RESUMO
Cancer involves a series of diseases where cellular growth is not controlled. Cancer is a leading cause of death worldwide, and the burden of cancer incidence and mortality is rapidly growing, mainly in developing countries. Many drugs are currently used, from chemotherapeutic agents to immunotherapy, among others, along with organ transplantation. Treatments can cause severe side effects, including remission and progression of the disease with serious consequences. Increased glycolytic activity is characteristic of cancer cells. Triosephosphate isomerase is essential for net ATP production in the glycolytic pathway. Notably, some post-translational events have been described that occur in human triosephosphate isomerase in which functional and structural alterations are provoked. This is considered a window of opportunity, given the differences that may exist between cancer cells and their counterpart in normal cells concerning the glycolytic enzymes. Here, we provide elements that bring out the potential of triosephosphate isomerase, under post-translational modifications, to be considered an efficacious target for treating cancer.
Assuntos
Neoplasias , Triose-Fosfato Isomerase , Humanos , Triose-Fosfato Isomerase/genética , Neoplasias/tratamento farmacológico , Processamento de Proteína Pós-Traducional , Ciclo Celular , Proliferação de CélulasRESUMO
Beyond the problem in public health that protist-generated diseases represent, understanding the variety of mechanisms used by these parasites to interact with the human immune system is of biological and medical relevance. Giardia lamblia is an early divergent eukaryotic microorganism showing remarkable pathogenic strategies for evading the immune system of vertebrates. Among various multifunctional proteins in Giardia, arginine deiminase is considered an enzyme that plays multiple regulatory roles during the life cycle of this parasite. One of its most important roles is the crosstalk between the parasite and host. Such a molecular "chat" is mediated in human cells by membrane receptors called Toll-like receptors (TLRs). Here, we studied the importance of the 3D structure of giardial arginine deiminase (GlADI) to immunomodulate the human immune response through TLRs. We demonstrated the direct effect of GlADI on human TLR signaling. We predicted its mode of interaction with TLRs two and four by using the AlphaFold-predicted structure of GlADI and molecular docking. Furthermore, we showed that the immunomodulatory capacity of this virulent factor of Giardia depends on the maintenance of its 3D structure. Finally, we also showed the influence of this enzyme to exert specific responses on infant-like dendritic cells.
Assuntos
Giardia , Giardíase , Animais , Humanos , Hidrolases , Imunidade , Imunomodulação , Simulação de Acoplamento Molecular , Receptores Toll-LikeRESUMO
Social confinement involves a series of temporary changes in the habits and lifestyles of individuals, severely affecting their regular activities and schedules and substantially modifying socio-familial behavior (SFB) and sleep quality (SQ). There is no literature reporting the effects of SFB changes on SQ during social confinement due to the COVID-19 outbreak. An observational transversal research design, with group comparison and correlation methods, was used to perform the present study. The results were analyzed as follows: (1) An exploratory factor analysis (EFA); (2) A description of the sample was determined by proportions comparisons of sleep habits between the different variables of interest; and (3) A linear regression model was analyzed to explore the predictive association of the negative effects of social isolation during the COVID-19 pandemic on SFB and SQ. In addition to the global SFB score, two SFB factors were identified as predictors affecting the SQ, SF-Habits, and SF-Emotional scores, suggesting a close balance between daily life activities and sleep health during critical social changes. Furthermore, two main risk factors resulted from the regression analysis: economic concerns and increased alcohol consumption. Therefore, the predictive capacity of economic concerns showed statistical significance in anticipating negative sleep quality scores. Overall, this suggests that sleep quality, economic concerns, schedules, and substance use were associated with the self-perception of coping skills, elucidating the importance of fostering habits related to schedules within the home and ensuring that all family members participate.
Assuntos
COVID-19 , Qualidade do Sono , COVID-19/epidemiologia , Humanos , Pandemias , Fatores de Risco , Isolamento Social , Inquéritos e QuestionáriosRESUMO
Human triosephosphate isomerase (HsTIM) is a central glycolytic enzyme and is overexpressed in cancer cells with accelerated glycolysis. Triple-negative breast cancer is highly dependent on glycolysis and is typically treated with a combination of surgery, radiation therapy, and chemotherapy. Deamidated HsTIM was recently proposed as a druggable target. Although thiol-reactive drugs affect cell growth in deamidated HsTIM-complemented cells, the role of this protein as a selective target has not been demonstrated. To delve into the usefulness of deamidated HsTIM as a selective target, we assessed its natural accumulation in breast cancer cells. We found that deamidated HsTIM accumulates in breast cancer cells but not in noncancerous cells. The cancer cells are selectively programmed to undergo cell death with thiol-reactive drugs that induced the production of methylglyoxal (MGO) and advanced glycation-end products (AGEs). In vivo, a thiol-reactive drug effectively inhibits the growth of xenograft tumors with an underlying mechanism involving deamidated HsTIM. Our findings demonstrate the usefulness of deamidated HsTIM as target to develop new therapeutic strategies for the treatment of cancers and other pathologies in which this post translationally modified protein accumulates.
Assuntos
Neoplasias da Mama , Triose-Fosfato Isomerase , Feminino , Glicólise , Humanos , Proteínas/metabolismo , Aldeído Pirúvico/metabolismo , Compostos de Sulfidrila , Triose-Fosfato Isomerase/metabolismoRESUMO
Natural products are an important source of bioactive molecules. However, the development of biological applications based on these compounds is hindered by intrinsic problems in their solubility, volatility, degradation, and bioavailability. Nanocarriers as drug administration systems promise to overcome these limitations by providing controlled and directed delivery. This review aims to present 1) the most frequently used nanocarriers as natural product administration systems, based on the progress of controlled and directed release, and 2) the challenges associated with the use of nanocarriers as therapeutic agents.
Assuntos
Produtos Biológicos/administração & dosagem , Produtos Biológicos/farmacocinética , Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanoestruturas/administração & dosagem , Animais , Produtos Biológicos/química , Humanos , Nanomedicina/métodosRESUMO
Giardiasis represents a latent problem in public health due to the exceptionally pathogenic strategies of the parasite Giardia lamblia for evading the human immune system. Strains resistant to first-line drugs are also a challenge. Therefore, new antigiardial therapies are urgently needed. Here, we tested giardial arginine deiminase (GlADI) as a target against giardiasis. GlADI belongs to an essential pathway in Giardia for the synthesis of ATP, which is absent in humans. In silico docking with six thiol-reactive compounds was performed; four of which are approved drugs for humans. Recombinant GlADI was used in enzyme inhibition assays, and computational in silico predictions and spectroscopic studies were applied to follow the enzyme's structural disturbance and identify possible effective drugs. Inhibition by modification of cysteines was corroborated using Ellman's method. The efficacy of these drugs on parasite viability was assayed on Giardia trophozoites, along with the inhibition of the endogenous GlADI. The most potent drug against GlADI was assayed on Giardia encystment. The tested drugs inhibited the recombinant GlADI by modifying its cysteines and, potentially, by altering its 3D structure. Only rabeprazole and omeprazole decreased trophozoite survival by inhibiting endogenous GlADI, while rabeprazole also decreased the Giardia encystment rate. These findings demonstrate the potential of GlADI as a target against giardiasis.
Assuntos
Giardia lamblia/efeitos dos fármacos , Giardíase/tratamento farmacológico , Hidrolases/metabolismo , Animais , Antiprotozoários/farmacologia , Simulação por Computador , Cisteína/química , Avaliação Pré-Clínica de Medicamentos/métodos , Reposicionamento de Medicamentos/métodos , Giardia lamblia/patogenicidade , Giardíase/imunologia , Tiomalato Sódico de Ouro/farmacologia , Humanos , Hidrolases/efeitos dos fármacos , Hidrolases/ultraestrutura , Omeprazol/farmacologia , Inibidores da Bomba de Prótons/farmacologia , Rabeprazol , Tiamina/análogos & derivados , Tiamina/farmacologia , Trofozoítos/efeitos dos fármacosRESUMO
Resumen Los objetivos primarios del presente estudio fueron determinar la validez de constructo, convergente y discriminante de la Escala Breve de Optimismo Interactivo-G (EBOI-G), en participantes de seis estados de México y calcular su consistencia interna. Participaron 3 289 mexicanos, 2 028 hombres y 1 243 mujeres (18 casos no contestaron cuál era su género). Su edad promedio = 30.43 años, DE = 10.52. Se usó el análisis factorial confirmatorio y análisis de regresión múltiple, y se encontraron buenos indicadores promedio de bondad de ajuste (e. g., CFI = .99; RMSEA = .07.). Se evaluó la validez convergente, r (3 289) = .52 (p = < .01; d = mediano), con la Escala de Satisfacción con la Vida. Se estimó la validez discriminante, r (3 289) r = -.19, con la Escala Breve de Disposición a la Ira (p = < .01; d = casi pequeño). El alfa = .70 (3 289); p = < .01; el omega = .76. Se concluye que hay evidencia parcial nacional que apoya el uso de la EBOI-G, debido a la carencia de una medida de este tipo en México, útil cuando menos para propósitos de investigación.
Abstract The primary objectives of this study were determining the construct, convergent, and discriminant validity of the Brief Interactive Optimism Scale-G (BIOS-G) in participants from six states of Mexico and estimating its internal consistency. In this study 3289 Mexicans participated (2028 men and 1243 women). The average age was = 30.43 years and SD = 10.52. Confirmatory factor analysis (CFA) and multiple regression analysis (MRA) were applied. There were appropriate fit indexes (e. g., CFI = .99; RMSEA = .07.). Convergent validity showed an r (3289) = .52 (p = < .01; d = medium), with the Satisfaction with Life Scale (SWLS) and the estimation of discriminant validity was r (3 289) r = -.19 with the Brief Scale for Assessing Anger Proneness (APS-G) (p = < .01; d = almost small), Alpha = .70 (3 289); p = < .01; omega = .76. The conclusion is that there is partial national evidence supporting the use of BIOS-G, because Mexico lacks a measure of this kind, being useful, at least, for research purposes.
Resumo Os objetivos primários do estudo foram determinar a validade convergente e discriminante do construto da Escala Breve de Otimismo Interativo-G (EBOI-G), em participantes de seis estados do México e calcular sua consistência interna. Participaram 3 289 mexicanos, sendo 2 028 homens e 1 243 mulheres. A média de idade foi = 30.43 anos, DP = 10.52. Foram utilizadas análises fatoriais confirmatórias e análises de regressão múltipla. Bons indicadores médios de qualidade de ajuste foram encontrados (por exemplo, CFI = .99; RMSEA = .07.) A validade convergente foi avaliada, r (3 289) = .52 (p = <.01; d = mediana), com a Escala de satisfação com a vida. A validade discriminante, r (3 289) = -.19 foi estimada com a Escala Breve de Disposição à Raiva (p = <.01; d = quase pequeno). O alfa = 0,70 (3 289); p = <0,01; o ômega = 0,76. Conclui-se que há evidências nacionais parciais que apoiam o uso da EBOI-G, devido à falta de uma medida desse tipo no México, sendo útil pelo menos para fins de pesquisa.
Assuntos
Humanos , Adulto , Otimismo , Psicometria , Psicopatologia , Saúde MentalRESUMO
RESUMEN Las manifestaciones cardiológicas del dengue son muy variadas, el virus puede penetrar al miocardio y producir una miocarditis aguda que, en ocasiones, puede pasar inadvertida y cursar de manera asintomática, con una evolución benigna; y en otras, puede producir alteraciones electrocardiográficas de trastornos del ritmo y la conducción o signos de disfunción ventricular que pueden llegar a la insuficiencia cardíaca grave. Se presenta el caso de un hombre de 21 años de edad, estudiante, con historia previa de salud, que ingresó en el Servicio de Cardiología con diagnóstico de dengue, confirmado por serología, complicado con un trastorno de la conducción (bloqueo aurículo-ventricular de grado avanzado 2:1) en relación a una miocarditis aguda por dengue. Este problema puede observarse en áreas en las que el dengue constituye un problema emergente, por lo que es de vital importancia su conocimiento para diseñar estrategias de prevención y tratamiento de las complicaciones.
ABSTRACT Dengue's cardiological manifestations are diverse; the virus is able to enter the myocardium and cause acute myocarditis that sometimes may go unnoticed and be asymptomatic, with benign outcomes; while in others, it may produce electrocardiographic rhythm and conduction disturbances or signs of ventricular dysfunction that could lead to severe heart failure. We present the case of a 21-year-old man, a student, previously healthy, who was admitted to the Department of Cardiology with a diagnosis of dengue confirmed by serology and complicated with conduction disorders (2:1 advanced atrioventricular block) related to acute myocarditis due to dengue. This problem can be seen in areas where dengue is an emerging problem. Therefore it is critical to be aware of it in order to design strategies for prevention and treatment of complications.
Assuntos
Dengue , Bloqueio Atrioventricular , MiocarditeRESUMO
The treatment of ovarian cancer should be appropriate, since clinical and surgical decisions may affect the prognosis; the surgery must be performed by an expert oncological surgeon or gynecological oncologist, it's fundamental roles are cancer staging and cytoreduction. The concept of staging surgery in early stages has its justification in the fact that up to 11% of "early ovarian cancers" will have metastasis in different sites of the peritoneal cavity at the time of diagnosis. In advanced stages of epithelial ovarian cancer, the goal is the complete cytoreduction of all visible macroscopic disease, since this variable is the most strongly associated with increased overall survival and disease-free period. The ideal time for cytoreductive surgery in relation to chemotherapy (before or after) is still under debate. In 2010 a randomized trial (EORTC) was published, comparing 310 patients initially operated (followed by adjuvant chemotherapy) versus 322 patients initially treated with neoadjuvant chemotherapy (followed by cytoreductive surgery); no significant differences in overall survival between groups were found. Another important factor playing a role in survival and in the probability of surgical cytoreductive success is tumor biology; there has been described a clear difference between serous and mucinous tumors, but some groups advocate that maximal surgical effort in mucinous tumors may compensate morbidity with an increase in survival. The extension of resection in cytoreduction is still controversial; some authors have confirmed that the most important factor is the residual disease and that radical surgery is superior to non-radical surgery in terms of overall survival. The need and extent of lymphadenectomy in advanced cancer will be treated in another chapter of this issue. Undoubtedly, an important factor is to perform procedures in specialized centers.
Assuntos
Procedimentos Cirúrgicos de Citorredução/métodos , Neoplasias Ovarianas/cirurgia , Feminino , HumanosRESUMO
Endometriosis is one of the most frequent gynecological diseases in reproductive age women, but its etiology is not completely understood. Endometriosis is characterized by progesterone resistance, which has been explained in part by a decrease in the expression of the intracellular progesterone receptor in the ectopic endometrium. Progesterone action is also mediated by nongenomic mechanisms via membrane progesterone receptors (mPRs) that belong to the class II members of the progesterone and adipoQ receptor (PAQR) family. The aim of the present study was to evaluate the expression at mRNA and protein levels of mPR members in the eutopic and ectopic endometrium of women with endometriosis. Total RNA and total protein were isolated from control endometrium (17 samples), eutopic endometrium (17 samples), and ectopic endometrium (9 samples). The expression of PAQR7 (mPRα), PAQR8 (mPRß), and PAQR6 (mPRδ) at mRNA and protein levels was evaluated by RT-qPCR and Western blot, whereas PAQR5 (mPRγ) gene expression was evaluated by RT-qPCR. Statistical analysis between comparable groups was performed using one-way ANOVA followed by Tukey's multiple comparisons test with a confidence interval of 95 %. The analysis of gene expression showed that PAQR7 and PAQR5 expression was lower in both eutopic and ectopic endometrium as compared to the endometrium of women without endometriosis, whereas the expression of PAQR8 and PAQR6 was only reduced in eutopic endometrium. Furthermore, mPRα and mPRß protein content was decreased in the ectopic endometrium of women with endometriosis. Our results demonstrate a decrease in the expression and protein content of mPRs in eutopic and ectopic endometrium of patients with endometriosis, which could contribute to the progesterone resistance observed in patients with this disease.