freezes across 17 patients who received CB ablation for paroxysmal AF, measuring vital signs and freeze characteristics. Only one freeze was associated with both hypotension and bradycardia, constituting a true VR. Several freezes were associated with hypotension only that did not respond to atropine administration, suggesting that these responses are not associated with a VR. Hypotensive responses were significantly associated with ice bubble bursts during CB deflation. Unlike the true VR reported in patients undergoing conscious sedation, the presence of acute hypotension shortly after CB deflation cannot be used as a predictor for long-term ablation outcomes.

2.
F1000Res ; 12: 432, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37533483

RESUMO

Background: The complement system is made up of an abundance of unique plasma proteins that play an important role in innate immunity and inflammation, aiding in the fight against pathogenic microbes and viral diseases. The purpose of this study was to evaluate the serum complement C4 concentration in COVID-19 patients in Khartoum and compare them to healthy controls. Methods: A total of 100 samples were collected, 50 samples from COVID-19 patients who presented as cases and 50 samples from people who were evidently healthy. Overall, 33 (66%) the patient populations in the case group were not in the hospital's intensive care unit (ICU), compared to 17 (34%) who were. The concentrations of C4 in each serum sample were calculated in milligrams per deciliter. SPSS version (20) was used to analyze the data. Results: The means level of complement C4 (mg/dL) were 37.44 ±18.618, 23.90 ±10.229 in the case group and in the control group, respectively. There was a statistically significant difference in complement C4 level between case and control (p-values ≤0.01). In addition, the mean complement C4 level in the ICU and non-ICU case groups was 25.00±17.85 and 43.85±15.712 mg/dL, respectively. There was a statistically significant variance in complement C4 level between ICU and non-ICU (p-values ≤0.01). Furthermore, the cases were divided into four age groups: 20-40, 40-60, 60-80, and over 80 years old. The one-way ANOVA test showed no statistically significant differences between age categories in complement C4 level (P = 0.735) Conclusions: The case group had a higher mean level of complement C4 than the control group, which could be understood by the stimulation of the complement cascade during the COVID-19 illness. Furthermore, the complement C4 level in severe COVID-19 patients was lower than in non-severe COVID-19.


Assuntos
COVID-19 , Complemento C4 , Humanos , Adulto Jovem , Adulto , Idoso de 80 Anos ou mais , Complemento C4/metabolismo , Complemento C3/análise , Complemento C3/metabolismo , Estudos de Casos e Controles
3.
Case Rep Oncol ; 16(1): 188-203, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37033700

RESUMO

Novel coronavirus-19 (COVID-19) variants continue to spread worldwide with the development of highly transmissible strains. Several guidelines addressing management of cancer patients during the COVID-19 pandemic have been published, primarily based upon expert opinion. The COVID-19 pandemic has affected all aspects of breast cancer care including screening, diagnosis, treatment, and long-term follow-up. Recent reports indicate that mRNA COVID-19 vaccines can provoke lymphadenopathy in both cancer patients and healthy individuals. Unilateral axillary lymphadenopathy (UAL) post-COVID-19 vaccination is a challenging presentation for cancer patients because of the potential for misinterpretation as malignancy. The World Health Organization's target to vaccinate 70% of the world's population by mid-2023 is likely to increase the incidence of post-COVID-19 vaccination UAL. In this article, we review the published evidence regarding UAL post-COVID-19 vaccination and present diverse cases of breast cancer patients where false-positive UAL post-COVID-19 vaccination proved to be a therapeutic challenge. The United Arab Emirates (UAE) vaccination program is well ahead of other countries in the world, having accomplished the target of 100% vaccination of the population with at least one dose. Therefore, an increasing number of recently vaccinated patients are likely to present with UAL, detected by surveillance imaging, post-vaccination. We have therefore made recommendations regarding the management of cancer patients with UAL post-COVID-19 vaccination in order to avoid misdiagnosis and unnecessary imaging or invasive biopsy procedures.

4.
Skin Pharmacol Physiol ; 36(1): 16-26, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36455520

RESUMO

INTRODUCTION: Heparin is a commonly used anti-coagulant administered either by intravenous or subcutaneous injection for a systemic effect or topically for the treatment of peripheral vascular disorders. OBJECTIVE: This study aimed to formulate heparin in non-ionic colloidal carrier systems (CCSs) having enhanced percutaneous absorption for systemic and topical administration. METHODS: Five CCSs were developed and characterized for their rheological properties, droplet size, and drug loading. The percutaneous absorption of heparin was evaluated in vitro using Franz diffusion cells with rats' skin and with the aid of a developed high-pressure chromatography method. Furthermore, the efficacy of two developed heparin CCSs was tested percutaneously in rats by measuring the response against the time in comparison to subcutaneous administration. RESULTS: The rheograms and droplet size measurements showed that the developed drug delivery systems have Newtonian properties with a droplet size between 109 and 460 nm. As much as 500 mg of heparin could be loaded in around 5 mL of CCS. Furthermore, using Franz diffusion cells, a diffusion rate of 19.216 ± 2.01 USP U/cm2.h could be achieved for heparin-loaded CCSs. Moreover, the estimated percutaneous in vivo relative bioavailability in comparison to subcutaneous administration could reflect that at least more than 50% of the drug passed through the skin. CONCLUSION: The developed novel non-toxic CCSs containing heparin can be good candidates for percutaneous administration as alternative delivery systems for subcutaneous and intravenous invasive administration.


Assuntos
Heparina , Pele , Ratos , Animais , Administração Cutânea , Heparina/metabolismo , Heparina/farmacologia , Pele/metabolismo , Absorção Cutânea , Sistemas de Liberação de Medicamentos/métodos , Preparações Farmacêuticas
6.
Proc (Bayl Univ Med Cent) ; 34(6): 710-711, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34732997

RESUMO

Ventricular premature contractions are often located in the left ventricular outflow tract (LVOT). Components of the normal atrioventricular conduction apparatus are located just below the aortic valve in proximity to the membranous septum, between the noncoronary cusp and right coronary cusp. We present a case of injury to the bundle of His during an ablation of a ventricular premature contraction in the LVOT below the left coronary cusp, remote from the bundle of His, due to pressure from the proximal shaft of the catheter between the noncoronary cusp and the right coronary cusp.

7.
Materials (Basel) ; 14(19)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34640088

RESUMO

In this report, the heating efficiencies of γ-Fe2O3 and hybrid γ-Fe2O3-TiO2 nanoparticles NPs under an alternating magnetic field (AMF) have been investigated to evaluate their feasible use in magnetic hyperthermia. The NPs were synthesized by a modified sol-gel method and characterized by different techniques. X-ray diffraction (XRD), Mössbauer spectroscopy and electron microscopy analyses confirmed the maghemite (γ-Fe2O3) phase, crystallinity, good uniformity and 10 nm core sizes of the as-synthesized composites. SQUID hysteresis loops showed a non-negligible coercive field and remanence suggesting the ferromagnetic behavior of the particles. Heating efficiency measurements showed that both samples display high heating potentials and reached magnetic hyperthermia (42 °C) in relatively short times with shorter time (~3 min) observed for γ-Fe2O3 compared to γ-Fe2O3-TiO2. The specific absorption rate (SAR) values calculated for γ-Fe2O3 (up to 90 W/g) are higher than that for γ-Fe2O3-TiO2 (~40 W/g), confirming better heating efficiency for γ-Fe2O3 NPs. The intrinsic loss power (ILP) values of 1.57 nHm2/kg and 0.64 nHm2/kg obtained for both nanocomposites are in the range reported for commercial ferrofluids (0.2-3.1 nHm2/kg). Finally, the heating mechanism responsible for NP heat dissipation is explained concluding that both Neel and Brownian relaxations are contributing to heat production. Overall, the obtained high heating efficiencies suggest that the fabricated nanocomposites hold a great potential to be utilized in a wide spectrum of applications, particularly in magnetic photothermal hyperthermia treatments.

8.
Case Rep Infect Dis ; 2021: 9216825, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34336317

RESUMO

INTRODUCTION: Coupled with the increasing use of indwelling vascular catheters and prosthetic cardiac valves is an uptrend in sepsis secondary to fungemia. An insidious onset often shrouds the initial diagnosis, contributing to poor outcomes. Candida infective endocarditis (CIE) is a feared complication of candidemia, associated with high mortality rates. It requires prolonged hospital stays for medical and, often, surgical management. We report a case of a massive intracardiac Candida mass in an adult with native valve CIE. CASE: A 51-year-old male on chronic total parenteral nutrition (TPN) because of bowel resection presented with fevers, night sweats, and unintentional weight loss. He was febrile and tachycardiac on admission, with a benign physical examination. Laboratory workup showed elevated inflammatory markers and an acute kidney injury. Extended blood cultures showed growth of Candida glabrata (C. glabrata) and Candida dubliniensis (C. dubliniensis). Transthoracic (TTE) and transesophageal echocardiography revealed a large mobile right atrial mass (4 cm × 6 cm × 2.5 cm), extending to the right ventricular outflow tract. Since he was a poor surgical candidate, management with micafungin was initiated and continued for 8 weeks. He responded well to the regimen with resolution of the fungal mass on follow-up TTE 3 months later. In anticipation of the future need for TPN, he continues on lifelong suppressive oral fluconazole. CONCLUSION: CIE may be an insidious complication of indwelling central venous catheters, necessitating a high index of suspicion. Conservative management, with antifungal therapy, can yield favorable outcomes in poor surgical candidates.

9.
Heart Rhythm O2 ; 2(3): 239-246, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34337574

RESUMO

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia in adults. Research suggests that autonomic nervous (ANS) system dysfunction contributes to AF pathophysiology. Animal studies have shown that low-level electromagnetic fields (LL-EMF) are potentially capable of AF suppression. This study evaluated the safety and efficacy of LL-EMF in suppressing AF in humans. OBJECTIVE: To investigate the impact of LL-EMF on AF inducibility in humans. METHODS: Patients presenting for ablation of paroxysmal AF were randomized to a sham protocol or LL-EMF (3.2 × 10-8 G at 0.89 Hz) applied via a Helmholtz coil around the head. AF was induced via atrial pacing, and was cardioverted if duration was greater than 15 minutes. The protocol was then run for 60 minutes, followed by reinduction of AF. The primary endpoint was the duration of pacing-induced AF after protocol completion compared between groups. RESULTS: Eighteen patients completed the study protocol (n = 10 sham, n = 8 LL-EMF). Pacing-induced AF duration in the LL-EMF group was 11.0 ± 3.43 minutes shorter than control after protocol completion (CI 3.72-18.28 minutes, P = .03). A smaller proportion of LL-EMF patients experienced spontaneous firing initiating an AF episode (0/7 vs 5/6, P = .0047). A significantly greater proportion of patients in the control group required direct current cardioversion after 1 hour (0.78 vs 0.13, P = .02). CONCLUSION: In patients with paroxysmal AF, LL-EMF stimulation results in shorter episodes of pacing-induced AF and a reduced likelihood of spontaneous firing initiating an episode of AF.

10.
Addiction ; 116(9): 2398-2408, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33404141

RESUMO

BACKGROUND AND AIM: Buprenorphine (BUP) maintenance treatment for opioid use disorder (OUD) begins with supervised daily dosing. We estimated the clinical effectiveness of a novel incentivised medication adherence and abstinence monitoring protocol in BUP maintenance to enable contingent access to increasing take-home medication supplies. DESIGN: Two-arm, single-centre, pragmatic, randomised controlled trial of outpatient BUP maintenance, with during-treatment follow-ups at 4 weeks, 8 weeks, 12 weeks and 16 weeks. SETTING: Inpatient and outpatient addictions treatment centre in the United Arab Emirates. PARTICIPANTS: Adults with OUD, voluntarily seeking treatment. INTERVENTIONS: The experimental condition was 16 weeks BUP maintenance with incentivised adherence and abstinence monitoring (I-AAM) giving contingent access to 7-day, then 14-day, then 21-day and 28-day medication supply. The control, treatment-as-usual (TAU) was 16 weeks BUP maintenance, with contingent access to 7-day then 14-day supply. MEASUREMENTS: The primary outcome was number of negative urine drug screens (UDS) for opioids, with non-attendance or otherwise missed UDS, imputed as positive for opioids. The secondary outcome was retention in treatment (continuous enrolment to the 16-week endpoint). FINDINGS: Of 182 patients screened, 171 were enrolled and 141 were randomly assigned to I-AAM (70 [49.6%]) and to TAU (71 [50.4%]. Follow-up rates at 4 weeks, 8 weeks, 12 weeks and 16 weeks were 91.4%, 85.7%, 71.0%, 60.0% respectively in I-AAM and 84.5%, 83.1%, 69.0%, 56.3% in TAU. By intention-to-treat, the absolute difference in percentage negative UDS for opioids was 76.7% (SD = 25.0%) in I-AAM versus 63.5% (SD = 34.7%) in TAU (mean difference = 13.3%; 95% CI = 3.2%-23.3%; Cohen's d = 0.44; 95% CI = 0.10-0.87). In I-AAM, 40 participants (57.1%) were retained versus 33 (46.4%) in TAU (odds ratio = 1.54; 95% CI = 0.79-2.98). CONCLUSIONS: Buprenorphine maintenance with incentivised therapeutic drug monitoring to enable contingent access to increasing take-home medication supplies increased abstinence from opioids compared with buprenorphine maintenance treatment-as-usual, but it did not appear to increase treatment retention.


Assuntos
Buprenorfina , Transtornos Relacionados ao Uso de Opioides , Adulto , Analgésicos Opioides/uso terapêutico , Buprenorfina/uso terapêutico , Humanos , Adesão à Medicação , Antagonistas de Entorpecentes/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Resultado do Tratamento
11.
Plast Reconstr Surg Glob Open ; 8(7): e3001, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32802685

RESUMO

The columella is an underrepresented part of rhinoplasty. The objective of this study was to assess the outcome of columella correction following rhinoplasty and to assess any differences in the open and endonasal approach. METHODS: This is a retrospective study involving 65 rhinoplasty patients, who were divided into 2 groups depending on whether they had an open or endonasal approach. Fifteen patients underwent the open procedure, and 50 patients underwent the endonasal approach. Patients who underwent endonasal rhinoplasty were compared with open rhinoplasty patients in terms of their final outcome, with a focus on the columellar correction. The classification by Rohrich and Liu and Gunter's distance between the nasal axis and columella were used to assess the correction. RESULTS: The overall incidence of columellar correction was 90% in the endonasal group (45 of 50 patients) and 67% in the open approach group (10 of 15 patients); a comparison shows a P value of 0.043 (<0.05). An estimated 49 of 50 patients (98%) from the endonasal group saw a reduction in the nasal axis-columella distance when compared with the open rhinoplasty group, who saw a reduction in 12 of 15 patients (80%); statistical analysis shows a P value of 0.036 (<0.05). The quantitative reduction in this distance in all patients when compared between the 2 groups had a P value of <0.001, suggesting a greater overall reduction using the endonasal approach. This may be related to differences in distribution of the deformities within the 2 groups. CONCLUSIONS: There is no standard way to correct the columella, but it is important to identify the deformity and the need to correct it. In our patients, we found comparable outcomes in achieving a satisfactory columella in the open and endonasal groups.

12.
Med Hypotheses ; 140: 109640, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32143072

RESUMO

INTRODUCTION: Electrical storm (ES) is cardiac electrical instability characterized by recurrent episodes of ventricular tachyarrhythmias. ES is associated with increased mortality and morbidity, hence requires prompt intervention. Treatment of underlying etiology is of prime importance in termination of ES. Anti-arrhythmic medications serve as an adjunctive therapy in suppression of ES by reducing myocardial excitability. The anti-arrhythmic conventionally employed is amiodarone in combination with non-selective beta-blockers to reduce the adrenergic input to myocardium. However, anti-arrhythmics at increased concentrations can lead to adverse systemic effects including hemodynamic instability. HYPOTHESIS: We hypothesize 1. The use of intravenous or oral anti-arrhythmic therapy for patients in electrical storm is limited by their toxicities and blood pressure lowering effect. Corollary 1. Injection of anti-arrhythmic medications into the pericardial space, an extra-vascular structure encasing the heart, provides an option for use of higher concentration of anti-arrhythmic while limiting systemic absorption. Corollary 2. The pericardial space has direct communication to the epicardium, the outer most layer of cardiac muscle, spatial proximity may allow for effective therapeutic options in electrical storm. We present experimental and clinical evidence in support of these hypothesis.

13.
Beilstein J Nanotechnol ; 11: 1891-1904, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33447500

RESUMO

Free and partially encapsulated manganese ferrite (MnFe2O4) nanoparticles are synthesized and characterized regarding structure, surface, and electronic and magnetic properties. The preparation method of partially encapsulated manganese ferrite enables the formation of a hybrid nanoparticle/tube system, which exhibits properties of manganese ferrite nanoparticles inside and attached to the external surface of the tubes. The effect of having manganese ferrite nanoparticles inside the tubes is observed as a shift in the X-ray diffraction peaks and as an increase in stress, hyperfine field, and coercivity when compared to free manganese ferrite nanoparticles. On the other hand, a strong charge transfer from the multiwall carbon nanotubes is attributed to the attachment of manganese ferrite nanoparticles outside the tubes, which is detected by a significant decrease in the σ band emission of the ultraviolet photoemission spectroscopy signal. This is followed by an increase in the density of states at the Fermi level of the attached manganese ferrite nanoparticles in comparison to free manganese ferrite nanoparticles, which leads to an enhancement of the metallic properties.

14.
Fukushima J Med Sci ; 65(3): 99-108, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31656254

RESUMO

Stress is an inevitable part of nursing life. Nurses need to respond to their stressful environment contents to reduce negative consequences. We examined the role of dimensions of emotional intelligence in predicting coping reactions to stress in 201 college nursing practitioners in this cross-sectional study between November 2017 and January 2018. The nurses appraised their own emotions, but they were not sure that appraised others' emotions, regulated their and others' emotions. They could cope with new ideas and faced obstacles. Most of the nurses were moderately stressed. Those nurses were not able to regulate their own emotions were determined to have a higher level of perceived stress. Active coping, positive reframing and acceptance were the most prevalent coping mechanisms. The investigation showed that others' emotion appraisal was a predictor for self-blame reaction, and emotion utilization was the predictor for positive reframing and self-blame.


Assuntos
Adaptação Psicológica , Emoções , Profissionais de Enfermagem/psicologia , Estresse Ocupacional/psicologia , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Apoio Social
15.
Circ Arrhythm Electrophysiol ; 12(9): e007414, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31431051

RESUMO

BACKGROUND: Despite the publication of several randomized clinical trials comparing catheter ablation (CA) with medical therapy (MT) in patients with atrial fibrillation (AF), the superiority of one strategy over another is still questioned by many. In this meta-analysis of randomized controlled trials, we compared the efficacy and safety of CA with MT for AF. METHODS: We systematically searched MEDLINE, EMBASE, and other online sources for randomized controlled trials of AF patients that compared CA with MT. The primary outcome was all-cause mortality. Secondary outcomes included cardiovascular hospitalizations and recurrence of atrial arrhythmia. Subgroup analyses stratified by the presence of heart failure with reduced ejection fraction, type of AF, age, and sex were performed. Risk ratios (RRs) with 95% CIs were calculated using a random effects model, and Mantel-Haenszel method was used to pool RR. RESULTS: Eighteen randomized controlled trials comprising 4464 patients (CA, n=2286; MT, n=2178) were included. CA resulted in a significant reduction in all-cause mortality (RR, 0.69; 95% CI, 0.54-0.88; P=0.003) that was driven by patients with AF and heart failure with reduced ejection fraction (RR, 0.52; 95% CI, 0.35-0.76; P=0.0009). CA resulted in significantly fewer cardiovascular hospitalizations (hazard ratio, 0.56; 95% CI, 0.39-0.81; P=0.002) and fewer recurrences of atrial arrhythmias (RR, 0.42; 95% CI, 0.33-0.53; P<0.00001). Subgroup analyses suggested that younger patients (age, <65 years) and men derived more benefit from CA compared with MT. CONCLUSIONS: CA is associated with all-cause mortality benefit, that is driven by patients with AF and heart failure with reduced ejection fraction. CA reduces cardiovascular hospitalizations and recurrences of atrial arrhythmia for patients with AF. Younger patients and men appear to derive more benefit from CA.


Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/terapia , Ablação por Cateter/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Humanos , Resultado do Tratamento
16.
Org Lett ; 21(16): 6378-6382, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31361506

RESUMO

We investigated the ultrasonication-mediated effects on the Fmoc-based solid-phase peptide synthesis (SPPS). Our study culminated with the development of an ultrasound-assisted strategy (US-SPPS) that allowed for the synthesis of different biologically active peptides (up to 44-mer), with a remarkable savings of material and reaction time. Noteworthy, ultrasonic irradiation did not exacerbate the main side reactions and improved the synthesis of peptides endowed with "difficult sequences", placing the US-SPPS among the current high-efficient peptide synthetic strategies.

17.
World J Plast Surg ; 8(2): 259-261, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31309066

RESUMO

Pilar cysts are common cysts on the scalp and hair bearing area of the body. We found one such cyst on the dorsum of the thumb. There have been previous reports of them in the finger tips as a very rare occurrence. The site of this lesion supports the theory of a possible origin from the nail matrix. These lesions, even when found at unusual sites should have pilar cyst as a differential diagnosis. They must always be excised and subjected to careful histopathology to rule out proliferating trichilemmal cysts, which carry a rare risk of malignancy.

18.
Plast Reconstr Surg Glob Open ; 7(4): e2179, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31321181

RESUMO

BACKGROUND: A large proportion of scars in clinical practice represent good candidates for surgical revision by virtue of their unfavorable characteristics and relative orientation with respect to skin relaxed tension lines. W-plasty is a very popular excisional revision technique, which involves breaking up the scar margins into small triangular components, which are advanced and interdigitated without any rotation or transposition. METHODS: We performed an extensive literature search using Pubmed MEDLINE, Web of Science, and Embase using the following keywords [W-plasty] AND [scar] AND [revision]. We retrieved 13 articles pertinent to the indications, geometrical design, and technical evolution of the W-plasty scar revision variants. We formulate indications for the use of isosceles/equilateral as opposed to scalene triangle W-plasty and integrate our experience with regards to the choice of geometrical design for different bodily regions. CONCLUSIONS: W-plasty represents a popular technique in reconstructive plastic surgery practice. We believe that the exact W-plasty design should be guided by the relaxed skin tension line definition and to this effect propose 2 main variants of geometrical design pertinent to the index anatomical site.

19.
J Med Chem ; 62(3): 1455-1467, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30615452

RESUMO

In accordance with their common but also divergent physiological actions, human urotensin II (1) and urotensin II-related peptide (2) could stabilize specific urotensin II receptor (UTR) conformations, thereby activating different signaling pathways, a feature referred to as biased agonism or functional selectivity. Sequential N-methylation of the amides in the conserved core sequence of 1, 2, and fragment U-II4-11 (3) shed light on structural requirements involved in their functional selectivity. Thus, 18 N-methylated UTR ligands were synthesized and their biological profiles evaluated using in vitro competition binding assays, ex vivo rat aortic ring bioassays and BRET-based biosensor experiments. Biological activity diverged from that of the parent structures contingent on the location of amide methylation, indicating relevant hydrogen-bond interactions for the function of the endogenous peptides. Conformational analysis of selected N-methyl analogs indicated the importance of specific amide residues of 2 for the distinct pharmacology relative to 1 and 3.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Hormônios Peptídicos/farmacologia , Urotensinas/farmacologia , Animais , Células CHO , Cricetulus , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/síntese química , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ligantes , Masculino , Metilação , Ressonância Magnética Nuclear Biomolecular , Hormônios Peptídicos/síntese química , Hormônios Peptídicos/metabolismo , Conformação Proteica , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Urotensinas/síntese química , Urotensinas/metabolismo
20.
J Oncol ; 2019: 9293560, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31929800

RESUMO

Urotensin-II (UT-II) and its receptor (UTR) are involved in the occurrence of different epithelial cancers. In particular, UTR was found overexpressed on colon, bladder, and prostate cancer cells. The conjugation of ligands, able to specifically bind receptors that are overexpressed on cancer cells, to liposome surface represents an efficient active targeting strategy to enhance selectivity and efficiency of drug delivery systems. The aim of this study was to develop liposomes conjugated with UT-II (LipoUT) for efficient targeting of cancer cells that overexpress UTR. The liposomes had a mean diameter between 150 nm and 160 nm with a narrow size distribution (PI ≤ 0.1) and a doxo encapsulation efficiency of 96%. Moreover, the conjugation of UT-II to liposomes weakly reduced the zeta potential. We evaluated UTR expression on prostate (DU145, PC3, and LNCaP) and colon (WIDR and LoVo) cancer cells by FACS and western blotting analysis. UTR protein was expressed in all the tested cell lines; the level of expression was higher in WIDR, PC3, and LNCaP cells compared with LoVo and DU145. MTT cell viability assay showed that LipoUT-doxo was more active than Lipo-doxo on the growth inhibition of cells that overexpressed UTR (PC3, LNCaP, and WIDR) while in LoVo and DU145 cell lines, the activity was similar to or lower than that one of Lipo-doxo, respectively. Moreover, we found that cell uptake of Bodipy-labeled liposomes in PC3 and DU145 was higher for LipoUT than the not-armed counterparts but at higher extent in UTR overexpressing PC3 cells (about 2-fold higher), as evaluated by both confocal and FACS. In conclusion, the encapsulation of doxo in UT-II-targeted liposomes potentiated its delivery in UTR-overexpressing cells and could represent a new tool for the targeting of prostate and colon cancer.

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