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1.
J Neurochem ; 2023 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-38037434

RESUMO

NMDA receptors (NMDARs) play an important role in synaptic plasticity both in physiological and pathological conditions. GluN2A and GluN2B are the most expressed NMDAR regulatory subunits, in the hippocampus and other cognitive-related brain structures. GluN2B is characteristic of immature structures and GluN2A of mature ones. Changes in GluN2A expression were associated with complex phenotypes that led to complex neurodevelopmental disorders, including the occurrence of seizures. However, little is known about the role of GluN2A in these phenotypes. In this work, we reduced GluN2A expression in mature neuronal cultures and observed an altered GluN2A/GluN2B ratio. Furthermore, those neurons exhibit an increase in immature dendritic spines and dendritic branching, as well as an increased response to glutamate stimulus. This phenotype (considering GluN2A/GluN2B ratio, index branching and glutamate response) resembles those observed at immature neuronal stages in vitro. We propose that this immature phenotype led to a higher response to glutamate stimulus which, in vivo, would be the basis of reduced threshold for seizure onset in GluN2A-pathological conditions.

2.
Proc Natl Acad Sci U S A ; 117(42): 26123-26134, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33008881

RESUMO

The dynamical structure factor is one of the experimental quantities crucial in scrutinizing the validity of the microscopic description of strongly correlated systems. However, despite its long-standing importance, it is exceedingly difficult in generic cases to numerically calculate it, ensuring that the necessary approximations involved yield a correct result. Acknowledging this practical difficulty, we discuss in what way results on the hardness of classically tracking time evolution under local Hamiltonians are precisely inherited by dynamical structure factors and, hence, offer in the same way the potential computational capabilities that dynamical quantum simulators do: We argue that practically accessible variants of the dynamical structure factors are bounded-error quantum polynomial time ([Formula: see text])-hard for general local Hamiltonians. Complementing these conceptual insights, we improve upon a novel, readily available measurement setup allowing for the determination of the dynamical structure factor in different architectures, including arrays of ultra-cold atoms, trapped ions, Rydberg atoms, and superconducting qubits. Our results suggest that quantum simulations employing near-term noisy intermediate-scale quantum devices should allow for the observation of features of dynamical structure factors of correlated quantum matter in the presence of experimental imperfections, for larger system sizes than what is achievable by classical simulation.

3.
Development ; 145(14)2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-29866901

RESUMO

Based on functional evidence, we have previously demonstrated that early ventral Notch1 activity restricts dorsoanterior development in Xenopus We found that Notch1 has ventralizing properties and abolishes the dorsalizing activity of ß-catenin by reducing its steady state levels, in a process that does not require ß-catenin phosphorylation by glycogen synthase kinase 3ß. In the present work, we demonstrate that Notch1 mRNA and protein are enriched in the ventral region from the beginning of embryogenesis in Xenopus This is the earliest sign of ventral development, preceding the localized expression of wnt8a, bmp4 and Ventx genes in the ventral center and the dorsal accumulation of nuclear ß-catenin. Knockdown experiments indicate that Notch1 is necessary for the normal expression of genes essential for ventral-posterior development. These results indicate that during early embryogenesis ventrally located Notch1 promotes the development of the ventral center. Together with our previous evidence, these results suggest that ventral enrichment of Notch1 underlies the process by which Notch1 participates in restricting nuclear accumulation of ß-catenin to the dorsal side.


Assuntos
Embrião não Mamífero/embriologia , Desenvolvimento Embrionário/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Receptor Notch1/metabolismo , Peixe-Zebra/embriologia , Animais , Embrião não Mamífero/citologia , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptor Notch1/genética , Xenopus laevis , Peixe-Zebra/genética , beta Catenina/genética , beta Catenina/metabolismo
4.
Neural Plast ; 2018: 5093048, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29706992

RESUMO

NMDA ionotropic glutamate receptors (NMDARs) are crucial in activity-dependent synaptic changes and in learning and memory. NMDARs are composed of two GluN1 essential subunits and two regulatory subunits which define their pharmacological and physiological profile. In CNS structures involved in cognitive functions as the hippocampus and prefrontal cortex, GluN2A and GluN2B are major regulatory subunits; their expression is dynamic and tightly regulated, but little is known about specific changes after plasticity induction or memory acquisition. Data strongly suggest that following appropriate stimulation, there is a rapid increase in surface GluN2A-NMDAR at the postsynapses, attributed to lateral receptor mobilization from adjacent locations. Whenever synaptic plasticity is induced or memory is consolidated, more GluN2A-NMDARs are assembled likely using GluN2A from a local translation and GluN1 from local ER. Later on, NMDARs are mobilized from other pools, and there are de novo syntheses at the neuron soma. Changes in GluN1 or NMDAR levels induced by synaptic plasticity and by spatial memory formation seem to occur in different waves of NMDAR transport/expression/degradation, with a net increase at the postsynaptic side and a rise in expression at both the spine and neuronal soma. This review aims to put together that information and the proposed hypotheses.


Assuntos
Memória/fisiologia , Plasticidade Neuronal/fisiologia , Subunidades Proteicas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Humanos , Aprendizagem/fisiologia , Potenciação de Longa Duração/fisiologia , Sinapses/metabolismo
5.
Gac Med Mex ; 154(5): 550-554, 2018.
Artigo em Espanhol | MEDLINE | ID: mdl-30407453

RESUMO

BACKGROUND: Dementias are rarely considered to be a main cause of death; therefore there are only few studies on Alzheimer's mortality covering long periods. OBJECTIVE: To describe mortality from Alzheimer's disease in México for the period from 1980 to 2014. METHOD: Cross-sectional study where, with official mortality data in Mexico according to codes 331.0 and G30, respectively, of the 9th and 10th revisions of the International Statistical Classification of Diseases and Related Health Problems, crude and standardized Alzheimer's disease mortality rates were obtained, both nationally and by states. RESULTS: From almost being inexistent, deaths from Alzheimer's disease went to a rate of 65.12 per 1000 females and 43.66 per 1000 males in the 2010-2014 five-year period. Throughout the study period, the age group with highest mortality rates for this cause were those older than 80 years, with 0.29 per 100,000 population in 1980-1984 and 55.02 in 100,000 in the 2010-2014 period. The region with the highest mortality was the northwest, with rates higher than 2.28 per 100,000 population. CONCLUSIONS: Mortality from Alzheimer's disease is a public health problem in Mexico with a growing trend, especially among women and older adults. Early diagnostic measures and opportune treatment are required in primary care in order to reduce this problem.


INTRODUCCIÓN: Raramente se considera a las demencias como causa principal de muerte, por consiguiente existen pocos estudios sobre la mortalidad por Alzheimer a través de largos periodos. OBJETIVO: Describir la mortalidad por enfermedad de Alzheimer en México durante el periodo 1980-2014. MÉTODO: Estudio transversal en el que, con datos oficiales de mortalidad en México según los códigos 331.0 y G30 de la novena y décima revisiones de la Clasificación Estadística Internacional de Enfermedades y Problemas Relacionados con la Salud, se obtuvieron tasas crudas y estandarizadas de mortalidad por enfermedad de Alzheimer, nacional y por entidad federativa. RESULTADOS: De ser casi inexistentes, en el quinquenio 2010-2014 se registraron tasas de 65.12 y 43.66 muertes por enfermedad de Alzheimer por cada 1000 mujeres y 1000 hombres, respectivamente. En todo el periodo estudiado, el grupo etario con las mayores tasas de mortalidad por esta causa fue el de mayores de 80 años, con 0.29 en 100 000 habitantes durante 1980-1984 y 55.02 durante 2010-2014. La región con mayor mortalidad fue la noroeste, con tasas mayores a 2.28 en 100 000 habitantes. CONCLUSIONES: La mortalidad por enfermedad de Alzheimer es un problema de salud pública en México con tendencia creciente, especialmente entre mujeres y adultos mayores. Se requieren medidas diagnósticas precoces y tratamiento oportuno en primer nivel para aminorar este problema.


Assuntos
Doença de Alzheimer/epidemiologia , Causas de Morte/tendências , Saúde Pública , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/mortalidade , Estudos Transversais , Feminino , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Fatores Sexuais
6.
World J Surg ; 41(2): 386-393, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27822727

RESUMO

BACKGROUND: Chronic lower limb ulcers constitute a public health problem, with important socioeconomic implications and high attention cost. This trial evaluates handcrafted vacuum-assisted therapy versus traditional treatment effectiveness for lower limbs ulcers. MATERIALS AND METHODS: It was a prospective randomized clinical trial conducted over 144 patients with lower limbs ulcers. Patients were randomized into two groups of 72 patients: Experimental group were treated with debridement, cure and a handcrafted vacuum-assisted device that was changed every 72 h. Control group was treated with debridement and cure with soap every 24 h. Ulcers were evaluated every 72 h and on 10th day. The presence of systemic inflammatory response, pain, granulation tissue and viability for discharge was registered and analyzed . RESULTS: After exclusion of 18 patients, 126 were included, 65.1% were men with an average of 58 years. Sole region ulcer by diabetic foot was the more frequent in both groups (73%). Leukocytes count, systemic inflammatory response and pain were significantly lower in experimental group (p < 0.05). Discharge criteria and granulation tissue were present earlier in experimental group (p < 0.05). CONCLUSION: Handcrafted vacuum-assisted system is a feasible and safe method to treat chronic ulcers. This system would benefit patients favoring earlier infection control, faster granulation tissue appearance and earlier discharge. Clinical trials registered in https://www.clinicaltrials.gov/ Number NCT02512159.


Assuntos
Úlcera da Perna/terapia , Tratamento de Ferimentos com Pressão Negativa , Adulto , Idoso , Idoso de 80 Anos ou mais , Desbridamento , Desenho de Equipamento , Feminino , Tecido de Granulação , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Escala Visual Analógica , Cicatrização , Adulto Jovem
7.
Rev Med Chil ; 145(5): 673-677, 2017 May.
Artigo em Espanhol | MEDLINE | ID: mdl-28898346

RESUMO

Although radioiodine (131-I) can be used as treatment of hyperthyroidism for patients in hemodialysis, its use is limited and the experience is mainly related to differentiated thyroid carcinoma. We report a 58 years old female on hemodialysis with recurrent hyperthyroidism after propylthiouracil treatment. She was successfully treated with 131-I and four months after the intervention her euthyroid state was confirmed. We measured 131-I activity in blood, dialysate liquid and other waste products, as well as patient radiation exposure rates. We found that 131-I elimination was prolonged through time with no major dependence on hemodialysis, as opposed to the elimination of 131-I in patients with thyroid carcinoma. This was probably due to high radiotracer uptake in hyper functioning thyroid tissue. Conversely, radiation content in dialysate wastes or equipment was minimal. Furthermore, the rate of both environmental exposure and exposure of nursing staff in charge of hemodialysis sessions, was minimal and met international security standards. In conclusion, I-131 therapy showed both appropriate effectiveness and safety in this case and may be considered as a suitable treatment alternative to thyroidectomy when antithyroid drugs are unsuccessful.


Assuntos
Hipertireoidismo/radioterapia , Radioisótopos do Iodo/uso terapêutico , Insuficiência Renal Crônica/terapia , Feminino , Humanos , Radioisótopos do Iodo/farmacocinética , Pessoa de Meia-Idade , Diálise Renal
8.
Aten Primaria ; 49(8): 465-472, 2017 Oct.
Artigo em Espanhol | MEDLINE | ID: mdl-28161071

RESUMO

OBJECTIVE: To identify the prevalence and type of intimate partner violence in women assigned at primary care health and estimates the risks for violence. DESIGN: Case (incident cases)-control. LOCATION: Primary health care unit in Cancun, Quintana Roo, Mexico. PARTICIPANTS: Women over 18years old living in couple at last 12months. MAIN MEASUREMENTS: Validated violence scale for Mexican population was evaluated: total partner violence, physical, psychological and sexual violence. History of violence and sociodemographic variables. Chi square for categorical variables and odds ratio (OR) for risk estimate was determined. RESULTS: The total intimate partner violence was 15.05%, psychological violence in 37.3%. Overall violence, age differences, socioeconomic status, marital status, history of violence and alcohol intake by the partner (P<.05) were observed. The risk increased in over 40 years old (OR: 2.09; 95%CI: 1.07 to 4.11), history of violence (OR: 5.9; 95%CI: 2.8 to 12.44) and alcohol intake by partner (OR=12.38; 95%CI: 2.15 to 29.59). Low socioeconomic status (OR: 0.384; 95%CI: 0.19 to 0.74) and free union (OR: 0.507; 95%CI: 0.27 to 0.95) were relation factors to lower intimate violence partner. CONCLUSIONS: Sexual violence predominated among users of primary health care and the risk that present this behavior increases with the consumption of alcoholic beverages in the couple and a history of violence, but the free union and socioeconomic status were possibility protected for violence.


Assuntos
Violência por Parceiro Íntimo/classificação , Violência por Parceiro Íntimo/estatística & dados numéricos , Adulto , Estudos de Casos e Controles , Feminino , Humanos , México , Atenção Primária à Saúde , Medição de Risco , Fatores de Risco
9.
World J Surg ; 40(11): 2603-2610, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27283187

RESUMO

BACKGROUND: Appendectomy is the most frequent and urgent gastrointestinal surgery. Overtime, the surgical techniques have been improved upon, in order to reduce complications, get better cosmetic results, and limit the discomfort associated with this procedure, by its high impact in the surgery departments. The traditional skin closure is associated with a poor cosmetic result and it requires stitches removal, alongside the pain associated with this procedure, and no benefits were demonstrated in the literature regarding separated stitches over intradermic stitch. This is a randomized controlled trial, and our objective is to compare two different skin closure techniques in open appendectomy. METHODS: A prospective randomized trial method was used, with a total number of 208 patients participating in the study, after acute appendicitis diagnosis in the emergency department. They were randomized into two groups: patients who would receive skin closure with a unique absorbable intradermic stitch (Group A) and another group that would receive the traditional closure technique, consistent in non-absorbable separated stitches (Group B). General characteristics like gender, age, Body Mass Index (BMI), comorbidities, and allergies were registered. Days of Evolution (DOE) until surgery, previous use of antibiotics, complicated or uncomplicated appendicitis, surgical time, and wound complications like skin infection, dehiscence, seroma or abscess were also registered in each case. RESULTS: 8 patients were excluded due to negative appendicitis during surgery and lack of follow-up. Two groups, each containing 100 patients, were formed. General characteristics and parity were compared, and no statistically significant differences were observed. Difference in the surgical time (Group A: 47.35 min vs Group B: 54.13 min, p < .001) and cases with complicated appendicitis (Group A: 58 and Group B:38, p = .005) were found to be statistically significant. Four wound complications were reported, and the incidence of seroma (Group A:0 and Group B:5, p = .02) and abscess (Group A:2 and Group B:8, p = .05) were found to have some statistical significant difference. In a multivariate analysis, a relationship was observed between BMI > 25 kg/m2 and seroma (p = .006), BMI > 25 kg/m2 and abscess (p = .02), surgical time >50 min and seroma (p < .001), >2 DOE and abscess (p = .001), and complicated appendicitis with seroma development (p = .03). CONCLUSION: Open appendectomy skin closure with a unique absorbable intradermic stitch is safe, with a reduced seroma and abscess incidence, compared to traditional closure, and an equivalent dehiscence and superficial infection incidence, allowing a lower hospital attention cost and length of hospital stay for treatment of complications. The relative risk of complications with traditional skin closure is 2.91 higher, compared to this new technique.


Assuntos
Técnicas de Fechamento de Ferimentos Abdominais , Abscesso/etiologia , Apendicectomia/métodos , Apendicite/cirurgia , Procedimentos Cirúrgicos Dermatológicos/métodos , Complicações Pós-Operatórias/etiologia , Técnicas de Sutura , Doença Aguda , Adolescente , Adulto , Apendicite/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Estudos Prospectivos , Seroma/etiologia , Técnicas de Sutura/instrumentação , Suturas , Adulto Jovem
10.
Rev Med Chil ; 144(3): 333-40, 2016 Mar.
Artigo em Espanhol | MEDLINE | ID: mdl-27299819

RESUMO

BACKGROUND: Thyroid dysfunction is common among patients infected with human immunodeficiency virus (HIV). It presents in different forms and has a multifactorial etiology. AIM: To determine the prevalence and features of thyroid dysfunction among patients infected with HIV. MATERIAL AND METHODS: A cross-sectional study of 127 patients infected with HIV aged 19 to 75 years (85% males). Patients with previous diagnoses of endocrine diseases and pregnant women were excluded. Participants responded a questionnaire about symptoms and the evolution of HIV infection. A blood sample was obtained to measure thyroid stimulating hormone, free thyroxin, viral load and CD4 count. RESULTS: Hypothyroidism was found 13 cases, hyperthyroidism in one case and hypothyroxinemia in eight cases. No difference in symptoms was found between patients with or without thyroid dysfunction. No significant differences were observed in CD4 count or the prevalence of co-infection with Hepatitis B virus among patients with thyroid dysfunction. No association between antiretroviral agents and thyroid dysfunction was observed. CONCLUSIONS: The thyroid abnormalities found in this group of HIV infected patients were usually asymptomatic. It may be advisable to systematically assess thyroid function in HIV infected patients.


Assuntos
Infecções por HIV/fisiopatologia , Doenças da Glândula Tireoide/fisiopatologia , Adulto , Idoso , Antirreumáticos/uso terapêutico , Contagem de Linfócito CD4 , Chile/epidemiologia , Estudos Transversais , Feminino , Infecções por HIV/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Estatísticas não Paramétricas , Inquéritos e Questionários , Doenças da Glândula Tireoide/epidemiologia , Glândula Tireoide/fisiopatologia , Tireotropina/sangue , Tiroxina/sangue , Carga Viral , Adulto Jovem
11.
Aten Primaria ; 48(9): 572-578, 2016 Nov.
Artigo em Espanhol | MEDLINE | ID: mdl-26880166

RESUMO

OBJECTIVE: To evaluate the pattern of breastfeeding and weaning as a risk of obesity in pre-school children from a Primary Care Unit. DESIGN: Cross-sectional analytical study LOCATION: Cancun, Quintana Roo (Mexico). PARTICIPANTS: Children from 2-4 years of age from a Primary Care Unit. MAIN MEASUREMENTS: Duration of total and exclusive breastfeeding, age and food utilized for complementary feeding reported by the mother or career of the child and nutritional status assessment evaluated by body mass index (BMI) ≥ 95 percentile. Determination of prevalence ratio (PR), odds ratio (OR), chi squared (x2), and binary logistic regression. RESULTS: The study included 116 children (55.2% girls) with a mean age of 3.2 years, with obesity present in 62.1%, Exclusive breastfeeding in 72.4% with mean duration of 2.3 months, and age at introducing solids foods was 5.0 months. There was a difference for breastfeeding and complementary feeding by gender sex (P<.05). A PR=3.9 (95% CI: 1.49-6.34) was calculated for exclusive breastfeeding and risk of obesity. The model showed no association between these variables and obesity in children CONCLUSIONS: Exclusive breastfeeding of less than three months is associated with almost 4 more times in obese children. There was a difference in age of complementary feeding, duration of breastfeeding, and formula milk consumption time for obese and non-obese children.


Assuntos
Aleitamento Materno , Fenômenos Fisiológicos da Nutrição do Lactente , Obesidade Infantil/epidemiologia , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Alimentos Infantis , Recém-Nascido , México
12.
Gac Med Mex ; 152(4): 479-85, 2016.
Artigo em Espanhol | MEDLINE | ID: mdl-27595251

RESUMO

OBJECTIVE: Identify factors related to preclinical depression in healthy adults, their risk factors and concordance with family doctor diagnostic. MATERIALS AND METHODS: Case-control study in adult from family medicine consulting room. Beck inventory for depression was applied. The correlation between depression and the diagnosis by the family physician was evaluated. Odds ratio (OR) was determined. RESULTS: Involved 138 patients randomly from four family medicine units (FMU) in the Northern Region of Quintana Roo, Mexico. The mean age 34.9 ± 11.4 years, 55.8% women, prevalence for depression was 26.1%. Being male OR: 3.76; 95% CI: 1.69-8.36, under 30 years OR: 2.76; 95% CI: 1.27-5.99, low socioeconomic status (SES) OR: 2.11; 95% CI: 0.97-4.59 and be married OR: 3.22; 95% CI: 1.41.-7.36 had depression risk. Diagnosis by the family physician and inventory Beck. Kappa Index 0.2, 95% CI: -0057-0176; p = 0.05. CONCLUSIONS: Almost a third of young adults have some depression degree in family medicine consulting room, it is necessary a depression screening for male patients, low SES, married, and under 30 years old, attending medical consultation familiar, for a early diagnosis and improve prognosis.


Assuntos
Depressão/epidemiologia , Programas de Rastreamento/métodos , Adolescente , Adulto , Fatores Etários , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Masculino , Estado Civil , México/epidemiologia , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Fatores de Risco , Fatores Sexuais , Fatores Socioeconômicos , Adulto Jovem
13.
J Sep Sci ; 37(21): 3125-32, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25137606

RESUMO

The assessment of the environmental fate of glyphosate and its degradation product (aminomethylphosphonic acid) is of great interest given the widespread use of the herbicide. Studies of adsorption-desorption and transport processes in soils require analytical methods with sensitivity, accuracy, and precision suitable for determining the analytes in aqueous equilibrium solutions of varied complexity. In this work, the effect of factors on the yield of the derivatization of both compounds with 9-fluorenylmethyl chloroformate for applying in aqueous solutions derived from soils was evaluated through factorial experimental designs. Interference effects coming from background electrolytes and soil matrices were established. The whole method had a linear response up to 640 ng/mL (R(2) > 0.999) under optimized conditions for high-performance liquid chromatography with fluorescence detection. Limits of detection were 0.6 and 0.4 ng/mL for glyphosate and aminomethylphosphonic acid, respectively. The relative standard deviation was 4.4% for glyphosate (20 ng/mL) and 5.9% for aminomethylphosphonic acid (10 ng/mL). Adsorption of compounds on four different soils was assessed. Isotherm data fitted well the Freundlich model (R(2) > 0.97). Kf constants varied between 93 ± 3.1 and 2045 ± 157 for glyphosate and between 99 ± 4.1 and 1517 ± 56 (µg(1-1/) (n)  mL(1/) (n) ( ) g(-1) ) for aminomethylphosphonic acid, showing the broad range of applicability of the proposed method.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Fluorenos/química , Glicina/análogos & derivados , Herbicidas/química , Organofosfonatos/química , Poluentes do Solo/química , Poluentes Químicos da Água/química , Adsorção , Glicina/química , Isoxazóis , Tetrazóis , Glifosato
14.
Obes Surg ; 34(6): 2042-2053, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38653888

RESUMO

INTRODUCTION: Previous studies have detected mitochondrial alterations in tissues of individuals with obesity and type 2 diabetes mellitus (T2DM). Metabolic surgery could be an effective treatment to improve mitochondrial morphology and reduce oxidative stress (OS). METHODS: An experimental study was carried out using 48 male Wistar rats, divided into 6 groups (n = 8): control (C), induced Metabolic Syndrome (MS); intervention with sleeve gastrectomy (SG), MS + SG with 6 weeks postoperatively (MS + SG6), MS + SG with 12 weeks postoperatively (MS + SG12), and MS + SG with 24 weeks postoperatively (MS + SG24). Biochemical markers indicative of MS (glycemia, cholesterol, and triglyceride levels) and oxidative stress markers (nitric oxide levels, Superoxide dismutase and Myeloperoxidase activity) were determined. To study mitochondrial morphology, tissue sections of the thoracic aorta, stomach, liver, heart, and kidney were observed by electron microscopy. RESULTS: MS group exhibited elevated glycemic values and dyslipidemia. SG and MS + SG groups showed improvements in glycemia and lipid profiles compared to MS. OS biomarkers indicated reduced oxidative stress in SG and MS + SG groups compared to MS. Electron microscopy revealed mitochondrial alterations in MS. SG group showed no changes compared to the control. MS + SG6 and MS + SG12 groups showed a recovery of mitochondrial morphology until reaching images similar to the control in MS + SG24. CONCLUSION: Metabolic surgery could improve mitochondrial function by restoring mitochondrial morphology and architecture and, consequently, reducing systemic oxidative stress and remitting associated metabolic alterations.


Assuntos
Gastrectomia , Síndrome Metabólica , Mitocôndrias , Estresse Oxidativo , Ratos Wistar , Animais , Síndrome Metabólica/metabolismo , Masculino , Ratos , Mitocôndrias/metabolismo , Modelos Animais de Doenças , Glicemia/metabolismo , Biomarcadores/metabolismo , Biomarcadores/sangue
15.
Res Sq ; 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38883779

RESUMO

While CD40 agonism is an attractive approach for activating antigen-presenting cells and initiating antitumor responses, previous attempts have encountered limited clinical efficacy coupled with toxicity. We previously demonstrated that interactions between the antibody Fc domain and the inhibitory receptor FcγRIIB are critical for enhanced antitumor activity. Here, we present the results of a phase 1 study on intratumoral administration of an anti-CD40 agonistic antibody (2141-V11) Fc-engineered to enhance FcγRIIB binding. Primary endpoints included safety, maximum tolerated dose (MTD), and recommended phase 2 dose. Secondary objectives included preliminary clinical activity and correlative studies from biospecimens. 2141-V11 was well-tolerated without dose-limiting toxicities and MTD was not reached. In ten evaluable patients with metastatic cancer, the overall response rate was 20%, with complete responses in two patients (melanoma and breast carcinoma) and stable disease in six patients. 2141-V11 induced tumor regression in injected and non-injected lesions, with increased leukocyte infiltration and tertiary lymphoid structures (TLS) formation in post-treatment biopsies. In a humanized mouse model for CD40 and FcγRs, 2141-V11 induced TLS formation in mice bearing orthotopic breast carcinoma, correlating with local and abscopal antitumor effects, systemic immune activation, and immune memory. These findings support the safety and efficacy of 2141-V11, warranting phase 2 studies and suggesting a unique mechanism of action for this Fc-enhanced immunotherapy (NCT04059588).

16.
Cancer Immunol Res ; 12(3): 322-333, 2024 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-38147316

RESUMO

Preclinical murine data indicate that fragment crystallizable (Fc)-dependent depletion of intratumoral regulatory T cells (Treg) is a major mechanism of action of anti-CTLA-4. However, the two main antibodies administered to patients (ipilimumab and tremelimumab) do not recapitulate these effects. Here, we investigate the underlying mechanisms responsible for the limited Treg depletion observed with these therapies. Using an immunocompetent murine model humanized for CTLA-4 and Fcγ receptors (FcγR), we show that ipilimumab and tremelimumab exhibit limited Treg depletion in tumors. Immune profiling of the tumor microenvironment (TME) in both humanized mice and humans revealed high expression of the inhibitory Fc receptor, FcγRIIB, which limits antibody-dependent cellular cytotoxicity/phagocytosis. Blocking FcγRIIB in humanized mice rescued the Treg-depleting capacity and antitumor activity of ipilimumab. Furthermore, Fc engineering of antibodies targeting Treg-associated targets (CTLA-4 or CCR8) to minimize FcγRIIB binding significantly enhanced Treg depletion, resulting in increased antitumor activity across various tumor models. Our results define the inhibitory FcγRIIB as an immune checkpoint limiting antibody-mediated Treg depletion in the TME, and demonstrate Fc engineering as an effective strategy to overcome this limitation and improve the efficacy of Treg-targeting antibodies.


Assuntos
Neoplasias , Linfócitos T Reguladores , Humanos , Animais , Camundongos , Ipilimumab/farmacologia , Ipilimumab/uso terapêutico , Antígeno CTLA-4 , Microambiente Tumoral , Neoplasias/tratamento farmacológico
17.
Anal Bioanal Chem ; 405(23): 7497-507, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23861183

RESUMO

Seven heavy polycyclic aromatic hydrocarbons (PAHs) of concern on the US Environmental Protection Agency priority pollutant list (benzo[a]anthracene, benzo[b]fluoranthene, benzo[k]fluoranthene, benzo[a]pyrene, dibenz[a,h]anthracene, benzo[g,h,i]perylene, and indeno[1,2,3-c,d]-pyrene) were simultaneously analyzed in extra virgin olive oil. The analysis is based on the measurement of excitation-emission matrices on nylon membrane and processing of data using unfolded partial least-squares regression with residual bilinearization (U-PLS/RBL). The conditions needed to retain the PAHs present in the oil matrix on the nylon membrane were evaluated. The limit of detection for the proposed method ranged from 0.29 to 1.0 µg kg(-1), with recoveries between 64 and 78 %. The predicted U-PLS/RBL concentrations compared favorably with those measured using high-performance liquid chromatography with fluorescence detection. The proposed method was applied to ten samples of edible oil, two of which presented PAHs ranging from 0.35 to 0.63 µg kg(-1). The principal advantages of the proposed analytical method are that it provides a significant reduction in time and solvent consumption with a similar limit of detection as compared with chromatography.

18.
Food Chem ; 426: 136561, 2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-37321119

RESUMO

The antibacterial activity (ABA) of honey is associated with the generation of reactive oxygen species (ROS), where polyphenols (PFs) play a key role due to their pro-oxidant action modulated by metallic cations. In this work, the contents of PFs, H2O2, OH radicals, Cu, Fe, Mn, Zn, and ABA against Staphylococcus epidermidis and Pseudomonas aeruginosa were determined in honeys from central Chile. Then, their relationships were evaluated through partial least squares regression. The average contents of phenolic acids, flavonoids and metals in honey ranged from 0.4 to 4 µg/g, 0.3-1.5 µg/g and 3-6 µg/g, respectively. All honeys showed accumulation of H2O2 (1-35 µg/g) and OH radicals. The PLS showed that gallic acid, p-coumaric acid, chrysin, kaempferol, Fe, and Mn stimulate the generation of ROS. Quercetin, Cu, and Zn showed marginal antioxidant effects. PFs favor the ABA of honey against both bacteria and H2O2 against S. epidermidis.


Assuntos
Mel , Espécies Reativas de Oxigênio , Mel/análise , Peróxido de Hidrogênio , Fenóis/análise , Antioxidantes , Minerais , Antibacterianos/farmacologia
19.
Environ Pollut ; 327: 121545, 2023 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-37004862

RESUMO

The fungicide chlorothalonil (CTL) and its metabolite hydroxy chlorothalonil (OH-CTL) constitute a risk of soil and water contamination, highlighting the need to find suitable soil remediation methods for these compounds. Surfactants can promote the bioavailability of organic compounds for enhanced microbial degradation, but the performance depends on soil and surfactant properties, sorption-desorption equilibria of contaminants and surfactants, and possible adverse effects of surfactants on microorganisms. This study investigated the influence of five surfactants [e.g., Triton X-100 (TX-100), sodium dodecyl sulphate (SDS), hexadecyltrimethylammonium bromide (HDTMA), Aerosol 22 and Tween 80] on the sorption-desorption, degradation, and mobility of CTL and OH-CTL in two volcanic and one non-volcanic soil. Sorption and desorption of fungicides depended on the sorption of surfactants on soils, surfactants' capacity to neutralize the net negative charge of soils, surfactants' critical micellar concentration, and pH of soils. HDTMA was strongly adsorbed on soils, which shifted the fungicide sorption equilibria by increasing the distribution coefficient (Kd) values. Contrarily, SDS and TX-100 lowered CTL and OH-CTL sorption on soils by decreasing the Kd values, which resulted in an efficient extraction of the fungicide compounds from soil. SDS increased the degradation of CTL, especially in the non-volcanic soil (DT50 values were 14 and 7 days in natural and amended soils, with final residues <7% of the initial dose), whereas TX-100 enabled an early start and sustenance of OH-CTL degradation in all soils. CTL and OH-CTL stimulated soil microbial activities without noticeable deleterious effects of the surfactants. SDS and TX-100 also reduced the vertical transport of OH-CTL in soils. Results of this study could be extended to soils in other regions of the world because the tested soils represent widely different physical, chemical, and biological properties.


Assuntos
Fungicidas Industriais , Poluentes do Solo , Tensoativos/química , Solo/química , Adsorção , Octoxinol/química , Poluentes do Solo/análise
20.
Artigo em Inglês | MEDLINE | ID: mdl-36815659

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver disease in the world. It is known that there is a pathogenic relation between liver damage and the inflammatory and oxidative environment present in Metabolic Syndrome (MS). OBJECTIVE: To study the pharmacological action of atorvastatin and metformin in an experimental model of MS. METHODS: We used 40 male rats (Wistar) divided into the following groups: Control (A) (n=8), induced MS (B) (n=8), MS + atorvastatin treatment (C)(n=8), MS + metformin treatment (D) (n=8) and MS + combined treatment (E) (n=8). MS was induced by administering 10% fructose in drinking water for 45 days. Atorvastatin 0.035 mg/day/rat, metformin 1.78 mg/day/rat, and a combination of both drugs were administered for 45 days. Metabolic, oxidative (nitric oxide, myeloperoxidase and superoxide dismutase) and inflammatory (fibrinogen) parameters were determined. Histological sections of liver were analyzed by light microscopy. RESULTS: The glycemia, lipid profile and TG/HDL-C index were altered in MS group. After pharmacological treatment, metabolic parameters improve significantly in all treated groups. Inflammatory and oxidative stress biomarkers increase in MS. Treated groups showed an increase in NO bioavailability, no difference in MPO activity and an increase in fibrinogen. Atorvastatin showed a decrease in SOD while Metformin and combination treatment showed an increase in SOD compared to MS. In MS, we observed histological lesions consistent with NAFLD. However, after a combined treatment, we observed total regression of these lesions. CONCLUSION: Our results showed that there is an important synergy between atorvastatin and metformin in improving liver involvement in MS.


Assuntos
Síndrome Metabólica , Metformina , Hepatopatia Gordurosa não Alcoólica , Masculino , Ratos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Metformina/farmacologia , Metformina/uso terapêutico , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Ratos Wistar , Fígado/patologia , Superóxido Dismutase , Modelos Teóricos
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